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)

• ClinicalTrials.gov Identifier: NCT02960217
• Recruitment Status: Terminated
• First Posted: November 9, 2016
• Results First Posted: April 24, 2020
• Last Update Posted: June 16, 2020
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
• Interventions: Drug: UX007; Drug: Placebo
• Enrollment: 44

Participant Flow

Recruitment Details
Pre-assignment Details	During a 6-week Run-in Period, participants recorded disabling paroxysmal movement disorder events in a daily electronic Glut1 DS movement disorder diary. One participant was randomized but did not receive any treatment due to a protocol violation; this participant was not included in any analysis population.

Arm/Group Title	Double-Blind UX007 Followed by Placebo	Double-Blind Placebo Followed by UX007
Arm/Group Description	Double-Blind Maintenance Phase: Participants received 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 then received placebo for 10 weeks. Participants had the option of rolling into the Open-Label Extension Phase, to continue UX007 treatment (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for up to 3 years.	Double-Blind Maintenance Phase: Participants received placebo for 10 weeks. After a washout period of 2 weeks, they then received UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks. Participants had the option of rolling into the Open-Label Extension Phase, to continue UX007 treatment (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for up to 3 years.
Period Title: Maintenance Phase: Treatment Period 1
Started [1]	22	21
Completed	21	21
Not Completed	1	0
Reason Not Completed
Adverse Event	1	0
[1] Randomized and treated
Period Title: Maintenance Phase: Crossover Washout
Started	21	21
Completed	21	21
Not Completed	0	0
Period Title: Maintenance Phase: Treatment Period 2
Started	21	21
Completed	20	18
Not Completed	1	3
Reason Not Completed
Adverse Event	0	1
Withdrawal by Subject	0	1
Lack of Efficacy	1	0
Other, Not Specified	0	1
Period Title: Open-Label Extension Phase
Started	20	13 [1]
Completed	0	0
Not Completed	20	13
Reason Not Completed
Adverse Event	1	0
Sponsor Decision	18	11
Lack of Efficacy	1	1
Other, Not Specified	0	1
[1] 5 participants completed the double blind period but did not continue in the open label period.

Baseline Characteristics

Arm/Group Title		Double-Blind UX007 Followed by Placebo	Double-Blind Placebo Followed by UX007	Total
Arm/Group Description		Double-Blind Maintenance Period: Participants received 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 then received placebo for 10 weeks. Participants had the option of rolling into the Open-Label Extension Period, to continue UX007 treatment for up to 3 years.	Double-Blind Maintenance Period: Participants received placebo for 10 weeks. After a washout period of 2 weeks, they then received UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks. Participants had the option of rolling into the Open-Label Extension Period, to continue UX007 treatment for up to 3 years.	Total of all reporting groups
Overall Number of Baseline Participants		22	21	43
Baseline Analysis Population Description		Full Analysis Set: all randomized participants who received at least 1 dose of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	22 participants	21 participants	43 participants
		23.41 (13.156)	18.37 (5.730)	20.95 (10.425)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	22 participants	21 participants	43 participants
< 18 years old		7 31.8%	9 42.9%	16 37.2%
>/= 18 years old		15 68.2%	12 57.1%	27 62.8%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	21 participants	43 participants
	Female	12 54.5%	12 57.1%	24 55.8%
	Male	10 45.5%	9 42.9%	19 44.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	21 participants	43 participants
	Hispanic or Latino	1 4.5%	0 0.0%	1 2.3%
	Not Hispanic or Latino	17 77.3%	17 81.0%	34 79.1%
	Unknown or Not Reported	4 18.2%	4 19.0%	8 18.6%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	22 participants	21 participants	43 participants
Black or African American		0 0.0%	1 4.8%	1 2.3%
White		18 81.8%	16 76.2%	34 79.1%
Missing		4 18.2%	4 19.0%	8 18.6%

Outcome Measures

1. Primary Outcome

Title	Maintenance Phase Movement Disorder Frequency
Description	The frequency of paroxysmal movement disorders captured as disabling movement disorder events (normalized to a 4-week rate) observed during the Maintenance Phase in participants treated with UX007 versus placebo, as recorded by the subject/caregiver in an event-based daily Glut1 DS symptom diary.
Time Frame	Maintenance Phase (up to Week 22)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	43	42
Median (Full Range); Unit of Measure: movement disorder events per 4 weeks
	14.26; (0.0 to 112.0)	11.81; (0.5 to 112.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Participants completing both UX007 treatment period and placebo period (n=42). Per protocol, when the normality 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 movement disorder event frequency.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2684
	Comments	Hodges-Lehmann estimate of the location shift with 95% confidence interval (CI) and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; -1.12 to 4.36
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Wilk-Shapiro test for normality
	Comments	[Not Specified]

2. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs
Description	An Adverse Event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. Serious adverse events (SAE) was defined as an AE 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; other important medical event. All reported AEs with with a start date that occurred or worsened 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 were defined as TEAEs. AEs were graded as 1=mild, 2=moderate, 3=severe, 4=life=threatening, 5=death.
Time Frame	From first dose of study drug through 30-35 days after final dose. Mean (SD) treatment duration was 65.7 (12.06) and 68.3 (7.04) days for double-blind UX007 and placebo, and 305.0 (122.71) days for open-label UX007.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo	Open-Label UX007
Arm/Group Description:	Double-Blind Maintenance Phase: Participants received UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Double-Blind Maintenance Phase: Participants received placebo for 10 weeks.	Open-Label Extension Phase: Participants continued UX007 treatment for up to 3 years.
Overall Number of Participants Analyzed	43	42	33
Measure Type: Count of Participants; Unit of Measure: Participants
TEAEs	40 93.0%	34 81.0%	28 84.8%
Serious TEAEs	2 4.7%	1 2.4%	2 6.1%
Treatment-Related TEAEs	33 76.7%	19 45.2%	17 51.5%
Treatment-Related Serious TEAEs	1 2.3%	0 0.0%	0 0.0%
Grade 3 or 4 TEAEs	4 9.3%	3 7.1%	3 9.1%
Grade 4 TEAEs	0 0.0%	0 0.0%	0 0.0%
Gastrointestinal TEAEs	32 74.4%	17 40.5%	18 54.5%
TEAEs Leading to Treatment Discontinuation	2 4.7%	1 2.4%	0 0.0%
TEAEs Leading to Study Discontinuation	2 4.7%	1 2.4%	0 0.0%
TEAEs Leading to Death	0 0.0%	0 0.0%	0 0.0%

3. Primary Outcome

Title	Baseline and Post-Baseline Columbia Suicide Severity Rating Scale (C-SSRS) Responses During Double-Blind Treatment Period
Description	The C-SSRS is a participant-rated questionnaire to assess suicidal ideation, suicidal behavior, and self-injurious behavior with no suicidal intent (yes or no responses). Positive responses (i.e., 'Yes') to C-SSRS questions correspond to events in these categories with the exception of the category 'No events'. Suicidal ideation includes the following subcategories: passive; active-nonspecific; active-method/no intent/no plan; active-intent/with or without method/no plan; active-method/intent/plan. Suicidal behavior includes the following subcategories: suicide attempt; interrupted attempt; aborted attempt; preparatory actions toward immanent suicidal behaviors; completed suicide. Suicidal ideation and/or suicidal behavior category includes participants with positive responses in the category suicidal ideation and/or suicidal behavior.
Time Frame	Baseline, up to Week 22

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants with a baseline (BL) and postbaseline (PB) assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	40	40
Measure Type: Count of Participants; Unit of Measure: Participants
BL: No Events	38 95.0%	38 95.0%
PB: No Events	40 100.0%	39 97.5%
BL: Suicidal Ideation	1 2.5%	1 2.5%
PB: Suicidal Ideation	0 0.0%	0 0.0%
BL: Suicidal Behavior	1 2.5%	1 2.5%
PB: Suicidal Behavior	0 0.0%	1 2.5%
BL: Suicidal Ideation and/or Behavior	2 5.0%	2 5.0%
PB: Suicidal Ideation and/or Behavior	0 0.0%	1 2.5%
BL: Self-Injurious Behavior, No Suicidal Intent	1 2.5%	1 2.5%
PB: Self-Injurious Behavior, No Suicidal Intent	0 0.0%	1 2.5%

