Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)

• Sponsor: Ultragenyx Pharmaceutical Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01993186
• Collaborator: (none)
• Enrollment: 36
• Locations: 14
• Arms: 2
• Actual Duration (Months): 42.7
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)	Drug: UX007; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Study to Assess the Safety and Efficacy of UX007 in Subjects With Glucose Transporter Type 1 Deficiency Syndrome
• Actual Study Start Date: Feb 28, 2014
• Actual Primary Completion Date: Sep 20, 2017
• Actual Study Completion Date: Sep 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: UX007 Participants randomized to receive UX007 enter a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continue treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Drug: UX007; oral liquid; Other Names: C7 oil triheptanoin glycerol triheptanoate glycerol trienanthate 1, 2, 3-trienanthoylglycerol trienanthin 2,3-di(heptanoyloxy)propyl heptanoate
Placebo Comparator: Placebo Participants randomized to receive placebo enter a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continue treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Drug: Placebo; oral liquid

Outcome Measures

Primary Outcome Measures

1. Percent Reduction From Baseline to Week 8 in Frequency of Total Seizures (Normalized to a 4-Week Rate) [Baseline, Week 8]

   Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.

2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Discontinuations Due to TEAEs During the Placebo-Controlled Period [Weeks 0 to 8]

   An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.

3. Number of Participants With TEAEs, Serious TEAEs and Discontinuations Due to TEAEs During the Extension Period [Weeks 9 to 52 plus 30 days]

   An AE was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.

Secondary Outcome Measures

1. Percent Reduction From Baseline to Week 8 in Frequency of Observable Seizures (Normalized to a 4-Week Rate) [Baseline, Week 8]

   Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. A negative value indicates an increase in frequency.

2. Percent Reduction From Baseline to Week 8 in Frequency of Absence Seizures (Normalized to a 4-Week Rate) [Baseline, Week 8]

   Reduction from baseline to Week 8 in frequency of absence seizures measured overnight by EEG. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.

3. Percentage of Participants With at Least a 50% Reduction From Baseline to Week 8 in Frequency of Total Seizures [Baseline, Week 8]

   Seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of total seizures. Includes observable generalized and partial-onset seizures measured for 6 weeks by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).

4. Percentage of Participants With at Least 50% Reduction From Baseline to Week 8 in Frequency of Observable Seizures [Baseline, Week 8]

   Observable seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of observable seizures. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological.

5. Percentage of Participants With at Least 50% Reduction From Baseline to Week 8 in Frequency of Absence Seizures [Baseline, Week 8]

   Absence seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of absence seizures. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).

6. Change From Baseline to Week 8 in Cambridge Neuropsychological Test Automated Battery (CANTAB), Reaction Time (RTI) Scores, Generalized Estimating Equation (GEE) [Baseline, Week 8]

   CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. RTI Simple choice reaction time standard deviation (RTISRTSD) assesses the cognitive domain of attention, with scores on a continuous range from 0 to 5000; lower scores indicate better function. RTI median simple choice reaction time (RTIMDSRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. RTI median 5-choice reaction time (RTIMDFRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. GEE statistical model.

7. Change From Baseline to Week 8 in CANTAB, Paired Associates Learning (PAL) Scores, GEE [Baseline, Week 8]

   CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. PAL total errors adjusted (PALTEA) assesses the cognitive domain of episodic memory/new learning, with scores on a discrete, ordinal scale from 0 to 137; lower scores indicate better function. PAL first trial memory score (PALFTMS) assesses the cognitive domain of episodic memory, with scores on a discrete, ordinal scale from 0 to 27; higher scores indicate better function. GEE statistical model.

8. Change From Baseline to Week 8 in CANTAB, Spatial Span (SSP) Span Length Scores, GEE [Baseline, Week 8]

   CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SSP Span Length (SSPSLF) assesses the cognitive domain of sequential memory, with scores on a discrete, ordinal scale from 2 to 9; higher scores indicate better function. GEE statistical model.

9. Change From Baseline to Week 8 in CANTAB, Spatial Working Memory (SWM) Scores, GEE [Baseline, Week 8]

   CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SWM between errors (SWMBE48) assesses the cognitive domain of working memory, with scores on a discrete, ordinal scale from 0 to 360; lower scores indicate better function. SWM strategy (SWMS68) assesses the cognitive domain of executive function/strategy, with scores on a discrete, ordinal scale from 4 to 28; lower scores indicate better function. GEE statistical model.

