A Study to Evaluate the Safety of Aceneuramic Acid Extended Release (Ace-ER; UX001) Tablets in Glucosamine (UDP-N-acetyl)-2-Epimerase (GNE) Myopathy (GNEM) (Also Known as Hereditary Inclusion Body Myopathy [HIBM]) Patients With Severe Ambulatory Impairment

• ClinicalTrials.gov Identifier: NCT02731690
• Recruitment Status: Terminated
• First Posted: April 7, 2016
• Results First Posted: February 19, 2019
• Last Update Posted: February 19, 2019
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Hereditary Inclusion Body Myopathy; Distal Myopathy With Rimmed Vacuoles; Distal Myopathy, Nonaka Type; GNE Myopathy; Quadriceps Sparing Myopathy; Inclusion Body Myopathy 2
• Intervention: Drug: Aceneuramic Acid Extended-Release
• Enrollment: 42

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	UX001 6g/Day
Arm/Group Description	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Period Title: Overall Study
Started	42
Completed	12
Not Completed	30
Reason Not Completed
Adverse Event	1
Withdrawal by Subject	3
Discontinuation of Study by Sponsor	26

Baseline Characteristics

Arm/Group Title		UX001 6g/Day
Arm/Group Description		Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Baseline Participants		42
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	42 participants
		46.0 (13.97)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	42 participants
	Female	25 59.5%
	Male	17 40.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	42 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	42 100.0%
	Unknown or Not Reported	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
White	Number Analyzed	42 participants
		31 73.8%
Asian	Number Analyzed	42 participants
		2 4.8%
Other (Not Specified)	Number Analyzed	42 participants
		9 21.4%
Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	41 participants
		10.63 (7.816)
		[1] Measure Description: GNEM-FAS Expanded Version Mobility subscale scores have 13 items and range from 0 to 52 with higher scores representing greater mobility.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
GNEM-FAS Upper Extremity Domain Score [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	41 participants
		15.20 (8.897)
		[1] Measure Description: GNEM-FAS Expanded Version Upper Extremity subscale scores have 9 items and range from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
GNEM-FAS Self-Care Domain Score [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	41 participants
		13.00 (7.413)
		[1] Measure Description: GNEM-FAS Expanded Version Self-Care subscale scores have 8 items range from 0 to 32 with higher scores representing greater independence with functional care activities.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
GNEM-FAS Total Score [1] [2]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	41 participants
		38.83 (23.116)
		[1] Measure Description: GNEM-FAS Expanded Version Total Score were calculated as the sum of the subscale Scores range from 0 to 120 with higher scores representing greater independence with functional activities.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
Hand-Held Dynamometry (HHD) Raw Strength: Average Grip [1] [2]; Mean (Standard Deviation); Unit of measure: Kgf
	Number Analyzed	41 participants
		5.535 (7.6778)
		[1] Measure Description: Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kilogram-force [kgf]) for each was recorded.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
HHD Raw Strength: Average Shoulder Abduction [1] [2]; Mean (Standard Deviation); Unit of measure: Kgf
	Number Analyzed	41 participants
		3.880 (4.4583)
		[1] Measure Description: Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
HHD Raw Strength: Average Wrist Extension [1] [2]; Mean (Standard Deviation); Unit of measure: Kgf
	Number Analyzed	41 participants
		3.532 (3.5177)
		[1] Measure Description: Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
HHD Lower Extremity Muscle Strength: Average Knee Extension [1] [2]; Mean (Standard Deviation); Unit of measure: Kgf
	Number Analyzed	41 participants
		10.50 (8.001)
		[1] Measure Description: Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.
HHD Raw Strength: Key Pinch [1] [2]; Mean (Standard Deviation); Unit of measure: Kgf
	Number Analyzed	41 participants
		1.790 (2.1614)
		[1] Measure Description: Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.; [2] Measure Analysis Population Description: Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
Description	An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any dose, in the view of either the Investigator or Ultragenyx, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect. TEAEs were defined as any AE that occurred after the first dose of study drug.
Time Frame	48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Count of Participants; Unit of Measure: Participants
TEAEs	30 71.4%
Serious TEAEs	1 2.4%
TEAEs Causing Study Drug Discontinuation	1 2.4%
TEAEs Causing Study Discontinuation	1 2.4%

2. Secondary Outcome

Title	Number of Participants Taking Prior and Concomitant Medications
Description	Prior medications are any medications which started before the date of the first dose of investigational product. Concomitant medications are any medications that are taken on or after the date of the first dose of investigational product excluding concomitant medications started after the date of the last dose of investigational product.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Count of Participants; Unit of Measure: Participants
Prior Medications	31
Concomitant Medications	33

3. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline In Physical Examinations
Description	Complete physical examinations included assessments of general appearance; head, eyes, ears, nose, and throat; the cardiovascular, dermatologic, lymphatic, respiratory, GI, musculoskeletal, and neurologic systems. The neurologic system examination included assessments of cognition, cranial nerves, motor function, coordination and gait, reflexes, and sensory function. Brief physical examinations included assessments of general appearance, cardiovascular and respiratory systems, and a focus on any presenting complaints.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Number; Unit of Measure: participants
	0

4. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline In Vital Signs
Description	Vital signs included seated systolic blood pressure and diastolic blood pressure, heart rate, respiration rate, and temperature.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Number; Unit of Measure: participants
	0

5. Secondary Outcome

Title	Number of Participants With Clinically Significant Changes From Baseline In Clinical Laboratory Results
Description	The clinical laboratory evaluations performed included serum chemistry, complete blood count (hematology), and urinalysis.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Number; Unit of Measure: participants
Hematology	0
Clinical Chemistry	2
Urinalysis	0

6. Secondary Outcome

Title	Number of Participants With Overall Suicidal Behaviors and/or Ideation at Baseline and Post-Baseline
Description	As evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS), a participant-rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses).
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	42
Measure Type: Count of Participants; Unit of Measure: Participants
Overall Suicidal Behaviors: Baseline	1
Overall Suicidal Behaviors: Post-Baseline	0
Non-Suicide Self-Injurious Behavior: Baseline	0
Non-Suicide Self-Injurious Behavior: Post-Baseline	0
Completed Suicide: Post-Baseline	0
Overall Suicidal Ideation: Baseline	7
Overall Suicidal Ideation: Post-Baseline	1

7. Secondary Outcome

Title	Change From Baseline in GNEM-FAS Expanded Version Mobility Domain Subscale Scores Over Time
Description	GNEM-FAS Expanded Version Mobility subscale scores have 13 items and range from 0 to 52 with higher scores representing greater mobility. Analyzed using a repeated measure generalized estimation equation (GEE) model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 12	0.16; (-0.33 to 0.64)
Week 24	-0.65; (-1.56 to 0.27)
Week 36	-0.69; (-1.57 to 0.18)
Week 48	-1.03; (-2.15 to 0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5303
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1646
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1189
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0706
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Baseline in GNEM-FAS Expanded Version Upper Extremity Domain Subscale Scores Over Time
Description	GNEM-FAS Expanded Version Upper Extremity subscale scores have 9 items and range from 0 to 36 with higher scores representing more skilled, independent use of the arms during functional activity performance. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 12	0.57; (-0.05 to 1.19)
Week 24	-0.62; (-1.50 to 0.26)
Week 36	-0.51; (-1.58 to 0.55)
Week 48	-1.91; (-3.93 to 0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0715
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1697
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3428
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0642
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Baseline in GNEM-FAS Expanded Version Self-Care Domain Subscale Scores Over Time
Description	GNEM-FAS Expanded Version Self-Care subscale scores have 8 items range from 0 to 32 with higher scores representing greater independence with functional care activities. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 12	-0.39; (-0.79 to 0.01)
Week 24	-0.71; (-1.43 to 0.01)
Week 36	-0.83; (-1.64 to -0.02)
Week 48	-0.40; (-1.78 to 0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0568
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0533
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0459
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5678
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

10. Secondary Outcome

Title	Change From Baseline in GNEM-FAS Expanded Version Total Scores Over Time
Description	GNEM-FAS Expanded Version Total Score were calculated as the sum of the subscale Scores range from 0 to 120 with higher scores representing greater independence with functional activities. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 12	0.35; (-0.89 to 1.58)
Week 24	-1.95; (-3.87 to -0.03)
Week 36	-2.02; (-4.46 to 0.42)
Week 48	-3.34; (-6.90 to 0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5810
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0465
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1047
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0661
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Baseline in HHD Raw Strength (Grip) Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: kgf
Week 12	0.258; (-0.103 to 0.620)
Week 24	0.128; (-0.377 to 0.632)
Week 36	0.038; (-0.724 to 0.799)
Week 48	-0.261; (-1.325 to 0.803)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1615
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6201
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9229
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6307
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline in HHD Raw Strength (Shoulder Abductors) Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: kgf
Week 12	0.339; (0.085 to 0.592)
Week 24	0.379; (-0.228 to 0.987)
Week 36	0.437; (0.075 to 0.800)
Week 48	-0.277; (-0.698 to 0.144)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0088
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2213
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0180
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1970
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline in HHD Raw Strength (Wrist Extensors) Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: kgf
Week 12	0.235; (-0.024 to 0.495)
Week 24	0.152; (-0.486 to 0.791)
Week 36	0.358; (-0.228 to 0.943)
Week 48	-0.123; (-0.924 to 0.678)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0752
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Statistical Test of Hypothesis	P-Value	0.6403
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Statistical Test of Hypothesis	P-Value	0.2316
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7635
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline in HHD Muscle Strength in Knee Extensors Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded. Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement.

