Study to Evaluate the Safety and Efficacy of Aceneuramic Acid Extended-Release (Ace-ER) Tablets in Patients With Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)

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ClinicalTrials.gov Identifier: NCT02736188

Recruitment Status : Terminated

First Posted : April 13, 2016

Results First Posted : February 19, 2019

Last Update Posted : March 24, 2023

View this study on Beta.ClinicalTrials.gov

Sponsor:

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
Intervention	Drug: Aceneuramic Acid Extended-Release Tablets
Enrollment	143

Participant Flow

Recruitment Details	143 participants were screened and enrolled across 14 total sites in the United States, Israel, United Kingdom, Italy, France, Canada, and Bulgaria. 87 participants rolled over from study UX001-CL301 (NCT02377921), 49 participants rolled over from study UX001-CL202 (NCT01830972), and 7 participants rolled over from UX001-CL203 (NCT02731690).
Pre-assignment Details	Of the143 participants who enrolled, 1 participant withdrew consent prior to receiving the first dose and is not included in the Safety Analysis Population presented below.


Arm/Group Title	Ace-ER 6 g/Day
Arm/Group Description	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day
Period Title: Overall Study
Started	142
Completed	0
Not Completed	142
Reason Not Completed
Discontinuation of Study by Sponsor	134
Adverse Event	1
Withdrawal by Subject	1
Other	6

Baseline Characteristics

Arm/Group Title		Ace-ER 6 g/Day
Arm/Group Description		4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description		4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day
Overall Number of Baseline Participants		142
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Safety Analysis Set: all participants who received at least one dose of study drug in UX001-CL302.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	142 participants
		74 (68)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	142 participants
	Female	74 52.1%
	Male	68 47.9%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	142 participants
	Hispanic or Latino	14 9.9%
	Not Hispanic or Latino	125 88.0%
	Unknown or Not Reported	3 2.1%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
White	Number Analyzed	142 participants
White		111 78.2%
Asian	Number Analyzed	142 participants
Asian		19 13.4%
Other, Not Specified	Number Analyzed	142 participants
Other, Not Specified		12 8.5%
Hand Held Dynamometry (HHD) Upper Extremity Composite Score (UEC) ^[1] [2] Mean (Standard Deviation) Unit of measure: Kgf
	Number Analyzed	87 participants
		52.98 (28.814)
		[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 in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score ^[1] [2] Mean (Standard Deviation) Unit of measure: Score on a scale
	Number Analyzed	87 participants
		24.17 (7.772)
		[1] Measure Description: GNEM-FAS Expanded Version Mobility subscale score has 13 items and ranges from 0 to 52 with higher scores representing greater mobility. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
GNEM-FAS Expanded Version Upper Extremity Score ^[1] [2] Mean (Standard Deviation) Unit of measure: Score on a scale
	Number Analyzed	87 participants
		27.53 (4.938)
		[1] Measure Description: GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items and ranges 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 in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
HHD Lower Extremity Composite (LEC) Score ^[1] [2] Mean (Standard Deviation) Unit of measure: Kgf
	Number Analyzed	86 participants
		51.91 (37.474)
		[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 in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Sit-to-Stand Test ^[1] [2] Mean (Standard Deviation) Unit of measure: Stands
	Number Analyzed	87 participants
		12.75 (4.977)
		[1] Measure Description: Lower extremity function was assessed using a sit-to-stand test. The number of times the participant can rise from a seated to a standing position in a 30-second period was recorded. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
30-second Weighted Arm Lift Test ^[1] [2] Mean (Standard Deviation) Unit of measure: Lifts
	Number Analyzed	72 participants
		30.93 (13.171)
		[1] Measure Description: Upper extremity function was assessed using a weighted arm lift test performed bilaterally. The number of times the participant can raise a 1 kg weight above the head in a 30-second period was recorded. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Six-Minute Walk Test (6MWT) ^[1] [2] Mean (Standard Deviation) Unit of measure: Meters
	Number Analyzed	83 participants
		359.4 (123.94)
		[1] Measure Description: The total distance walked (meters) in a 6-minute period was measured. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Percent Predicted Meters Walked in 6MWT ^[1] [2] Mean (Standard Deviation) Unit of measure: Percentage of predicted meters
	Number Analyzed	83 participants
		49.52 (16.962)
		[1] Measure Description: The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. Predicted 6MWT distance (meters) = 868.8 - (2.99 x Age) - (74.7 x Sex), where age is baseline age in years, and sex = 0 for males, and 1 for females. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Total Force in Knee Extensors ^[1] [2] Mean (Standard Deviation) Unit of measure: Kgf
	Number Analyzed	84 participants
		26.60 (9.746)
		[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 in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.
Percent of Predicted Total Force in Knee Extensors ^[1] [2] Mean (Standard Deviation) Unit of measure: Percent of predicted total force
	Number Analyzed	81 participants
		13.69 (15.323)
		[1] Measure Description: The percent predicted total force value of lower extremity muscle strength in the knee extensors was determined based on reference equations adjusting for age, gender, height, and weight. [2] Measure Analysis Population Description: Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.