10. Change From Baseline to Week 8 in Distance Traveled (in Meters) as Measured by 6-Minute Walk Test (6MWT) [Baseline, Week 8]

    Participants were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded.

11. Change From Baseline to Week 8 in Distance Traveled (in Percent Predicted) as Measured by 6MWT [Baseline, Week 8]

    Participants were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. The percent of predicted normal distance walked was determined based on published normative data.

12. Time (in Minutes) to Onset of Paroxysmal Exertional Dyskinesia (PED) as Measured During 6MWT Over Time Through Week 8 [Baseline, Week 4, Week 8]

    For the 6MWT, subjects were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. PED occurring during the 6MWT was assessed. (PED is characterized by transient abnormal, involuntary movements primarily affecting the legs and feet, and typically precipitated by prolonged exertion.)

13. Change From Baseline to Week 8 in Gross Motor Function Measure-88 (GMFM-88) Total Score [Baseline, Week 8]

    The GMFM-88 is a standardized observational measure of abilities that includes the following 5 domains: lying/rolling, sitting, crawling/kneeling, standing, and walking/running/jumping. The GMFM-88 scores include the following: Lying & Rolling Score, Range 0-100%, higher is better Sitting Score, Range 0-100%, higher is better Crawling & Kneeling Score, Range 0-100%, higher is better Standing Score, Range 0-100%, higher is better Walking, Running & Jumping Score, Range 0-100%, higher is better Total Score = (Sum of 5 Above Scores) / 5, Range 0-100%, higher is better.

14. Percent Reduction From Baseline Over Time in Frequency of Total Seizures (Normalized to a 4-Week Rate) [Baseline, Week 26, Week 31]

    Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.

15. Percent Reduction From Baseline Over Time in Frequency of Observable Seizures (Normalized to a 4-Week Rate) [Baseline, Week 26, Week 31, Week 36, Week 52]

    Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. A negative value indicates an increase in frequency.

16. Percent Reduction From Baseline Over Time in Frequency of Absence Seizures (Normalized to a 4-week Rate) [Baseline, Week 26, Week 31]

    Reduction from baseline to Week 8 in frequency of absence seizures measured overnight by EEG. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of Glut1 DS confirmed by SLC2A1 mutation

2. Males and females at least 1 of age at the time of informed consent

3. Average of at least 2 observable seizures (generalized or partial-onset [simple partial motor, complex partial, absence, or secondarily generalized seizures) in 4 weeks over the last 24 weeks, by subject or caregiver report

4. At least 2 observable seizures (generalized or partial-onset [simple partial motor, complex partial, or secondarily generalized seizures) in 4 weeks during the Baseline Period, with no 3-week seizure-free period during the Baseline Period OR absence seizures documented on Screening electroencephalogram (EEG)

5. Continuing to have seizures despite a prior or current use of at least 1 antiepileptic drug (AED)

6. Allowed to be on up to 3 concomitant AEDs that must have been stable in dose at least 2 weeks prior to the beginning of screening and anticipated to remain stable in dose through the end of the 8-week, placebo-controlled Treatment Period

7. Not on, or not fully compliant with a prescribed diet plan (e.g. KD)

8. Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening

9. Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures

10. Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, comply with accurate completion of the seizures diary, and likely to complete the 8 week, placebo-controlled, Treatment Period

11. Females of childbearing potential must have a negative pregnancy test at Screening, be willing to use an acceptable method of contraception, and have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have not reached menarche, had total hysterectomy, have been in menopause for at least two years, or have had tubal ligation at least one year prior to Screening.