Arm/Group Title	UX001 6g/Day
Arm/Group Description:	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed	41
Least Squares Mean (95% Confidence Interval); Unit of Measure: kgf
Week 12	0.80; (-0.12 to 1.73)
Week 24	1.35; (0.36 to 2.33)
Week 36	2.05; (0.52 to 3.58)
Week 48	2.45; (0.01 to 4.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0872
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0073
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0086
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0489
	Comments	Analyzed using a repeated measure GEE model, which includes the change from baseline as the dependent variable, visit as a fixed factor, and the baseline value as a covariate. Compound symmetry is used as the covariance structure.
	Method	GEE model
	Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Baseline in HHD Raw Strength (Key Pinch) Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximum voluntary isometric contraction against a dynamometer was used to measure bilateral strength in the following muscle groups: shoulder abductors, wrist extensors and knee extensors. Specialized dynamometers for the measurement of grip and key pinch strength were also used. The total force (in kgf) for each was recorded.
Time Frame	Baseline, Weeks 12, 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants with a baseline measurement and at least 1 postbaseline measurement at given time point.

Arm/Group Title		UX001 6g/Day
Arm/Group Description:		Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
Overall Number of Participants Analyzed		41
Mean (Standard Deviation); Unit of Measure: kgf
Week 12	Number Analyzed	41 participants
		0.110 (0.7083)
Week 24	Number Analyzed	30 participants
		0.112 (0.6534)
Week 36	Number Analyzed	23 participants
		0.049 (0.8090)
Week 48	Number Analyzed	11 participants
		0.318 (0.9509)

Adverse Events

Time Frame	48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Ace-ER 6 g/Day
Arm/Group Description	Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
All-Cause Mortality
	Ace-ER 6 g/Day
	Affected / at Risk (%)
Total	0/42 (0.00%)
Serious Adverse Events
	Ace-ER 6 g/Day
	Affected / at Risk (%)
Total	1/42 (2.38%)
Infections and infestations
Pyelonephritis † 1	1/42 (2.38%)
Sepsis † 1	1/42 (2.38%)
Renal and urinary disorders
Nephrolithiasis † 1	1/42 (2.38%)
1 Term from vocabulary, MedDRA 17.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ace-ER 6 g/Day
	Affected / at Risk (%)
Total	26/42 (61.90%)
Gastrointestinal disorders
Abdominal distension † 1	7/42 (16.67%)
Abdominal pain upper † 1	6/42 (14.29%)
Dyspepsia † 1	3/42 (7.14%)
Dysphagia † 1	3/42 (7.14%)
Flatulence † 1	7/42 (16.67%)
Nausea † 1	3/42 (7.14%)
General disorders
Fatigue † 1	3/42 (7.14%)
Oedema peripheral † 1	3/42 (7.14%)
Infections and infestations
Upper respiratory tract infection † 1	7/42 (16.67%)
Urinary tract infection † 1	3/42 (7.14%)
Injury, poisoning and procedural complications
Fall † 1	4/42 (9.52%)
Metabolism and nutrition disorders
Diabetes mellitus † 1	3/42 (7.14%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/42 (7.14%)
Back pain † 1	3/42 (7.14%)
Muscular weakness † 1	4/42 (9.52%)
Pain in extremity † 1	4/42 (9.52%)
Nervous system disorders
Headache † 1	3/42 (7.14%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	3/42 (7.14%)
1 Term from vocabulary, MedDRA 17.1; † 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: 1-888-756-8657
• EMail: medinfo@ultragenyx.com

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02731690
• Other Study ID Numbers: UX001-CL203
• First Submitted: March 24, 2016
• First Posted: April 7, 2016
• Results First Submitted: January 7, 2019
• Results First Posted: February 19, 2019
• Last Update Posted: February 19, 2019