Outcome Measures

1.Primary Outcome


Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs
Description	An AE was defined as any untoward medical occurrence associated with t...
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. The severity of all AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: grade1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death.
Time Frame	From first dose of study drug through the end of treatment plus 30 days (+5 days). Mean (SD) duration of treatment was 256.3 (101.54) days.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all participants who received at least one dose of study drug in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day
Overall Number of Participants Analyzed	142
Measure Type: Count of Participants Unit of Measure: Participants
TEAEs	104 73.2%
Serious TEAEs (SAEs)	7 4.9%
Deaths	0 0.0%
Grade 3 or 4 TEAEs	11 7.7%
TEAEs Leading to Study Drug Discontinuation	2 1.4%
TEAEs Leading to Study Discontinuation	1 0.7%

2.Primary Outcome


Title	Change From Baseline in HHD UEC Score Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximu...
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. The UEC is derived from the sum of the average of the right and left total force (measured in kgf). Analyzed using a repeated measure generalized estimation equation (GEE) model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: kgf
Week 8	0.88 (-0.75 to 2.51)	0.09 (-1.05 to 1.23)
Week 16	0.10 (-1.47 to 1.67)	-0.26 (-1.26 to 0.74)
Week 24	-1.40 (-2.92 to 0.12)	-0.49 (-2.13 to 1.15)
Week 48	-2.24 (-4.95 to 0.47)	-2.18 (-4.30 to -0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4287
	Comments	Baseline is fit into the model as a covariate.
	Method	generalized estimating equation (GEE)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% -1.17 to 2.77
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7031
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95% -1.49 to 2.21
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4253
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95% -3.14 to 1.32
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9747
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95% -3.49 to 3.38
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time
Description	GNEM-FAS Expanded Version Mobility subscale score has 13 items and ran...
Description	GNEM-FAS Expanded Version Mobility subscale score has 13 items and ranges from 0 to 52 with higher scores representing greater mobility. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
Week 8	-0.12 (-0.66 to 0.42)	0.15 (-0.35 to 0.65)
Week 16	-0.30 (-0.87 to 0.27)	-0.12 (-0.72 to 0.49)
Week 24	-0.78 (-1.31 to -0.25)	-0.34 (-0.92 to 0.23)
Week 48	-0.73 (-1.43 to -0.03)	-0.45 (-1.67 to 0.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4721
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95% -1.01 to 0.47
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6611
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95% -1.02 to 0.64
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2760
	Comments	[Not Specified]
	Method	GEE model
	Comments	Baseline is fit into the model as a covariate.