Exclusion Criteria:

1. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeding 3 times the upper limit of normal at Screening

2. Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of the investigator, places the subject at increased risk for adverse effects

3. Prior use of triheptanoin within 30 days prior to Screening

4. History of, or current suicidal ideation, behavior and/or attempts

5. Pregnant and/or breastfeeding an infant at Screening

6. Participants unwilling or unable to discontinue use of a prohibited medication or other substance that may confound study objectives

7. Use of any investigational product (drug or supplement, including medium chain triglyceride [MCT] oil) within 30 days prior to Screening, or at any time during the study

8. Has a condition of such severity and acuity, in the opinion of the investigator, that it warrants immediate surgical intervention or other treatment

9. Has a concurrent disease or condition, or laboratory abnormality that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study, or would interfere with study participation or introduces additional safety concerns (e.g., diabetes mellitus, other concurrent neurological or psychiatric disorders)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Colorado - University of Colorado, Denver, School of Medicine	Aurora	Colorado	United States	80045
2	Miami Children's Research Institute	Miami	Florida	United States	33155
3	Neurology & Epilepsy Research Center	Orlando	Florida	United States	32819
4	Columbia University - Department of Neurology	New York	New York	United States	10032
5	Columbia University Medical Center	New York	New York	United States	10032
6	Cook Children's Hospital	Fort Worth	Texas	United States	76104
7	University of Texas Neurometabolic Clinic	Houston	Texas	United States	77030
8	Seattle Children's Hospital	Seattle	Washington	United States	98105
9	Melbourne Brain Centre	Heidelberg	Victoria	Australia	3084
10	Service de Neurologie Pédiatrique et des Maladies Métaboliques - INSERM U1141 Hôpital Robert Debré - APHP	Paris	Cedex 19	France	75935
11	Sheba University Medical Center	Tel Aviv		Israel
12	Unita' Operativa Neurologia Pediatrica e Malattie Muscolari Istituto "Giannina Gaslini"	Genova		Italy
13	Hospital Sant Joan de Deu	Barcelona		Spain
14	Newcastle University	Newcastle Upon Tyne		United Kingdom

Sponsors and Collaborators

• Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Study Documents (Full-Text)

• Study Protocol - Nov 30, 2015
• Statistical Analysis Plan - Jan 11, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT01993186
• Other Study ID Numbers: UX007G-CL201
• First Posted: Nov 25, 2013
• Last Update Posted: Jun 19, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by Ultragenyx Pharmaceutical Inc: Glucose Transporter Type 1 Deficiency Syndrome Glut1
• Additional relevant MeSH terms: Carbohydrate Metabolism, Inborn Errors; Syndrome; Glycerol

Study Results

Participant Flow

Pre-assignment Detail	Beginning with the Screening visit, participants recorded seizure frequency during a 6-week Baseline Period. If the participant did not meet the seizure count criteria, the participant was considered a screen failure and was not randomized.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Period Title: Double-Blind Placebo-Controlled Period
STARTED	25	11
COMPLETED	23	11
NOT COMPLETED	2	0
Period Title: Double-Blind Placebo-Controlled Period
STARTED	23	11
COMPLETED	16	5
NOT COMPLETED	7	6

Baseline Characteristics

Arm/Group Title	UX007	Placebo	Total
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Total of all reporting groups
Overall Participants	25	11	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.86 (5.107)	15.24 (13.795)	14.28 (8.525)
Age, Customized (Count of Participants)
2 years to < 12 years	8 32%	7 63.6%	15 41.7%
12 years to < 18 years	12 48%	1 9.1%	13 36.1%
18 years to < 65 years	5 20%	3 27.3%	8 22.2%
Sex: Female, Male (Count of Participants)
Female	15 60%	7 63.6%	22 61.1%
Male	10 40%	4 36.4%	14 38.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%	1 9.1%	3 8.3%
Not Hispanic or Latino	21 84%	9 81.8%	30 83.3%
Unknown or Not Reported	2 8%	1 9.1%	3 8.3%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 9.1%	1 2.8%
Asian	1 4%	0 0%	1 2.8%
Black or African American	0 0%	1 9.1%	1 2.8%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	0 0%
White	23 92%	9 81.8%	32 88.9%
Other (Not Specified)	1 4%	0 0%	1 2.8%
Total Seizure Frequency Per 4 Weeks (seizures per 4 weeks) [Median (Full Range) ]
Median (Full Range) [seizures per 4 weeks]	96.6	2.1	35.7

Outcome Measures

1. Primary Outcome

Title	Percent Reduction From Baseline to Week 8 in Frequency of Total Seizures (Normalized to a 4-Week Rate)
Description	Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
Median (Full Range) [percent reduction of seizures per 4 wks]	12.6	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% confidence interval (CI) and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5812
	Comments
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate
	Estimated Value	13.45
	Confidence Interval	(2-Sided) 90%; -38.63 to 80.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Discontinuations Due to TEAEs During the Placebo-Controlled Period
Description	An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.
Time Frame	Weeks 0 to 8