4. Secondary Outcome

Title	Change From Period Baseline in 12 Minute Walk Test (12MWT) Distance at Treatment Week 10
Description	Walking capacity and endurance, as determined by the distance in meters walked in 12 minutes during the 12MWT.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	36	38
Least Squares Mean (Standard Error); Unit of Measure: meters
	-15.9 (25.63)	-33.0 (24.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Number of participants in this analysis completed both UX007 treatment period and placebo treatment period (n=34).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6419
	Comments	Hodges-Lehmann estimate of the location shift with 95% CI and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	25.00
	Confidence Interval	(2-Sided) 95%; -62.5 to 91.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Period Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Health Assessment Questionnaire (Adult Form) Physical Function Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Physical Function Mobility Domain, increases in score indicate greater mobility.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	-0.9 (0.67)	-0.9 (0.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9513
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -2.0 to 1.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.91
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8214
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Fatigue Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Fatigue Domain, decreases in score indicate less fatigue.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	2.9 (1.40)	0.9 (1.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1572
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -0.8 to 4.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.32
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8451
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

7. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Sleep Disturbance Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Sleep Disturbance Domain, decreases in score indicate less sleep disturbance.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	0.4 (1.24)	0.7 (1.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8345
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -3.8 to 3.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.66
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2894
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Pain Interference Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases in scores indicate less pain interference.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	4.5 (1.64)	3.7 (1.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Number of participants in this analysis completed both UX007 treatment period and placebo treatment period (n=21).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4898
	Comments	Hodges-Lehmann estimate of the location shift with 95% CI and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -5.4 to 5.8
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Cognitive Function Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. The Cognitive Function Domain measures cognitive function impairment. Decreases in score indicate less cognitive function impairment.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	2.0 (1.29)	1.2 (1.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5853
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -2.2 to 3.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.42
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1066
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

10. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Social Roles and Activities Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Social Roles and Activities Domain, decreases in score indicate worse /less or decrease of performance in social roles and activities.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	-4.1 (1.35)	-2.3 (1.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1875
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -4.6 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.33
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2034
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Anxiety Score at Treatment Week 10
Description	The 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). It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Anxiety Domain, decreases in scores indicate less anxiety.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized adult participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	23	25
Least Squares Mean (Standard Error); Unit of Measure: T-score
	3.1 (1.49)	0.5 (1.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1138
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; -0.7 to 5.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.56
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1478
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Mobility Score at Treatment Week 10
Description	The 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) via parent/proxy. It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Mobility Domain, decreases in score indicate less mobility.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized pediatric participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	16	13
Least Squares Mean (Standard Error); Unit of Measure: T-score
	-1.0 (1.62)	0.0 (1.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5505
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -4.6 to 2.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.62
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4459
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Upper Extremity Score at Treatment Week 10
Description	The 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) via parent/proxy. It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Upper Extremity Domain, decreases in score indicate less upper extremity movement.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized pediatric participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	16	13
Least Squares Mean (Standard Error); Unit of Measure: T-score
	-0.4 (1.91)	1.3 (2.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5544
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -8.1 to 4.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.84
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1104
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Fatigue Score at Treatment Week 10
Description	The 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) via parent/proxy. It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Fatigue Domain, decreases in score indicate less fatigue.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized pediatric participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	16	13
Least Squares Mean (Standard Error); Unit of Measure: T-score
	-1.8 (2.40)	-0.6 (2.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7145
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -8.5 to 6.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.27
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8255
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Pain Interference Score at Treatment Week 10
Description	The 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) via parent/proxy. It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Pain Interference Domain, decreases in score indicate less pain interference.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized pediatric participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	16	13
Least Squares Mean (Standard Error); Unit of Measure: T-score
	3.2 (1.84)	1.6 (1.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4176
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -2.5 to 5.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.82
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6557
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

16. Secondary Outcome

Title	Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Peer Relationships Score at Treatment Week 10
Description	The 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) via parent/proxy. It uses a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. For the Peer Relationships Domain, decreases in score indicate worse functioning in peer relationships.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized pediatric participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	16	13
Least Squares Mean (Standard Error); Unit of Measure: T-score
	2.0 (1.57)	-0.0 (1.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0935
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for participant within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -0.4 to 4.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.09
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7267
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

17. Secondary Outcome

Title	Clinical Global Impression - Improvement (CGI-I) at Treatment Week 10
Description	Participant/caregiver global impression of change in clinical status using the CGI-I. The CGI-I is a 7-point scale that assesses how much the participant's condition has improved or worsened relative to a baseline state at the beginning of the intervention and rated as: 1=very much better; 2=much better; 3=a little better; 4=no change; 5=a little worse; 6=much worse; 7=very much worse.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	38	40
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	3.5 (0.20)	3.6 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8329
	Comments	Based on an ANCOVA model including covariate for study baseline CGI-S score, fixed effects for treatment sequence, treatment group, period, and a random effect for subject within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2348
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

