Conditions: Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 44
Healthy volunteers: no

Brief summary:
The primary objective of the study was to evaluate the efficacy and safety of UX007 in the treatment of disabling paroxysmal movement disorders associated with Glut1 DS.

Detailed description:

Arms:
arm 1: Participants will first receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks. After a washout period of 2 weeks, they will then receive placebo for 10 weeks.

Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years. arm 2: Participants will first receive Placebo for 10 weeks. After a washout period of 2 weeks, they will then receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.

Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years.

Interventions: intervention 1: UX007 intervention 2: Placebo
Intervention descriptions: intervention 1: liquid for oral (PO) administration intervention 2: liquid safflower oil for PO administration

Protocol document:
Prot_000.pdf: 
Proprietary and Confidential 
Page 1 
 
TITLE PAG 
A Phase 3, randomized, double-blind, placebo-controlled, crossover study to assess the 
efficacy and safety of UX007 in the treatment of movement disorders associated with 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) 
Protocol Number: 
UX007G-CL301 
Original Protocol: 
08 Dec 2015 
Amendment 1: 
24 Aug 2016 
Amendment 2: 
02 Feb 2017 
Amendment 3: 
10 July 2018 
 
Investigational Product: 
UX007 (triheptanoin) 
Indication: 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) 
IND Number: 
118855 
EudraCT Number: 
2015-005536-17 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Sponsor’s Responsible 
Medical Officer: 
Melanie Brandabur, MD  
Medical Director  
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA  USA 94949 
 
 
Coordinating Investigator:   Darryl DeVivo, MD 
 
Columbia University Medical Center 
 
New York, NY USA 10032 
 
This study is to be performed in compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. 
 
Confidentiality Statement:  This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx). Unauthorized disclosure, reproduction, 
transmission, or use of this document or information is strictly prohibited. By accepting this document, the 
recipient agrees that the information it contains will not be disclosed without written authorization from 
Ultragenyx, except to the extent required to satisfy Institutional Review Board /Ethics Committee procedures, to 
obtain written informed consent from potential subjects, or as required by law. 
PPD


Protocol Number:  UX007G-CL301  
Protocol Amendment 1 
24 Aug 2016 
 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL301 Amendment 1 
24 August 2016 
Original Protocol UX007G-CL301 (dated 08 December 2015) has been modified by 
Amendment 1 to incorporate feedback from regulatory authorities and to modify or clarify 
certain study endpoints based on functional pilot studies and Glut1 DS patient interviews.  
Minor edits and typographical corrections have also been made.  The major protocol changes 
which impact study design and conduct are summarized below: 
1. Primary Efficacy Endpoint: Disabling Paroxysmal Movement Events  
The primary endpoint was revised to capture only movement disorder events that are 
disabling to the subject.  Disabling events are defined in this study as any movement 
disorder events which limit one’s physical functioning and ability to perform 
activities of daily living.   
 
Rationale: In capturing disabling events, the daily electronic Glut1 DS symptom 
diary was revised to support the Health Authority’s suggestion to evaluate 
improvement in “ability to perform activities of daily living”.  This approach aims to 
evaluate changes that constitute clinically meaningful improvement in this patient 
population and also provides insight into the burden of illness caused by Glut1 DS. 
 
2. Secondary Efficacy Endpoints: 12 Minute Walk Test  
The 12 Minute Walk Test was added as a secondary endpoint in the Schedule of 
Events (Table 2.2 and Table 2.3) and in Sections 6.1.2, 7.5.2.3, 7.5.5, and 7.6.3. 
 
Rationale: Walking impairments have been reported in patients with Glut1 DS.  
The 12MWT provides an objective assessment of walking capacity and endurance 
and was added to the study based on the Health Authority’s advice to include a 
measure that evaluates change in performance of a functional outcome such as 
walking ability.  The 12MWT was also selected as a measure of endurance to 
challenge the energy metabolism deficiency and assess potential treatment response. 
 
3. Secondary Efficacy Endpoints: Removal of SF-10/SF-12 and addition of 
PROMIS® item bank-based questionnaire 
A Patient-Reported Outcomes Measurement Information System (PROMIS®)-based 
questionnaire was added as a secondary endpoint to the Schedule of Events and to 
Sections 6.1.2, 7.5.2.6, 7.5.5, and 7.6.3 to assess health-related quality of life.  
The SF-10 and SF-12 assessments were removed as secondary endpoints from the 
protocol.   
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 1 
24 Aug 2016 
 
 
 
Proprietary and Confidential 
Page 3 
Rationale: The PROMIS® item bank questionnaire was added as a patient-based 
assessment of health-related quality of life.  Items are selected from the PROMIS® 
item to develop a questionnaire that evaluates concepts such as physical function, 
mobility, upper extremity function, fatigue, pain, and social health which have been 
reported as important impacts for Glut1 DS patients.  SF-10 and SF-12 Health 
Surveys, which are more generalized assessments, were removed. 
 
4. Secondary Endpoints: CANTAB modification 
The Cambridge Neuropsychological Test Automated Battery (CANTAB) was limited 
to certain study sites as noted in the Synopsis and in Sections 6.1.2, 7.5.2.7, 7.5.5, and 
7.6.3. 
 
Rationale: To reduce the burden at study sites, the CANTAB will be administered at 
only select sites. 
 
5. Exploratory Endpoints: Removal of SARA and AIMS 
The SARA and AIMS measures were removed as secondary endpoints from the 
Schedule of Events (Table 2.2 and Table 2.3) and from Sections 6.1.2, 7.5.2.6, 7.5.5, 
and 7.6.3. 
 
Rationale: In a functional pilot study conducted by the Sponsor, the SARA and AIMS 
assessments did not capture the episodic ataxia and abnormal involuntary movements 
experienced by this population in a clinic setting; therefore, these assessments were 
removed from the study. 
 
6. Exploratory Endpoint: Addition of Wearable Activity Monitor 
An optional wrist-worn actigraphy device was added as an exploratory endpoint in 
the Schedule of Events (Table 2.2 and Table 2.3) and in Sections 6.1.3, 7.5.2.9, 7.5.5, 
and 7.6.3. 
 
Rationale: As fatigue, energy deficiencies, and disabling dyskinesia events commonly 
interfere with a patient’s ability to participate in home and community activities, a 
wrist-worn actigraphy device has been added to evaluate the impact of Glut1 DS on 
activity levels in a real-life setting at select study sites where feasible.   
 
7. Exploratory Endpoint: Addition of Canadian Occupational Performance 
Measure 
The Canadian Occupational Performance Measure (COPM) was added as an 
exploratory endpoint in the Schedule of Events (Table 2.2 and Table 2.3) and in 
Sections 6.1.3, 7.5.2.9, 7.5.5, and 7.6.3. 
 
Rationale: Following the Health Authority’s suggestion to include measures that 
evaluate subjects’ ability to perform activities of daily living and assess productivity, 
the Canadian Occupational Performance Measure (COPM) will be used to assess 
performance areas of self-care, leisure, and productivity. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 1 
24 Aug 2016 
 
 
 
Proprietary and Confidential 
Page 4 
8. Schedule of Events: The titration period was increased from one week to two weeks 
to allow subjects more time to reach the target dose.  The Schedule of Events 
(Table 2.2 and Table 2.3) and other sections have been modified to reflect the 
increase in titration period and, subsequently, increased length of the crossover study. 
 
Rationale: By increasing the titration period, subjects will have more flexibility in the 
time period taken to reach the target dose. 
 
9. Exclusion Criteria: A change was made in the Exclusion Criteria in the synopsis and 
in Section 7.3.2 to exclude subjects with feeding or nutritional issues that, in the 
opinion of the dietitian, may compromise their ability to consistently administer study 
drug. 
 
Rationale: Subjects with feeding issues may not be able to comply with regular 
dosing of study drug.  The addition of this criterion will enable dietitians to exclude 
patients that are likely to be noncompliant with consistent study drug administration. 
 
10. Contraception Methods: The list of examples of highly effective contraception 
methods was updated in Section 7.5.4.5. 
Rationale: This change was made to better clarify the acceptable methods of 
contraception in compliance with the Clinical Trial Facilitation Group (CTFG) 
advice. 
11. Record Retention: Study records will be retained for at least 25 years after the end 
of the clinical trial as updated in Section 8.4.3. 
Rationale: The language in Section 8.4.3 was updated to reflect that study records 
will be retained for at least 25 years after the clinical trial. 
12. End of Study: The synopsis (Duration of Treatment) and Sections 7.4.4.1 and 7.5.1 
were updated to clarify that the End of Study is the last subject’s Safety Follow-up 
Phone Call (30-35 days after the Final Dose). 
Rationale: This change was made to clearly define the End of Study. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 2 
02 Feb 2017 
 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL301 Amendment 2 
02 February 2017 
UX007G-CL301 Amendment 1 (dated 24 August 2016) has been modified by Amendment 2 
to incorporate feedback from regulatory authorities: 
1. Safety Measures and General Assessments: Lipid Profile and Electrocardiogram 
Lipid profile (Section 7.5.4.5) and electrocardiogram (Section 7.5.4.6) assessments 
were added as additional measures to evaluate the safety of UX007.   
Rationale: Regular lipid profile (subjects aged 18 or older) and ECG evaluations have 
been added for routine safety monitoring.      
2. Adverse Events: Clarification of Adverse Events 
An additional statement has been added to the Adverse Events (Section 7.5.4.10) as 
well as to footnotes within the Schedules of Events (Table 2.2 and Table 2.3) to 
specify that increases in frequency or severity or changes in type of Glut1 DS 
associated symptoms (including seizures, movement disorders, behavioral 
abnormalities, and cognitive function) will be classified as adverse events.   
Rationale: Specific language was added to the Study Reference Manual and to the 
Protocol to clarify that the worsening of Glut1 DS associated symptoms will be 
appropriately recorded as adverse events.   
3. Selection of Doses: Inclusion of Maximum Dose 
Section 7.4.4 has been modified to include the addition of a maximum daily UX007 
dose. 
Rationale: While additional dosing information is available within the Pharmacy 
Manual, the Protocol has been amended to include this relevant information. 
4. Study Conduct: Clarification of Amendment Implementation 
Section 8.1.1 has been modified to include Competent Health Authority approval 
prior to implementation of the protocol and substantial protocol amendments. 
Rationale: This statement has been included to document that substantial protocol 
amendments follow Ultragenyx standard operating procedures regarding Competent 
Health Authority approval. 
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 2 
CLINICAL STUDY PROTOCOL AMENDMENT 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL301 Amendment 3 
10 July 2018 
UX007G-CL301 Amendment 2 (dated 02 February 2017) has been modified by Amendment 
3 to incorporate sequential testing procedure for the analysis of secondary endpoints, to add 
additional unscheduled clinic or phone visits, to add clarification to the assessments and 
schedule of events, and to continue evaluation of efficacy assessments during the Extension 
Period. The key changes to the study protocol are summarized below. Additional minor 
changes have also been made for consistency and clarity but are not included in this 
summary. 
 
1. Regarding diary usage during Study Periods Treatment Period 1 and 2 and the Open-
label Extension Phase, references to the “electronic daily Glut1 DS symptom diary” 
and “electronic study medication diary” have been replaced with a “daily Glut1 DS 
symptom diary” and “study medication diary” in Section 7.5.2.1, Section 7.4.7, and 
throughout the protocol. 
 
Rationale: The study will utilize a paper diary to capture movement disorders and 
daily consumption of study drug as a back-up in the event of an unexpected 
performance issue with the daily electronic diary during Treatment Period 1 and 2 and 
the Open Label Extension Phase. The paper diaries are not intended to be used during 
Screening or during the Run-in Period. 
 
2. The order of study endpoints was modified in the synopsis and in Section 6.1 and the 
planned methods of analyses were updated in Section 7.6.3. 
 
Rationale: The study endpoint order and planned methods of efficacy analyses were 
changed  to incorporate sequential testing procedure for the secondary endpoints. 
 
3. In Section 7.1, the duration of the Run-in Period was modified to allow extension 
beyond the previously designated 6 weeks at the discretion of the Sponsor and the 
Principal Investigator.   
 
Rationale: This modification was made to allow flexibility should any study 
implementation issues preclude randomization following the 6-week Run-in Period as 
scheduled.  
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 3 
4. Language to allow unscheduled clinic visits or telephone calls at the site’s discretion 
was added to the synopsis, Section 7.5.1, and Section 7.5.4.11.  
 
Rationale: Unscheduled visits and telephone calls were added to provide additional 
dietitian follow up and other study support as needed. 
 
5. Language was added to Section 7.5.2.1 to specify that “Respondents should maintain 
≥ 80% compliance with daily Glut1 DS symptom diary completion during the Run-in 
Period, Treatment Period 1, Washout Period and Treatment Period 2.” 
 
Rationale: This modification was added to encourage sites to provide additional 
oversight to ensure that subjects complete Glut1 DS symptom diary.   
 
6. Head circumference was added to vital sign assessment in Section 7.5.4.2. 
 
Rationale: This assessment was added to the protocol to be consistent with the Case 
Report Forms (CRFs) which are currently collecting this information as part of the 
scheduled clinic visits.   
 
7. Changes to the Schedule of Events include the following: 
a. Study drug dispensation was added at Week 22 in Table 2.2 and in the text in 
Section 7.4.7. 
 
Rationale: this modification reflects that all subjects will receive UX007 at 
Week 22 (End of Treatment Period 2 Visit) to begin the open-label Extension 
Period. 
 
b. Dietary assessment and review of the 3-day diary was added to Baseline Visit 
2 (Week 12) in Table 2.2. 
 
Rationale: Language was added for additional dietary assessment to ensure 
that subjects’ diets remain isocaloric and well-balanced throughout the study. 
 
c. In Table 2.3, the End of Treatment Visit (Week 178) and Early Termination 
Visits were differentiated into separate columns. 
 
Rationale: This modification was performed to clarify the different 
assessments occurring during the Week 178 and Early Termination clinic 
visits.   
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 4 
d. The Cambridge Neuropsychological Test Automated Battery (CANTAB), 
12 Minute Walk Test (12MWT), and the Patient/Caregiver Clinical Global 
Impression – Improvement (CGI-I) assessments were added to the Extension 
Clinic Visits and Early Termination Visit in Table 2.3. 
 
Rationale: These assessments were added through the Extension Period for 
evaluation of long-term efficacy.   
 
e. In Table 2.3, the “Suicide Ideation and Behavior Assessment” was changed to 
“Columbia Suicide Severity Rating Scale”.  
 
Rationale: This was a clarification made for consistent use of the 
nomenclature used in Table 2.2. Throughout the study, suicidal ideation is 
assessed via the Columbia Suicide Severity Rating Scale. 
 
f. Review of the Study Medication Diary was added to clinic visits within 
Table 2.3. 
 
Rationale: This clarification reflects the text in Section 7.5.1 which states that 
review of the Study Medication Diary is performed throughout the Extension 
Period.   
 
g. Dietitian Consultation and Review of Study Medication Diary were made into 
separate assessments in Table 2.2. 
 
Rationale: This clarification was to reflect that these assessments are 
completed by two different clinical functions (dietitian and study coordinator, 
respectively).   
 
h. The frequency of neurological exams was modified within Table 2.3 to occur 
at every clinic visit (previously, only at Weeks 82 and 130).  
 
Rationale: This clarification was made to reflect the text in Section 7.5.4.4 
which states that neurological examinations occur at “subsequent clinic visits” 
throughout the study. 
 
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 5 
2 SYNOPSIS 
TITLE OF STUDY: 
A Phase 3, randomized, double-blind, placebo-controlled, crossover study to assess the efficacy 
and safety of UX007 in the treatment of movement disorders associated with Glucose Transporter 
Type 1 Deficiency Syndrome (Glut1 DS) 
PROTOCOL NUMBER: 
UX007G-CL301 
STUDY SITES: 
Approximately 20 global sites  
NUMBER OF SUBJECTS PLANNED: 
The study will enroll approximately 40 subjects who experience disabling paroxysmal movement 
disorders  
PHASE OF DEVELOPMENT: 
Phase 3 
RATIONALE: 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare, severely debilitating 
disease characterized by seizures, developmental delay, and movement disorders. 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 brain’s primary source of energy, this 
disorder results in a chronic state of cerebral energy deficiency. Current management of Glut1 DS 
consists of the ketogenic diet (KD) which has been shown to be effective in controlling seizures 
associated with Glut1 DS (Pong et al. 2012, Pearson et al. 2013). However, there is less evidence 
supporting the effects of KD on movement disorders experienced by Glut1 DS patients.  
Symptoms can vary considerably with respect to both frequency and severity (Pearson et al. 2013). 
The clinical presentation of Glut1 DS may manifest as epilepsy, cognitive/developmental delays, 
movement disorders, or an assortment of all of these elements (Klepper et al. 2016). 
The movement disorders associated with Glut1 DS are well documented and occur across the 
patient spectrum. Pearson et al (2013) describe abnormal gait (typically ataxic or spastic-ataxic 
gait), dystonia and chorea as common motor disorders observed in Glut1 DS patients, with most 
patients exhibiting more than one motor abnormality (Pearson et al. 2013). The range of movement 
disorders that Glut1 DS patients experience may also be continuous and/or paroxysmal in nature. 
Paroxysmal symptoms are commonly triggered by fasting and/or exercise, as well as other 
provoking factors, suggesting that these are energy dependent manifestations and may be 
responsive to the delivery of energy substrates to the brain. In a qualitative research study, patients 
and caregivers were asked to report the types of movement disorders experienced and to describe 
any disability associated with the movement disorder events. Participants reported a wide variety 
of episodic movement disorders and difficulty performing many activities during the movement 
disorder events. Participants described significant motor problems with mobility, including 
impaired walking/running ability and trouble with balance, including falls. Caregivers/patients also 
reported difficulty with activities from movement disorders affecting their upper extremities, 
including problems with self-care functions such as dressing and feeding, and fine motor function 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 6 
e.g. writing. These movement disorders also often limited participation in sports and school 
activities. In addition to difficulty performing motor tasks, caregivers and patients described the 
impact of the movement disorders on social and emotional aspects of life, including 
embarrassment, social isolation and difficulty making friends (reference: data on file).  
In a recent, open-label Phase 2 study, paroxysmal manifestations improved significantly (p=0.028) 
in six evaluable patients, in response to treatment with triheptanoin (Mochel et al. 2015). 
Subjects were asked to record all paroxysmal non-epileptic manifestations including motor 
(e.g., hyperkinetic movement disorders, speech disorder, and limb weakness) and non-motor 
(e.g. fatigue, headache, sleep disturbance, disorientation, and mood disorder) events prior to and 
post treatment with triheptanoin. The numbers of motor and non-motor events were markedly 
reduced during treatment with triheptanoin followed by an increase in these paroxysmal events 
when triheptanoin treatment was subsequently withdrawn. Subjects were also asked to score 
changes in their clinical condition since the start of triheptanoin therapy. Patient-reported clinical 
global impression of improvement (CGI-I) scores demonstrated a clear improvement after the 
triheptanoin treatment period followed by worsening of their condition on withdrawal of treatment, 
tracking the temporal profile of changes in frequency of paroxysmal manifestations. Physicians 
also rated the severity of the study subjects based on their clinical experience with Glut1 DS and 
considered these subjects, in whom paroxysmal events were the primary manifestation of the 
disease, to be moderately to markedly ill. The most common motor manifestations included muscle 
stiffness, movement disorder, and weakness. All of these symptoms decreased in frequency when 
treatment with triheptanoin was initiated. During Baseline in the Mochel study, functional 
31P-nuclear magnetic resonance spectroscopy (f-MRS) showed no change in Pi/PCr ratio during 
brain activation in the Non KD population. After the UX007 treatment period, the bioenergetics 
profile normalized; repeated measures ANOVA (p= 0.014), with an increase in Pi/PCr ratio during 
visual stimulation and a significant decrease during recovery (p= 0.021). Increased Pi/PCr ratio 
during brain activation reflected a proportional elevation of ADP, allowing increased 
mitochondrial ATP production with UX007. After treatment withdrawal, the f-MRS profile 
reverted to the baseline levels (Mochel et al. 2015). These data suggest that UX007 improves 
energy availability for brain function.  
The severity of the motor symptoms can range from mild to quite severe. In the latter cases, the 
dystonic postures may involve axial or orobuccal musculature and be accompanied by dysphoria 
and inconsolable crying (Pons et al. 2010), suggesting a profound effect on quality of life. 
The non-motor manifestations may also be very disturbing to patients. In the Mochel study, 
fatigue, headache and sleep disturbance were the most common non-motor manifestations. 
The total score of non-motor manifestations was improved with the initiation of UX007. 
Paroxysmal non-motor manifestations may also include confusion, lethargy, somnolence, 
paroxysmal episodes of pain, drowsiness, dysphoria, and weakness (Pons et al. 2010, Urbizu et al. 
2010, Gras et al. 2014, Roze et al. 2015). In one series of 33 patients, headaches occurred in 6% 
and cyclic vomiting was reported in 46% (Ito et al. 2015). All may detract significantly from the 
day-to-day function and quality of life of the patient and potentially also for the family caregiver. 
Paroxysmal manifestations of Glut1 DS, both motor and non-motor, may therefore be considered a 
significant unmet medical need for this patient population. 
The proposed mechanism for both paroxysmal motor and non-motor manifestations appears to be 
related to a brain energy deficit related to energy expenditure (Weber et al. 2008, Wang et al. 
2012).  
Since glucose transfer into the brain relies on serum glucose levels, conditions leading to transient 
serum hypoglycemia such as fasting or exercise would be expected to result in a variety of 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 7 
paroxysmal manifestations. The types of paroxysmal manifestations depend on the area of the 
brain that is relatively energy deficient. For example, failure to meet the energy demand of the 
growing cortex in infancy likely results in seizures; cerebellar energy deprivation would lead to 
worsening ataxia; and energy loss in the basal ganglia (along with thalamocortical 
hypometabolism) would result in paroxysmal movement disorders, such as dystonia, chorea, or 
tremors (Pons et al. 2015, Akman et al. 2015).  
There are currently no approved therapies for the movement disorder events associated with Glut1 
DS. Triheptanoin, a triglyceride composed of three heptanoate (C7 fatty acid) esters, 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. The proposed Phase 3 study is designed to assess the 
efficacy and safety of UX007 (triheptanoin) in reducing the frequency of disabling paroxysmal 
movement disorder events in Glut1 DS patients. By focusing on disabling movement disorder 
events, the study will capture clinically meaningful events which limit physical functioning and 
activities of daily living. This study will assess patients who are not currently treated with KD, as 
this diet may affect some energy-dependent symptoms in Glut1 DS. The study will also evaluate 
the pharmacokinetics (PK) of energy-containing metabolites and correlate these to the potential 
treatment effects. 
STUDY DESIGN AND METHODOLOGY: 
UX007G-CL301 is a randomized, double-blind, placebo-controlled, crossover study to assess the 
efficacy and safety of UX007 in Glut1 DS. The study will enroll approximately 40 pediatric, 
adolescent, and adult subjects who are not on KD and are having disabling paroxysmal movement 
disorders. A movement disorder event is defined in this study as a period of time when the subject 
experiences one or more movement disorder symptoms, including symptoms that are experienced 
during a movement disorder event alone or significant worsening of continuous movement 
disorders. In this study, movement disorder events are defined as disabling if they affect or limit a 
subject’s activities of daily living. 
During the 6-week Run-in Period, subjects will record disabling paroxysmal movement disorder 
events in a daily electronic Glut1 DS symptom diary; if the minimum criterion for number of 
events is not met or subjects complete <80% of the daily electronic Glut1 DS symptom diary, the 
subject will be considered a screen failure and will not be randomized. Individuals may be allowed 
to rescreen, at the discretion of the Principal Investigator, subject to approval by the Medical 
Monitor. At the discretion of the Sponsor and Principal Investigator, the Run-In Period may be 
extended beyond 6 weeks. 