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all participants who received at least one dose of investigational product.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
TEAE	22 88%	9 81.8%
Serious TEAE	1 4%	0 0%
Grade 3 or 4 TEAE	2 8%	0 0%
TEAE Leading to Study Discontinuation	0 0%	0 0%
TEAE Leading to Death	0 0%	0 0%
Gastrointestinal TEAE	18 72%	5 45.5%
Related TEAE	18 72%	5 45.5%
Related Serious TEAE	0 0%	0 0%
Related Gastrointestinal TEAE	17 68%	4 36.4%
UX007 Emergent AE	22 88%	0 0%
Serious UX007 Emergent AE	1 4%	0 0%

3. Primary Outcome

Title	Number of Participants With TEAEs, Serious TEAEs and Discontinuations Due to TEAEs During the Extension Period
Description	An AE was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.
Time Frame	Weeks 9 to 52 plus 30 days

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all participants who received at least one dose of investigational product.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	23	11
TEAE	21 84%	11 100%
Serious TEAE	2 8%	0 0%
Grade 3 or 4 TEAE	1 4%	0 0%
TEAE Leading to Study Discontinuation	1 4%	0 0%
TEAE Leading to Death	0 0%	0 0%
Gastrointestinal TEAE	15 60%	10 90.9%
Related TEAE	19 76%	8 72.7%
Related Serious TEAE	0 0%	0 0%
Related Gastrointestinal TEAE	13 52%	8 72.7%
UX007 Emergent AE	21 84%	11 100%
Serious UX007 Emergent AE	2 8%	0 0%

4. Secondary Outcome

Title	Percent Reduction From Baseline to Week 8 in Frequency of Observable Seizures (Normalized to a 4-Week Rate)
Description	Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with observable seizures.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	17	10
Median (Full Range) [percent reduction in seizures per 4 wks]	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% CI and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8197
	Comments
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate
	Estimated Value	0
	Confidence Interval	(2-Sided) 90%; -51.23 to 84.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percent Reduction From Baseline to Week 8 in Frequency of Absence Seizures (Normalized to a 4-Week Rate)
Description	Reduction from baseline to Week 8 in frequency of absence seizures measured overnight by EEG. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with absence seizures.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	17	6
Median (Full Range) [percent reduction in seizures per 4 wks]	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	Non-parametric post-hoc analysis: Hodges-Lehmann estimate of the location shift with 90% CI and Wilcoxon Rank Sum test p-value, based on Wilcoxon rank-sum test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7276
	Comments
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate
	Estimated Value	0
	Confidence Interval	(2-Sided) 90%; 0 to 37.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With at Least a 50% Reduction From Baseline to Week 8 in Frequency of Total Seizures
Description	Seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of total seizures. Includes observable generalized and partial-onset seizures measured for 6 weeks by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
Number [percentage of participants]	20.0 80%	36.4 330.9%

7. Secondary Outcome

Title	Percentage of Participants With at Least 50% Reduction From Baseline to Week 8 in Frequency of Observable Seizures
Description	Observable seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of observable seizures. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with observable seizures.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	17	10
Number [percentage of participants]	5.9 23.6%	30.0 272.7%

8. Secondary Outcome

Title	Percentage of Participants With at Least 50% Reduction From Baseline to Week 8 in Frequency of Absence Seizures
Description	Absence seizure response, defined as the percentage of participants with at least 50% reduction from randomization to Week 8 in frequency of absence seizures. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec).
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with absence seizures.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	17	6
Number [percentage of participants]	23.5 94%	16.7 151.8%