18. Secondary Outcome

Title	Duration of Movement Disorder Events During Maintenance Phase
Description	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 electronic Glut1 DS symptom diary.
Time Frame	Maintenance Phase (up to 22 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants (or parent/proxy) who received at least 1 dose of study drug.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	43	42
Mean (Standard Deviation); Unit of Measure: hours
	0.9 (1.98)	0.7 (1.53)

19. Secondary Outcome

Title	Change From Period Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB), Spatial Span (SSP) Span Length Scores at Treatment Week 10
Description	Cognitive function as measured by the CANTAB. 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 assesses the cognitive domain of sequential memory, with scores on a discrete, ordinal scale from 2 to 9; higher scores indicate better function.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	13	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.1 (0.31)	0.6 (0.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0315
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Number of participants in this analysis completed both UX007 treatment period and placebo treatment period (n=13).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2425
	Comments	Hodges-Lehmann estimate of the location shift with 95% CI and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.5 to 0.5
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Change From Period Baseline in CANTAB, Spatial Working Memory Between Errors (SWMBE) Scores at Treatment Week 10
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SWMBE assesses the cognitive domain of working memory, with scores on a discrete, ordinal scale from 0 to 360; lower scores indicate better function.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	13	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-0.2 (2.94)	0.2 (2.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0072
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Number of participants in this analysis completed both UX007 treatment period and placebo treatment period (n=12).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0000
	Comments	Hodges-Lehmann estimate of the location shift with 95% CI and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -14.5 to 13.5
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Change From Period Baseline in CANTAB, Spatial Working Memory Strategy (SWMS) Scores at Treatment Week 10
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. SWMS assesses the cognitive domain of executive function/strategy, with scores on a discrete, ordinal scale from 4 to 28; lower scores indicate better function.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	13	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.6 (0.77)	-0.4 (0.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1076
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for subject within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -0.3 to 2.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.54
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7698
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

22. Secondary Outcome

Title	Change From Baseline in CANTAB, Paired Associates Learning Total Errors (PALTEA) at Treatment Week 10
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. 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.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants (or parent/proxy) who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	13	15
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-2.0 (4.74)	-8.5 (4.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0138
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	Number of participants in this analysis completed both UX007 treatment period and placebo treatment period (n=13).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3907
	Comments	Hodges-Lehmann estimate of the location shift with 95% CI and Wilcoxon Rank Sum test p-value are based on Wilcoxon rank-sum test.
	Method	Wilcoxon Rank Sum test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate (Median Diff.)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -3.5 to 20.5
	Estimation Comments	[Not Specified]

23. Secondary Outcome

Title	Change From Baseline in CANTAB, Paired Associates Learning First Trial Memory Score (PALFTMS) at Treatment Week 10
Description	CANTAB measures neuropsychological function using a standardized, computerized battery of tests designed to assess visual memory, working memory, new learning and reaction time. PALFTMS assesses the cognitive domain of episodic memory, with scores on a discrete, ordinal scale from 0 to 27; higher scores indicate better function.
Time Frame	Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants (or parent/proxy) who received at least 1 dose of study drug. Participants who had an assessment.