3URWRFRO1XPEHU8;*&/
3URWRFRO$PHQGPHQW
-XO\

3URSULHWDU\DQG&RQILGHQWLDO
3DJH
$WWKHHQGRIWKH5XQLQ3HULRGHOLJLEOHVXEMHFWVZLOOEHUDQGRPL]HGUDWLRWRRQHRI
WZRWUHDWPHQWVHTXHQFHV8;SODFHERRUSODFHER8;$W5DQGRPL]DWLRQVXEMHFWVZLOO
EHJLQDZHHNGRXEOHEOLQG7UHDWPHQW3HULRG7UHDWPHQW3HULRGZLOOFRQVLVWRIDZHHN
WLWUDWLRQSHULRGDQGDQZHHN0DLQWHQDQFH3HULRG$WWKHHQGRI7UHDWPHQW3HULRGVXEMHFWVZLOO
GLVFRQWLQXHWUHDWPHQWDQGEHJLQDZHHNZDVKRXWSHULRGWRPLQLPL]HDQ\SRWHQWLDOFDUU\RYHU
HIIHFW6XEMHFWVZLOOFURVVRYHUWRWKHVHFRQGUDQGRPL]HGGRXEOHEOLQGWUHDWPHQWDVVLJQPHQW
SODFHERWR8;8;WRSODFHERIRUDQDGGLWLRQDOZHHNVGXULQJ7UHDWPHQW3HULRG
7UHDWPHQW3HULRGZLOOFRQVLVWRIDZHHNWLWUDWLRQSHULRGDQGDQZHHN0DLQWHQDQFH3HULRG
$WWKHHQGRIWKHEOLQGHGFURVVRYHUSHULRG:HHNDOODFWLYHVXEMHFWVZLOOKDYHWKHRSWLRQRI
UROOLQJLQWRWKHRSHQODEHO([WHQVLRQ3HULRGWRFRQWLQXH8;WUHDWPHQWIRUXSWR\HDUVRUXQWLO
RQHRIWKHIROORZLQJRFFXUVWKHVXEMHFWZLWKGUDZVFRQVHQWWKHVXEMHFWLVGLVFRQWLQXHGIURPWKH
VWXG\DWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRUWKHVWXG\LVWHUPLQDWHGRUXQWLOFRPPHUFLDODYDLODELOLW\
RIWKHVWXG\GUXJLQDVXEMHFW¶VUHJLRQZKLFKHYHURFFXUVILUVW/RQJWHUPVDIHW\DQGPDLQWHQDQFH
RIHIIHFWRI8;ZLOOEHDVVHVVHGGXULQJWKHRSHQODEHO([WHQVLRQ3HULRG$VWXG\VFKHPDWLFLV
SURYLGHGLQ)LJXUH$6DIHW\)ROORZXS3KRQH&DOOZLOOEHFRQGXFWHGGD\VDIWHUWKHODVW
GRVHRI8;*&/VWXG\GUXJ
)LJXUH8;*&/6WXG\6FKHPDWLF
2%-(&7,9(6
7KHSULPDU\REMHFWLYHRIWKHVWXG\LVWR
x
(YDOXDWHWKHHIILFDF\DQGVDIHW\RI8;LQWKHWUHDWPHQWRIGLVDEOLQJSDUR[\VPDO
PRYHPHQWGLVRUGHUVDVVRFLDWHGZLWK*OXW'6
(1'32,176
(QGSRLQWVZLOOEHHYDOXDWHGIRU8;DQGSODFHERWUHDWPHQW
3ULPDU\(QGSRLQW
7KHSULPDU\HQGSRLQWLVWKHIUHTXHQF\RIGLVDEOLQJSDUR[\VPDOPRYHPHQWGLVRUGHUVFDSWXUHGDV
PRYHPHQWGLVRUGHUHYHQWVREVHUYHGGXULQJWKH0DLQWHQDQFH3HULRGRIWUHDWPHQWDVUHFRUGHGE\
WKHVXEMHFWFDUHJLYHULQDQHYHQWEDVHGGDLO\*OXW'6V\PSWRPGLDU\


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 9 
Secondary Endpoints  
• 
Duration of disabling paroxysmal movement disorder events observed during the 
Maintenance Period of treatment, as recorded by the subject/caregiver in an event-based 
daily Glut1 DS symptom diary 
• 
Walking capacity and endurance, as determined by the distance walked in 12 minutes 
during the 12 Minute Walk Test (12MWT) 
• 
Patient/caregiver global impression of change in clinical status using the Clinical Global 
Impression – Improvement (CGI-I)  
• 
Health-related quality of life assessing physical function, mobility, upper extremity 
function, fatigue, pain and social health using a PROMIS®-based questionnaire 
• 
Cognitive function as measured by the Cambridge Neuropsychological Test Automated 
Battery (CANTAB) (assessed at select sites) 
Exploratory Endpoints  
• 
Self-care, productivity, and leisure performance assessed by the Canadian Occupational 
Performance Measure (COPM) 
• 
Physician global impression of change in clinical status using the Clinical Global 
Impression – Severity scale (CGI-S) and Clinical Global Impression – Improvement 
(CGI-I) 
• 
Activity levels as measured by a wrist-worn actigraphy device at select study sites, where 
feasible. Endpoints include mean daytime activity, mean nighttime activity, and percent 
time in moderate or higher intensity activity  
• 
Frequency and duration of disabling paroxysmal movement disorder events over time 
throughout the three-year open-label extension period  
• 
PK data for UX007 metabolites  
Safety Endpoints  
• 
Adverse events, including the subject incidence of adverse events (AEs), treatment related 
AEs, serious adverse events (SAEs), AEs leading to discontinuation and fatal AEs 
• 
Clinically significant changes in vital signs, clinical laboratory test results, and 
electrocardiogram (ECG) 
• 
Change in suicidal ideation & behavior assessment as measured by the Columbia Suicide 
Severity Rating Scale (C-SSRS) 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 10 
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, aged ≥6 years old at the time of informed consent 
3) At least 8 disabling paroxysmal movement disorder events in the 12 weeks prior to the 
Screening, by subject or caregiver report 
          OR 
At least 6 disabling paroxysmal movement disorder events in any 6 consecutive week 
period, over the last 12 week period prior to the Screening, by subject or caregiver report 
4) At least 4 disabling paroxysmal movement disorder events in the first 6 weeks of Run-in 
Period, reported in the daily electronic Glut1 DS symptom diary 
5) ≥80% compliance with daily electronic Glut1 DS symptom diary completion during the 
Run-in Period 
6) Not on KD, modified KD, or ketosis-inducing modified-fat diet for at least 3 months prior 
to Screening 
7) Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening  
8) Provide written or verbal assent (if possible) and written informed consent by the patient 
(if an adult), or by a legally authorized representative after the nature of the study has been 
explained, and prior to any research-related procedures 
9) Must, in the opinion of the Investigator, be willing and able to complete key aspects of the 
study and be likely to complete the 22-week, placebo-controlled, treatment period  
10) Patient (or caregiver) must, in the opinion of the Investigator, be able to comply with 
accurate completion of the study daily Glut1 DS symptom diary 
11) Females of child-bearing potential must have a negative urine pregnancy test at Screening 
and Baseline and be willing to have additional pregnancy tests during the study. Females 
considered not to be of childbearing potential include those who have not experienced 
menarche, are post-menopausal (defined as having no menses for at least 12 months 
without an alternative medical cause) or are permanently sterile due to total hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy.  
12) Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug  
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1) Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of the 
Investigator, places the subject at increased risk for adverse effects 
2) Prior use of triheptanoin within 30 days prior to Screening 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 11 
3) History of, or current suicidal ideation, behavior and/or attempts per C-SSRS at Screening 
or Baseline  
4) Pregnant and/or breastfeeding an infant at Screening or Baseline 
5) Participants unwilling or unable to discontinue use of a prohibited medication or other 
substance that may confound study objectives (Section 7.4.6.1 [MCT oil, barbiturates, 
pancreatic lipase inhibitors, KetoCal or other KD supplements, and/or KD]) 
6) Glut1 DS treatment regimen, including AEDs, should be stable for at least 30 days prior to 
Screening 
7) Use of any investigational product (drug, medical food, or supplement, including medium 
chain triglyceride [MCT] oil, including coconut oil) within 30 days prior to Screening 
8) 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   
9) Feeding or nutrition that, in the opinion of the dietitian, potentially affects consistent 
administration of study drug 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 12 
INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: 
UX007 (triheptanoin) is a liquid, intended for oral (PO) administration. UX007 is a colorless to 
yellow oil supplied in 1 L round, translucent high-density polyethylene (HDPE) or 1 L round 
amber colored glass bottles. Subjects will be dosed according to an age- and weight-based strategy 
(Table 2.1), up to a maximum daily administration of 130g. For subjects within 25% predicted 
BMI, actual body weight will be used to calculate the appropriate dose per the subject’s age 
category. Adjusted body weight will be used for subjects with greater than 25% predicted BMI, to 
account for metabolic activity found in adipose tissue versus lean muscle. Adjusted body weight 
will be calculated in kilograms, using the following formula:  
Formula 1# Adjusted Body Weight = Ideal Body Weight + [25% × (Actual Body Weight − Ideal 
Body Weight)] 
UX007 dosing will be initiated using a 2-week titration schedule until the subject has reached 
his/her target total daily dose. If a subject has not reached the target total daily dose by the end of 
the 2-week titration period, dose titration should continue until the maximum tolerated dose is 
reached. For detailed information regarding dosing and titration, please refer to the Study 
Reference Manual. 
Table 2.1:  Age-based UX007 Target Total Daily Dose  
Age Range 
UX007 dose (g/kg/day) 
that is estimated 
equivalent to 30% total 
caloric intake 
6 – 9 Years 
2.5 
10 – 14 Years 
2 
15 – 20 Years 
1.5 
21 and Over 
1.2 
 
The total daily dose will be divided into 4 equal doses mixed with food or drink (or formula, as 
appropriate), and administered PO or by gastronomy tube at breakfast, lunch, dinner, and before 
bed. The dose may be divided into smaller more frequent doses with food or drink as needed. 
The  il should not be taken without thoroughly mixing with food or drink. The dose should not be 
adjusted due to changes in age and/or weight during Periods 1 and 2. 
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: 
Placebo will consist of safflower oil matching the attributes of UX007 oil. Dose level, titration, and 
mode of administration will be identical to that of UX007 during the double-blind Treatment 
Period. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 13 
DURATION OF TREATMENT: 
The planned duration of treatment in this study is approximately 3.5 years, consisting of a 6-week 
Run- in Period, a 22-week placebo-controlled, crossover Treatment Period, followed by an 
optional, open-label Extension Period. All subjects who have completed the 22-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. A Safety Follow-up Phone Call will be 
conducted 30-35 days after the last dose of UX007G-CL301 study drug. The last subject’s Safety 
Follow-up Phone Call is the End-of-Study Time Point. 
CRITERIA FOR EVALUATION: 
Primary and Secondary Efficacy Assessments:    
Disabling Paroxysmal Movement Disorders 
• 
Subject Daily Glut1 DS symptom Diary: An event-based Glut1 DS symptom diary 
will allow the subject/caregiver to capture quantitative and qualitative aspects of 
disabling paroxysmal movement disorder events 
Functional Outcome: Walking Capacity  
• 
12 Minute Walk Test (12MWT): The 12MWT is a variation of the 6MWT used to 
assess walking capacity and endurance as a functional outcome.  
Health-related Quality of Life 
• The Patient Reported Outcomes Measurement Information System (PROMIS®):  
A patient/proxy reported questionnaire selected from the PROMIS®-item bank to 
assess physical function, mobility, upper extremity function, fatigue, pain and 
social health. 
 
Clinical Status: Patient Impression of Global Symptom and Disease Severity 
• 
Patient impression of severity and change: The global impression of disease 
severity (using a 4-point Likert scale) at the start of the study and the degree of 
change in clinical status (CGI-I) as assessed by the patient/caregiver (7-point 
Likert scale) since the start of the study  
Cognitive Function 
• 
Cambridge Neuropsychological Test Automated Battery (CANTAB): 
Neuropsychological function measured using a standardized, computerized battery 
of tests designed to assess cognitive domains relevant to Glut1 DS subjects such as 
attention and memory tests. CANTAB will be performed at select study sites. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 14 
Exploratory Outcome Measures: 
Clinical Status: Physician Impression of Global Symptom and Disease Severity  
• 
Physician impression of severity and change: Physicians will rate disease severity 
at Baseline (CGI-S) and continue to rate severity for the duration of the study 
using a 4-point Likert scale. Physicians will also record the degree of change in 
clinical status (CGI-I) using a 7-point Likert scale at post treatment visits. 
Pharmacokinetic analysis of UX007 metabolites 
• 
PK Analysis: a summary of PK analysis data and descriptive statistics will be 
completed 
Activity Levels 
• 
Actigraphy Device: A wrist-worn actigraphy device will assess the impact of 
Glut1 DS on activity levels during the last 10 days of the Run-In Period, the last 
10 days of Treatment Period 1 and the last 10 days of Treatment Period 2. 
Endpoints include mean daytime activity, mean night time activity, and percent 
time in moderate or higher intensity activity. Actigraphy device will be used at 
select study sites, where feasible. 
Qualitative Assessment  
• 
Canadian Occupational Performance Measure: COPM will assess the impact of 
Glut1 DS on performance areas of self-care, productivity, and leisure.  
 
Safety Assessments: 
• 
Incidence, frequency, severity, and relatedness of AEs and SAEs, including 
clinically significant changes from Baseline to scheduled time points in in vital 
signs, clinical laboratory test results, and ECG 
• 
Vital signs, weight, physical examination  
• 
Pregnancy testing, suicidal ideation, via the Columbia Suicide Severity Rating 
Scale (C-SSRS) 
STATISTICAL METHODS: 
A full description of the statistical evaluations will be provided in the Statistical Analysis Plan 
(SAP). 
Sample Size: 
Based on the targeted patient population and eligibility criteria, it is estimated that the subjects 
receiving placebo will have a mean frequency of 8 disabling paroxysmal movement disorder 
events per 4 weeks, while subjects receiving UX007 will have a mean frequency of 4 disabling 
paroxysmal movement disorder events per 4 weeks, and a standard deviation of the difference of 
7.4. A total sample size of 40 subjects (20 subjects in each treatment sequence) will have at least 
85% power to detect such difference between UX007 and placebo groups. This sample size 
assumption incorporates a projected discontinuation rate of 15%. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 15 
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 they 
actually received for the safety analysis. 
Efficacy Analysis: 
The primary analysis will compare the frequency of paroxysmal movement disorders captured as 
disabling movement disorder events (normalized to a 4 week rate) observed during the 
Maintenance Period of treatment with UX007 to the frequency of disabling movement disorders 
captured as movement disorder events (normalized to a 4 week rate) observed during the 
Maintenance Period of treatment with placebo, as recorded by the subject/caregiver in an event-
based daily Glut1 DS symptom diary. 
The primary endpoint will be analyzed based on the efficacy analysis set using a weighted 
ANCOVA model, with study baseline frequency of movement disorder as a covariate, treatment 
sequence, treatment group and period as fixed effects, and a random effect for subject within the 
sequence. When there is strong evidence suggesting that the normality assumption is not met, 
Wilcoxon rank-sum test will be considered as the primary analysis to assess the primary endpoint. 
The specific model will be defined in the SAP. The hypothesis that there is no difference in mean 
frequency of disabling paroxysmal movement disorder events per 4 weeks between treatment 
groups will be tested at the α=0.05 (2-sided) level. 
For change-from-baseline efficacy endpoints, the baseline will be the last measurement taken prior 
to or on the first dose date of the first period for computation of the change from baseline value. 
The baseline measurement will be recorded before the dose is administered.  
If the primary analysis for the primary efficacy endpoint is statistically significant, then a 
sequential testing strategy will be implemented for selected secondary efficacy endpoints in the 
following order: 
• 
Duration of disabling paroxysmal movement disorder events  
• 
Change from Baseline in 12MWT distance 
• 
Patient/caregiver global impression of change in clinical status using the Clinical Global 
Impression – Improvement (CGI-I)  
Safety Analysis: 
All treatment emergent AEs (TEAEs) will be included in the analysis. Subject incidence of TEAE 
will be summarized by actual treatment received using the safety analysis set. Subject incidence of 
TEAE resulting in death, discontinuation and serious TEAE by actual treatment received will also 
be summarized. For C-SSRS, the percentage of subjects reporting any treatment emergent suicidal 
ideation and any treatment emergent suicidal behavior will be summarized descriptively by actual 
treatment received and visit week, respectively.  
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 16 
Table 2.2:  Schedule of Events (Screening; Run-in; Period 1; Washout; and Period 2) 
ASSESSMENT 
Screening 
Visit 
Week -6 
6-week 
Run-in 
Period 
TREATMENT PERIOD 1 
2-week 
Washout 
TREATMENT PERIOD 2 
Baseline 
1 
Phone Visits  
1, 2, and 3 
End of 
Treatment 
1 
Baseline 
2  
(End of 
Washout) 
Phone Visits  
4, 5, and 6    
End of 
Treatment 2 
Week 0 
(± 3 days) 
Weeks 2, 4, 
and 6 
(± 3 days) 
Week 10 
(± 3 days) 
Week 12 
 ±3 days 
Weeks 14, 16, 
and 18 
(± 3 days) 
Week 22 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
SAFETY ASSESSMENTS 
Vital Signs 
X 
 
X 
 
X 
 
X 
 
X 
Physical 
Examination 
X 
 
X 
 
X 
 
X 
 
X 
Neurological 
Examination 
 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
X 
 
X 
 
X 
 
X 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
Columbia Suicide 
Severity Rating 
Scale (C-SSRS)1 
X 
 
X 
 
X 
 
X 
 
X 
Clinical Laboratory 
Tests2 
X 
 
X 
 
X 
 
X 
 
X 
Electrocardiogram 
(ECG) 
 
 
X 
 
X 
 
 
 
X 
Urine Pregnancy 
Test (If 
appropriate)3 
X 
 
X 
 
X 
 
X 
 
X 
Adverse Events4, 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 17 
ASSESSMENT 
Screening 
Visit 
Week -6 
6-week 
Run-in 
Period 
TREATMENT PERIOD 1 
2-week 
Washout 
TREATMENT PERIOD 2 
Baseline 
1 
Phone Visits  
1, 2, and 3 
End of 
Treatment 
1 
Baseline 
2  
(End of 
Washout) 
Phone Visits  
4, 5, and 6    
End of 
Treatment 2 
Week 0 
(± 3 days) 
Weeks 2, 4, 
and 6 
(± 3 days) 
Week 10 
(± 3 days) 
Week 12 
 ±3 days 
Weeks 14, 16, 
and 18 
(± 3 days) 
Week 22 
(± 3 days) 
EFFICACY ASSESSMENTS 
Daily Glut1 DS  
Symptom Diary 
Training 
X 
 
 
 
 
 
 
 
 
Daily Glut1 
Symptom DS Diary 
Review  
 
 
X 
X 
X 
 
X 
X 
X 
Daily Glut1 DS 
Symptom Diary 
Completion 6 
 
X 
X 
X 
X 
X 
X 
X 
X 
12MWT 
X 
 
X 
 
X 
 
X 
 
X 
CANTAB7 
X 
 
X 
 
X 
 
X 
 
X 
PROMIS® 
Questionnaire 
 
 
X 
 
X 
 
X 
 
X 
Patient: Clinical 
Global Impression 
of Severity 
 
 
X 
 
 
 
 
 
 
Patient: Clinical 
Global Impression 
of Improvement 
 
 
 
 
X 
 
X 
 
X 
Physician: Clinical 
Global Impression 
of Severity 
 
 
X 
 
X 
 
X 
 
X 
Physician: Clinical 
Global Impression 
of Improvement  
 
 
 
 
X 
 
X 
 
X 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 18 
ASSESSMENT 
Screening 
Visit 
Week -6 
6-week 
Run-in 
Period 
TREATMENT PERIOD 1 
2-week 
Washout 
TREATMENT PERIOD 2 
Baseline 
1 
Phone Visits  
1, 2, and 3 
End of 
Treatment 
1 
Baseline 
2  
(End of 
Washout) 
Phone Visits  
4, 5, and 6    
End of 
Treatment 2 
Week 0 
(± 3 days) 
Weeks 2, 4, 
and 6 
(± 3 days) 
Week 10 
(± 3 days) 
Week 12 
 ±3 days 
Weeks 14, 16, 
and 18 
(± 3 days) 
Week 22 
(± 3 days) 
Canadian 
Occupational 
Performance 
Measurement 
 
 
X 
 
X 
 
X 
 
X 
Actigraphy 
Training8 
X 
 
 
 
 
 
 
 
 
Actigraphy8 
 
X 
 
 
X 
 
 
 
X 
SPECIALTY LABORATORY ASSESSMENTS 
UX007 Metabolites9 
 
 
X 
 
X 
 
X 
 
X 
BHB for ketosis 
detection 
X 
 
X 
 
X 
 
X 
 
X 
TREATMENT & DIETARY ASSESSMENTS 
Dietary Assessment 
and Consultation & 
Training on 3-day 
Diet Diary 
X 
 
 
 
 
 
 
 
 
Dietary 
Assessment& 
Review of 3-day 
Diet Diary 
 
 
X 
 
X 
 
X 
 
X 
Dietitian 
Consultation  
 
 
X 
X 
X 
 
X 
X 
X 
Daily Study 
Medication Diary6 
 
 
X 
X 
X 
 
X 
X 
X 
Review of Study 
Medication Diary 
 
 
X 
X 
X 
 
X 
X 
X 
Daily Treatment 
with IP/Placebo  
 
 
X 
X 
X 
 
X 
X 
X 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 19 
ASSESSMENT 
Screening 
Visit 
Week -6 
6-week 
Run-in 
Period 
TREATMENT PERIOD 1 
2-week 
Washout 
TREATMENT PERIOD 2 
Baseline 
1 
Phone Visits  
1, 2, and 3 
End of 
Treatment 
1 
Baseline 
2  
(End of 
Washout) 
Phone Visits  
4, 5, and 6    
End of 
Treatment 2 
Week 0 
(± 3 days) 
Weeks 2, 4, 
and 6 
(± 3 days) 
Week 10 
(± 3 days) 
Week 12 
 ±3 days 
Weeks 14, 16, 
and 18 
(± 3 days) 
Week 22 
(± 3 days) 
Dispense Study 
Drug 
 
 
X 
 
 
 
X 
 
X10 
Treatment 
Compliance & 
Accountability 
 
 
 
X 
X 
 
 
X 
X 
1 Suicidal ideation and behavior will be assessed in subjects who are ≥ 10 years of age at each visit 
2 For subjects ≥ 18 years old, 1ipid profile blood tests (LDL, HDL, total cholesterol, and triglycerides) will be assessed at Baseline 1 (Week 0), End of Treatment 
1 (Week 10), and End of Treatment 2 (Week 22) after an overnight fast (8-12 hours).  
3 For females of child-bearing potential  
4 Plasma metabolite samples will be collected at time of SAE, if feasible  
5 The definition of an AE also encompasses any increases in frequency or severity, or changes in type of Glut1 DS-associated symptoms, including but not 
limited to seizures, movement disorders, behavioral abnormalities, cognitive function, etc.  
6 Glut1 DS symptom diary and study medication diary will be completed daily by the patient/caregiver. Review of the daily diaries will be performed at clinic or 
phone visits as indicated (or more frequently if needed) 
7 CANTAB will be performed at select study sites 
8 An actigraphy device will be worn on the last 10 days of the Run-in Period, the last 10 days of Treatment Period 1, and the last 10 days of Treatment Period 2 
at select study sites, where feasible. Training for the actigraphy device will be provided at the Screening Visit. 
9 Blood for plasma at Baseline Visits will be collected pre-dose. Blood for plasma at End of Treatment visits 1 and 2 will be collected approximately 90 minutes 
post dose.  
10 Beginning at Week 22, all subjects will be dispensed UX007 for the open-label Extension Period 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 20 
Table 2.3:  Schedule of Events (Extension and Safety Follow-up) 
ASSESSMENT 
EXTENSION 
END OF 
TREATMENT VISIT 
EARLY 
TERMINATION 
VISIT 
SAFETY 
FOLLOW-UP 
Extension Visits 
Extension Phone Visits 
End of Treatment 
Visit 
Early Termination 
Visit 
Follow-up Phone 
Call10 
Weeks 34, 58, 82, 106, 
130, 154  
(± 2 weeks) 
Weeks 26, 30, 46, 70, 
94, 118, 142  
(± 2 weeks) 
Week 178 (±2 weeks) 
Final Dose (+4 weeks) 
30-35 Days after Final 
Dose 
SAFETY ASSESSMENTS 
Vital Signs 
X 
 
X 
X 
 
Physical Examination 
X 
 
X 
X 
 
Neurological 
Examination 
X 
 
X 
X 
 
Height1 
X 
 
X 
X 
 
Weight 
X 
 
X 
X 
 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)2 
X 
 
X 
X 
 
Clinical Laboratory 
Tests3 
X 
 
X 
X 
 
Electrocardiogram 
(ECG)4 
Weeks 58, 106, and 
154 Only 
 
 
X4 
 
Urine Pregnancy Test 
(If appropriate)5 
X 
 
X 
X 
 
Adverse Events6 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 
Daily  Glut1 DS 
Symptom Diary review 
X 
X 
X 
X 
 
Daily Glut1 DS 
Symptom Diary 
completion7 
X 
X 
X 
X 
 
12MWT 
X 
 
X 
X 
 
CANTAB8 
X 
 
X 
X 
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 21 
ASSESSMENT 
EXTENSION 
END OF 
TREATMENT VISIT 
EARLY 
TERMINATION 
VISIT 
SAFETY 
FOLLOW-UP 
Extension Visits 
Extension Phone Visits 
End of Treatment 
Visit 
Early Termination 
Visit 
Follow-up Phone 
Call10 
Weeks 34, 58, 82, 106, 
130, 154  
(± 2 weeks) 
Weeks 26, 30, 46, 70, 
94, 118, 142  
(± 2 weeks) 
Week 178 (±2 weeks) 
Final Dose (+4 weeks) 
30-35 Days after Final 
Dose 
Patient: Clinical Global 
Impression of 
Improvement  
X 
 
X 
X 
 
PROMIS® 
Questionnaire 
X 
 
X 
X 
 
Physician: Clinical 
Global Impression of 
Severity 
X 
 
X 
X 
 
Physician: Clinical 
Global Impression of 
Improvement  
X 
 
X 
X 
 
Canadian Occupational 
Performance Measure 
X 
 
X 
X 
 
SPECIALTY LABORATORY ASSESSMENTS 
UX007   Metabolites9 
Week 34 Only9 
 
 
 
 
BHB for ketosis 
detection  
X 
 
X 
X 
 
In-clinic dose 
Week 34 Only9 
 
 
 
 
TREATMENT & DIETARY ASSESSMENTS 
Dietary Assessment/ 
Consultation & Review 
of 3-day Diet Diary 
X 
 
X 
X 
 
Daily Study 
Medication Diary7 
X 
X 
 
 
 
Review of Study 
Medication Diary 
X 
 
X 
X 
 
Daily Treatment with 
IP 
X 
X 
 
 
 
Dispense Study Drug 
X 
 
 
 
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 22 
ASSESSMENT 
EXTENSION 
END OF 
TREATMENT VISIT 
EARLY 
TERMINATION 
VISIT 
SAFETY 
FOLLOW-UP 
Extension Visits 
Extension Phone Visits 
End of Treatment 
Visit 
Early Termination 
Visit 
Follow-up Phone 
Call10 
Weeks 34, 58, 82, 106, 
130, 154  
(± 2 weeks) 
Weeks 26, 30, 46, 70, 
94, 118, 142  
(± 2 weeks) 
Week 178 (±2 weeks) 
Final Dose (+4 weeks) 
30-35 Days after Final 
Dose 
Treatment Compliance 
& Accountability 
X 
X 
X 
X 
 