9. Secondary Outcome

Title	Change From Baseline to Week 8 in Cambridge Neuropsychological Test Automated Battery (CANTAB), Reaction Time (RTI) Scores, Generalized Estimating Equation (GEE)
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. RTI Simple choice reaction time standard deviation (RTISRTSD) assesses the cognitive domain of attention, with scores on a continuous range from 0 to 5000; lower scores indicate better function. RTI median simple choice reaction time (RTIMDSRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. RTI median 5-choice reaction time (RTIMDFRT) assesses the cognitive domain of reaction time, with scores on a continuous range from 100 to 5100; lower scores indicate better function. GEE statistical model.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set, CANTAB: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
RTISRTSD	41.698 (42.3539)	44.082 (53.3552)
RTIMDSRT	15.512 (15.9204)	-48.157 (48.8781)
RTIMDFRT	-14.723 (14.1862)	49.112 (58.4722)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	RTISRTSD
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.384
	Confidence Interval	(2-Sided) 90%; -114.44 to 109.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 68.1231
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	RTIMDSRT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8849
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	63.669
	Confidence Interval	(2-Sided) 90%; -23.6 to 150.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 53.0537
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	RTIMDFRT
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1463
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-63.835
	Confidence Interval	(2-Sided) 90%; -163.59 to 35.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 60.6496
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline to Week 8 in CANTAB, Paired Associates Learning (PAL) Scores, GEE
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. PAL total errors adjusted (PALTEA) assesses the cognitive domain of episodic memory/new learning, with scores on a discrete, ordinal scale from 0 to 137; lower scores indicate better function. PAL first trial memory score (PALFTMS) assesses the cognitive domain of episodic memory, with scores on a discrete, ordinal scale from 0 to 27; higher scores indicate better function. GEE statistical model.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set, CANTAB: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
PALTEA	-10.082 (2.4784)	-27.849 (11.3061)
PALFTMS	2.574 (0.6833)	3.105 (2.0766)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	PALTEA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9378
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	17.768
	Confidence Interval	(2-Sided) 90%; -1.26 to 36.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.5659
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	PALFTMS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5959
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.531
	Confidence Interval	(2-Sided) 90%; -4.13 to 3.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.1853
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline to Week 8 in CANTAB, Spatial Span (SSP) Span Length Scores, GEE
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SSP Span Length (SSPSLF) assesses the cognitive domain of sequential memory, with scores on a discrete, ordinal scale from 2 to 9; higher scores indicate better function. GEE statistical model.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set, CANTAB: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
Least Squares Mean (Standard Error) [score on a scale]	0.019 (0.2387)	-0.041 (0.4246)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	SSPSLF
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4522
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 90%; -0.76 to 0.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4988
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline to Week 8 in CANTAB, Spatial Working Memory (SWM) Scores, GEE
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SWM between errors (SWMBE48) assesses the cognitive domain of working memory, with scores on a discrete, ordinal scale from 0 to 360; lower scores indicate better function. SWM strategy (SWMS68) assesses the cognitive domain of executive function/strategy, with scores on a discrete, ordinal scale from 4 to 28; lower scores indicate better function. GEE statistical model.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set, CANTAB: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) CANTAB assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	25	11
SWMBE48	1.003 (1.4582)	2.240 (1.8036)
SWMS68	0.060 (0.4794)	0.022 (0.4279)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	SWMBE48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3017
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.237
	Confidence Interval	(2-Sided) 90%; -5.15 to 2.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.381
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	SWMS68
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5235
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline CANTAB score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.038
	Confidence Interval	(2-Sided) 90%; -1.03 to 1.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.6495
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline to Week 8 in Distance Traveled (in Meters) as Measured by 6-Minute Walk Test (6MWT)
Description	Participants were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set - 6MWT: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) 6MWT assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	23	11
Least Squares Mean (Standard Error) [meters]	-10.336 (14.8614)	-3.439 (16.1506)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	6MWT distance traveled
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6205
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline value, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-6.897
	Confidence Interval	(2-Sided) 90%; -43.874 to 30.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.4806
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline to Week 8 in Distance Traveled (in Percent Predicted) as Measured by 6MWT
Description	Participants were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. The percent of predicted normal distance walked was determined based on published normative data.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set - 6MWT: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) 6MWT assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	23	11
Least Squares Mean (Standard Error) [percent of predicted distance]	-1.338 (2.4752)	0.016 (2.6398)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	6MWT distance traveled (percent predicted)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6476
	Comments	One-sided p-value. Additional model covariates include the corresponding baseline value, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.354
	Confidence Interval	(2-Sided) 90%; -7.236 to 4.527
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.5759
	Estimation Comments