Arm/Group Title	Double-Blind UX007	Double-Blind Placebo
Arm/Group Description:	UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Placebo for 10 weeks.
Overall Number of Participants Analyzed	13	15
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-0.1 (1.12)	0.9 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5233
	Comments	Based on an ANCOVA model including covariate for period baseline value, fixed effects for treatment sequence, treatment group, period, and a random effect for subject within the sequence.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -4.4 to 2.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.51
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-Blind UX007, Double-Blind Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6918
	Comments	[Not Specified]
	Method	Wilk-Shapiro Test for Normality
	Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug through 30-35 days after final dose. Mean (SD) treatment duration was 65.7 (12.06) and 68.3 (7.04) days for double-blind UX007 and placebo, respectively, and 305.0 (122.71) days for open-label UX007.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	DB UX007	DB Placebo	OL UX007
Arm/Group Description	Double-Blind Maintenance Phase: Participants received UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.	Double-Blind Maintenance Phase: Participants received placebo for 10 weeks.	Open-Label Extension Phase: Participants continued UX007 treatment (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for up to 3 years.
All-Cause Mortality
	DB UX007	DB Placebo	OL UX007
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/43 (0.00%)	0/42 (0.00%)	0/33 (0.00%)
Serious Adverse Events
	DB UX007	DB Placebo	OL UX007
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/43 (4.65%)	1/42 (2.38%)	2/33 (6.06%)
Injury, poisoning and procedural complications
Head Injury † 1	1/43 (2.33%)	0/42 (0.00%)	0/33 (0.00%)
Musculoskeletal and connective tissue disorders
Limb Asymmetry † 1	0/43 (0.00%)	0/42 (0.00%)	1/33 (3.03%)
Nervous system disorders
Movement Disorder † 1	1/43 (2.33%)	0/42 (0.00%)	1/33 (3.03%)
Psychomotor Hyperactivity † 1	0/43 (0.00%)	1/42 (2.38%)	0/33 (0.00%)
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	DB UX007	DB Placebo	OL UX007
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	36/43 (83.72%)	26/42 (61.90%)	22/33 (66.67%)
Gastrointestinal disorders
Abdominal Discomfort † 1	4/43 (9.30%)	0/42 (0.00%)	0/33 (0.00%)
Abdominal Pain † 1	6/43 (13.95%)	1/42 (2.38%)	5/33 (15.15%)
Abdominal Pain Upper † 1	14/43 (32.56%)	6/42 (14.29%)	7/33 (21.21%)
Anal Incontinence † 1	3/43 (6.98%)	0/42 (0.00%)	0/33 (0.00%)
Constipation † 1	1/43 (2.33%)	1/42 (2.38%)	3/33 (9.09%)
Diarrhoea † 1	22/43 (51.16%)	5/42 (11.90%)	9/33 (27.27%)
Nausea † 1	7/43 (16.28%)	5/42 (11.90%)	4/33 (12.12%)
Vomiting † 1	13/43 (30.23%)	8/42 (19.05%)	8/33 (24.24%)
General disorders
Fatigue † 1	3/43 (6.98%)	5/42 (11.90%)	3/33 (9.09%)
Gait Disturbance † 1	0/43 (0.00%)	1/42 (2.38%)	2/33 (6.06%)
Pyrexia † 1	4/43 (9.30%)	1/42 (2.38%)	2/33 (6.06%)
Infections and infestations
Gastroenteritis † 1	3/43 (6.98%)	0/42 (0.00%)	1/33 (3.03%)
Gastroenteritis Viral † 1	0/43 (0.00%)	1/42 (2.38%)	2/33 (6.06%)
Influenza † 1	3/43 (6.98%)	0/42 (0.00%)	2/33 (6.06%)
Viral Upper Respiratory Tract Infection † 1	5/43 (11.63%)	2/42 (4.76%)	2/33 (6.06%)
Investigations
Blood Ketone Body Increased † 1	3/43 (6.98%)	2/42 (4.76%)	0/33 (0.00%)
Weight Increased † 1	3/43 (6.98%)	1/42 (2.38%)	2/33 (6.06%)
Metabolism and nutrition disorders
Decreased Appetite † 1	5/43 (11.63%)	1/42 (2.38%)	1/33 (3.03%)
Nervous system disorders
Dizziness † 1	1/43 (2.33%)	2/42 (4.76%)	2/33 (6.06%)
Dyskinesia † 1	3/43 (6.98%)	2/42 (4.76%)	3/33 (9.09%)
Headache † 1	7/43 (16.28%)	6/42 (14.29%)	6/33 (18.18%)
Psychiatric disorders
Aggression † 1	4/43 (9.30%)	0/42 (0.00%)	0/33 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	2/43 (4.65%)	0/42 (0.00%)	3/33 (9.09%)
Oropharyngeal Pain † 1	4/43 (9.30%)	3/42 (7.14%)	1/33 (3.03%)
1 Term from vocabulary, MedDRA 20.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc
• Phone: 1-888-756-8567
• EMail: medinfo@ultragenyx.com

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02960217
• Other Study ID Numbers: UX007G-CL301
• First Submitted: November 7, 2016
• First Posted: November 9, 2016
• Results First Submitted: April 8, 2020
• Results First Posted: April 24, 2020
• Last Update Posted: June 16, 2020