1 Height only to be collected in the extension period for subjects under the age of 20 
2 Suicidal ideation and behavior will be assessed in subjects who are ≥ 10 years of age at each visit 
3 For subjects ≥ 18 years old, 1ipid profile blood tests (LDL, HDL, total cholesterol, and triglycerides) will be at clinic extension visits after an overnight fast (8-
12 hours). 
4 ECG will be performed at Weeks 58, 106, 154 during the Extension Period (or Early Termination, if applicable). ECG will not be performed at Early 
Termination visit if the assessment was conducted within 3 months of termination. 
5 For females of child-bearing potential 
6 The definition of an AE also encompasses any increases in frequency or severity, or changes in type of Glut1 DS-associated symptoms, including but not 
limited to seizures, movement disorders, behavioral abnormalities, cognitive function, etc. 
7 Glut1 DS symptom diary and study medication diary will be completed by the patient/caregiver. Review of the daily diaries will be performed at clinic or 
phone visits as indicated. 
8 CANTAB will performed at select study sites. 
9 Blood for plasma metabolites will be collected at the Week 34 visit only (pre-dose (within 15 minutes) and at [± 5 minutes] 30, 90, and 120 minutes post dose).  
10 Safety-Follow-up Phone Call to be conducted 30-35 days after last dose of UX007G-CL301study drug, even in cases of Early Termination. The site personnel 
will initiate this safety follow-up telephone call to collect information on any ongoing or new AEs, serious adverse events (SAEs), and concomitant 
medications. Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, are resolved.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 23 
3 TABLE OF CONTENTS 
1 TITLE PAGE .......................................................................................................................1 
2 SYNOPSIS ...........................................................................................................................5 
3 TABLE OF CONTENTS ...................................................................................................23 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................26 
5 INTRODUCTION .............................................................................................................29 
5.1 Overview of Glucose Transporter Type 1 Deficiency Syndrome .............................29 
5.2 Brief Overview of UX007 Development ..................................................................30 
5.2.1 
Brief Description of the Investigational Product .........................................30 
5.2.2 
Nonclinical Studies ......................................................................................32 
5.2.3 
Previous Clinical Studies .............................................................................34 
5.3 Summary of Overall Risks and Potential Benefits ....................................................35 
5.4 Study Rationale .........................................................................................................36 
6 STUDY OBJECTIVES ......................................................................................................37 
6.1 Study Endpoints ........................................................................................................37 
6.1.1 
Primary Endpoint ........................................................................................37 
6.1.2 
Secondary Endpoints ...................................................................................37 
6.1.3 
Exploratory Endpoints .................................................................................37 
6.1.4 
Safety Endpoints ..........................................................................................38 
7 INVESTIGATIONAL PLAN ............................................................................................39 
7.1 Overall Study Design and Plan .................................................................................39 
7.2 Discussion of Study Design, Including Choice of Control Group ............................40 
7.3 Selection of Study Population ...................................................................................41 
7.3.1 
Inclusion Criteria .........................................................................................42 
7.3.2 
Exclusion Criteria ........................................................................................43 
7.3.3 
Removal of Subjects from Therapy or Assessment ....................................44 
7.4 Treatments .................................................................................................................45 
7.4.1 
Investigational Product ................................................................................45 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 24 
7.4.2 
Reference Therapy ......................................................................................45 
7.4.3 
Method of Assigning Subjects to Treatment Groups ..................................45 
7.4.4 
Selection of Doses .......................................................................................46 
7.4.5 
Blinding .......................................................................................................47 
7.4.6 
Prior and Concomitant Therapy ..................................................................48 
7.4.7 
Treatment Compliance ................................................................................49 
7.5 Study Procedures and Assessments ..........................................................................49 
7.5.1 
Visit Schedule ..............................................................................................49 
7.5.2 
Efficacy Measures .......................................................................................50 
7.5.3 
Drug Concentration Measurements and Bioassays .....................................53 
7.5.4 
Safety Measures & General Assessments ...................................................53 
7.5.5 
Appropriateness of Measures ......................................................................58 
7.6 Statistical Methods and Determination of Sample Size ............................................59 
7.6.1 
Determination of Sample Size .....................................................................59 
7.6.2 
Analysis Populations ...................................................................................59 
7.6.3 
Planned Methods of Analysis ......................................................................59 
7.6.4 
Pharmacokinetic and Bioassay Analyses ....................................................62 
7.6.5 
Interim Analysis ..........................................................................................62 
7.6.6 
Data Monitoring Committee .......................................................................62 
8 STUDY CONDUCT ..........................................................................................................63 
8.1 Ethics .........................................................................................................................63 
8.1.1 
Institutional Review Board or Ethics Committee and Competent 
Health Authority .........................................................................................63 
8.1.2 
Ethical Conduct of Study ............................................................................63 
8.1.3 
Subject Information and Consent ................................................................63 
8.2 Investigators and Study Administrative Structure ....................................................64 
8.3 Investigational Product Accountability .....................................................................65 
8.4 Data Handling and Record Keeping .........................................................................65 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 25 
8.4.1 
Case Report Forms and Source Documents ................................................65 
8.4.2 
Data Quality Assurance ...............................................................................65 
8.4.3 
Record Retention .........................................................................................66 
8.5 Reporting and Follow-up of Adverse Events ............................................................66 
8.5.1 
Definition of Adverse Events ......................................................................66 
8.5.2 
Severity of Adverse Events .........................................................................67 
8.5.3 
Relationship of Adverse Events to Study Drug ...........................................68 
8.5.4 
Adverse Event Reporting ............................................................................68 
8.5.5 
Communication Plan ...................................................................................70 
8.6 Financing and Insurance ...........................................................................................71 
8.7 Publication Policy .....................................................................................................71 
9 REFERENCES ..................................................................................................................72 
10 SIGNATURE PAGE .........................................................................................................77 
 
LIST OF TABLES 
Table 2.1:  Age-based UX007 Target Total Daily Dose .........................................................12 
Table 2.2:  Schedule of Events (Screening; Run-in; Period 1; Washout; and Period 2) .........16 
Table 2.3:  Schedule of Events (Extension and Safety Follow-up) .........................................20 
Table 7.4.4.1:  Age- based UX007 Target Total Daily Dose ..................................................46 
Table 7.5.4.5.1:  Clinical Laboratory Assessments .................................................................55 
 
LIST OF FIGURES 
Figure 2.1:  UX007G-CL301 Study Schematic .........................................................................8 
Figure 5.2.1.1.1:  Proposed mechanism of UX007 action in Glut1 DS ...................................32 
Figure 7.1.1:  UX007G-CL301 Study Schematic ....................................................................40 
 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 26 
4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
12MWT 
12 Minute Walk Test 
ADA 
Americans with Disabilities Act 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
APBD 
adult polyglucosan body disease 
AST 
aspartate aminotransferase 
BHB 
beta-hydroxybutyrate 
BHP 
beta-hydroxypentanoic 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 
COPM 
Canadian Occupational Performance Measure 
CSF 
Cerebral spinal fluid 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EEG 
Electroencephalogram 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAOD 
fatty acid oxidation disorders 
FDA 
Food and Drug Administration (United States) 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
Glut1 
glucose transporter type 1 
Glut1 DS 
glucose transporter type 1 deficiency syndrome 
GMP 
Good Manufacturing Practice 
GSD II 
glycogen storage disease type II 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 27 
HDL 
high density lipoprotein 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
IRB 
IST 
Institutional Review Board 
Investigator-sponsored Trial 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
KD 
ketogenic diet 
LC-FAOD 
long-chain fatty acid oxidation disorders 
LDL 
low density lipoprotein 
L 
liter 
MCT 
medium chain triglyceride 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
PED 
paroxysmal exertional dyskinesia 
PK 
Pharmacokinetic 
PO 
oral, by mouth, per os 
PROMIS® 
Patient Reported Outcomes Measurement Information System 
PT 
Preferred Term 
RBC 
red blood cell 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions 
TCA 
tricarboxylic acid 
TK 
Toxicokinetic 
US 
United States 
UX007 
Investigational Product/study drug, triheptanoin 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 28 
WBC 
white blood cell 
WHO 
World Health Organization 
 
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. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 29 
5 INTRODUCTION 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare, severely debilitating 
disease characterized by seizures, developmental delay, and movement disorders. Glut1 DS 
is caused by a mutation in the solute carrier family 2, member 1(SLC2A1) gene, encoding the 
Glut1 protein responsible for transporting glucose across the blood brain barrier. 
Because glucose is the primary source of energy for the brain, this disorder results in a 
chronic state of cerebral energy deficiency.  
5.1 
Overview of Glucose Transporter Type 1 Deficiency Syndrome 
Glut1 DS is a rare disease with an estimated birth incidence of 1:90,000 (Coman et al. 2006). 
This birth incidence translates to an estimated prevalence of ~8,500 in the US and Europe. 
Most commonly Glut1 DS is inherited in an autosomal dominant manner; approximately 
90 % of individuals with autosomal dominant Glut1 DS have a de novo heterozygous 
mutation in SLC2A1, and about 10% have a clinically-affected parent  
(Wang et al. 1993-2015). Autosomal recessive transmission has also been described in 
rare cases. 
The laboratory hallmark of Glut1 DS is a low cerebrospinal fluid glucose concentration 
(<60 mg/dL or 3.3 mmol/L in all cases reported to date; <40 mg/dL or 2.2 mmol/L in the 
majority of cases). Decreased 3-O-methyl-D-glucose uptake in erythrocytes is observed and 
is abnormally low in almost all suspected cases of Glut1 DS (Wang et al. 1993-2015). 
Molecular genetic testing may also be used to detect pathogenic SLC2A1 variants, however 
some reports estimate approximately 20% to 30% do not carry mutations in SLC2A1 
(Klepper et al. 2007, Klepper 2008, Verrotti et al. 2012). 
Symptoms can vary considerably with respect to both frequency and severity  
(Pearson et al. 2013). The clinical presentation of Glut1 DS may manifest as epilepsy, 
cognitive/developmental delays, movement disorders, or an assortment of all of these 
elements (Klepper et al. 2016). Recently, there has been a dramatic expansion in the range of 
clinical syndromes that are recognized to occur with Glut1 DS including patients with milder 
forms of epilepsy, patients with non­epileptic syndromes characterized by both persistent and 
paroxysmal movement disorders, and patients with varying degrees of cognitive impairment 
(Pearson et al. 2013). 
Movement disorders associated with Glut1 DS are well documented and occur across the 
patient spectrum. Pearson et al (2013) describe abnormal gait (typically ataxic or spastic-
ataxic gait), dystonia and chorea as common motor disorders observed in Glut1 DS patients, 
with most patients exhibiting more than one motor abnormality (Pearson et al. 2013). The 
range of movement disorders that Glut1 DS patients experience may also be continuous 
and/or paroxysmal in nature. Paroxysmal symptoms are commonly triggered by fasting and 
exercise, amongst other potential provoking factors, suggesting that these are energy 
dependent manifestations and may be responsive to the delivery of energy substrates to the 
brain.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 30 
The non-motor manifestations may also be very disturbing to patients. In the Mochel study, 
fatigue, headache and sleep disturbance were the most common non-motor manifestations. 
The total score of non-motor manifestations was improved with the initiation of UX007. 
Paroxysmal non-motor manifestations may also include confusion, lethargy, somnolence, 
paroxysmal episodes of pain, drowsiness, dysphoria, and weakness (Pons et al. 2010, Urbizu 
et al. 2010, Gras et al. 2014, Roze et al. 2015). In one series of 33 patients, headaches 
occurred in 6% and cyclic vomiting was reported in 46% (Ito et al. 2015) All may detract 
significantly from the day-to-day function and quality of life of the patient and potentially 
also for the family caregiver. Paroxysmal manifestations of Glut1 DS, both motor and non-
motor, may therefore be considered a significant unmet medical need for this patient 
population. 
The proposed mechanism for both paroxysmal motor and non-motor manifestations appears 
to be related to a brain energy deficit related to energy expenditure (Weber et al. 2008, Wang 
et al. 2012).  
Since glucose transfer into the brain relies on serum glucose levels, conditions leading to 
transient serum hypoglycemia such as fasting or exercise would be expected to result in a 
variety of paroxysmal manifestations. The types of paroxysmal manifestations depend on the 
area of the brain that is relatively energy deficient. For example, failure to meet the energy 
demand of the growing cortex in infancy likely results in seizures; cerebellar energy 
deprivation would lead to worsening ataxia; and energy loss in the basal ganglia (along with 
thalamocortical hypometabolism) would result in paroxysmal movement disorders, such as 
dystonia, chorea, or tremors (Pons et al. 2015, Akman et al. 2015).  
Current management of Glut1 DS consists of the ketogenic diet (KD) which has been shown 
to be effective in controlling seizures associated with Glut1 DS (Pong et al. 2012, Pearson et 
al. 2013). However, there is less evidence supporting the effects of KD on movement 
disorders experienced by Glut1 DS patients and a there is a continued effort to understand 
any potential effect that KD may have on these symptoms. 
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: 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 31 
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 liter (L), high density 
polyethylene (HDPE) or round, amber-colored glass bottles. UX007 is manufactured, 
packaged, and labeled according to Good Manufacturing Practice (GMP) regulations. 
5.2.1.1 
Mechanism of Action in Glut1 DS 
UX007 (triheptanoin) is metabolized to heptanoate, which in turn is further metabolized to 
4- and 5-carbon ketone bodies. These metabolites bypass the Glut1 transporter to cross the 
blood-brain-barrier via the monocarboxylate transporter or potentially by mass action 
diffusion for heptanoate, and provide an alternative energy source to the brain 
(Figure 5.2.1.1.1). Once in the brain, the metabolites may be further metabolized by both glia 
and neurons to generate effective compounds to deliver energy. These metabolites also have 
the ability to provide propionyl-CoA in order to resupply intermediates of the TCA cycle 
(i.e. anaplerosis) within the brain as well as support gluconeogenesis and glycogen 
production. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 32 
Figure 5.2.1.1.1:  Proposed mechanism of UX007 action in Glut1 DS 
 
5.2.2 
Nonclinical Studies 
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have been 
published and further support the safety of UX007. These studies provide data on the 
absorption, metabolism, and toxicity of triheptanoin when administered intravenously and 
PO at doses up to 40% the recommended caloric intake. Furthermore, triheptanoin has 
been found to be effective in 4 animal models of epilepsy, similar to that of other AEDs 
(Borges et al. 2012, Willis et al. 2010, Thomas et al. 2012, Kim et al. 2013). Studies of 
potential clinical significance and relevance to this protocol are summarized below; 
additional details are provided in the IB.  
Triheptanoin is metabolized rapidly in the gut to form glycerol and heptanoate that is further 
metabolized in the liver to C4- and C5-ketone bodies (Kinman et al. 2006, Deng et al. 2009). 
In the mouse model of Glut1 DS, triheptanoin administration led to the delivery of 
heptanoate to the brain which was metabolized into glucose and neurotransmitter 
intermediates, consistent with an important role of the odd-chain length C7 structure in 
restoring central nervous system metabolism (Marin-Valencia et al. 2013).  
Three non-GLP toxicology studies have been conducted: one acute study in rats at doses up 
to 5 ml/kg (CL74-95-1045), one 9 month toxicity study in rats at doses up to 1.14 g/kg/day 
(Ataide et al. 2009); a rat 9-month chronic study), and one dermal sensitization study in 
guinea pigs (CL74-95-1045). There were no systemic toxic effects in any study, although 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 33 
hepatic steatosis was observed in all groups, including control animals, in the 9-month study. 
This is likely due to the high fat content in the diet and easier diffusion absorption of medium 
chain fat without bile (rats have no gall bladder), which is generally much less well tolerated 
in rat compared to human. Microscopic changes were observed in the intestinal cells but this 
effect was seen in all groups including controls. The dermal sensitization study indicated that 
triheptanoin is not a dermal sensitizer.  
A Good Laboratory Practice (GLP) 9-month study in juvenile Yucatan minipigs was 
performed to further evaluate the toxicity and toxicokinetic (TK) profile of UX007 and 
five metabolites, including the C7 fatty acid heptanoic acid, two C5 ketone bodies 
(3-hydroxyvaleric acid and 3-ketovaleric acid), and two C4 ketone bodies (acetoacetic acid 
and beta hydroxyl butyric acid). There was no evidence of triheptanoin accumulation in 
plasma after daily dosing in feed at doses as high as 50% of daily caloric intake. 
Systemic exposure to triheptanoin and its metabolites was evident from the dose-related 
increase in plasma levels; there was no evidence of accumulation in plasma of triheptanoin 
and the metabolites after daily dosing for 9 months. No adverse treatment-related clinical 
signs were noted in any of the minipigs during the study and no treatment-related deaths 
occurred. No obvious treatment-related differences in body weight, body weight gain, 
hematology profiles, organ weights or diagnostic pathology were seen in minipigs receiving 
UX007 at 10, 30 or 50% of the caloric intake after 9-months of treatment. Alterations in 
clinical pathology (serum chemistry and hematology) profiles were considered secondary to 
the diet of the treated animals being lower in protein, iron and/or other nutrients. UX007 was 
well-tolerated at up to 50% of daily caloric intake and did not result in any evidence of 
systemic toxicity. As such, the 50% caloric replacement was considered the no-observed-
adverse-effect level (NOAEL) for UX007 following 9-months of treatment. 
A standard battery of genotoxicity tests was performed with UX007, including a Bacterial 
Reverse Mutation Test in Salmonella typhimurium and Escherichia (Ames), an In Vitro 
Mammalian Chromosome Aberration Test in human peripheral blood lymphocytes 
(Chromosomal Aberration), and a Mammalian Erythrocyte Micronucleus Test in rat bone 
marrow (Rat Micronucleus). UX007 was negative in all of these assays.  
Developmental and Reproductive Toxicology (DART) GLP studies have also been 
conducted. The fertility study (Seg I) in rats did not reveal any impact on male or female 
fertility assessments. Furthermore, the embryo-fetal development (EFD; Seg II) studies in 
rats and rabbits did not reveal any impact on development of the fetus after exposure to 
UX007 during pregnancy. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 34 
5.2.3 
Previous Clinical Studies 
Clinical Studies in Glut1 DS Patients with Movement Disorders 
In a recent, open-label Phase 2 study, paroxysmal manifestations improved significantly 
(p=0.028) in six evaluable patients, in response to treatment with triheptanoin  
(Mochel et al. 2015). In the study, subjects were asked to record all paroxysmal 
manifestations including motor (epileptic and non-epileptic) and non-motor (e.g. fatigue, 
headache, sleep disturbance, disorientation, and mood disorder) events prior to and post 
treatment with triheptanoin. The numbers of motor and non-motor events were reduced 
during treatment with triheptanoin followed by an increase in these paroxysmal events when 
triheptanoin treatment was subsequently withdrawn. Subjects were also asked to score 
changes in their clinical condition since the start of triheptanoin therapy. Patient-reported 
clinical global impression of improvement (CGI-I) scores demonstrated a clear improvement 
after the triheptanoin treatment period followed by worsening of their condition on 
withdrawal of treatment, tracking the temporal profile of changes in frequency of paroxysmal 
manifestations. Physicians also rated the severity of the study subjects based on their clinical 
experience with Glut1 DS and considered these subjects, in whom paroxysmal events were 
the primary manifestation of the disease, to be moderately to markedly ill. The most common 
motor manifestations included muscle stiffness, movement disorder, and weakness. All of 
these symptoms decreased in frequency when treatment with triheptanoin was initiated.  
Studies in Glut1 DS Patients with Other Clinical Manifestations and Other Indications  
More than 450 patients with various metabolic disorders of energy deficiency including 
Glut1 DS, have been treated with triheptanoin for periods up to 16 years with evidence of 
clinical benefit and no significant safety issues reported. In addition, over 100 patients with 
various metabolic disorders from our sponsored studies and expanded access and Investigator 
initiated studies, have been treated with UX007 with evidence of clinical benefit and no 
significant safety issues reported. These data support the safety of triheptanoin when 
administered at the proposed weight-based clinical dose range in adults and pediatric patients 
as young as neonates.  
Triheptanoin has been studied for over a decade in a large cohort of patients with 
fatty-acid oxidation disorders (FAOD) as part of a compassionate use program  
(Roe et al. 2002, Roe et al. 2006, Roe et al. 2008, Barone et al. 2012). Ultragenyx is currently 
developing UX007 as a substrate replacement therapy for long-chain FAOD (LC-FAOD).  
Patients with other disorders have also been treated with triheptanoin, including those with 
pyruvate carboxylase deficiency (Mochel et al. 2005), Huntington’s disease  
(Mochel et al. 2010), adult polyglucosan body disease (APBD) (Roe et al. 2010), glycogen 
storage disease 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. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 35 
Triheptanoin was studied in 14 Glut1 DS subjects (including 11 pediatric subjects) in a 
clinical trial sponsored by Dr. Juan Pascual at the University of Texas, Southwestern. 
The results of this open-label study suggest clinical activity with triheptanoin in reducing the 
frequency of absence seizures (Pascual et al. 2014). No patient experienced serious or 
unexpected adverse events (AE). One patient (7%) discontinued triheptanoin therapy after 
3 weeks owing to gastric discomfort. One other patient (7%) experienced significant (10%) 
weight gain at 2 months that did not lead to discontinuation. This patient did not follow 
recommended dietary and nutritional advice to decrease extra sources of fat and simple 
sugars. Two patients (14%) experienced diarrhea and/or digestive discomfort within days of 
treatment initiation; symptoms resolved by reducing the triheptanoin dose by one-half and 
gradually increasing the amount to the target levels over several days. 
Current Studies Sponsored by Ultragenyx 
The Phase 2 randomized, double-blind, placebo-controlled study to assess the safety and 
efficacy of UX007 in pediatric, adolescent, and adult Glut1 DS patients experiencing seizures 
has recently completed study conduct (UX007G-CL201, data analysis ongoing). In addition, 
a prospective open-label Phase 2 study to assess safety and clinical effects of UX007 in 
subjects with LC-FAOD (UX007-CL201) is completed. Both studies have extensions into 
which subjects could enroll once they completed participation in the parent study 
(UX007G-CL202 and UX007-CL202, respectively).  
The IB provides additional information on UX007 effects in humans and associated 
Reference Safety Information. 
5.3 
Summary of Overall Risks and Potential Benefits 
UX007 is intended as a substrate replacement therapy to improve metabolism in patients with 
Glut1 DS. UX007 is being developed to address the needs of Glut1 DS patients who have 
paroxysmal movement disorder events. There exists a significant unmet medical need in 
these patients. 
Over 450 patients with Glut1 DS and LC-FAOD or other diseases of energy metabolism have 
been treated with UX007 as part of clinical trials or expanded access (compassionate use) 
programs. Of these, >50 subjects were pediatric subjects with some as young as neonates; 
23 received over 5 years treatment with triheptanoin. These data support the safety of 
triheptanoin when administered in pediatric patients as young as neonates.  
Nonclinical studies evaluating triheptanoin and its metabolites in mice and rats have been 
published and further support the safety of triheptanoin in the Glut1 DS population. 
Data from the animal pharmacokinetic (PK), TK, and toxicity studies indicate that 
triheptanoin is well absorbed after oral dosing and is well-tolerated without overt toxicities at 
doses as high as 1.14 g/kg in mice and 50% daily caloric intake in juvenile minipigs for 
9 months, with no signs of hepatic or renal injury. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 36 
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 had no significant 
safety issues in humans and no toxicology or adverse pharmacology findings were 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). Commonly reported adverse effects are gastrointestinal distress and 
excessive weight gain at high doses. Both of these issues appear to resolve when triheptanoin 
is consumed in small doses mixed with foods throughout the day and when total caloric 
intake is appropriately managed. The current overall risk-benefit ratio of UX007 supports 
further clinical development for the treatment of Glut1 DS. 
5.4 
Study Rationale 
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare, severely debilitating 
disease characterized by seizures, developmental delay, and movement disorders. 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 cerebral energy deficiency. Current 
management of Glut1 DS consists of the ketogenic diet (KD) which has been shown to be 
effective in controlling seizures associated with Glut1 DS (Pong et al. 2012, Pearson et al. 
2013). However, there is less evidence supporting the effects of KD on movement disorders 
experienced by Glut1 DS patients.  
The proposed mechanism for both paroxysmal motor and non-motor manifestations appear to 
be related to an energy deficit in the basal ganglia related to energy expenditure  
(Weber et al. 2008, Wang et al. 2012). These symptoms may be relieved to some extent by 
the KD, which also suggests an energy-dependent mechanism of action. 
There are currently no approved therapies for the movement disorder events associated with 
Glut1 DS. Triheptanoin, a triglyceride composed of three heptanoate (C7 fatty acid) esters, 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. The proposed Phase 3 study is designed to 
assess the efficacy and safety of UX007 (triheptanoin) in reducing the frequency of episodic 
movement disorder events in Glut1 DS patients. This study will assess patients who are not 
currently treated with the ketogenic diet (KD), as this diet may affect some energy-dependent 
symptoms in Glut1 DS.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 37 
6 STUDY OBJECTIVES 
The primary objective of the study is to:  
• Evaluate the efficacy and safety of UX007 in the treatment of disabling paroxysmal 
movement disorders associated with Glut1 DS 
6.1 
Study Endpoints 
Endpoints will be evaluated for UX007 and placebo treatment. 
6.1.1 
Primary Endpoint 
The primary endpoint is the frequency of disabling paroxysmal movement disorders captured 
as movement disorder events observed during the Maintenance Period of treatment, as 
recorded by the subject/caregiver in an event-based daily Glut1 DS symptom diary.  
6.1.2 
Secondary Endpoints 
• Duration of disabling paroxysmal movement disorder events observed during 
Maintenance Period of treatment, as recorded by the subject/caregiver in an event-based 
daily Glut1 DS symptom diary  
• Walking capacity and endurance, as determined by the distance walked in 12 minutes in 
the 12 Minute Walking Test 
• Patient/caregiver global impression of change in clinical status using the Clinical Global 
Impression – Improvement (CGI-I) 
• Health-related quality of life assessing physical function, mobility, upper extremity 
function, fatigue, pain and social health using a PROMIS®-based questionnaire  
• Cognitive function as measured by the Cambridge Neuropsychological Test Automated 
Battery (CANTAB) (assessed at select sites) 
 
6.1.3 
Exploratory Endpoints 
• Self-care, productivity, and leisure performance assessed by the Canadian Occupational 
Performance Measure (COPM) 
• Physician global impression of change in clinical status using the Clinical Global 
Impression – Severity scale (CGI-S) and Clinical Global Impression – Improvement 
(CGI-I) 
• Activity levels as measured by a wrist-worn actigraphy device at select study sites, where 
feasible. Endpoints include mean daytime activity, mean nighttime activity, and percent 
time in moderate or higher intensity activity  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 38 
• Frequency and duration of disabling paroxysmal movement disorder events over time 
throughout the three year open-label Extension Period  
• PK data for UX007 metabolites  
 
6.1.4 
Safety Endpoints 
• Adverse events, including the subject incidence of adverse events (AEs), treatment 
related AEs, serious adverse events (SAEs), AEs leading to discontinuation and fatal 
AEs. 
• Clinically significant changes in vital signs, clinical laboratory test results, and 
electrocardiogram (ECG) 
• Change in suicidal ideation & behavior assessment as measured by the Columbia Suicide 
Severity Rating Scale (C-SSRS)  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 39 
7 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
UX007G-CL301 is a randomized, double-blind, placebo-controlled, crossover study to assess 
the efficacy and safety of UX007 in Glut1 DS. The study will enroll approximately 
40 pediatric, adolescent, and adult subjects who are not on KD and are having disabling 
paroxysmal movement disorder events. In this study, movement disorder events are defined 
as disabling if they affect or limit a subject’s physical functioning and activities of daily 
living such as caring for oneself, performing manual tasks, walking, standing, lifting things, 
bending, eating/swallowing, speaking, seeing, sleeping, attending or participating in 
school/work, or doing sports/exercise. 
During the 6-week Run-in Period, subjects will record disabling paroxysmal movement 
disorder events in a daily electronic Glut1 DS symptom diary; if the minimum criterion for 
number of events is not met (or subjects complete <80% of the daily electronic Glut1 DS 
symptom diary), the subject will be considered a screen failure and will not be randomized. 
Individuals may be allowed to rescreen, at the discretion of the Principal Investigator, subject 
to approval by the Medical Monitor. At the discretion of the Sponsor and Principal 
Investigator, the Run-In Period may be extended beyond 6 weeks. 
At the end of the Run-in Period, eligible subjects will be randomized (1:1 ratio) to one of 
two treatment sequences (UX007/placebo or placebo/UX007). At Randomization, subjects 
will begin a 10-week double-blind Treatment Period 1. At the end of Treatment Period 1, 
subjects will discontinue treatment and begin a 2-week washout period to minimize any 
potential carryover effect. Subjects will crossover to the second randomized, double-blind 
treatment assignment (placebo to UX007, UX007 to placebo) for an additional 10 weeks 
during Treatment Period 2. At the end of the blinded crossover period (Week 22), all subjects 
will have the option of rolling into the open-label Extension Period, to continue UX007 
treatment for up to 3 years or until approval. Long-term safety and maintenance of effect of 
UX007 will be assessed during the open-label Extension Period. A Safety Follow-up Phone 
Call will be conducted 30-35 days after the last dose of UX007G-CL301 study drug. 
Figure 7.1.1 provides a schematic of the study design. 
Dosing will be initiated in both Treatment Periods using a 2-week titration schedule until the 
subject has reached their age-related target dose (Table 7.4.4.1). If a subject has not reached 
the target dose by the end of the 2-week Titration Period, dose titration should continue until 
the maximum tolerated dose is reached. The age-related target dose of UX007 will be 
administered PO mixed thoroughly into food or drink (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 young children, decreasing to 1-2 g/kg for older children, adolescents, and adults.  
   