15. Secondary Outcome

Title	Time (in Minutes) to Onset of Paroxysmal Exertional Dyskinesia (PED) as Measured During 6MWT Over Time Through Week 8
Description	For the 6MWT, subjects were instructed to walk the length of a pre-measured 20-30 meter course in a hallway for 6 consecutive minutes. The total distance walked (meters) in a 6 minute period was recorded. PED occurring during the 6MWT was assessed. (PED is characterized by transient abnormal, involuntary movements primarily affecting the legs and feet, and typically precipitated by prolonged exertion.)
Time Frame	Baseline, Week 4, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set - 6MWT: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) 6MWT assessment performed. Participants with at least 1 PED.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	3	0
Week 4	4.7 (4.73)
Week 8	1.8 (1.30)

16. Secondary Outcome

Title	Change From Baseline to Week 8 in Gross Motor Function Measure-88 (GMFM-88) Total Score
Description	The GMFM-88 is a standardized observational measure of abilities that includes the following 5 domains: lying/rolling, sitting, crawling/kneeling, standing, and walking/running/jumping. The GMFM-88 scores include the following: Lying & Rolling Score, Range 0-100%, higher is better Sitting Score, Range 0-100%, higher is better Crawling & Kneeling Score, Range 0-100%, higher is better Standing Score, Range 0-100%, higher is better Walking, Running & Jumping Score, Range 0-100%, higher is better Total Score = (Sum of 5 Above Scores) / 5, Range 0-100%, higher is better.
Time Frame	Baseline, Week 8

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set - GMFM-88: Subset of participants taking UX007 during the treatment period in the efficacy analysis set who had a baseline and at least 1 post baseline (Week 4 or Week 8) GMFM-88 assessment performed.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	21	11
Least Squares Mean (Standard Error) [score on a scale]	3.209 (2.3669)	1.642 (2.6690)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX007, Placebo
	Comments	GMFM-88 UX007-Placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3435
	Comments	One-sided p-value. Additional model covariates include baseline GMFM-88 total score, visit and the interaction between visit and treatment.
	Method	GEE model
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.568
	Confidence Interval	(2-Sided) 90%; -4.83 to 7.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.8899
	Estimation Comments

17. Secondary Outcome

Title	Percent Reduction From Baseline Over Time in Frequency of Total Seizures (Normalized to a 4-Week Rate)
Description	Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 26, Week 31

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with an assessment at given time point.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	22	11
Week 26	7.8	0.0
Week 31	42.7	5.3

18. Secondary Outcome

Title	Percent Reduction From Baseline Over Time in Frequency of Observable Seizures (Normalized to a 4-Week Rate)
Description	Reduction from baseline over time in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 26, Week 31, Week 36, Week 52

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with observable seizures and an assessment at given time point.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	15	10
Week 26	0.0	-27.7
Week 31	23.6	0.0
Week 36	42.5	-49.8
Week 52	31.0	-10.3

19. Secondary Outcome

Title	Percent Reduction From Baseline Over Time in Frequency of Absence Seizures (Normalized to a 4-week Rate)
Description	Reduction from baseline to Week 8 in frequency of absence seizures measured overnight by EEG. Absence seizures from EEG include absence awake (>=10 sec), absence sleep (>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.
Time Frame	Baseline, Week 26, Week 31

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Set: all randomized participants who received at least one dose of investigational product. Participants with absence seizures and an assessment at given time point.

Arm/Group Title	UX007	Placebo
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).	Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period. Following completion of the Week 8 study visit, placebo participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
Measure Participants	14	4
Week 26	0.0	0.0
Week 31	0.0	0.0