3URWRFRO1XPEHU8;*&/
3URWRFRO$PHQGPHQW
-XO\

3URSULHWDU\DQG&RQILGHQWLDO
3DJH
)LJXUH8;*&/6WXG\6FKHPDWLF


'LVFXVVLRQRI6WXG\'HVLJQ,QFOXGLQJ&KRLFHRI&RQWURO*URXS
7KHFKRLFHRIVWXG\GHVLJQLVEDVHGRQWKHKHWHURJHQHLW\RIWKHSRSXODWLRQWREHVWXGLHG
7KHLPSDLUPHQWRIJOXFRVHWUDQVSRUWLQWRWKHEUDLQLQ*OXW'6UHVXOWVLQDQHQHUJ\GHILFLWLQ
YDULRXVEUDLQUHJLRQVLQFOXGLQJWKHFRUWH[EDVDOJDQJOLDDQGFHUHEHOOXP'DPDJHWRWKHVH
EUDLQUHJLRQVPD\UHVXOWLQFKURQLFGHILFLWVVXFKDVFRJQLWLYHGHOD\VSDVWLFLW\DWD[LDRU
G\VWRQLFSRVWXULQJ*UDVHWDO$JDLQVWWKLVEDFNJURXQGRIQHXURORJLFLPSDLUPHQWWKH
SDWLHQWPD\DOVRKDYHDFXWHSHULRGVRIDGGLWLRQDOLPSDLUPHQWVXFKDVVHL]XUHVPRYHPHQW
GLVRUGHUVRUZRUVHQLQJDWD[LD3RQVHWDO6RPHSDWLHQWVHVSHFLDOO\WKRVHGHVFULEHGDV
µQRQFODVVLFDO¶PD\KDYHPLQLPDOFRJQLWLYHLPSDLUPHQWQHYHUKDYHVHL]XUHVDQGSUHVHQWLQ
WKHLUWHHQVRUODWHUDVDVXEVHWRIDJURXSRIGLVRUGHUVFDOOHG3DUR[\VPDO'\VNLQHVLDV
/HHQHWDO
7KHYDULDELOLW\LQWKHW\SHVIUHTXHQF\DQGVHYHULW\RIWKHSDUR[\VPDOPRYHPHQWGLVRUGHUVLQ
*OXW'6DFURVVRYHUVWXG\GHVLJQZDVFKRVHQEHFDXVHLWZLOODOORZFRPSDULVRQRIWKH
UHVSRQVHVRIWKHVDPHKHWHURJHQHRXVJURXSWRERWKWUHDWPHQWDQGSODFHER
$OWKRXJKWKHNHWRJHQLFGLHW.'LVRIWHQXVHGDVDWUHDWPHQWIRUVHL]XUHVLQ*OXW'6
.OHSSHUHWDOLWVXVHLQWUHDWLQJ*OXW'6PRYHPHQWGLVRUGHUVLVOHVV
ZHOOHVWDEOLVKHG3RQVHWDO7KH.'PD\EHYLHZHGDVDEXUGHQIRUIDPLOLHVDQGLV
RIWHQGLIILFXOWWRPDLQWDLQDVFKLOGUHQUHDFKDGROHVFHQFHHYHQZKHQLWKDVEHHQHIIHFWLYHLQ
VHL]XUHFRQWUROHDUOLHULQOLIH0DQ\SDWLHQWVZLWKPRYHPHQWGLVRUGHUVVXFKDV3DUR[\VPDO
'\VNLQHVLDQHYHUKDGVHL]XUHVDQGPD\QHYHUKDYHEHHQWUHDWHGZLWK.',PSOHPHQWDWLRQRI
WKH.'ZRXOGEHH[WUHPHO\GLIILFXOWLQDSRSXODWLRQWKDWLVOLNHO\WREHROGHUVHL]XUHIUHH
DQGXQGHUOHVVSDUHQWDOFRQWUROWKDQWKH\RXQJHUSRSXODWLRQLQZKRPVHL]XUHVDUHD
SURPLQHQWIHDWXUH
,QD3KDVHVWXG\SDUR[\VPDOPDQLIHVWDWLRQVLPSURYHGVLJQLILFDQWO\S LQ
HYDOXDEOHSDWLHQWVLQUHVSRQVHWRWUHDWPHQWZLWKWULKHSWDQRLQ0RFKHOHWDO
7KHSURSRVHG3KDVHVWXG\LVGHVLJQHGWRDVVHVVWKHHIILFDF\DQGVDIHW\RI8;
WULKHSWDQRLQLQUHGXFLQJWKHIUHTXHQF\RIGLVDEOLQJSDUR[\VPDOPRYHPHQWGLVRUGHUHYHQWV
LQ*OXW'6SDWLHQWVZKRDUHQRWRQ.'


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 41 
7.3 
Selection of Study Population 
The study will be conducted in pediatric, adolescent, and adult Glut1 DS patients (aged 
≥ 6 years). The age range of ≥ 6 years old was selected for this Phase 3 study because this 
age is consistent with the presentation of movement disorders and paroxysmal exertional 
dyskinesia associated with Glut1 DS (Alter et al. 2014), and is an appropriate patient 
population to accurately capture these manifestations with an event based daily Glut1 DS 
symptom diary. 
Enrollment may include subjects from countries other than those with active sites; enrollment 
under these circumstances will be at the discretion of the Sponsor. 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, as will subjects with a BHB 
level greater than 1 mmol/L. There is less evidence supporting the effects of KD on 
movement disorders experienced by Glut1 DS patients and there is a continued effort to 
understand any potential effect that KD may have on these symptoms. Nevertheless, KD is 
prescribed in many 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.  
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 will take all reasonable measures to ensure the 
protection and safety of this population by complying with all local or regional laws and 
regulations. Appropriate pediatric expertise will be available at all trial sites with children 
enrolled, and efforts will be focused on minimizing risk, fear, pain and distress during 
conduct of the study. 
The energy impairment in Glut1 DS produces variable manifestations according to the area 
of the brain most affected, but also due to other factors, such as severity of the SLC2A1 
mutation, nutritional status, patient activity level and emotional state (Pons et al. 2010, Gras 
et al. 2014); this results in a wide variety of phenotypes and clinical manifestations. 
The clinical presentation also tends to evolve as the patient becomes older. It has been noted 
that seizures are more prominent in early life, with movement disorders becoming more 
evident in late childhood and early adolescence (Alter et al. 2014, Gras et al. 2014). 
Seizure types in Glut1 DS are variable and may include Generalized Tonic-Clonic, Partial 
Complex, Myoclonic, Focal and Absence (Mullen et al. 2010, Leen et al. 2010). 
Movement disorders due to Glut1 DS may also be variable, not only from patient to 
patient but within the same patient, probably due to factors involving lack of brain energy. 
Some patients may have movement disorders as a relatively chronic part of the clinical 
presentation; moderate ataxia or mild dystonic posturing of the hand when walking, for 
example. These findings may become more pronounced at times, possibly provoked by 
factors such as a fasting, fatigue or exercise (Pons et al. 2010). In addition, patients with 
relatively normal baseline neurologic status may also experience episodic movements 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 42 
including dystonic posturing of one or more extremities, myoclonic jerks, or choreic 
movements. Some of this latter group may have been diagnosed with Paroxysmal 
Dyskinesias and may have minimal or no other symptoms of Glut1 DS. The movements in 
this subset of patients are frequently provoked by exercise (Erro et al. 2014). 
Patients experiencing all types of disabling paroxysmal movement disorders from Glut1 DS 
will be included in 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, aged ≥6 years old at the time of informed consent 
3. At least 8 disabling paroxysmal movement disorder events in the 12 weeks prior to 
Screening, by subject or caregiver report 
          OR 
At least 6 disabling paroxysmal movement disorder events in any 6 consecutive week 
period, over the last 12 week period prior to Screening, by subject or caregiver report 
4. At least 4 disabling paroxysmal movement disorder events in the first 6 weeks of the 
Run-in Period, reported in the daily electronic Glut1 DS symptom diary 
5. ≥80% compliance with daily electronic Glut1 DS symptom diary completion during the 
Run-in Period 
6. Not on KD, modified KD, or ketosis-inducing modified-fat diet for at least 3 months 
prior to Screening  
7. Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening  
8. Provide written or verbal assent (if possible) and written informed consent by the patient 
(if an adult), or by a legally authorized representative after the nature of the study has 
been explained, and prior to any research-related procedures 
9. Must, in the opinion of the Investigator, be willing and able to complete key aspects of 
the study and be likely to complete the 22-week, placebo-controlled, Treatment Period 
10. Patient (or caregiver) must, in the opinion of the Investigator, be able to comply with 
accurate completion of the study daily Glut1 DS symptom diary  
11. Females of child-bearing potential must have a negative urine pregnancy test at Screening 
and Baseline and be willing to have additional pregnancy tests during the study. Females 
considered not to be of childbearing potential include those who have not experienced 
menarche, are post-menopausal (defined as having no menses for at least 12 months 
without an alternative medical cause) or are permanently sterile due to total 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 43 
12. Participants of child‐bearing potential or fertile males with partners of child-bearing 
potential who are sexually active must consent to use a highly effective method of 
contraception as determined by the site Investigator from the period following the signing 
of the informed consent through 30 days after last dose of study drug 
7.3.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of the 
Investigator, places the subject at increased risk for adverse effects 
2. Prior use of triheptanoin within 30 days prior to Screening 
3. History of, or current suicidal ideation, behavior and/or attempts per C-CSSRS at 
Screening or Baseline 
4. Pregnant and/or breastfeeding an infant at Screening or Baseline 
5. Participants unwilling or unable to discontinue use of a prohibited medication or other 
substance that may confound study objectives (Section 7.4.6.1 [MCT oil, barbiturates, 
pancreatic lipase inhibitors, KetoCal or other KD supplements, and/or KD]) 
6. Glut1 DS treatment regimen, including AEDs, should be stable for at least 30 days prior 
to Screening  
7. Use of any investigational product (drug, medical food, or supplement, including medium 
chain triglyceride [MCT] oil, including coconut oil) within 30 days prior to Screening 
8. 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 
9. Feeding or nutrition that, in the opinion of the dietitian, potentially affects consistent 
administration of study drug 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 44 
7.3.3 
Removal of Subjects from Therapy or Assessment 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason. The Investigator and Ultragenyx also have the right to 
remove subjects from the study. Ultragenyx must be notified of all subject withdrawals as 
soon as possible. Ultragenyx also reserves the right to discontinue the study at any time for 
either clinical or administrative reasons and to discontinue participation of an individual 
subject or Investigator due to poor enrollment or noncompliance, as applicable. 
Subjects will be removed from the study for the following reasons:  
• An illness or AE that, in the judgment of the Investigator or Ultragenyx, might place the 
subject at risk or affect study conduct (Section 8.5.4) 
• Pregnancy of the subject or partner of a subject 
Subjects may be removed from the study for the following reasons: 
• Initiation of KD or similar diet resulting in a BHB > 1 mmol/L 
• Use of prohibited medications 
• At the request of the subject (withdraws consent), Investigator, or Ultragenyx, for 
administrative or other reasons 
• Protocol deviation or noncompliance 
If a subject discontinues from the study prior to End of Treatment 2, every reasonable effort 
should be made to perform the Early Termination Visit procedures as soon as possible after 
the last dose of investigational product, and at most, within four weeks of discontinuation. 
Subjects who withdraw or are removed from the study after receiving study drug may be 
replaced on a case-by-case basis, at the discretion of Ultragenyx. 
7.3.3.1 
Stopping Rules 
A Data Monitoring Committee (DMC) will be constituted for Study UX007G-CL301 and 
will act in an advisory capacity to monitor the safety of study subjects on a routine basis 
throughout the trial (Section 7.6.6). The DMC may provide advice to Ultragenyx in any 
determination of whether study enrollment should be paused or if the study should be 
stopped.  
Individual subjects who experience an unexpected and possibly, probably, or definitely 
drug-related SAE (Section 8.5.3) that represents a change in the nature or an increase in 
frequency of the serious event from their prior medical history will be evaluated as to 
whether the subject will continue on the study.  
Regulatory Authorities, as well as the IRBs/ECs, will be informed should unexpected and 
possibly, probably, or definitely study drug-related SAEs occur. A full evaluation of the 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 45 
event will be performed in order to make a decision regarding what actions to take, including 
whether to recommend stopping the study. Regulatory Authorities, as well as IRBs/ECs, will 
be informed if the study is paused or stopped. If the Sponsor deems it appropriate to restart 
the trial following an internal safety review, this will be done only following approval by 
Regulatory Authorities.  
7.4 
Treatments 
At the Week 0 (Baseline 1) and at Weeks 12 (Baseline 2), 22, 34, 58, 82, 106, 130, and 154, 
subjects will be dispensed an adequate supply of study drug per their weight-based target 
total daily dose. Beginning at Week 22, all subjects will be dispensed UX007 for the open-
label Extension Period. Due to the extended time between scheduled clinic visits, additional 
supplies of study drug may be shipped directly to the subject or a designated pharmacy for 
logistical purposes, per country regulations and upon Sponsor approval. 
7.4.1 
Investigational Product 
UX007 (triheptanoin) is a liquid, intended for PO administration. UX007 is a colorless to 
yellow oil supplied in 1 L round, translucent high-density polyethylene (HDPE) or 1 L round 
amber-colored glass bottles. UX007 is manufactured, packaged, and labeled according to 
GMP regulations. For additional information, refer to the Pharmacy Manual. 
The total daily dose will be divided into 4 equal doses, mixed with food or drink (or formula, 
as appropriate), and administered PO or by gastronomy tube at breakfast, lunch, dinner, and 
before bed. The dose may be divided into smaller more frequent doses with food or drink as 
needed. The oil should not be taken without mixing thoroughly with food or drink.   
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 via 
an Interactive Web Randomization System (IWRS) based on a randomization schedule 
developed by an independent third-party vendor to maintain blinding.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 46 
7.4.4 
Selection of Doses  
The UX007 dose and regimen for this study was selected based on the extensive clinical 
information derived from over 15 years of clinical experience in a variety of diseases. 
Approximately 200 subjects have received triheptanoin treatment, 51 of which involved 
pediatric patients as young as neonates, with 23 of these 51 patients with over 5 years of 
treatment duration (Roe et al. 2002, Roe et al. 2006, Mochel et al. 2010). 
UX007 (triheptanoin) is a liquid, intended for oral (PO) administration. UX007 is a 
colorless to yellow oil supplied in 1 L round, translucent high-density polyethylene (HDPE) 
or 1 L round amber colored glass bottles. Subjects will be dosed according to an age- and 
weight-based strategy (Table 7.4.4.1), up to a maximum daily administration of 130g. For 
subjects within 25% predicted BMI, actual body weight will be used to calculate the 
appropriate dose per the subject’s age category. Adjusted body weight will be used for 
subjects with greater than 25% predicted BMI, to account for metabolic activity found in 
adipose tissue versus lean muscle. Adjusted body weight will be calculated in kilograms, 
using the following formula: 
Formula 1# Adjusted Body Weight = Ideal Body Weight + [25% × (Actual Body 
Weight − Ideal Body Weight)] 
UX007 dosing will be initiated using a 2-week titration schedule until the subject has reached 
his/her target total daily dose. If a subject has not reached the target total daily dose by the 
end of the 2-week titration period, dose titration should continue until the maximum tolerated 
dose is reached. For detailed information regarding dosing and titration, please refer to the 
Study Reference Manual. 
Table 7.4.4.1:  Age- based UX007 Target Total Daily Dose 
Age Ranges 
UX007 dose (g/kg/day) that is estimated equivalent to 30% total caloric 
intake 
6 - 9 Years 
2.5 
10 - 14 years 
2 
15 - 20 years 
1.5 
21 and Over 
1.2 
 
The total daily dose will be divided into 4 equal doses, mixed with food or drink (or formula, 
as appropriate), and administered PO or by gastronomy tube at breakfast, lunch, dinner, and 
before bed. The dose may be divided into smaller more frequent doses with food or drink as 
needed. The oil should not be taken without thoroughly mixing with food or drink. The dose 
should not be adjusted due to changes in age and/or weight during Treatment Periods 1 
and 2. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 47 
The data support the safety of triheptanoin when administered at approximately 1-4 g/kg 
depending on age. Previous clinical data also suggest an age-dependent dose that relates to 
the relatively higher energy requirements for young children versus older children versus 
adults. The 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, adolescents, and adults. 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 
efficacy.  
7.4.4.1 
Study Duration 
Subject participation during the double-blind treatment period (including the Run-in Period, 
Baseline, Treatment Period 1, Washout, and Treatment Period 2) will be 28 weeks in 
duration; the Extension Period allows patients to receive UX007 for up to 3 additional years, 
or until one of the following occurs: the subject withdraws consent, the subject is 
discontinued from the study at the discretion of the Investigator or Ultragenyx, the study is 
terminated, or until commercial availability of the study drug in the subject’s region, which 
occurs first. The total treatment duration enables a long-term assessment of the efficacy and 
safety of UX007 in Glut1 DS subjects with movement disorders. A Safety Follow-up Phone 
Call will be conducted 30-35 days after the last dose of UX007G-CL301study drug. The last 
subject’s Safety Follow-up Phone Call is the defined End-of-Study Time Point.  
7.4.5 Blinding 
The Titration and Maintenance Periods (Weeks 0-22) will be conducted as a randomized, 
double-blind, placebo-controlled, crossover study. Double-blind conditions will be 
established during this period so that neither the sponsor, subject, or site personnel involved 
in study conduct will know the identity of a subject’s treatment. After all subjects have 
completed the double-blind period, unblinding of the study will occur. All subjects who 
complete the double-blind portion of the study will be eligible to receive open-label UX007 
during the Extension Period 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 an IWRS 
• Labeling of study drug with the study number and a unique kit number 
• Packaging and delivery of study drug supplies to sites in a manner that maintains blinding 
of site personnel 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 48 
• Matched appearance of investigational product and placebo 
The Investigator and site personnel will remain blinded to the randomization code during the 
study. Treatment assignment for an individual subject should be unblinded by the 
Investigator only in an emergency, and only if knowledge of the treatment assignment is 
urgently needed for the clinical management or welfare of the subject. Treatment should be 
provided in accordance with the medical condition and with regard to the information 
provided in the IB. The Investigator should contact the medical monitor before unblinding, 
when possible, but priority should be given to the safety of the subject. 
Individual subject treatment assignment may be unblinded by the sponsor to satisfy expedited 
reporting requirements of regulatory authorities. The system to unblind treatment assignment 
will be maintained and executed through an IWRS which will be available 24 hours a day, 
7 days a week. 
If a subject’s treatment assignment is unblinded prior to completion of the double-blind 
portion of the study, the subject may be discontinued from the study and may not be eligible 
to participate in the open-label Extension Period.  
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, including coconut oil  
• KetoCal or other KD supplements and medical foods containing MCT oil 
• Barbiturates   
• Pancreatic lipase inhibitors (e.g. Orlistat) due to possible inhibition of metabolism of 
tripheptanoin.  
In the event of an emergency, any medication deemed necessary by the treating physician 
should be used as needed. 
7.4.6.2 
Permitted Medications 
Other than the medications specifically prohibited in this protocol (Section 7.4.6.1), subjects 
may receive concomitant medications as required. Medications (investigational, prescription, 
over-the-counter, and herbal) and nutritional supplements taken during 30 days prior to 
Screening will be reviewed and recorded in the CRF. The Glut1 DS treatment regimen, 
including AEDs, should be stable for at least 30 days prior to Screening, and for the duration 
of the double-blind treatment period through Week 22. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 49 
7.4.7 
Treatment Compliance 
At the Week 0 (Baseline Period 1) and at Weeks 12, 22, 34, 58, 82, 106, 130, and 154, 
subjects will be dispensed an adequate supply of study drug per their weight-based target 
total daily dose. Due to the extended time between scheduled clinic visits, additional supplies 
of study drug may be shipped directly to the subject or a designated pharmacy for logistical 
purposes, per country regulations and upon Sponsor approval. Subjects and/or caregivers will 
use a study medication diary to record daily consumption of study drug. Subjects will be 
instructed to return all used (empty study drug containers) study drug to the site at the next 
visit. Site personnel will maintain a record of all medication dispensed to each subject and 
returned to the site. Over the course of the study for each subject, each bottle dispensed must 
be accounted for (returned to the site empty, partial, or full), and reconciled to the 
consumption reported in the daily Study Medication diary. Metabolite levels may also be 
used as supportive measures of treatment compliance (Section 7.5.3). Refer to the Pharmacy 
Manual for additional information on study drug accountability.  
7.5 
Study Procedures and Assessments 
Whenever possible, study site staff (including trained clinicians, dietitians, physical 
therapists, and the Investigator or site designee) performing the assessments should be 
consistent from visit to visit throughout the 22-week double blind period. The parameters to 
be assessed, along with timing of assessments, are provided in the Schedule of Events 
(Table 2.2 and Table 2.3). Refer to the Study Reference Manual for additional details on 
specific assessments and the suggested order of administration.  
The effects on Glut1 DS clinical features will be studied over the blinded Treatment and 
Open-label Extension Periods of the study.  
7.5.1 
Visit Schedule 
Informed consent must be obtained prior to any Screening procedures. Subjects will return to 
the clinic at Baseline (Week 0), Weeks 10, 12, and 22 during the double-blind crossover 
portion of the study; and at Weeks 34, 58, 82, 106, 130, 154, and 178 during the extension 
period (Table 2.2 and Table 2.3). For subjects who discontinue prior to completing the study, 
every reasonable effort should be made to perform the Early Termination visit procedures as 
soon as possible after the last dose of investigational product, or at least within 4 weeks of 
discontinuation. Telephone visits will occur at Weeks 2, 4, 6, 14, 16 & 18 during the 
double-blind crossover portion of the study and at Weeks 26, 30, 46, 70, 94, 118, and 142 
during the Extension Period, where information related to adverse event and concomitant 
medications, as well as Glut1 DS symptom and study medication diary reviews, dose 
titration, and compliance will occur. Unscheduled clinic visits or telephone calls may be 
arranged at the site’s discretion to provide additional dietitian follow up and other study 
support. A Safety Follow-up Phone Call will be conducted 30-35 days after the last dose of 
UX007G-CL301 study drug. The site personnel will initiate this safety follow-up telephone 
call to collect information on any ongoing or new AEs, SAEs, and concomitant medications. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 50 
Appropriate follow-up should continue until all safety concerns, in the Investigator’s opinion, 
are resolved. 
7.5.2 
Efficacy Measures 
The concept for evaluation is to study the effects of UX007 treatment of disabling movement 
disorder events 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 number of disabling paroxysmal movement disorder 
events observed during the Maintenance Period of Treatment Periods 1 and 2, as recorded by 
the subject/caregiver in an event-based daily Glut1 DS symptom diary. The effect of UX007 
treatment on Glut1 DS will also be assessed by evaluating additional criteria impacting motor 
and neurological function, along with relevant biomarkers and metabolites. Secondary and 
exploratory efficacy endpoints related to the effects of UX007 will help to define whether 
UX007 has effects on movement disorders experienced by Glut1 DS patients. The efficacy 
measures and assessments are described below; planned analysis of efficacy endpoints is 
described in Section 7.6.3. If, in the judgement of the Investigator, a patient is not able to 
safely perform an assessment, it does not need to be conducted at that study visit. Refer to the 
Study Reference Manual for additional details on the efficacy measures. 
7.5.2.1 
Subject Daily Glut1 DS Symptom Diary: Paroxysmal Movement Disorders of 
Glut1 DS  
An event-based, daily Glut1 DS symptom diary will allow the subject/caregiver to capture 
quantitative and qualitative aspects of disabling paroxysmal movement manifestations of 
Glut1 DS, including but not limited to, frequency, duration, impact, and symptom type. 
A movement disorder event is defined for this study as a period of time when the subject 
experiences one or more movement disorder symptoms, including symptoms that are 
experienced during a movement disorder event alone or significant worsening of continuous 
movement disorders. In this study, movement disorder events are defined as disabling if they 
affect or limit a subject’s physical functioning and activities of daily living, and this 
definition closely aligns with the definitions of disability provided by the World Health 
Organization (WHO) and the Americans with Disabilities Act (ADA). Disabling movement 
disorder events will be characterized in the daily Glut1 DS symptom diary as those that 
affect/limit major life activities such as caring for oneself, performing manual tasks, walking, 
standing, lifting things, bending, eating/swallowing, speaking, seeing, sleeping, attending or 
participating in school/work, or doing sports/exercise. The daily Glut1 DS symptom diary 
has been developed for both self- and caregiver-reporting based on age and cognitive ability. 
Diary reporters, whether the subject or caregiver, must complete a diary training module at 
the Screening Visit; reporters must remain constant throughout the Run-in Period, Treatment 
Period 1, Washout Period, and Treatment Period 2 (Weeks -6 to 22). Respondents should 
maintain ≥80% compliance with daily Glut1 DS symptom diary completion during the Run-
in Period, Treatment Period 1, Washout Period and Treatment Period 2. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 51 
7.5.2.2 
Functional Outcome: 12 Minute Walk Test (12MWT) 
The 12MWT is a variation of the 6MWT used to assess endurance through walking 
(McGavin et al. 1976, Cooper 1968). The 12MWT will be administered by a trained clinician 
in accordance with general principles set forth in the American Thoracic Society (ATS) 
guidelines (ATS 2002) established for the 6MWT. Subjects will be observed by trained study 
staff throughout the duration of the 12MWT, and the test will not be performed if there are 
any concerns as to whether the subjects can reliably and safely complete the 12MWT. 
Subjects who meet the safety criteria will be instructed to walk the length of a pre-measured 
20 meter course in a hallway for 12 consecutive minutes. Traffic cones will be used to 
standardize the lap distance. The subject will walk laps around the cones until the time period 
has expired. Instructions and encouragement will be given according to the script provided in 
the ATS guidelines with accommodations made for young children to improve compliance 
and understanding. The distance walked at the end of 12 minutes will be recorded in meters. 
The distance walked after 6 minutes will also be recorded. The percent of predicted normal 
values will be calculated for the 6MWT distance using age appropriate reference data 
(Gibbons et al. 2001, Geiger et al. 2007). HR and BP will both be recorded before the 
12MWT along with post-test HR. The test may be discontinued at any time at the discretion 
of the administering clinician if there are concerns about the occurrence of any major safety 
event, including the onset of dizziness, chest pain, muscle pain, and respiratory distress.  
7.5.2.3 
Clinical Status: Patient Global Impression of Severity and Improvement  
Patient/caregiver global impression of change in clinical status will be assessed using the 
Clinical Global Impression - Severity scale (CGI-S) pretreatment and Clinical Global 
Impression - Improvement (CGI-I) post-treatment.  
Patients will be asked to rate the severity of their overall condition at the start of the study 
using a 4-point Likert rating scale.  
Patients will be asked to rate the change in their overall condition since the start of the study 
using a 7-point Likert rating scale. 
7.5.2.4 
Clinical Status: Physician Global Impression of Severity and Improvement  
Physicians will rate disease severity at pretreatment (CGI-S) and continue to rate severity for 
the duration of the study. Physicians will also record the degree of change in clinical status 
(CGI-I) at post treatment visits. 
Physicians will be asked to rate the severity of the subject’s overall condition at the start of 
the study using a 4-point Likert rating scale.  
Physicians will be asked to rate severity and change in the subject’s overall condition since 
the start of the study using a 4- and 7-point Likert rating scale, respectively. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 52 
7.5.2.5 
Health-Related Quality of Life: PROMIS® questionnaire 
The Patient-Reported Outcomes Measurement Information System (PROMIS®) was 
developed by the National Institutes of Health and uses domain-specific measures to assess 
patient well-being (Broderick et al. 2013, NIH 2015). The PROMIS® contains a bank of 
questions from which relevant items have been extracted and used to create a questionnaire 
to measure physical function, mobility, upper extremity function, fatigue, pain and social 
health. The PROMIS® questionnaires have been developed for both self- and proxy-report 
based on age and cognitive ability. The version used at Baseline 1 (Week 0) will be 
administered throughout Treatment Periods 1 and 2. If a subject ages out of the pediatric 
version during the Extension Period, the adult questionnaire may be administered at the 
discretion of the PI and Medical Monitor.  
7.5.2.6 
Cognitive Function  
Cambridge Neuropsychological Test Automated Battery (CANTAB): Neuropsychological 
function measured using a standardized, non-verbal, computerized battery of tests designed 
to assess cognitive domains relevant to Glut1 DS such as attention and memory. 
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). 
The CANTAB tests will be administered by a trained clinician at select sites in a 
standardized order to minimize variability.  
7.5.2.7 
Activity Levels 
A wrist-worn activity monitor (actigraphy device) will assess the impact of Glut1 DS on 
activity at select study sites, where feasible. Endpoints (including mean daytime activity, 
mean night time activity, and percent time in moderate or higher intensity activity) will be 
measured during the last 10 days of the Run-in Period, the last 10 days of Treatment Period 
1, and the last 10 days of Treatment Period 2.   
7.5.2.8 
Qualitative Assessment 
The Canadian Occupational Performance Measure (COPM) was developed as an evidence-
based patient-centered tool to enable individuals/caregivers to identify and prioritize 
everyday issues that restrict or impact their performance in everyday life (Law et al. 1990). 
The COPM will be used to assess performance areas of self-care, leisure, and productivity.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 53 
7.5.3 
Drug Concentration Measurements and Bioassays 
To assess the UX007 metabolites, blood samples will be collected at Baseline 1 and 2, End of 
Treatment 1 and 2, and at Week 34. Blood for plasma at Baseline Visits will be collected 
pre-dose (within 15 minutes). Blood for plasma at End of Treatment visits will be collected 
approximately 90 minutes post dose. At Week 34, subjects will be administered one of their 
4 daily doses (preferably their 2nd dose of the day) in order to collect appropriately timed PK 
samples (i.e., pre-dose and at [± 5 minutes] 30, 90, and 120 minutes post-dose). For each 
sample collection, the time elapsed since last study drug administration will be recorded on 
the CRF. The following UX007 metabolites will be assessed: 
• Beta-hydroxypentanoate (BHP):  Baseline 1 and 2, End of Treatment 1 and 2, and 
Week 34 visit 
• Beta-hydroxybutyrate (BHB):   
• To monitor UX007 metabolites at Baseline 1 and 2, End of Treatment 1 and 2, and 
Week 34 
• For Ketosis detection at Screening (to confirm that the subject is not in a state of 
ketosis upon entry to the study) and each subsequent clinic visit in the double-blind 
Treatment and Extension periods. 
• Plasma heptanoate: Baseline 1 and 2; End of Treatment 1 and 2; Week 34; and may be 
assessed at other Extension visits at Sponsor discretion  
• Plasma acylcarnitines: Baseline 1 and 2; End of Treatment 1 and 2; Week 34; and may be 
assessed at other Extension visits at Sponsor discretion 
Refer to the Study Reference Manual for additional details. 
7.5.4 
Safety Measures & General Assessments 
General assessments include medical history and demographics. Safety will be evaluated by 
the incidence, frequency, severity, and relatedness of AEs and SAEs, including clinically 
significant changes from baseline to scheduled time points in vital signs and clinical 
laboratory evaluations. Pregnancy testing (or pregnancy of partner), suicidal ideation and 
behavior assessments, and concomitant medications will also be monitored. Refer to the 
Study Reference Manual for additional details. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 54 
7.5.4.1 
Medical History 
Medical history will be obtained at the Screening Visit. General medical information 
includes subject demographics (date of birth, ethnicity, and sex) and a history of major 
medical illnesses, diagnoses, and surgeries. The review will also include an assessment of 
phenotypic characteristics associated with Glut1 DS, including seizures, cognitive 
impairment, movement disorders, and microcephaly. The specific history of Glut1 DS will be 
recorded, along with date of onset, clinical presentation, and date and method of confirmed 
diagnosis. Any available family history of Glut1 DS will be noted including diagnosis, 
disease course, treatment and outcome. Please refer to Section 7.5.4.9 for Concomitant 
Medications reporting instructions. 
7.5.4.2 
Vital Signs, Height, 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, temperature in degrees Celsius (°C), and head circumference (cm). Vital signs 
measurements will be performed at every clinic visit before any additional assessments are 
completed; clinically significant changes will be recorded as AEs.  
Height (in centimeters), and weight (in kilograms) will be obtained using a scale. 
7.5.4.3 
Physical Examination 
Complete physical examinations will be performed at Screening and focused physical 
examination will be completed at all subsequent clinic visits, including Early Termination. 
The complete physical examination will include assessments of general appearance; head, 
eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, 
gastrointestinal, and musculoskeletal systems. Clinically significant changes will be recorded 
as AEs.  
7.5.4.4 
Neurological Examination 
A neurological examination will be performed by a neurologist at Baseline 1 (Week 0) and 
subsequent clinic visits, including Early Termination. Neurological examinations must 
evaluate, at a minimum, the following domains: Cranial nerves II-XII, motor function 
(dexterity, tone, and strength), sensory, cerebellar, gait, and deep tendon reflexes. Changes in 
the neurological exam will be recorded, and the emergence of clinically significant 
abnormalities will be reported as AEs.  
7.5.4.5 
Clinical Laboratory Tests 
The clinical laboratory evaluations to be performed in this study include routine serum 
chemistry, lipid profile (in adults aged 18 or older), hematology, urinalysis, and ketosis 
detection; specific analytes are listed in Table 7.5.4.5.1. Clinical laboratory testing will be 
performed at each scheduled clinic visit (or Early Termination visit) and analyzed by a 
central laboratory. Blood and urine samples will be collected. Overnight fasting (8-12 hours) 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 55 
is required prior to lipid profile tests at Baseline 1 (Week 0), End of Treatment 1 (Week 10) 
and End of Treatment 2 (Week 22) as well as every 24 weeks during the Extension Period 
(Weeks 34, 58, 82, 106, 130, 154, and 178 or Early Termination Visit). Lipid profile 
evaluations will be performed only in adults (aged 18 or older). Fasting is not required for 
clinical laboratory tests in subjects < 18 years old or in subjects ≥ 18 years old prior to 
clinical visits when lipid profile assessments are not being performed (Screening or Baseline 
Visit 2). Clinically significant changes will be recorded as AEs. Refer to the Study Reference 
Manual for additional details. 
Table 7.5.4.5.1:  Clinical Laboratory Assessments 
Chemistry 
Hematology 
Urinalysis 
Ketosis Detection 
Lipid Profile 
Alanine 
aminotransferase 
(ALT) 
Hematocrit 
Appearance 
Beta-
hydroxybutyrate 
(BHB) 
Low-density 
lipoprotein (LDL) 
Alkaline 
phosphatase 
Hemoglobin 
Color 
 
High-density 
lipoprotein (HDL) 
Aspartate 
aminotransferase 
(AST) 
Platelet count 
pH 
 
Triglycerides 
Bilirubin (total) 
Red blood cell 
(RBC) count 
Specific gravity 
 
Total cholesterol 
Blood urea 
nitrogen (BUN) 
White blood cell 
(WBC) count 
Ketones 
 
 
Calcium 
 
Protein  
 
 
Chloride 
 
Glucose  
 
 
Serum creatinine 
 
Pregnancy test  
(if applicable) 
 
 
Gamma-glutamyl 
transpeptidase 
(GGT) 
 
 
 
 
Serum glucose 
 
 
 
 
Potassium 
 
 
 
 
Protein (albumin 
and total) 
 
 
 
 
Sodium 
 
 
 
 
Creatine Kinase 
 
 
 
 
 
Subjects who experience SAEs assessed as possibly, probably, or definitely related to study 
drug or other AE of concern may, at the discretion of the Investigator (and/or medical 
monitor), have additional blood or urine samples taken for safety laboratory tests. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 56 
7.5.4.6 
Electrocardiogram 
A standard 12-lead ECG will be performed at a resting heart rate during the Baseline 1 visit 
(Week 0), End of Treatment 1 (Week 10), and End of Treatment 2 (Week 22), and every 
48 weeks throughout the Extension Period (Weeks 58, 106, and 154 or Early Termination 
visit, if applicable). ECG will not be performed at the Early Termination visit if the 
assessment has been performed within 3 months of termination. ECG results will be read 
locally by qualified personnel. Abnormal findings and clinically significant changes from 
baseline will be recorded as AEs. 
7.5.4.7 
Pregnancy Testing 
Female subjects of childbearing potential will have urine pregnancy tests at Screening and at 
all clinic visits (or Early Termination). Females considered not of childbearing potential 
include those who have not reached menarche, are post-menopausal (defined as having no 
menses for at least 12 months without an alternative medical cause), or are permanently 
sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Female subjects with a positive pregnancy test at Screening or Baseline will not be enrolled 
in the study; Pregnancy in subject or partner must be reported (Section 8.5); pregnant 
subjects will be discontinued from the study. Additional pregnancy tests may be performed at 
any time in which pregnancy status is in question. A serum pregnancy test will be performed 
in the event of a positive or equivocal urine pregnancy test result, or can be performed if 
pregnancy test by urine is not feasible. 
Experience with UX007 (triheptanoin) in pregnant women is limited. The study drug may 
involve risks to a pregnant female or unborn baby which are currently unknown. 
Sexually active males or females of childbearing potential must use highly effective 
contraception determined by the Investigator during heterosexual intercourse throughout the 
study period and for 30 days after stopping the study drug. Examples of highly effective 
methods (CTFG 2014) include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system ( IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence (i.e., refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments, when this is in line with the preferred and 
usual lifestyle of the subject) 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 57 
7.5.4.8 
Suicidal Ideation and Behavior Assessments 
Assessment of suicidal ideation and behavior is a regular part of development programs 
involving AEDs and other neurologic drugs with central nervous system activity  
(FDA Draft Guidance 2012). The Columbia Suicide Severity Rating Scale (C-SSRS) is a 
standardized suicidal rating instrument used to assess the suicidal ideation and behavior in an 
at-risk population (Posner et al. 2011). To prospectively assess suicidal ideation and 
behavior, the C-SSRS will be administered by a clinician. Depending on the cognitive state 
of the subject, some questions within the C-SSRS may be deemed by the Investigator to be 
inappropriate to ask the subject and can be omitted. Suicidal ideation and behavior will be 
assessed in subjects who are ≥ 10 years of age at each visit. The Baseline questionnaire will 
be administered at Screening; 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. 
7.5.4.9 
Concomitant Medications 
Concomitant medications will be reviewed and recorded in the subject’s CRF at each 
study visit, beginning at Screening. 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. Glut1 DS treatment history, including UX007 (triheptanoin) 
treatment history, and relevant concomitant medications will be recorded (start date, stop 
date, dose, dose regimen) during the 30 days prior to Screening, during the study, and 
30 days following the last administration of study drug. 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 procedures and/or 
concomitant therapy, including physical/occupational therapy, will be recorded.  
7.5.4.10 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 in vital signs, clinical laboratory, or ECG parameters will be 
recorded as AEs or SAEs, if appropriate, as well as any increases in frequency or severity or 
changes in type of Glut1 DS associated symptoms (including but not limited to seizures, 
movement disorders, behavioral abnormalities, cognitive function, etc.).  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 58 
A blood sample will be collected for UX007 metabolite concentrations in the event of an 
SAE, if feasible. 
7.5.4.11 Dietary Assessment and Consultation  
A dietary consultation which includes nutrition assessment and training on completion of the 
3-day diet diary will occur at Screening. Subjects and/or caregivers are required to maintain a 
record of the subject’s 3-day diet diary for a consecutive 3-day period (representative of the 
subject’s typical diet) approximately 7 days prior to the next clinic visit. The initial 3-day diet 
history obtained prior to the Baseline 1 Visit (along with plasma level of BHB ≤ 1 mmol/L at 
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 diary will be 
reviewed by the site dietitian, or designee, at each applicable visit to the clinic so that the diet 
remains isocaloric and well-balanced. The dietitian, or designee, will also telephone subjects 
and/or caregivers at Weeks 0, 2, 4, 6, 10, 12, 14, 16, 18, and 22 to provide dietary advice and 
support and review of the study medication diary. Unscheduled clinic visits or telephone calls 
may be arranged at the site’s discretion to provide additional dietitian follow up and other 
study support. Refer to the Study Reference Manual for details on the dietary assessment.  
7.5.5 
Appropriateness of Measures 
The efficacy parameters to be evaluated in this study encompass the characteristic phenotype 
observed in Glut1 DS affected individuals. The clinical assessments in the study employ 
standard measures used in other diseases and conditions that impact the central nervous and 
skeletal muscle systems.  
A daily Glut1 DS symptom diary will be used by subjects and/or caregivers to capture 
disabling paroxysmal movement disorder events, completed on a daily basis, thereby 
minimizing recall bias. A 12 Minute Walk Test (12MWT) is included as a quantitative, 
objective measurement of endurance and walking capacity.  
Physician- and patient/caregiver-reported outcomes are also included to assess health-related 
quality of life and activities of daily living including CGI severity and change scales. 
Health-related quality of life is further supported by the PROMIS® questionnaire which 
includes assessment of physical function, mobility, upper extremity function, fatigue, pain 
and social health. The CANTAB is included as a measure of cognitive function at select 
sites. 
Because Glut1 DS symptoms including fatigue, energy deficiencies, and disabling dyskinesia 
events may limit a subject’s ability to participate in everyday activities, activity levels may 
be assessed by a wrist-worn actigraphy device. A qualitative component will also be 
investigated with the Canadian Occupational Performance Measure (COPM) with a specific 
focus on the performance areas of self-care, leisure, and school/work productivity.  
UX007 metabolites will be assessed using blood samples. The panel has been included to 
provide additional metabolite data on peak levels at steady-state. Where possible, timing of 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 59 
assessments has been coordinated with standard safety laboratory tests to minimize risk and 
discomfort and avoid unnecessary sampling. 
The safety parameters to be evaluated in this study include standard assessments such as 
recording of medical history, AEs and SAEs, physical examination, vital signs and weight, 
ECG, serum chemistry, lipid profile, urinalysis and hematology, concomitant medications, 
and other routine clinical and laboratory procedures. For patients ≥10 years of age, suicidal 
ideation and behavior will be assessed at each clinic visit as an additional safety measure 
given the central nervous system involvement with Glut1 DS.  
7.6 
Statistical Methods and Determination of Sample Size 
7.6.1 
Determination of Sample Size 
Based on the targeted patient population and eligibility criteria, it is estimated that during a 
6 week duration, the subjects receiving placebo will have a mean frequency of 8 disabling 
paroxysmal movement disorders per 4 weeks, while subjects receiving UX007 will have a 
mean frequency of 4 disabling paroxysmal movement disorders per 4 weeks, and a standard 
deviation of the difference of 7.4. A total sample size of 40 subjects (20 subjects in each 
treatment sequence) will have at least 85% power to detect such difference between UX007 
and placebo groups. This sample size assumption incorporates a projected discontinuation 
rate of 15%. 
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 
Planned Methods of Analysis 
Analysis of Primary Endpoint 
The primary analysis will compare the frequency of paroxysmal movement disorders 
captured as disabling movement disorder events (normalized to a 4 week rate) observed 
during the Maintenance Period of treatment with UX007 to the frequency of movement 
disorders captured as movement disorder events (normalized to a 4 week rate) observed 
during the Maintenance Period of treatment with placebo, as recorded by the 
subject/caregiver in an event-based daily Glut1 DS symptom diary.  
The primary analysis will be performed using a weighted ANCOVA model, with study 
baseline frequency of movement disorder as a covariate, treatment sequence, treatment group 
and period as fixed effects, and a random effect for subject within the sequence.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 60 
When there is strong evidence suggesting that the normality assumption is not met, Wilcoxon 
rank-sum test will be considered as the primary analysis to assess the primary endpoint 
Analyses of Secondary Endpoints 
If the primary analysis for the primary efficacy endpoint is statistically significant, then a 
sequential testing strategy will be implemented for selected secondary efficacy endpoints in 
the following order: 
• Duration of disabling paroxysmal movement disorder events analyzed by weighted 
ANCOVA model 
• Change from baseline in 12MWT distance analyzed by ANCOVA model 
• Patient/caregiver global impression of change in clinical status using the Clinical Global 
Impression – Improvement (CGI-I)  analyzed by ANCOVA model 
When there is strong evidence that the assumption is not met, Wilcoxon rank-sum test will be 
considered as the primary analysis to assess treatment difference. 
• For the rest of the secondary endpoints, change from Baseline to the end of Maintenance 
Period in PROMIS domain scores and change from Baseline to the end of Maintenance 
Period in CANTAB scores will be analyzed by ANCOVA model.  
Analyses of Exploratory Endpoints 
ANCOVA model will be applied to analysis the following exploratory endpoints: 
• Change from Baseline to the end of Maintenance Period in Canadian Occupational 
Performance Measure (COPM) scores 
• Physician global impression of change in clinical status using the Clinical Global 
Impression – Severity scale (CGI-S) and Clinical Global Impression – Improvement 
(CGI-I) 
• Change from study baseline in activity levels measured by a wrist-worn actigraphy 
device  
7.6.3.1 
General Principle 
A general description of the statistical methods to be used to analyze the efficacy and safety 
of the study drug is outlined below. The analyses planned in this protocol will be expanded in 
the SAP to include detailed description of the analyses. The SAP will be finalized and 
approved prior to the database lock. Any deviations from the analyses described in the 
protocol and SAP will be noted in the final clinical study report. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 61 
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. In general, missing data will be treated as missing and no 
statistical imputation method will be used unless stated otherwise. The procedures for 
handling missing, unused, or spurious data, along with the detailed method for analyses, will 
be presented in the SAP. 
Descriptive statistics will be used to summarize the data. For quantitative variables, the 
mean, standard deviation, median, quartile, minimum, and maximum will be provided. 
For categorical data, the frequency and percent distributions will be provided. 
The number of subjects randomized, who complete each of the treatment periods, and 
discontinue the study will be summarized. Demographics (age, gender, race, ethnicity, and 
region) and other baseline disease characteristics will be summarized using descriptive 
statistics. 
7.6.3.2 
Efficacy Analysis 
The primary endpoint will be analyzed based on the efficacy analysis set using a 
mixed-model ANCOVA model with fixed effects for treatment sequence, treatment group, 
period, and a random effect for subject within the sequence. The specific model will be 
defined in the SAP. The hypothesis that there is no difference in mean frequency of disabling 
paroxysmal movement disorder events per 4 weeks between treatment groups will be tested 
at the α=0.05 (2-sided) level. 
For change-from-baseline efficacy endpoints, the baseline will be the last measurement taken 
prior to or on the first dose date of the first period for computation of the change from 
baseline value. The secondary efficacy endpoints will be analyzed using the same method as 
for the primary endpoint.  
7.6.3.3 
Safety Analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class, Preferred 
Term (PT), relationship to study drug, and severity. All reported AEs with onset during the 
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 study drug during the double-blind period, and 
also throughout the study including the open-label 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 
will be used in the summary of laboratory data. The frequency and percentage of subjects 
who experience abnormal clinical laboratory results (i.e. outside of reference ranges) and/or 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 62 
clinically significant abnormalities (as determined by the Investigator) will be presented for 
each clinical laboratory measurement. For C-SSRS, the percentage of subjects reporting any 
treatment emergent suicidal ideation and any treatment emergent suicidal behavior will be 
summarized descriptively by treatment group and visit week, respectively. The SAP will 
provide additional details on the planned safety analyses. 
7.6.4 
Pharmacokinetic and Bioassay Analyses 
Descriptive statistics, including mean, standard deviation, coefficient of variation, 
geometric mean, median, minimum, and maximum will be calculated for each plasma 
UX007 metabolite (BHB, BHP, acylcarnitine, and heptanoate) at each sampling time point to 
evaluate 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. Results for each plasma UX007 metabolite will be provided. 
7.6.5 
Interim Analysis 
No formal interim analysis is planned for this study.  
7.6.6 
Data Monitoring Committee 
An independent DMC that includes members with expertise in movement disorders will act 
in an advisory capacity to monitor subject safety on a routine basis throughout the trial. 
A review of blinded and unblinded safety data will be conducted by the DMC periodically. 
Ad hoc meetings will be held if indicated based on observed events. The roles and 
responsibilities of the DMC will be defined in the DMC Charter. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 63 
8 STUDY CONDUCT 
8.1 
Ethics 
8.1.1 
Institutional Review Board or Ethics Committee and Competent Health 
Authority 
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), if applicable, 
must be submitted to the Competent Health Authority and 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 Competent Health Authority and 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. Competent 
Health Authority and 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 Competent Health 
Authority and 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. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 64 
It is the Investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The Investigator must explain 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. Subjects under the age of 18 years (or 16 years, depending on the region) 
will provide written assent (if possible), and his/her legally authorized representative 
(parent or legal guardian) will provide written informed consent for such subjects. 
Minors who reach legal age during the course of the study must provide written informed 
consent when eligible.  
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. Subjects will be given a copy of 
the signed ICF and will be provided any new information during the course of the study that 
might affect their continued participation in the study. The Investigator or a qualified 
designee will be available to answer each subject's questions throughout the study, and all of 
the subject's questions must be answered to the subject's satisfaction. If the protocol is 
amended and the ICF is revised, each subject will be required to provide written informed 
consent again using the revised ICF. 
The date of written informed consent will be documented in each potential subject’s CRF. 
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
8.2 
Investigators and Study Administrative Structure  
Each Investigator must provide Ultragenyx and/or its designee a completed and signed 
Form FDA 1572 and a Financial Disclosure Form. All Sub-investigators must be listed on 
Form FDA 1572 and Financial Disclosure Forms must be completed for all Sub-investigators 
listed on Form FDA 1572. 
Ultragenyx and/or its designee will be responsible for managing and monitoring the clinical 
trial to ensure compliance with FDA and ICH GCP guidelines. Ultragenyx's trained 
designated representative (the monitor) will conduct regular visits to the clinical site, 
to perform source document verification. The monitor will verify the Investigator's ongoing 
qualifications, inspect clinical site facilities, and inspect study records, including proof of 
IRB/EC review, with the stipulation that subject confidentiality will be maintained in 
accordance with local and federal regulations, including HIPAA requirements. 
A Coordinating Investigator will be identified for multicenter trials. The Coordinating 
Investigator will be selected on the basis of active participation in the trial, thorough 
knowledge of the therapeutic area being studied, and the ability to interpret data. The 
Coordinating Investigator will read and sign the Clinical Study Report (CSR) in accordance 
with regulatory authority requirements. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 65 
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 
will be properly packaged for transport. Refer to the Pharmacy Manual for further details on 
packaging and shipping. 
A drug accountability record must be maintained for all study drug received, dispensed, 
returned, and/or lost during the study. This record must be kept current and made available to 
the study monitor for inspection. To ensure the subject is dispensed the correct amount of 
study drug and captured throughout Treatment Periods 1 and 2 as well as the Extension 
Visits, final titrated dose will be recorded in the IWRS. 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 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 66 
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 uninterpretable data will be resolved in coordination with the Investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The Investigator and all other site personnel agree 
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. The Investigator is required to guaranty access 
to these documents and to cooperate with and support such audits and inspections. 
8.4.3 
Record Retention 
All study records must be retained for at least 25 years after the end of the clinical trial or in 
accordance with national law. Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, but not less 
than 25 years. Ultragenyx must be notified should the Investigator/institution be unable to 
continue maintenance of subject files for the full 25 years. All study records must be stored 
in a secure and safe facility. 
8.5 
Reporting and Follow-up of Adverse Events 
8.5.1 
Definition of Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) products. 
Suspected Adverse Reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an adverse event or 
suspected adverse reaction that, in the view of either the Investigator or Sponsor, places the 
patient or subject at immediate risk of death. Life-threatening AEs do not include an AE or 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 67 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
Serious adverse event (SAE) or serious suspected adverse reaction is an adverse event or 
suspected adverse reaction that at any dose, in the view of either the Investigator or 
Ultragenyx, results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
Note that hospitalizations planned prior to study enrollment (e.g. for elective surgeries) are 
not considered SAEs. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
Important medical events that may not result in death, be immediately life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
8.5.2 
Severity of Adverse Events 
Wherever possible, the severity of all AEs will be graded using the NCI CTCAE 
(Version 4.03). The majority of AEs can be graded using this system. 
If an AE cannot be graded using the CTCAE criteria, it should be graded as mild, moderate, 
severe, life-threatening, or death using the following definitions. 
• Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and of a minor 
irritant type, causing no loss of time from normal activities. Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate (Grade 2): Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by simple 
therapeutic measures; moderate experiences may cause some interference with 
functioning. 
• Severe (Grade 3): Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of death 
or are disabling. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 68 
• 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”, the following note of clarification is provided:  The term "severe" is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or 
severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This is not the same as "serious" which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
8.5.3 
Relationship of Adverse Events to Study Drug 
The Investigator will assess the potential relationship of the AE to study drug using the 
following descriptions. 
Categories of attributions for “Unrelated” events: 
• Unrelated:  This category applies to an AE that is clearly not related to the 
investigational agent/procedure. 
• Unlikely Related:  This category applied to an AE that is doubtfully related to the 
investigational agent/procedure.  
Categories of attributions for “Related” events: 
• Possibly Related: This category applies to an AE that may be related to the 
investigational agent/procedure. 
• Probably Related: This category applies to an AE that is likely related to the 
investigational agent/procedure.  
• Definitely Related: This category applies to an AE that is clearly related to the 
investigational agent/procedure. 
For the purposes of reporting to regulatory agencies, AEs deemed as Definitely, Probably or 
Possibly Related will be considered Related and those deemed Unrelated or Unlikely Related 
will be considered Unrelated. 
8.5.4 
Adverse Event Reporting  
8.5.4.1 
General 
All AEs (i.e. any new or worsening in severity or frequency of a preexisting condition) with 
onset after the subject signs consent for study participation must be promptly documented on 
the CRF. The 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.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 69 
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. 
8.5.4.2 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting 
Ultragenyx or its designee must be notified of any SAE that occurs at any time during the 
reporting period within 24 hours of the Investigator, designee, or site personnel’s knowledge 
of the event. SAEs will be reported by completing and submitting SAE report forms to 
Ultragenyx or its designee.  
Follow-up SAE information must be submitted in a timely manner as additional information 
becomes available. All SAEs regardless of relationship to study drug must be followed to 
resolution or stabilization if improvement is not expected.  
All deaths, regardless of causality, occurring from the signing of the Informed Consent until 
30 days following the last dose of study drug are to be reported as SAEs to Ultragenyx or its 
designee within 24 hours of knowledge.  
8.5.4.3 
Pregnancy in Subject or Partner, and Requirements for Immediate Reporting 
Ultragenyx or its designee must be notified of the occurrence of any pregnancy in a subject 
or subject’s partner that occurs during the reporting period within 24 hours of the 
Investigator, designee, or site personnel’s knowledge of the event. Pregnancies will be 
reported by completing and submitting Pregnancy Notification forms to Ultragenyx or 
designee. Reported pregnancy of a subject or a subject’s partner, while participating in the 
study, will be monitored for the full duration and/or followed until the outcome of the 
pregnancy is known. In the event of a pregnancy in the partner of a subject, the Investigator 
should make every effort to obtain the female partner’s consent for release of protected 
health information. 
Ultragenyx or its designee must be notified of the outcome of the pregnancy within 24 hours 
of the Investigator, designee, or site personnel’s knowledge of the outcome. Pregnancy 
outcomes will be reported by completing and submitting Pregnancy Outcome forms to 
Ultragenyx or designee.  