Adverse Events

Time Frame	Placebo-controlled period from first dose of study drug through Week 8. Extension period: Week 9 up to Week 52 plus 30 days.
Arm/Group Title	Placebo Controlled Period / UX007		Placebo Controlled Period / Placebo		Extension Period / UX007
Arm/Group Description	Participants randomized to receive UX007 entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.		Participants randomized to receive placebo entered a 2-week dose titration period to achieve study drug treatment comprising up to 35% of total daily calories or to the maximum tolerated dose level and maintained at the 35% total daily calorie dose level for a 6-week treatment period.		Following completion of the Week 8 study visit, placebo and UX007 participants continued treatment with open-label UX007 at the 35% dose level for an additional 44 weeks (Weeks 8-52).
All Cause Mortality
	Placebo Controlled Period / UX007		Placebo Controlled Period / Placebo		Extension Period / UX007
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/11 (0%)		0/34 (0%)
Serious Adverse Events
	Placebo Controlled Period / UX007		Placebo Controlled Period / Placebo		Extension Period / UX007
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		0/11 (0%)		2/34 (5.9%)
Injury, poisoning and procedural complications
Subcutaneous Haematoma	0/25 (0%)		0/11 (0%)		1/34 (2.9%)
Nervous system disorders
Seizure	0/25 (0%)		0/11 (0%)		1/34 (2.9%)
Status Epilepticus	1/25 (4%)		0/11 (0%)		2/34 (5.9%)
Other (Not Including Serious) Adverse Events
	Placebo Controlled Period / UX007		Placebo Controlled Period / Placebo		Extension Period / UX007
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/25 (84%)		9/11 (81.8%)		31/34 (91.2%)
Gastrointestinal disorders
Abdominal Discomfort	2/25 (8%)		0/11 (0%)		0/34 (0%)
Abdominal Pain	7/25 (28%)		1/11 (9.1%)		3/34 (8.8%)
Abdominal Pain Upper	7/25 (28%)		0/11 (0%)		5/34 (14.7%)
Breath Odour	0/25 (0%)		0/11 (0%)		2/34 (5.9%)
Constipation	2/25 (8%)		0/11 (0%)		5/34 (14.7%)
Diarrhoea	9/25 (36%)		3/11 (27.3%)		18/34 (52.9%)
Flatulence	1/25 (4%)		1/11 (9.1%)		2/34 (5.9%)
Nausea	5/25 (20%)		0/11 (0%)		5/34 (14.7%)
Vomiting	11/25 (44%)		2/11 (18.2%)		15/34 (44.1%)
General disorders
Pyrexia	2/25 (8%)		0/11 (0%)		6/34 (17.6%)
Infections and infestations
Gastroenteritis Viral	1/25 (4%)		0/11 (0%)		2/34 (5.9%)
Otitis Media Acute	0/25 (0%)		1/11 (9.1%)		0/34 (0%)
Sinusitis	1/25 (4%)		0/11 (0%)		2/34 (5.9%)
Upper Respiratory Tract Infection	0/25 (0%)		2/11 (18.2%)		2/34 (5.9%)
Viral Upper Respiratory Tract Infection	3/25 (12%)		1/11 (9.1%)		6/34 (17.6%)
Injury, poisoning and procedural complications
Contusion	0/25 (0%)		1/11 (9.1%)		2/34 (5.9%)
Fall	0/25 (0%)		1/11 (9.1%)		2/34 (5.9%)
Head Injury	0/25 (0%)		1/11 (9.1%)		2/34 (5.9%)
Ligament Sprain	0/25 (0%)		1/11 (9.1%)		0/34 (0%)
Lip Injury	0/25 (0%)		1/11 (9.1%)		0/34 (0%)
Investigations
Weight Increased	3/25 (12%)		1/11 (9.1%)		1/34 (2.9%)
Metabolism and nutrition disorders
Decreased Appetite	1/25 (4%)		1/11 (9.1%)		5/34 (14.7%)
Musculoskeletal and connective tissue disorders
Back Pain	0/25 (0%)		1/11 (9.1%)		1/34 (2.9%)
Nervous system disorders
Clonic Convulsion	0/25 (0%)		1/11 (9.1%)		0/34 (0%)
Dizziness	2/25 (8%)		0/11 (0%)		1/34 (2.9%)
Headache	3/25 (12%)		0/11 (0%)		3/34 (8.8%)
Seizure	0/25 (0%)		0/11 (0%)		2/34 (5.9%)
Psychiatric disorders
Abnormal Behaviour	0/25 (0%)		0/11 (0%)		3/34 (8.8%)
Agitation	1/25 (4%)		0/11 (0%)		2/34 (5.9%)
Insomnia	0/25 (0%)		0/11 (0%)		2/34 (5.9%)
Reproductive system and breast disorders
Dysmenorrhoea	0/25 (0%)		0/11 (0%)		2/34 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	0/25 (0%)		0/11 (0%)		3/34 (8.8%)
Oropharyngeal Pain	0/25 (0%)		0/11 (0%)		2/34 (5.9%)
Skin and subcutaneous tissue disorders
Acne	2/25 (8%)		0/11 (0%)		0/34 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.