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 70 
8.5.5 
Communication Plan 
8.5.5.1 
Serious Adverse Drug Reaction Reporting 
Ultragenyx or its designee will submit suspected unexpected serious adverse reactions 
(SUSAR) to appropriate Regulatory Authorities (including Competent Authorities in all 
Member States concerned), Ethics Committees, and Investigators as per local laws and 
regulations. Fatal and life-threatening SUSARs will be submitted no later than 7-calendar 
days of first knowledge of the event and follow-up information submitted within an 
additional eight (8) days. All other SUSARs will be submitted within 15-calendar days of 
first knowledge of the event.  
The Investigator will notify the IRBs/Research Ethics Boards (REB)/ECs of SAEs and urgent 
safety matters, in accordance with IRB/REB/EC requirements and local laws and regulations. 
A copy of this notification must be provided to Ultragenyx or its designee.  
8.5.5.2 
Urgent Safety Matters and Non-SUSAR Reporting 
Principal Investigators are required to report any urgent safety matters to Ultragenyx or its 
designee within 24 hours. Ultragenyx or its designee will inform the Regulatory Authorities, 
ECs, and Investigators of any events (e.g. change to the safety profile of UX007, major 
safety findings) that may occur during the clinical trial that do not fall within the definition of 
a SUSAR but may affect the safety of subjects participating in the clinical trials, as required, 
in accordance with applicable laws and regulations. The reporting period for urgent safety 
issues is the period from the signing of the ICF through 30 days following the last dose of 
study drug. 
The Investigator will notify the IRBs/ REB/ECs of urgent safety matters, in accordance with 
IRB/REB/EC requirements and local laws and regulations. A copy of this notification must 
be provided to Ultragenyx or its designee. 
Non-SUSARs will be maintained in the Ultragenyx safety database and provided in annual 
and/or periodic reports as per local laws and regulations. Ultragenyx or its designee will 
prepare and submit annual safety reports and/or other aggregate periodic summary reports to 
Regulatory Authorities and ECs, as per local laws and regulations.  
8.5.5.3 
Pregnancy Reporting 
Reported pregnancy of a subject or a subject’s partner, while participating in the study, will 
be monitored for the full duration and/or followed until the outcome of the pregnancy is 
known. Any pregnancy-associated SAEs will be reported as per the SUSAR reporting 
process indicated in Section 8.5.4.3. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 71 
8.5.5.4 
Safety Contact Information 
Drug Safety 
Medical Monitor 
PrimeVigilance 
Fax:     
 
e-mail: 
 
Melanie Brandabur, MD  
Telephone: 
  
Mobile:      
 
e-mail:        
 
 
8.6 
Financing and Insurance 
Financing and insurance for this clinical trial will be addressed in clinical trial agreements 
with the study site. 
8.7 
Publication Policy 
Any publication or presentation by the Investigator and/or the Institution based on data or 
results resulting from the Ultragenyx study shall only be done in strict accordance with the 
Publication section in the Clinical Trial Agreement executed between Ultragenyx and the 
Institution and/or the Investigator. 
PPD
PPD
PPD
PPD
PPD


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 72 
9 REFERENCES 
Akman, CI, Provenzano, F, Wang, D, Engelstad, K, Hinton, V, Yu, J, Tikofsky, R, Ichese, M 
and De Vivo, DC. 2015. "Topography of brain glucose hypometabolism and epileptic 
network in glucose transporter 1 deficiency." Epilepsy Res 110:206-15. 
Alter, AS, Engelstad, K, Hinton, VJ, Montes, J, Pearson, TS, Akman, CI and De Vivo, DC. 
2014. "Long-Term Clinical Course of Glut1 Deficiency Syndrome." J Child Neurol. 
Ataide, TR, de Oliveira, SL, da Silva, FM, Vitorino, LGC, Tavares, MCN and Sant'Ana, 
AEG. 2009. "Toxicological analysis of the chronic consumption of diheptanoin and 
triheptanoin in rats." Int.J.Food Sci.Tech 44:484-92. 
ATS. 2002. "American Thoracic Society Statement: Guidelines for the six-minute walk test." 
Am.J.Respir, Crit.Care Med 166 (1):111-17. 
Barone, A, DeWard, S, Payne, N, Goldstein, A and Vockley, J. 2012. "Triheptanoin therapy 
for inherited disorders of fatty acid oxidation.  Poster presentation. ." Society for Inherited 
Metabolic Disorders Annual Meeting, Charlotte, NC, Mar 31 – Apr 3, 2012. 
Borges, K and Sonnewald, U. 2012. "Triheptanoin--a medium chain triglyceride with odd 
chain fatty acids: a new anaplerotic anticonvulsant treatment?" Epilepsy Res. 100 (3):239-44. 
Broderick, JE, DeWitt, EM, Rothrock, N, Crane, PK and Forrest, CB. 2013. "Advances in 
Patient-Reported Outcomes: The NIH PROMIS Measures." EGEMS (Wash DC) 1 (1):1015. 
Coman, DJ, Sinclair, KG, Burke, CJ, Appleton, DB, Pelekanos, JT, O'Neil, CM, Wallace, 
GB, Bowling, FG, Wang, D, De Vivo, DC and McGill, JJ. 2006. "Seizures, ataxia, 
developmental delay and the general paediatrician: glucose transporter 1 deficiency 
syndrome." J.Paediatr.Child Health 42 (5):263-67. 
Cooper, KH. 1968. "A means of assessing maximal oxygen intake. Correlation between field 
and treadmill testing." JAMA 203 (3):201-4. 
Deng, S, Zhang, GF, Kasumov, T, Roe, CR and Brunengraber, H. 2009. "Interrelations 
between C4 ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver." 
J.Biol.Chem. 284 (41):27799-807. 
Erro, R, Sheerin, UM and Bhatia, KP. 2014. "Paroxysmal dyskinesias revisited: a review of 
500 genetically proven cases and a new classification." Mov Disord 29 (9):1108-16. 
FDA. Draft Guidance 2012. Guidance for Industry: Suicidal Ideation and Behavior:  
Prospective Assessment of Occurrence in Clinical Trials (Draft), Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf.  Accessed 07 Jul 2013. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 73 
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 
Pediatr 150 (4):395-9. 
Gibbons, WJ, Fruchter, N, Sloan, S and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J Cardiopulm.Rehabil. 
21 (2):87-93. 
Gras, D, Roze, E, Caillet, S, Meneret, A, Doummar, D, Billette de Villemeur, T, Vidailhet, M 
and Mochel, F. 2014. "GLUT1 deficiency syndrome: an update." Rev Neurol (Paris) 170 
(2):91-9. 
IND 65827. "One Time Emergency Use of Anaplerotic Dietary Therapy (Triheptanoin) for 
Congestive Heart Failure & Cardiomyopathy under Charles Roe MD, Baylor Research 
Institute." 
Ito, Y, Takahashi, S, Kagitani-Shimono, K, Natsume, J, Yanagihara, K, Fujii, T and Oguni, 
H. 2015. "Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in 
Japan." Brain Dev 37 (8):780-9. 
Kim, TH, Borges, K, Petrou, S and Reid, CA. 2013. "Triheptanoin reduces seizure 
susceptibility in a syndrome-specific mouse model of generalized epilepsy." Epilepsy Res. 
103 (1):101-05. 
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-E66. 
Klepper, J. 2008. "Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic 
diet." Epilepsia 49 Suppl 8:46-49. 
Klepper, J and Leiendecker, B. 2007. "GLUT1 deficiency syndrome--2007 update." Dev Med 
Child Neurol 49 (9):707-16. 
Klepper, J, Leiendecker, B, Eltze, C and Heussinger, N. 2016. "Paroxysmal Nonepileptic 
Events in Glut1 Deficiency." Mov Disord Clin Pract 3 (6):607-10. 
Law, M, Baptiste, S, McColl, M, Opzoomer, A, Polatajko, H and Pollock, N. 1990. "The 
Canadian occupational performance measure: an outcome measure for occupational therapy." 
Can J Occup Ther 57 (2):82-7. 
Leen, WG, Klepper, J, Verbeek, MM, Leferink, M, Hofste, T, van Engelen, BG, Wevers, 
RA, Arthur, T, Bahi-Buisson, N, Ballhausen, D, Bekhof, J, van Bogaert, P, Carrilho, I, 
Chabrol, B, Champion, MP, Coldwell, J, Clayton, P, Donner, E, Evangeliou, A, Ebinger, F, 
Farrell, K, Forsyth, RJ, de Goede, CG, Gross, S, Grunewald, S, Holthausen, H, Jayawant, S, 
Lachlan, K, Laugel, V, Leppig, K, Lim, MJ, Mancini, G, Marina, AD, Martorell, L, 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 74 
McMenamin, J, Meuwissen, ME, Mundy, H, Nilsson, NO, Panzer, A, Poll-The, BT, 
Rauscher, C, Rouselle, CM, Sandvig, I, Scheffner, T, Sheridan, E, Simpson, N, Sykora, P, 
Tomlinson, R, Trounce, J, Webb, D, Weschke, B, Scheffer, H and Willemsen, MA. 2010. 
"Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of 
a treatable disorder." Brain 133 (Pt 3):655-70. 
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):175-82. 
McGavin, CR, Gupta, SP and McHardy, GJ. 1976. "Twelve-minute walking test for 
assessing disability in chronic bronchitis." Br Med J 1 (6013):822-3. 
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):305-12. 
Mochel, F, Duteil, S, Marelli, C, Jauffret, C, Barles, A, Holm, J, Sweetman, L, Benoist, JF, 
Rabier, D, Carlier, PG and Durr, A. 2010. "Dietary anaplerotic therapy improves peripheral 
tissue energy metabolism in patients with Huntington's disease." Eur.J.Hum.Genet. 18 
(9):1057-60. 
Mochel, F, Hainque, E, Gras, D, Adanyeguh, IM, Caillet, S, Heron, B, Roubertie, A, Kaphan, 
E, Valabregue, R, Rinaldi, D, Vuillaumier, S, Schiffmann, R, Ottolenghi, C, Hogrel, JY, 
Servais, L and Roze, E. 2015. "Triheptanoin dramatically reduces paroxysmal motor disorder 
in patients with GLUT1 deficiency." J Neurol Neurosurg Psychiatry. 
Mullen, SA, Suls, A, De Jonghe, P, Berkovic, SF and Scheffer, IE. 2010. "Absence 
epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency." 
Neurology 75 (5):432-40. 
NIH. 2015. PROMIS  2015 [cited January 2015]. Available from 
http://www.nihpromis.org/default.aspx#6. 
Pascual, JM, Liu, P, Mao, D, Kelly, DI, Hernandez, A, Sheng, M, Good, LB, Ma, Q, Marin-
Valencia, I, Zhang, X, Park, JY, Hynan, LS, Stavinoha, P, Roe, CR and Lu, H. 2014. 
"Triheptanoin for Glucose Transporter Type I Deficiency (G1D): Modulation of Human 
Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement." JAMA 
Neurol. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 75 
Pearson, TS, Akman, C, Hinton, VJ, Engelstad, K and De Vivo, DC. 2013. "Phenotypic 
spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS)." 
Curr.Neurol.Neurosci.Rep. 13 (4):342. 
Pong, AW, Geary, BR, Engelstad, KM, Natarajan, A, Yang, H and De Vivo, DC. 2012. 
"Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes." 
Epilepsia 53 (9):1503-10. 
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):275-81. 
Pons, R and De Vivo, DC. 2015. "Movement Disorders in Glucose Transporter Type 1 
Deficiency." J Pediatr Neurol (EFirst). 
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, 
Melvin, GA, Greenhill, L, Shen, S and Mann, JJ. 2011. "The Columbia-Suicide Severity 
Rating Scale: initial validity and internal consistency findings from three multisite studies 
with adolescents and adults." Am J Psychiatry 168 (12):1266-77. 
Roe, CR, Bottiglieri, T, Wallace, M, Arning, E and Martin, A. 2010. "Adult Polyglucosan 
Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of 
defective methylation pathways." Mol.Genet.Metab 101 (2-3):246-52. 
Roe, CR and Mochel, F. 2006. "Anaplerotic diet therapy in inherited metabolic disease: 
therapeutic potential." J.Inherit.Metab Dis. 29 (2-3):332-40. 
Roe, CR, Sweetman, L, Roe, DS, David, F and Brunengraber, H. 2002. "Treatment of 
cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an 
anaplerotic odd-chain triglyceride." J.Clin.Invest 110 (2):259-69. 
Roe, CR, Yang, BZ, Brunengraber, H, Roe, DS, Wallace, M and Garritson, BK. 2008. 
"Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy." Neurology 
71 (4):260-64. 
Roze, E, Méneret, A and Vidailhet, M. 2015. "Chapter 48 - Paroxysmal Movement 
Disorders: Clinical and Genetic Features." In Movement Disorders (Second Edition), edited 
by M. S. LeDoux, 767-78. Boston: Academic Press. 
Thomas, NK, Willis, S, Sweetman, L and Borges, K. 2012. "Triheptanoin in acute mouse 
seizure models." Epilepsy Res. 99 (3):312-17. 
Urbizu, A, Cuenca-Leon, E, Raspall-Chaure, M, Gratacos, M, Conill, J, Redecillas, S, Roig-
Quilis, M and Macaya, A. 2010. "Paroxysmal exercise-induced dyskinesia, writer's cramp, 
migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense 
mutation." J Neurol Sci 295 (1-2):110-3. 


Protocol Number:  UX007G-CL301  
Protocol Amendment 3 
10 July 2018 
 
 
 
Proprietary and Confidential 
Page 76 
Verrotti, A, D'Egidio, C, Agostinelli, S and Gobbi, G. 2012. "Glut1 deficiency: when to 
suspect and how to diagnose?" Eur J Paediatr Neurol 16 (1):3-9. 
Wang, D, Pascual, JM and De Vivo, D. 1993-2015. "Glucose Transporter Type 1 Deficiency 
Syndrome." In GeneReviews(R), edited by R. A. Pagon, M. P. Adam, H. H. Ardinger, T. D. 
Bird, C. R. Dolan, C. T. Fong, R. J. H. Smith and K. Stephens. Seattle (WA): University of 
Washington, Seattle. 
Wang, D, Pascual, JM and De Vivo, D. 2012. "Glucose Transporter Type 1 Deficiency 
Syndrome." In GeneReviews, edited by R. A. Pagon, M. P. Adam, T. D. Bird, C. R. Dolan, 
C. T. Fong and K. Stephens. Seattle (WA). 
Weber, YG, Storch, A, Wuttke, TV, Brockmann, K, Kempfle, J, Maljevic, S, Margari, L, 
Kamm, C, Schneider, SA, Huber, SM, Pekrun, A, Roebling, R, Seebohm, G, Koka, S, Lang, 
C, Kraft, E, Blazevic, D, Salvo-Vargas, A, Fauler, M, Mottaghy, FM, Munchau, A, Edwards, 
MJ, Presicci, A, Margari, F, Gasser, T, Lang, F, Bhatia, KP, Lehmann-Horn, F and Lerche, 
H. 2008. "GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and 
induce hemolytic anemia by a cation leak." J Clin Invest 118 (6):2157-68. 
Willis, S, Stoll, J, Sweetman, L and Borges, K. 2010. "Anticonvulsant effects of a 
triheptanoin diet in two mouse chronic seizure models." Neurobiol.Dis. 40 (3):565-72. 
 


Protocol Number: UX007G-CL301
Protocol Amendment 3
10 July 2018
ultrogeny^
pharmoceuficd
10 SIGNATURE PAGE
Protocol Title: A Phase 3, randomized, double-blind, placebo-controlled, crossover study to
assess the efficacy and safety ofUXOO? in the treatment of movement disorders associated
with Glucose Transporter Type 1 Deficiency Syndrome (Glutl DS)
Protocol Number: UX007G-CL301 Amendments
I have read Protocol UX007G-CL301. I agree to conduct the study as detailed in this protocol
and in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and all
applicable regulatory requirements and guidelines.
Investigator Signature Date
Printed Name:
Accepted for the Sponsor:
n?
As the Sponsor representative, I confirm that Ultragenyx will comply with all Sponsor
obligations as detailed in all applicable regulations and guidelines. I will ensure the
Investigator is informed of all relevant information that becomes available during the conduct
of this study.
 I
Melanie Brandabur, MD Date
Medical Director
Ultragenyx Pharmaceutical Inc.
Proprietary and Confidential Page 77
PPD
PPD

SAP_001.pdf: 
6WXG\1XPEHU8;*&/
6WDWLVWLFDO$QDO\VLV3ODQ
6HS9HUVLRQ


3DJH
3URSULHWDU\DQG&RQILGHQWLDO



67$7,67,&$/$1$/<6,63/$1


7LWOH
$3KDVH5DQGRPL]HG'RXEOH%OLQG3ODFHER
&RQWUROOHG&URVVRYHU6WXG\WR$VVHVVWKH(IILFDF\DQG
6DIHW\RI8;LQWKH7UHDWPHQWRI0RYHPHQW
'LVRUGHUV$VVRFLDWHGZLWK*OXFRVH7UDQVSRUWHU7\SH
'HILFLHQF\6\QGURPH*OXW'6
3URWRFRO
8;*&/
,QYHVWLJDWLRQDO3URGXFW 8;7ULKHSWDQRLQ
3KDVH

6SRQVRU
8OWUDJHQ\[3KDUPDFHXWLFDO,QF
/HYHURQL&RXUW
1RYDWR&$86$
$XWKRU

0DQDJHU%LRVWDWLVWLFLDQ%LRPHWULFV

'DWH
6HS
9HUVLRQ1XPEHU







PPD


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 2 
Proprietary and Confidential 
STATISTICAL ANALYSIS PLAN 
SUMMARY OF CHANGES AND RATIONALE 
UX007G-CL301 Version 2.0 
05 September 2018 
 
The Statistical Analysis Plan for UX007G-CL301 (Version 1.0, dated 13 Dec 2017) has been 
amended with major changes summarized below. 
1. Section 4.6 has been included to define subgroups for analysis. Section 8.8.1 and 
Appendix A include now the statistical methods for analyses of the subgroups defined 
in Section 4.6.  
Rationale: to examine the treatment effect in these subgroups. 
2. Revised section 5.8 to define PROMIS final T scores from the PROMIS online scoring 
system. 
Rationale: PROMIS final T scores will be used for analysis as this is calibrated score   
based on a relevant reference population. 
3. Added language in section 4.3 to have 12MWT, Patient/caregiver CGI-I, and 
CANTAB during OLE period as exploratory endpoint and added language in section 
8.8.3 to specify corresponding analysis. 
Rationale: In Protocol Amendment 3, these assessments were added through the   
Extension Period for evaluation of long-term efficacy. 
4. In section 3.1, added statement “At the discretion of the Sponsor and Principal 
Investigator, the Run-In Period may be extended beyond 6 weeks.” 
Rationale: to be consistent with Protocol Amendment 3. 
5. In section 8.9.3, add “head circumference” to vital sign assessment.  
Rational: to be consistent with Protocol Amendment 3. 
6. Appendix B and C have been changed to follow Protocol Amendment 3 
Rational: to be consistent with Protocol Amendment 3. 
7. In section  5.6 and section 7.3, modify the language for clarification.  
Rational: revised for clarification. 
 
 
 
 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 3 
Proprietary and Confidential 
TABLE OF CONTENTS 
1 INTRODUCTION .............................................................................................................. 9 
2 STUDY OBJECTIVES ..................................................................................................... 10 
2.1 Primary Objective .................................................................................................... 10 
3 STUDY DESIGN .............................................................................................................. 11 
3.1 Overall Study Design and Plan ................................................................................ 11 
3.2 Discussion of Study Design, Including Choice of Control Group ........................... 12 
3.3 Study Duration ......................................................................................................... 13 
3.4 Randomization and Stratification Factors ................................................................ 13 
3.5 Blinding .................................................................................................................... 13 
3.6 Sample Size Considerations ..................................................................................... 14 
3.7 Interim Analysis ....................................................................................................... 14 
3.8 Primary Analysis ...................................................................................................... 14 
3.9 Final Analysis .......................................................................................................... 14 
3.10 Data Monitoring Committee (DMC) ....................................................................... 14 
4 STUDY ENDPOINTS AND COVARIATES .................................................................. 15 
4.1 Primary Efficacy Endpoints ..................................................................................... 15 
4.2 Secondary Efficacy Endpoints ................................................................................. 15 
4.3 Exploratory Efficacy Endpoints ............................................................................... 16 
4.4 Safety Endpoints ...................................................................................................... 16 
4.5 Covariates ................................................................................................................. 16 
4.6 Subgroups ................................................................................................................. 17 
5 DEFINITIONS .................................................................................................................. 18 
5.1 Study Day ................................................................................................................. 18 
5.2 Study Week/Treatment Week .................................................................................. 18 
5.3 Duration of Exposure ............................................................................................... 18 
5.4 Age ........................................................................................................................... 19 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 4 
Proprietary and Confidential 
5.5 Baseline .................................................................................................................... 19 
5.6 Movement Disorder Frequency and Total Duration ................................................ 19 
5.7 Percent Predicted Six Minute Walk Test (6MWT) Distance ................................... 20 
5.8 PROMIS Scores ....................................................................................................... 21 
5.9 Physician and Patient/Caregiver CGI Scales ........................................................... 21 
5.10 COPM ...................................................................................................................... 22 
5.11 Activity measurements by Actigraphy Device ........................................................ 22 
6 ANALYSIS POPULATIONS .......................................................................................... 23 
6.1 Screened Population ................................................................................................. 23 
6.2 Full Analysis Set ...................................................................................................... 23 
6.3 Per Protocol Set ........................................................................................................ 23 
6.4 Safety Analysis Set .................................................................................................. 23 
7 DATA SCREENING AND ACCEPTANCE ................................................................... 24 
7.1 General Principles .................................................................................................... 24 
7.2 Handling of Missing and Incomplete Data .............................................................. 24 
7.2.1 
Missing Date Imputation for Medical History ........................................... 24 
7.2.2 
Missing Date Imputation for AEs and Concomitant Medications ............. 24 
7.3 Visit Time Windows ................................................................................................ 25 
7.4 Unscheduled or Early Termination Visits ................................................................ 27 
7.5 Software ................................................................................................................... 28 
8 STATISTICAL METHODS OF ANALYSES ................................................................. 29 
8.1 General Principles .................................................................................................... 29 
8.2 Subject Accountability ............................................................................................. 29 
8.3 Protocol Deviations .................................................................................................. 29 
8.4 Demographic and Baseline Characteristics .............................................................. 29 
8.5 Disease Characteristics and Medical History ........................................................... 30 
8.6 Investigational Product Administration ................................................................... 30 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 5 
Proprietary and Confidential 
8.6.1 
Extent of Exposure ..................................................................................... 30 
8.6.2 
Measurement of Treatment Compliance .................................................... 30 
8.6.3 
Diet Diary Review ...................................................................................... 30 
8.7 Prior and Concomitant Medication .......................................................................... 31 
8.8 Efficacy Analyses .................................................................................................... 31 
8.8.1 
Analyses of Primary Efficacy Endpoint ..................................................... 31 
8.8.2 
Analyses of Secondary Efficacy Endpoints ............................................... 33 
8.8.3 
Analyses of Exploratory Efficacy Endpoints ............................................. 34 
8.9 Safety Analyses ........................................................................................................ 35 
8.9.1 
Adverse Events ........................................................................................... 35 
8.9.2 
Clinical Laboratory Parameters .................................................................. 36 
8.9.3 
Vital Signs .................................................................................................. 37 
8.9.4 
Electrocardiogram ...................................................................................... 37 
8.9.5 
Suicidal Ideation and Behavior .................................................................. 38 
8.10 PK Analyses ............................................................................................................. 38 
9 REFERENCES ................................................................................................................. 39 
10 APPENDICES .................................................................................................................. 41 
10.1 Appendix A. Efficacy Endpoint Summary Table .................................................... 41 
10.2 Appendix B. Schedule of Events (Screening; Run-in; Period I; Washout; and 
Period II) .................................................................................................................. 44 
10.3 Appendix C. Schedule of Events (Extension and Safety Follow-up) ...................... 48 
 
LIST OF TABLES 
Table 1:  Visit Mapping Window for Movement Disorder Diary .......................................... 26 
Table 2:  Visit Window for Other Scheduled Efficacy and Safety Assessments ................... 27 
 
 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 6 
Proprietary and Confidential 
LIST OF FIGURES 
Figure 1:  UX007G-CL301 Study Schematic ......................................................................... 12 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 7 
Proprietary and Confidential 
ABBREVIATIONS 
12MWT 
12-Minute Walk Test 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CGI-I 
Clinical Global Impression – Improvement  
CGI-S 
Clinical Global Impression – Severity  
COPM 
Canadian Occupational Performance Measure 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DB 
Double-Blind 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration (United States) 
Glut1 
Glucose Transporter Type 1 
Glut1 DS 
Glucose Transporter Type 1 Deficiency Syndrome 
IWRS 
Interactive Web Randomization System 
KD 
Ketogenic Diet 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOT 
Motor Screening Test 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OLE 
Open-Label Extension 
PAL 
Paired Associates Learning  
PALFTMS 
Paired Associates Learning First Trial Memory Score 
PALTEA 
Paired Associates Learning Total Errors (Adjusted) 
PK 
Pharmacokinetics 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 8 
Proprietary and Confidential 
SI 
Le Système International d’Unités (International System of Units) 
SOC 
System Organ Class 
SSP 
Spatial Span 
SSPSLF 
Spatial Span Length 
SWM 
Spatial Working Memory 
SWMBE48 
Spatial Working Memory Between Errors 
SWMS68 
Spatial Working Memory Strategy 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
UX007 
Triheptanoin 
WHO 
World Health Organization  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 9 
Proprietary and Confidential 
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-CL301 Protocol Amendment 3 dated 
10July2018. This is the first amendment of SAP for this study. Changes from these 
guidelines must be substantiated by sound statistical reasoning and documented in the 
clinical study report (CSR). 
The data collected in this study will evaluate the efficacy and safety of UX007 (triheptanoin) 
in the treatment of disabling paroxysmal movement disorders associated with Glucose 
Transporter Type 1 Deficiency Syndrome (Glut1 DS) compared to placebo. The primary 
efficacy endpoint for this study is the frequency of disabling paroxysmal movement disorder 
events during 8 weeks of maintenance treatment. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 10 
Proprietary and Confidential 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
• Evaluate the efficacy and safety of UX007 in the treatment of disabling paroxysmal 
movement disorders associated with Glut1 DS 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 11 
Proprietary and Confidential 
3 STUDY DESIGN 
As background for the statistical methods presented below, this section provides an overview 
of the study design. The protocol is the definitive reference for all matters discussed in what 
follows in this section. 
3.1 
Overall Study Design and Plan 
UX007G-CL301 is a randomized, double-blind (DB), placebo-controlled, crossover study to 
assess the efficacy and safety of UX007 in the treatment of movement disorders associated 
with Glut1 DS. The study will enroll approximately 40 pediatric, adolescent, and adult 
subjects who are not on ketogenic diet (KD) and are having disabling paroxysmal movement 
disorder events. In this study, movement disorder events are defined as disabling if they 
affect or limit a subject’s physical functioning and activities of daily living such as caring for 
oneself, performing manual tasks, walking, standing, lifting things, bending, 
eating/swallowing, speaking, seeing, sleeping, attending or participating in school/work, or 
doing sports/exercise. 
During the 6-week Run-in Period, subjects will record disabling paroxysmal movement 
disorder events in a daily electronicGlut1 DS movement disorder diary; if the minimum 
criterion for number of events is not met, or subjects complete <80% of the daily 
electronicGlut1 DS movement disorder diary, the subject will be considered a screen failure 
and will not be randomized. Individuals may be allowed to rescreen, at the discretion of the 
Principal Investigator, subject to approval by the Medical Monitor. At the discretion of the 
Sponsor and Principal Investigator, the Run-In Period may be extended beyond 6 weeks. 
At the end of the Run-in Period, eligible subjects will be randomized (1:1) to one of two 
treatment sequences (UX007/placebo or placebo/UX007). At Randomization, subjects will 
begin a 10-week double-blind Treatment Period I. At the end of Treatment Period I, subjects 
will discontinue treatment and begin a 2-week washout period to minimize any potential 
carryover effect. Subjects will crossover to the second, double-blind treatment assignment 
(placebo to UX007, UX007 to placebo) for an additional 10 weeks during Treatment Period 
II. Dosing will be initiated in both treatment periods using a 2-week titration schedule until 
the subject has reached his/her age-related target dose. If a subject has not reached the target 
dose by the end of the 2-week titration period, dose titration should continue until the 
maximum tolerated dose is reached. At the end of the blinded crossover period (Week 22), 
all subjects will have the option of rolling into the Open-Label Extension (OLE) Period, to 
continue UX007 treatment for up to 3 years or until approval. A safety follow-up phone call 
will be conducted 30-35 days after the last dose of UX007G-CL301 study drug.  
Figure 1 provides a schematic of the study design. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 12 
Proprietary and Confidential 
Figure 1:  UX007G-CL301 Study Schematic 
 
3.2 
Discussion of Study Design, Including Choice of Control Group 
The choice of the crossover study design is based on the heterogeneity of the population to be 
studied. The impairment of glucose transport into the brain in Glut1 DS results in an energy 
deficit in various brain regions, including the cortex, basal ganglia and cerebellum. 
Damage to these brain regions may result in chronic deficits, such as cognitive delay, 
spasticity, ataxia or dystonic posturing (Gras et al. 2014). Against this background of 
neurologic impairment, the patient may also have acute periods of additional impairment, 
such as seizures, movement disorders or worsening ataxia (Pons et al. 2010). Some patients, 
especially those described as ‘non-classical’ may have minimal cognitive impairment, never 
have seizures, and present in their teens or later as a subset of a group of disorders called 
Paroxysmal Dyskinesias (Leen et al. 2010). 
Given the variability in the types, frequency and severity of the paroxysmal movement 
disorders in Glut1 DS, a crossover study design was chosen because it will allow comparison 
of the responses of the same heterogeneous group to both treatment and placebo. 
Although the KD is often used as a treatment for seizures in Glut1 DS (Klepper et al. 2007), 
its use in treating Glut1 DS movement disorders is less well established (Pons et al. 2010). 
The KD may be viewed as a burden for families and is often difficult to maintain as children 
reach adolescence, even when it has been effective in seizure control earlier in life. 
Many patients with movement disorders, such as Paroxysmal Dyskinesia, never had seizures 
and may never have been treated with KD. Implementation of the KD would be extremely 
difficult in a population that is likely to be older, seizure-free, and under less parental control 
than the younger population in whom seizures are a prominent feature. 
In a Phase 2 study, paroxysmal manifestations improved significantly (p=0.028) in 6 
evaluable patients, in response to treatment with UX007 (Mochel et al. 2015). The proposed 
Phase 3 study is designed to assess the efficacy and safety of UX007 in reducing the 
frequency of disabling paroxysmal movement disorder events in Glut1 DS patients who are 
not on KD. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 13 
Proprietary and Confidential 
3.3 
Study Duration 
Subject participation during the DB Treatment Period (including the Run-in Period, Baseline, 
Treatment Period I, Washout, and Treatment Period II) will be 28 weeks in duration; the 
OLE Period allows patients to receive UX007 for up to 3 additional years, or until one of the 
following occurs: the subject withdraws consent, the subject is discontinued from the study at 
the discretion of the Investigator or Ultragenyx, the study is terminated, or until commercial 
availability of the study drug in the subject’s region, which occurs first. The total treatment 
duration enables a long-term assessment of the efficacy and safety of UX007 in Glut1 DS 
subjects with movement disorders. A safety follow-up phone call will be conducted 
30-35 days after the last dose of UX007G-CL301 study drug. The last subject’s safety 
follow-up phone call is the defined end-of-study time point. 
The schedule of assessments is shown in Section 10.2 Appendix B and Section 10.3 
Appendix C. 
3.4 
Randomization and Stratification Factors 
Eligible subjects will be enrolled in the study and sequentially assigned an identification 
number. Subjects will be randomized in a 1:1 ratio to UX007/Placebo or Placebo/UX007 
treatment sequence via an Interactive Web Randomization System (IWRS) based on a 
randomization schedule developed by an independent third-party vendor to maintain 
blinding. The randomization procedure will be performed without stratification. 
3.5 
Blinding 
The Titration and Maintenance Periods (Weeks 0-22) will be conducted as a randomized, 
double-blind, placebo-controlled, crossover study. Double-blind conditions will be 
established during this period so that neither the sponsor, subject, or site personnel involved 
in study conduct will know the identity of a subject’s treatment. After all subjects have 
completed the double-blind period, unblinding of the study will occur post the double-blind 
portion of the study database is locked. All subjects who complete the double-blind portion 
of the study will be eligible to receive open-label UX007 during the Extension Period to 
assess long-term safety and duration of effect. 
The Investigator and site personnel will remain blinded to the randomization code during the 
double-blind portion of the study. Treatment assignment for an individual subject should be 
unblinded by the Investigator only in an emergency e.g., event concerning subject safety, and 
only if knowledge of the treatment assignment is urgently needed for the clinical 
management or welfare of the subject. The Investigator should contact the medical monitor 
before unblinding, when possible, but priority should be given to the safety of the subject.  
If a subject’s treatment assignment is unblinded prior to completion of the double-blind 
portion of the study, the subject may be discontinued from the study and may not be eligible 
to participate in the open-label Extension Period. Detailed blinding procedures are specified 
in the study protocol. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 14 
Proprietary and Confidential 
3.6 
Sample Size Considerations 
The primary efficacy parameter is number of disabling paroxysmal movement disorder 
events observed during the Maintenance Period of Treatment Periods I and II. Based on the 
targeted patient population and eligibility criteria, it is estimated that during a 6 week 
duration, the subjects receiving placebo will have a mean frequency of 8 disabling 
paroxysmal movement disorders per 4 weeks, while subjects receiving UX007 will have a 
mean frequency of 4 disabling paroxysmal movement disorders per 4 weeks, and a standard 
deviation of the difference of 7.4. A total sample size of 40 subjects (20 subjects in each 
treatment sequence) will have at least 85% power to detect such difference between UX007 
and placebo groups at the two-sided 5% significance level. This sample size assumption 
incorporates a projected discontinuation rate of 15%. 
3.7 
Interim Analysis 
There is no interim analysis planned for this study. 
3.8 
Primary Analysis 
The primary analysis will occur when all subjects have completed the DB Treatment Period, 
or withdrawn from the study during the DB Treatment Period, whichever comes earlier. 
3.9 
Final Analysis 
The final analysis will occur when all subjects have completed the OLE Period, or withdrawn 
from the study, whichever comes earlier. 
Additional analyses may be performed after primary analysis during the course of the study 
at the discretion of the Sponsor. 
3.10 Data Monitoring Committee (DMC) 
An independent DMC with that includes members with expertise in movement disorders will 
act in an advisory capacity to monitor subject safety on a routine basis throughout the trial. 
The DMC may also provide advice to Ultragenyx in any determination of whether study 
enrollment should be paused or if the study should be halted. The detailed roles and 
responsibilities of the DMC are specified in the DMC Charter. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 15 
Proprietary and Confidential 
4 STUDY ENDPOINTS AND COVARIATES  
All data are collected according to the schedule of assessments (Section 10.2 Appendix B 
and Section 10.3 Appendix C). 
4.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is frequency of disabling paroxysmal movement disorder 
events during the maintenance treatment period, as recorded by the subject/caregiver in an 
event-based daily Glut1 DS symptom diary. 
4.2 
Secondary Efficacy Endpoints 
• Total duration of disabling paroxysmal movement disorder events during maintenance 
phase, as recorded by the subject/caregiver in an event-based daily Glut1 DS symptom 
diary  
• Change from period baseline to treatment week 10 in 12 Minute Walk Test (12MWT) 
distance  
• Patient/caregiver Clinical Global Impression – Improvement (CGI-I) score at treatment 
week 10 
• Change from period baseline to treatment week 10 in Patient Reported Outcomes 
Measurement Information System (PROMIS) scores (domain scores) 
• Change from period baseline to treatment week 10 in the following Cambridge 
Neuropsychological Test Automated Battery (CANTAB) scores (assessed at select sites) 
 Spatial Span (SSP): 
− Span Length (SSPSLF) 
 Spatial Working Memory (SWM): 
− Between Errors (SWMBE48) 
− Strategy (SWMS68) 
 Paired Associates Learning (PAL): 
− Total Errors (Adjusted) (PALTEA) 
− First Trial Memory Score (PALFTMS) 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 16 
Proprietary and Confidential 
4.3 
Exploratory Efficacy Endpoints 
• Change from period baseline in performance score and in satisfaction score as assessed 
by Canadian Occupational Performance Measure (COPM) at treatment week 10 
• Physician CGI-I score at treatment week 10 
• Change from period baseline in physician Clinical Global Impression-Severity (CGI-S) 
score at treatment week 10 
• Change from study baseline to treatment week 10 in mean daytime activity, mean 
nighttime activity, and percent time in moderate or higher intensity activity as measured 
by a wrist-worn actigraphy device at select study sites where feasible 
• Frequency of disabling paroxysmal movement disorder events over time throughout the 
three-year OLE period. 
• Total duration of disabling paroxysmal movement disorder events over time throughout 
the three-year OLE period 
• PK data for UX007 metabolites 
• Efficacy Endpoints during the three-year OLE period: 12MWT, Patient/caregiver CGI-I, 
CANTAB, Physician CGI-I, Physician CGI-S, performance score and satisfaction score 
as assessed by COPM, PROMIS scores (domain scores) 
4.4 
Safety Endpoints 
• Adverse events (AEs), including the subject incidence of AEs, treatment related AEs, 
serious adverse events (SAEs), AEs leading to discontinuation and fatal AEs 
• Vital signs 
• Clinical laboratory test results 
• Electrocardiogram (ECG) 
• Suicidal ideation and behavior assessment as measured by the Columbia Suicide Severity 
Rating Scale (C-SSRS) 
4.5 
Covariates 
For the analysis of covariate (ANCOVA) analysis, baseline (study baseline or period 
baseline) of the response variable will be included as the covariates, whenever appropriate. 
Sequence and period will also be included as the covariates, when analyzing the DB 
treatment data.  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 17 
Proprietary and Confidential 
4.6 
Subgroups 
Using information from the Ketogenic Diet CRF form, the following subgroups are identified 
to examine any potential treatment effect. 
1. Subjects who have never tried a prescribed diet plan to manage Glut1 symptoms. 
2. Subjects who have tried a prescribed diet plan to manage Glut1 symptom and the 
most recent prescribed diet (KD/Modified Atkins Diet/other) was discontinued due to 
lack of efficacy. 
3. Subjects who have tried a prescribed diet plan to manage Glut1 symptom and the 
most recent prescribed diet (KD/Modified Atkins Diet/other) was discontinued for a 
reason or reasons other than lack of efficacy. 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 18 
Proprietary and Confidential 
5 DEFINITIONS 
5.1 
Study Day 
• If the assessment date is on or after the first dose date of investigational product: 
• Study day = (assessment date – first dose date of investigational product + 1) 
• If the assessment date is prior to the first dose date of investigational product: 
• Study day = assessment date – first dose date of investigational product 
5.2 
Study Week/Treatment Week 
Study weeks are the time points recorded on CRF. 
For the DB treatment period, treatment weeks are defined as: 
• For subjects randomized to UX007/Placebo group 
 UX007 treatment week=study week 
 Placebo treatment week=study week-12 
• For subjects randomized to Placebo/UX007 group 
 Placebo treatment week=study week 
 UX007 treatment week=study week-12 
5.3 
Duration of Exposure  
• Duration of exposure to Investigational Product (IP) (Placebo or UX007), in days, is 
defined as: 
 During the DB Treatment Period: defined as last dose date of IP in the corresponding 
treatment period of the DB Period – first dose date of IP in the corresponding 
treatment period of the DB Period + 1 day 
• Duration of exposure to UX007, in days, is defined as: 
 During the OLE Period is defined as last dose date of UX007 in OLE Period – first 
dose date of UX007  in OLE Period + 1 day 
 During the whole study is defined as the sum of the duration of exposure to UX007 in 
days during the DB Treatment Period and the duration of exposure to UX007 in days 
during the OLE Period 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 19 
Proprietary and Confidential 
5.4 
Age 
Age will be derived based on the informed consent date as Age = (Inform Consent Date – 
Birth Date +1)/365.25. Age will be rounded down and keep 1 decimal place.  When date of 
birth is missing, then age recorded on case report form (CRF) at time of informed consent 
will be used. 
5.5 
Baseline 
• Movement Disorder: 
Study baseline for movement disorder frequency as recorded by the subject/caregiver in diary 
will be normalized to a 4-week rate as 
total number of movement disorder events during the 6 weeks run-in period ×  28 
number of days with diary data during the 6 weeks run-in period
 
Study baseline for total duration of movement disorder in hours will be normalized to a 
4-week rate as 
total duration of movement disorders in hours during the 6 weeks run-in period ×  28 
number of days with diary data during the 6 weeks run-in period
 
• For other efficacy endpoints, study baseline is defined as the last non-missing assessment 
prior to or on the date of the first dose of investigational product 
• For safety endpoints, study baseline is defined as the last non-missing assessment prior to 
or on the date of the first dose of investigational product 
Period baseline is defined as the last non-missing assessment prior to or on the date of the 
first dose of investigational product for each DB treatment period. A value from the first 
treatment period will not be considered as the period baseline for the second treatment 
period. 
5.6 
Movement Disorder Frequency and Total Duration 
For analyses, movement disorder frequency and total duration in hours will be normalized to 
a 4-week rate at each of the specified period: 
total number of movement disorders during the specified period ×  28 
number of days with diary data during the specified period
 
 total duration of movement disorders during the specified period ×  28 
number of days with diary data during the specified period
 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 20 
Proprietary and Confidential 
Mean duration in hours at each of the specified period is defined as: 
total duration of movement disorders during the specified period 
total number of movement disorders during the specified period  
The percentage of movement disorder free days is defined as 
total number days with of zero movement disorder
number of days with diary during the specified period *100% 
5.7 
Percent Predicted Six Minute Walk Test (6MWT) Distance 
To calculate the percent predicted 6MWT value, the following formulas will be applied 
(Geiger et al. 2007) for subjects aged <20 years old at randomization: 
𝐹𝐹𝑜𝑜𝑟𝑟 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀: 𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
196.72 + (39.81 ∗𝐴𝐴𝐴𝐴𝐴𝐴) −(1.36 ∗𝐴𝐴𝐴𝐴𝐴𝐴2) + (132.28 ∗𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡) ∗100 
 
𝐹𝐹𝐹𝐹𝐹𝐹 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹: 𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
188.61 + (51.50 ∗𝐴𝐴𝐴𝐴𝐴𝐴) −(1.86 ∗𝐴𝐴𝐴𝐴𝐴𝐴2) + (86.10 ∗𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡) ∗100 
 
Where: 
Xi = The percent predicted 6MWT result at time i for subject X 
X0i = The 6MWT (m) result at time i for subject X 
 
 
To calculate the percent predicted 6MWT value, the following formulas will be applied 
(Gibbons et al. 2001) for subjects aged ≥20 years old at randomization: 
𝑋𝑋𝑖𝑖 =
𝑋𝑋0𝑖𝑖
868.8 −(2.99 ∗𝐴𝐴𝐴𝐴𝐴𝐴) −(74.7 ∗𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊) ∗100 
Where: 
Xi = The percent predicted 6MWT result at time i for subject X 
X0i = The 6MWT (m) result at time i for subject X 
Women = an indicator variable:  equal to 1 if the subject is female and 0 if male 
The percent predicted 6MWT formulas will use the subject’s height (m) and age at the 
randomization visit throughout the study duration. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 21 
Proprietary and Confidential 
5.8 
PROMIS Scores 
The PROMIS questionnaires have been developed from the Adult and Pediatric PROMIS 
Item Banks (Broderick et al. 2013) (NIH 2015). Self- and proxy-report versions are available 
and use is based on participant age and cognitive ability. The responses collected from 
PROMIS questionnaires will be uploaded to the web-based application, HealthMeasures 
Scoring Service, to obtain the final T-scores for each domain listed below  
(http://www.healthmeasures.net/score-and-interpret/calculate-scores). 
For adults, T-scores will be derived for the following domains:  
• physical function  
• fatigue 
• sleep disturbance 
• pain interference 
• cognitive function 
• ability to participate in social roles and activities 
• anxiety  
For pediatric subjects (under the age of 18), T-scores will be derived for the following 
domains, 
• mobility  
• upper extremity 
• fatigue  
• pain interference 
• peer relationships 
5.9 
Physician and Patient/Caregiver CGI Scales 
Physician CGI-S score and patient/caregiver CGI-S score use a 4-point Likert scale 
(1 = Normal to 4 = Severe) to rate disease severity.  
Physician CGI-I score and patient/caregiver CGI-I score use a 7-point Likert scale  
(1 = Very much better to 7 = Very much worse) to record the degree of change in clinical 
status.  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 22 
Proprietary and Confidential 
5.10 COPM 
Up to five most important occupational performance problems as reported by the 
subject/parent/caregiver at the Study Week 0 visit will be scored using a scale of 1-10  
(1 = poor performance and low satisfaction to 10 = very good performance and high 
satisfaction) to provide a Performance score and a Satisfaction score for each of the 
occupational performance problems. 
The performance or satisfaction score can be derived as: 
Sum of performance or satisfication scores
Number of problems that were actually answered  
5.11 Activity measurements by Actigraphy Device 
A wrist-worn activity monitor (actigraphy device) will assess the impact of Glut1 DS on 
activity at select study sites, where feasible. The endpoints will be measured during the last 
10 days of the Run-in Period, the last 10 days of Treatment Period 1, and the last 10 days of 
Treatment Period 2. The endpoints are defined as following: 
Mean daytime activity: Average activity count during worn epochs between the hours of 
10 a.m. and 8 p.m in the last 10 days of the specified period. If there are no worn epochs, the 
value will be -1 
Mean nighttime activity: Average activity count during worn epochs between the hours of 
12 a.m. and 5 a.m in the last 10 days of the specified period. If there are no worn epochs, the 
value will be -1 
Percent time in moderate or higher intensity activity: The ratio of total minutes in moderate 
to vigorous physical activity to total wear minutes. This will be -1 if there no wear minutes. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 23 
Proprietary and Confidential 
6 ANALYSIS POPULATIONS 
6.1 
Screened Population 
The Screened Population will consist of all subjects who underwent at least one Screening 
Visit and received a subject identification number. 
6.2 
Full Analysis Set 
The Full Analysis Set will consist of all enrolled subjects who received at least one dose of 
investigational product. Subjects will be analyzed according to randomized treatment 
sequence. 
6.3 
Per Protocol Set 
The Per Protocol Set will consist of all subjects in the Full Analysis Set who meet the 
following criteria: 
• The percentage of days with non-missing movement disorder diary is at least 80% for the 
planned run-in period duration (6 weeks) and each of the two planned maintenance 
period durations (8 weeks). 
• The percentage of days with non-missing doses is at least 80% for each of the two 
planned maintenance period durations (8 weeks). 
• After titration period, the target dose (25%) of UX007 is reached for at least one day for 
the planned maintenance periods. 
6.4 
Safety Analysis Set 
The Safety Analysis Set will consist of all enrolled subjects who received at least one dose of 
investigational product. Subjects will be analyzed according to the actual treatment sequence. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 24 
Proprietary and Confidential 
7 DATA SCREENING AND ACCEPTANCE 
7.1 
General Principles 
Data will be reviewed periodically. Any questionable data will be reported to the clinical data 
manager promptly for query and resolution. 
7.2 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified for investigation and possible resolution by Data Management prior to the study 
database lock or snapshot. 
Unless specified otherwise, only the observed data will be presented. When a change from 
baseline is assessed, only patients with a baseline and at least one post-baseline measurement 
will be included in the analysis. 
7.2.1 
Missing Date Imputation for Medical History  
• If only day is missing, impute as 1. 
• If month is missing, impute as January 1st. 
• If year is missing, then no imputation will be done and the date will be missing.  
If the imputed date is earlier than the birth date, then the birth date will be used. 
7.2.2 
Missing Date Imputation for AEs and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for AEs and 
concomitant medications.  Note that the imputed values outlined here may not always 
provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
 If the month and year match the start date month and year of the first dose of 
investigational product in this study, then impute as the day of the first dose date. 
 Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
 If the year matches the start date year of the first dose of investigational product date 
in this study, then impute as the month and day of the first dose date in this study. 
 Otherwise, assign ‘January’.  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 25 
Proprietary and Confidential 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 
Missing Stop Dates and Not Ongoing 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December’. 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value, and the event will be considered ongoing. If the AE has been recorded as 
resolved/recovered, all efforts should be made to obtain the date from the Investigator. 
If the resulting end date is after the date of study completion/discontinuation/data cutoff, set 
the imputed end date as close to the date of study completion/discontinuation/data cutoff as 
possible without overwritten existing information. 
7.3 
Visit Time Windows 
Table 1 presents the assigned target study day and study day window for each study period. 
Movement disorder frequency and duration recorded on diary will be mapped to specified 
period according to Table 1 and actual visit days.  For other scheduled efficacy and safety 
assessments the visit window assigned and the corresponding target treatment days during 
which an actual visit may occur is specified in Table 2. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 26 
Proprietary and Confidential 
Table 1:  Visit Mapping Window for Movement Disorder Diary 
Period  
Planned 
Duration 
Target Study 
Day 
Study Day Window 
Run-In 
6 weeks 
[-42, 0] 
<1 
DB 
Treatment 
Period I 
Titration  
2 weeks 
[1,15] 
[1, 15] 
Maintenance 
8 weeks 
[16,71] 
For subjects who entered into washout 
period: [study day of first dose in Treatment 
Period I+15, the end of Treatment Period I]; 
For subjects who did not enter into washout 
period: ≥ study day of first dose in 
Treatment Period I+15 
Washout  
2 weeks 
[72,85] 
For subjects who entered into Treatment 
Period II[1]: [the end of Treatment Period 
I+1, study day of first dose in Treatment 
Period II-1]; 
For subjects who did not enter into 
Treatment Period II: ≥ the end of Treatment 
Period I +1 
DB 
Treatment 
Period II 
Titration  
2 weeks 
[86,99] 
[study day of first dose in Treatment Period 
II, study day of first dose in Treatment 
Period II+14] 
Maintenance 
8 weeks 
[100,155] 
For subjects who entered into extension 
period: [study day of first dose in Treatment 
Period II+15, the end of Treatment Period 
II]; 
For subjects who did not enter into OLE 
period: ≥ study day of first dose in 
Treatment Period II+15 
OLE 
Period 
Week 34 
12 weeks 
[156, 281] 
[study day of first OLE dose date, 281] 
Week 46 
12 weeks 
[282,365] 
[282,365] 
Week 58 
12 weeks 
[366, 449] 
[366, 449] 
Week 70 
12 weeks 
[450, 533] 
[450, 533] 
Week 82 
12 weeks 
[534, 617] 
[534, 617] 
Week 94 
12 weeks 
[618, 701] 
[618, 701] 
Week 106 
12 weeks 
[702, 785] 
[702, 785] 
Week 118 
12 weeks 
[786, 869] 
[786, 869] 
Week 130 
12 weeks 
[870, 953] 
[870, 953] 
Week 142 
12 weeks 
[954, 1037] 
[954, 1037] 
Week 154 
12 weeks 
[1038, 1121] 
[1038, 1121] 
Week 166 
12 weeks 
[1122, 1205] 
[1122, 1205] 
Week 178 
12 weeks 
≥1206 
≥1206 
[1] Enter into treatment Period II is defined as subjects having taken any Treatment Period II dosing 
[2] Enter into OLE phase is defined as subjects having taken any OLE phase dosing. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 27 
Proprietary and Confidential 
Table 2:  Visit Window for Other Scheduled Efficacy and Safety Assessments 
Period 
Study Week 
Treatment 
Week 
Target 
Day 
Study Day Window 
DB 
Treatment 
Period I 
Study Week 0 
Trt Week 0 
1 
≤1 
Study Week 2 
Trt Week 2 
15 
[2, 15] 
Study Week 10 
Trt Week 10 
71 
For subjects who entered into 
Treatment Period II[1]: [16, 78] 
For subjects who did not enter into 
Treatment Period II: ≥16 
DB 
Treatment 
Period II 
Study Week 12 
Trt Week 0 
85 
[79, study day of first dose in 
Treatment Period II] 
Study Week 14 
Trt Week 2 
99 
[study day of first dose in Treatment 
Period II+1, study day of first dose in 
Treatment Period II+15] 
Study Week 22 
Trt Week 10 
155 
For subjects who entered into OLE 
period[2]: [study day of first dose in 
Treatment Period II+16, the end of 
Treatment Period II]; 
 
For subjects who did not enter OLE 
period: ≥study day of first dose in 
Treatment Period II+16 
OLE Period 
Study Week 34 
 
239 
[study day of first OLE dose date, 281] 
Study Week 46 
 
323 
[282,365] 
Study Week 58 
 
407 
[366, 449] 
Study Week 70 
 
491 
[450, 533] 
Study Week 82 
 
575 
[534, 617] 
Study Week 94 
 
659 
[618, 701] 
Study Week 106 
 
743 
[702, 785] 
Study Week 118 
 
827 
[786, 869] 
Study Week 130 
 
911 
[870, 953] 
Study Week 142 
 
995 
[954, 1037] 
Study Week 154 
 
1079 
[1038, 1121] 
Study Week 166 
 
1163 
[1122, 1205] 
Study Week 178 
 
1247 
≥1206 
[1] Enter into treatment Period II is defined as subjects having taken any Treatment Period II dosing 
[2] Enter into OLE phase is defined as subjects having taken any OLE phase dosing. 
7.4 Unscheduled or Early Termination Visits 
For an unscheduled visit that occurred after the first dose date of IP, the unscheduled visit 
will be mapped into the closest post-baseline study scheduled visit for the assessment based 
on the study day of the unscheduled visit, and the target study day of the scheduled visit of 
the assessment in the protocol. If the unscheduled visit has the equal distance to the 2 study 
scheduled visits, it will be mapped to the later one. 
An unscheduled visit will only be mapped to a study visit within each study period during 
which it occurs. For example, if an unscheduled visit occurs during the Titration period of the 
DB Treatment Period I, it should be mapped to the study visit in the Titration period of the 
DB Treatment Period I.  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 28 
Proprietary and Confidential 
When there are more than one measurements mapped to the same scheduled visit (including 
the original measurement taken from the scheduled visit), the measurement taken on the 
scheduled visit will be used if it is not missing, otherwise the one closest to the target day 
will be used. If more than one visit has the equal distance to the target day then the later one 
will be used. If more than one measurement is collected on the same day, use the time or the 
sequence number to select the latest record. For listings and shift tables, all data points will 
be included. 
Early termination visit will follow the same rule for unscheduled visit as described above. 
7.5 
Software 
SAS® software version 9.4 or higher will be used to perform statistical analyses unless 
otherwise specified. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 29 
Proprietary and Confidential 
8 STATISTICAL METHODS OF ANALYSES 
8.1 
General Principles 
All statistical tests will be two-sided and tested at statistical significant level of 0.05. 
The statistical analyses will be reported using summary tables, figures, and data listings. 
Continuous variables will be summarized by number of subjects and mean, standard 
deviation (SD), standard error (SE) median, 25%th and 75%th quartile, minimum, and 
maximum values. Categorical variables will be summarized by number and percentage of 
subjects. All raw data obtained from the CRFs will be included in data listings. 
8.2 
Subject Accountability 
The number and percentage of subjects in each of the study populations (Screened 
Population, Full Analysis Set, Per Protocol Set and Safety Analysis Set) will be summarized 
by treatment sequence.  Subjects excluded from the analysis sets will be listed. 
The number and percentage of subjects who complete each of the two double-blind treatment 
periods, who complete the OLE Period, and who prematurely discontinue will be presented 
by treatment sequence. The reasons for premature discontinuation from treatment as recorded 
on CRFs will be summarized by treatment sequence as well.  
8.3 
Protocol Deviations 
Protocol deviations will be summarized for the Screened Population by treatment sequence 
and period. Both major and minor protocol deviations will be listed. The determination of 
major and minor protocol deviations will occur prior to unblinding.  
8.4 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment sequence for the Full Analysis Set for the 
following parameters: 
• Age at informed consent 
• Gender 
• Ethnicity 
• Race 
• Age at Glut1 DS diagnosis  


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 30 
Proprietary and Confidential 
8.5 
Disease Characteristics and Medical History 
Summary statistics will be presented for the Full Analysis Set by treatment sequence and 
overall, for the following parameters: 
• Duration of Glut1 DS symptom 
• Glut1 DS mutation description 
• Glut1 DS symptoms history including whether ongoing 
• KD history and reason for KD discontinuation 
Medical history will also be summarized by system organ class (SOC) and preferred term 
(PT) for the Full Analysis Set by treatment sequence.  
8.6 
Investigational Product Administration 
8.6.1 
Extent of Exposure 
Exposure duration to the investigational product will be summarized by treatment for the 
Safety Analysis Set for the DB Treatment Period, and the whole study.  
8.6.2 
Measurement of Treatment Compliance 
Dosing compliance for a specified period is defined as the investigational product actually 
taken by a subject during that period in ml divided by the investigational product expected 
for the same period in ml multiplied by 100.  
Descriptive statistics for dosing compliance will be summarized by treatment sequence and 
treatment for the Safety Analysis Set for the DB treatment and OLE Period. Number of days 
with non-missing dose will also be summarized by treatment sequence and treatment. 
The percentage of subjects who reach target dose within 2 weeks of titration period will be 
summarized by treatment for the DB Treatment Period. Time to reach target dose will also be 
summarized by treatment. 
8.6.3 
Diet Diary Review 
The following measures will be summarized by visit based on the 3-day Diet Diary Review: 
• Average Study Drug Calories, as calculated as the average of the 3 entries for study drug 
• Average Total Daily Calories 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 31 
Proprietary and Confidential 
8.7 
Prior and Concomitant Medication 
Prior medication is defined as any medication started before the date of the first dose of 
investigational product.  
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of investigational product. A medication started before the date of the first dose of 
investigational product and also taken after the date of first dose of investigational product 
will be counted both as a prior and concomitant medication. 
Both prior and concomitant medications will be coded by drug name and therapeutic class 
using World Health Organization (WHO) Drug Dictionary. Prior medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) code and preferred term by 
treatment sequence for the Safety Analysis Set. Similarly, concomitant medications will be 
summarized by treatment sequence for the Safety Analysis Set for the double blind treatment 
periods and the whole study.  
8.8 
Efficacy Analyses 
Efficacy analyses will be based on the Full Analysis Set, unless otherwise specified. 
Section 10.1 Appendix A summarizes the analysis strategy for efficacy endpoints. 
For weighted ANCOVA analysis, weight will be calculated by using number of non-missing 
diary days divided by the planned maintenance period duration (8 weeks). For Wilcoxon 
rank-sum test, the difference between responses of Treatment Period 1 and Period 2 will be 
ranked to make the non-parametric comparison between two treatment groups. 
8.8.1 
Analyses of Primary Efficacy Endpoint 
The primary endpoint is the frequency of movement disorder events during the maintenance 
treatment period. In the event of electronic diary failure, the back-up paper diary might be 
used during the days with missing data from electronic diary. Combined electronic diary data 
and paper diary data will be used. 
The primary analysis will be performed using a weighted ANCOVA model, with study 
baseline frequency of movement disorder as a covariate, treatment sequence, treatment group 
and period as fixed effects, and a random effect for subject within the sequence.  
After study unblinding, the normality assumption of ANCOVA model will be examined by 
using the Wilk-Shapiro test on the residuals from the ANCOVA model (Shapiro et al. 1965) 
When there is strong evidence suggesting that the normality assumption is not met (p value 
for Wilk-Shapiro test < 0.05) (Nornadiah 2011) (Yap et al. 2011), Wilcoxon rank-sum test 
will be considered as the primary analysis to assess treatment difference in movement 
disorder event frequency. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 32 
Proprietary and Confidential 
The following sensitivity analyses will be performed. 
• To analyze the percent change from study baseline in the frequency of movement 
disorder during the maintenance period, the primary weighted ANCOVA model will be 
performed. 
• Wilcoxon rank-sum test will be performed to assess treatment difference in movement 
disorder event frequency. 
• The primary weighted ANCOVA based on the frequency of movement disorder events 
will be performed based on Per Protocol Set. 
• In case paper diary is used as back up, sensitivity analysis excluding paper diary will be 
considered. The primary weighted ANCOVA based on the frequency of movement 
disorder events will be performed. 
• If subjects discontinued during the 2-week titration period or missed one treatment period 
entirely, impute the movement disorder frequency during the maintenance period using 
the frequency during the titration period if titration period data is available, otherwise, the 
study baseline will be used to impute the movement disorder frequency during the 
maintenance period. Then the ANCOVA model based on the frequency of movement 
disorder events during maintenance phase will be performed, with study baseline 
frequency of movement disorder as a covariate, treatment sequence, treatment group and 
period as fixed effects, and a random effect for subject within the sequence. 
Movement disorder frequency during the maintenance period will also be summarized by the 
subgroup: reporting type of movement disorder diary (caregiver mode or subject mode). 
The change from study baseline to maintenance phase in percentage of movement disorder 
free days will be analyzed using the primary weighted ANCOVA model. 
Subgroup analysis by prior KD/Modified Atkins Diet will be conducted for the frequency of 
movement disorder events using the primary weighted ANCOVA model. If wilcoxon 
rank-sum test is used as the primary analysis to assess treatment difference in movement 
disorder event frequency, Wilcoxon rank-sum test will be used to perform the above 
subgroup analysis. Only point estimate and 95% CI will be presented for the subgroup 
analysis.  
Test Carryover effect 
The carryover effect will be tested as the significance of sequence effect. If the carryover 
effect is non-ignorable (p value < 0.05), analysis including only the first-period data will be 
considered. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 33 
Proprietary and Confidential 
8.8.2 
Analyses of Secondary Efficacy Endpoints 
If the primary analysis for the primary efficacy endpoint is statistically significant, then a 
hierarchically sequential hypothesis testing strategy will be implemented for the selected 
secondary efficacy endpoints in the following sequence at level 0.05 until first non-rejection: 
• Total duration of movement disorder events during maintenance period 
• Change from period baseline to treatment week 10 in 12MWT distance 
• Patient/caregiver CGI-I score at treatment week 10 
The primary analysis for the selected secondary efficacy endpoints are: 
• For total duration of movement disorder events during maintenance period, the weighted 
ANCOVA model will be used with study baseline as a covariate, treatment sequence, 
treatment group, and period as fixed effects, and a random effect for subject within the 
sequence. 
• For change from period baseline to treatment week 10 in 12MWT distance, the 
ANCOVA model will be used with period baseline as a covariate, treatment sequence, 
treatment group, period as fixed effects, and a random effect for subject within the 
sequence. 
• For Patient/caregiver CGI-I score at treatment week 10, the ANCOVA model will be 
used with Patient/caregiver CGI-S study baseline as a covariate, treatment sequence, 
treatment group, period as fixed effects, and a random effect for subject within the 
sequence. 
• After study unblinding, the normality assumption of ANCOVA model will be examined 
by using the Wilk-Shapiro test on the residuals from the ANCOVA model. When there is 
strong evidence that the assumption is not met (p value for Wilk-Shapiro test < 0.05), 
Wilcoxon rank-sum test will be considered as the primary analysis to assess treatment 
difference. 
In addition, the following sensitivity analyses for total duration of movement disorder and 
12MWT distance will be performed: 
• The weighted ANCOVA based on total duration of movement disorder events during 
maintenance period will be performed based on Per Protocol Set. The mean duration of 
movement disorder events during maintenance period will be summarized. 
• In case there is missing data in 12MWT distance, the following ordered procedure of 
missing data imputation will be considered: if the subject is missing post-baseline data at 
treatment week 10, impute the corresponding period baseline. If the subject is missing the 
second period baseline, impute the study baseline as the period baseline for the second 
period. If the subject is missing study baseline but has compete second period data, then 
only count the subjects for the second period 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 34 
Proprietary and Confidential 
And then the primary ANCOVA model based on the 12MWT distance will be performed. 
• Change from period baseline to treatment week 10 in the first 6MWT distance and 
percent predicted 6MWT distance will be analyzed by the ANCOVA model with period 
baseline as a covariate, treatment sequence, treatment group, period as fixed effects, and a 
random effect for subject within the sequence. 
For the rest of the secondary endpoints, change from period baseline to treatment week 10 in 
PROMIS domain scores and change from period baseline to treatment week 10 in CANTAB 
scores, the primary analysis are: 
• ANCOVA model with period baseline as a covariate, treatment sequence, treatment 
group, period as fixed effects, and a random effect for subject within the sequence will be 
used. 
• After study unblinding, the normality assumption of ANCOVA model will be examined 
by using the Wilk-Shapiro test on the residuals from the ANCOVA model. When the 
assumption is not met (p value for Wilk-Shapiro test < 0.05), Wilcoxon rank-sum test 
will be considered as the primary analysis to assess treatment difference. If any of the 
domains fails the normality check, the Wilcoxon rank-sum test will be considered as 
primary analysis for all domains. 
8.8.3 
Analyses of Exploratory Efficacy Endpoints 
An ANCOVA model with period baseline as a covariate, treatment sequence, treatment 
group, period as fixed effects, and a random effect for subject within the sequence, will be 
used to analyze change from period baseline to treatment week 10 in performance score and 
change from period baseline to treatment week 10 in satisfaction score as assessed by 
COPM.  
An ANCOVA model with study baseline as a covariate, treatment sequence, treatment group, 
period as fixed effects, and a random effect for subject within the sequence, will be used to 
analyze the following other efficacy endpoints: 
• Physician CGI-I score at treatment week 10, the Physician CGI-S study baseline will be 
used as an explanatory variable 
• Physician CGI-S score at treatment week 10, the Physician CGI-S period baseline will be 
used as an explanatory variable 
• Change from study baseline to treatment week 10 in mean daytime activity, mean 
nighttime activity, and percent time in moderate or higher intensity activity as measured 
by a wrist-worn actigraphy device at select study sites where feasible  
Frequency, mean duration and total duration of disabling paroxysmal movement disorder 
events over time throughout the three-year OLE period will be summarized. Change from 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 35 
Proprietary and Confidential 
study baseline in percentage of movement disorder free days during the three-year OLE 
period will also be summarized. 
Efficacy Endpoints during the three-year OLE period including 12MWT, Patient/caregiver 
CGI-I, CANTAB, Physician CGI-I, Physician CGI-S, performance score and satisfaction 
score as assessed by COPM, PROMIS scores (domain scores) will be summarized and study 
baseline will be used. 
8.9 
Safety Analyses 
All safety analyses will be performed using the Safety Analysis Set. Safety parameters will 
include AEs, clinical laboratory parameters, vital signs, ECG parameters, and other safety 
parameters. No statistical comparisons will be performed. 
8.9.1 
Adverse Events 
Adverse events will be coded by SOC and PT using the Medical Dictionary for Regulatory 
Activities (MedDRA). AEs during Run-In period will be summarized. 
A treatment emergent adverse event (TEAE) will be considered and assigned to the treatment 
group (UX007 or Placebo) if the AE (classified by preferred term) start date occurs or 
worsens in severity on or after the first dose of study drug in the corresponding treatment 
period and before the first dose of study drug in the next treatment period. For example, an 
AE will be assigned to the treatment in Treatment Period I if it occurred during the wash out 
period. An AE that occurs within 30 days after the last dose of study drug in the last 
treatment period will be assigned to the last treatment period.  
The incidence of subjects reporting TEAEs in each treatment and treatment sequence will be 
tabulated by SOC and PT; by SOC, PT, and severity; and by SOC, PT, and relationship to 
study drug. If more than one event occurs with the same preferred term for the same subject, 
the subject will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarizations by severity and by relationship to the study drug. 
The incidence of subjects reporting TEAEs by treatment and treatment period will also be 
summarized by SOC and PT for each of the following categories: 
• All TEAEs 
• Treatment related TEAEs 
• Grade 3 or 4 TEAEs   
• Serious TEAEs 
• Serious and related TEAEs 
• TEAEs leading to study discontinuation 
• TEAEs leading to treatment discontinuation 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 36 
Proprietary and Confidential 
• TEAEs leading to death 
Exposure adjusted TEAE incidence is defined as total number of occurrences of an event 
summed across all subjects by treatment divided by the total exposure duration. A TEAE 
which occurred during the wash-out period will be considered and counted into the first 
treatment period. Exposure adjusted TEAE incidence will be summarize by treatment, and 
period.  
Detailed listings for all AEs, TEAEs, serious TEAEs, AEs leading to study/treatment 
discontinuation, and death will also be generated. 
8.9.2 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values (in SI units) and changes from study 
baseline values at each assessment time point will be presented by treatment sequence for 
clinical laboratory parameters specified in the protocol. Change from period baseline by 
treatment and treatment week during DB period will also be presented. 
The clinical laboratory parameters include the following: 
• Chemistry: Alanine aminotransferase (ALT), Alkaline phosphatase, Aspartate 
aminotransferase (AST), Bilirubin (total), Blood urea nitrogen (BUN), Calcium, 
Chloride, Serum creatinine, Gamma-glutamyl transpeptidase (GGT), Serum glucose, 
Potassium, Protein (albumin and total), Sodium, Creatine Kinase 
• Hematology: Hematocrit, Hemoglobin, Platelet count, Red blood cell (RBC) count, 
White blood cell (WBC) count 
• Urinalysis: Appearance, Color, pH, Specific gravity, Ketones, Protein, Glucose, 
Pregnancy test (if applicable) 
• Ketosis Detection: Betahydroxybutyrate (BHB) 
• Lipid Profile: Low-density lipoprotein (LDL), High-density lipoprotein (HDL), 
Triglycerides, Total cholesterol 
The frequency and percentage of subjects who experience abnormal clinical laboratory 
results (i.e. outside of reference ranges) and/or clinically significant abnormalities 
(as determined by the Investigator) after study drug administration will be presented for each 
clinical laboratory measurement by treatment sequence and period. 
Hy’s Law criteria will be applied against test results. Subjects with serum total bilirubin  
>2 × ULN and alanine aminotransferase (ALT) or aspartate aminotransferase  
(AST) >3 × ULN will be considered positive for Hy’s law status. Shift tables will be 
produced by treatment sequence: 
• Hy’s Law negative at study baseline, remaining Hy’s Law negative throughout the DB 
treatment period 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 37 
Proprietary and Confidential 
• Hy’s Law negative at study baseline, becoming Hy’s Law positive at any point during the 
DB treatment period 
• Hy’s Law positive at study baseline and Hy’s Law negative throughout the DB treatment 
period 
• Hy’s Law positive at study baseline and Hy’s Law positive at any point during the DB 
treatment period 
• Hy’s Law negative at study baseline, remaining Hy’s Law negative throughout the study 
• Hy’s Law negative at study baseline, becoming Hy’s Law positive at any point during the 
study 
• Hy’s Law positive at study baseline and Hy’s Law negative throughout the study 
• Hy’s Law positive at study baseline and Hy’s Law positive at any point during the study 
A data listing of all subjects who are Hy’s Law positive will be produced. 
8.9.3 
Vital Signs 
Descriptive statistics for observed values and changes from study baseline values at each 
visit will be presented by treatment sequence and period for the following vital signs: 
• Temperature (°C) 
• Respiration Rate (breaths/min) 
• Heart Rate (beats/min) 
• Systolic Blood Pressure (mmHg) 
• Diastolic Blood Pressure (mmHg) 
• Weight (kg) 
• Head circumference (cm) 
8.9.4 
Electrocardiogram 
The results from ECG (normal and abnormal) will be summarized. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 38 
Proprietary and Confidential 
8.9.5 
Suicidal Ideation and Behavior 
The number and percentage of subjects with suicidal ideation or suicidal behavior will be 
presented at study baseline and post-baseline by category, treatment sequence and period. 
If more than one suicidal ideation or suicidal behavior was reported for the same period/visit, 
the one with greatest severity will be used for the same period/visit in the summary.  
8.10 PK Analyses 
Plasma levels of UX007 metabolites will be summarized using descriptive statistics by study 
visit and treatment group. Standard non-compartmental analysis will be conducted to 
estimate PK parameters (such as Cmax, Tmax, AUC) for UX007 metabolites of importance 
when there are sufficient data points. Descriptive statistics will be provided for PK 
parameters for UX007 metabolites. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 39 
Proprietary and Confidential 
9 REFERENCES 
Broderick, JE, DeWitt, EM, Rothrock, N, Crane, PK, and Forrest, CB. 2013. "Advances in 
Patient-Reported Outcomes: The NIH PROMIS Measures." EGEMS (Wash DC) 1 (1):1015. 
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 
Pediatr 150 (4):395-9. 
Gibbons, WJ, Fruchter, N, Sloan, S, and Levy, RD. 2001. "Reference values for a multiple 
repetition 6-minute walk test in healthy adults older than 20 years." J Cardiopulm.Rehabil. 
21 (2):87-93. 
Gras, D, Roze, E, Caillet, S, Meneret, A, Doummar, D, Billette de Villemeur, T, Vidailhet, 
M, and Mochel, F. 2014. "GLUT1 deficiency syndrome: an update." Rev Neurol (Paris) 170 
(2):91-9. 
Klepper, J, and Leiendecker, B. 2007. "GLUT1 deficiency syndrome--2007 update." Dev 
Med Child Neurol 49 (9):707-16. 
Leen, WG, Klepper, J, Verbeek, MM, Leferink, M, Hofste, T, van Engelen, BG, Wevers, 
RA, Arthur, T, Bahi-Buisson, N, Ballhausen, D, Bekhof, J, van Bogaert, P, Carrilho, I, 
Chabrol, B, Champion, MP, Coldwell, J, Clayton, P, Donner, E, Evangeliou, A, Ebinger, F, 
Farrell, K, Forsyth, RJ, de Goede, CG, Gross, S, Grunewald, S, Holthausen, H, Jayawant, S, 
Lachlan, K, Laugel, V, Leppig, K, Lim, MJ, Mancini, G, Marina, AD, Martorell, L, 
McMenamin, J, Meuwissen, ME, Mundy, H, Nilsson, NO, Panzer, A, Poll-The, BT, 
Rauscher, C, Rouselle, CM, Sandvig, I, Scheffner, T, Sheridan, E, Simpson, N, Sykora, P, 
Tomlinson, R, Trounce, J, Webb, D, Weschke, B, Scheffer, H, and Willemsen, MA. 2010. 
"Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of 
a treatable disorder." Brain 133 (Pt 3):655-70. 
Mochel, F, Hainque, E, Gras, D, Adanyeguh, I, Caillet, S, Rinaldi, D, Heron, B, Kaphan, E, 
Hogrel, J-Y, Servais, L, and Roze, E. 2015. "Triheptanoin dramatically reduces the frequency 
of paroxysmal Movement Disorders in GLUT1 deficiency." Mov Disord 30 (Suppl. 1):S568-
S633. 
NIH. 2015. PROMIS  2015 [cited January 2015]. Available from 
http://www.nihpromis.org/default.aspx#6. 
Nornadiah, MH. 2011. "Yap Bee Wah Power Comparisons of Shapiro-Wilk, Kolmogorov-
Smirnov Lilliefors and Anderson-Darling Tests." Journal of Statistical Modeling and 
Analytics 2 (1):21-33. 
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. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 40 
Proprietary and Confidential 
Shapiro, SS, and Wilk, MB. 1965. "An Analysis of Variance Test for Normality (Complete 
Samples)." Biometrika (52):591-611. 
Yap, BW, and Sim, CH. 2011. "Comparisons of various types of normality tests." Journal of 
Statistical Computation and Simulation 81 (12):2141-2155. 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 41 
Proprietary and Confidential 
10 APPENDICES 
10.1 Appendix A. Efficacy Endpoint Summary Table 
Endpoint 
Approach 
Statistical 
Method 
Analysis 
Population 
Missing 
Data 
Imputation 
(Yes/No) 
Primary Endpoint 
Frequency of disabling 
paroxysmal movement disorder 
events during maintenance 
period 
P 
Weighted ANCOVA 
FAS 
No 
S 
Wilcoxon Rank-Sum 
Test 
FAS 
No 
Weighted ANCOVA of 
the percent change from 
study baseline in the 
frequency of movement 
disorder during the 
maintenance period 
FAS 
No 
Weighted ANCOVA 
with Per Protocol Set 
FAS 
No 
Weighted ANCOVA 
(excluding back-up paper 
diary data) 
FAS 
No 
Weighted ANCOVA of 
the change from study 
baseline to maintenance 
phase in percentage of 
movement disorder free 
days 
FAS 
No 
ANCOVA 
FAS 
Yes 
Weighted ANCOVA 
with subgroups by prior 
KD/Modified Atkins 
Diet 
FAS 
No 
Secondary Endpoints 
Change from period baseline to 
treatment week 10 in 12MWT 
distance 
P 
ANCOVA 
FAS 
No 
S 
ANCOVA 
FAS 
Yes 
ANCOVA of change 
from period baseline to 
treatment week 10 in 
6MWT distance and 
percent predicted 6MWT 
distance 
FAS 
No 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 42 
Proprietary and Confidential 
Endpoint 
Approach 
Statistical 
Method 
Analysis 
Population 
Missing 
Data 
Imputation 
(Yes/No) 
ANCOVA of change 
from period baseline to 
treatment week 10 in 
percent predicted 6MWT 
distance 
FAS 
No 
Change from period baseline to 
treatment week 10 in PROMIS 
scores 
P 
ANCOVA 
FAS 
No 
Patient/caregiver CGI-I score at 
treatment week 10 
P 
ANCOVA 
FAS 
No 
Total duration of disabling 
paroxysmal movement disorder 
events during maintenance 
period 
P 
Weighted ANCOVA 
FAS 
No 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Page 43 
Proprietary and Confidential 
Endpoint 
Approach 
Statistical 
Method 
Analysis 
Population 
Missing 
Data 
Imputation 
(Yes/No) 
Change from period baseline to 
treatment week 10 in CANTAB 
scores 
P 
ANCOVA 
FAS 
No 
Other Efficacy Endpoints 
Percent change from study 
baseline in frequency of 
disabling paroxysmal movement 
disorder events over time 
P 
Descriptive Statistics 
FAS 
No 
Percent change from study 
baseline in total duration of 
disabling paroxysmal movement 
disorder events over time 
P 
Descriptive Statistics 
FAS 
No 
Physician CGI-S score at 
treatment week 10 
P 
ANCOVA 
FAS 
No 
Physician CGI-I score at 
treatment week 10 
P 
ANCOVA 
FAS 
No 
Change from study baseline to 
treatment week 10 in mean 
daytime activity, mean nighttime 
activity, and percent time in 
moderate or higher intensity 
activity 
P 
ANCOVA 
FAS 
No 
Change from period baseline to 
treatment week 10 in COPM 
performance and satisfaction 
scores 
P 
ANCOVA 
FAS 
No 
FAS = Full Analysis Set; P = Primary; S = Sensitivity. 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 44 
10.2 Appendix B. Schedule of Events (Screening; Run-in; Period I; Washout; and Period II) 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 45 
 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 46 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 47 
 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 48 
10.3 Appendix C. Schedule of Events (Extension and Safety Follow-up) 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 49 
 


Study Number:  UX007G-CL301  
Statistical Analysis Plan 
05 Sep 2018, Version 2.0 
 
 
Proprietary and Confidential 
Page 50