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95% -1.22 to 0.35
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6977
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95% -1.69 to 1.13
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time
Description	GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items a...
Description	GNEM-FAS Expanded Version Upper Extremity subscale score has 9 items and ranges 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 baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
Week 8	0.68 (0.15 to 1.22)	-0.02 (-0.55 to 0.51)
Week 16	0.34 (-0.21 to 0.89)	-0.40 (-0.99 to 0.19)
Week 24	0.26 (-0.41 to 0.93)	-0.17 (-1.01 to 0.67)
Week 48	-0.82 (-2.16 to 0.51)	-0.48 (-1.03 to 0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0648
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% -0.04 to 1.45
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0692
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% -0.06 to 1.55
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4317
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95% -0.65 to 1.52
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6416
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95% -1.78 to 1.10
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximu...
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. The LEC is derived from the sum of the average of the right and left total force (measured in kgf). Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: kgf
Week 8	0.01 (-2.01 to 2.04)	-0.77 (-3.65 to 2.11)
Week 16	-1.63 (-3.95 to 0.34)	-0.98 (-3.77 to 1.81)
Week 24	-0.60 (-3.90 to 2.71)	-0.10 (-3.82 to 3.62)
Week 48	-0.32 (-4.02 to 3.39)	-4.47 (-7.45 to -1.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6546
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% -2.65 to 4.22
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7054
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95% -3.97 to 2.69
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8441
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95% -5.45 to 4.45
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0864
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	4.15
	Confidence Interval	(2-Sided) 95% -0.59 to 8.90
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time
Description	Lower extremity function was assessed using a sit-to-stand test. The n...
Description	Lower extremity function was assessed using a sit-to-stand test. The number of times the participant can rise from a seated to a standing position in a 30-second period was recorded. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: stands
Week 8	0.02 (-0.43 to 0.46)	-0.05 (-0.61 to 0.51)
Week 16	-0.04 (-0.49 to 0.40)	0.14 (-0.39 to 0.66)
Week 24	0.06 (-0.43 to 0.56)	-0.41 (-0.94 to 0.12)
Week 48	-0.39 (-1.36 to 0.57)	-0.36 (-1.11 to 0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8603
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95% -0.65 to 0.78
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6154
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95% -0.86 to 0.51
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1999
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95% -0.25 to 1.20
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9568
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95% -1.25 to 1.18
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time
Description	Upper extremity function was assessed using a weighted arm lift test p...
Description	Upper extremity function was assessed using a weighted arm lift test performed bilaterally. The number of times the participant can raise a 1 kg weight above the head in a 30-second period was recorded. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: lifts
Week 8	0.26 (-1.00 to 1.52)	-0.19 (-0.90 to 0.53)
Week 16	0.03 (-1.22 to 1.27)	0.59 (-0.50 to 1.68)
Week 24	0.13 (-0.98 to 1.24)	-0.14 (-1.33 to 1.06)
Week 48	-1.58 (-3.60 to 0.45)	-1.17 (-2.55 to 0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5447
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95% -1.00 to 1.90
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5051
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95% -2.22 to 1.09
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7478
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.27
	Confidence Interval	(2-Sided) 95% -1.36 to 1.90
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7429
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95% -2.86 to 2.04
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Change From Baseline in Meters Walked in 6MWT Over Time
Description	The total distance walked (meters) in a 6-minute period was measured. ...
Description	The total distance walked (meters) in a 6-minute period was measured. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: meters
Week 8	-1.40 (-8.34 to 5.53)	-3.41 (-7.92 to 1.10)
Week 16	-3.91 (-12.03 to 4.20)	-1.93 (-8.32 to 4.47)
Week 24	-2.73 (-10.81 to 5.35)	-6.88 (-13.43 to -0.33)
Week 48	-13.91 (-25.58 to -2.25)	-21.89 (-38.51 to -5.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6434
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95% -6.48 to 10.49
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7118
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-1.99
	Confidence Interval	(2-Sided) 95% -12.53 to 8.55
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4399
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	4.15
	Confidence Interval	(2-Sided) 95% -6.39 to 14.69
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4430
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	7.98
	Confidence Interval	(2-Sided) 95% -12.41 to 28.37
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time
Description	The total distance walked (meters) in a 6-minute period was measured, ...
Description	The total distance walked (meters) in a 6-minute period was measured, and the percent predicted distance based on normative data for age and gender was estimated. Predicted 6MWT distance (meters) = 868.8 - (2.99 x Age) - (74.7 x Sex), where age is baseline age in years, and sex = 0 for males, and 1 for females. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: percent of predicted distance
Week 8	-0.17 (-1.12 to 0.79)	-0.45 (-1.09 to 0.20)
Week 16	-0.49 (-1.60 to 0.61)	-0.24 (-1.15 to 0.67)
Week 24	-0.38 (-1.49 to 0.73)	-0.96 (-1.88 to -0.03)
Week 48	-1.94 (-3.56 to -0.31)	-2.93 (-5.04 to -0.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6428
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95% -0.90 to 1.46
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7334
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95% -1.72 to 1.21
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4409
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95% -0.89 to 2.04
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4687
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95% -1.69 to 3.68
	Estimation Comments	[Not Specified]

10.Secondary Outcome


Title	Change From Baseline in Total Force in Knee Extensors Over Time
Description	Hand held dynamometry testing was used to measure strength. The maximu...
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. Bilateral total force was defined as the average of the right and left force (measured in kgf). Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: kgf
Week 8	0.50 (-0.77 to 1.78)	-0.64 (-1.53 to 0.25)
Week 16	-0.95 (-2.03 to 0.14)	-0.75 (-2.05 to 0.55)
Week 24	0.33 (-1.33 to 2.00)	-0.46 (-2.15 to 1.23)
Week 48	0.63 (-2.30 to 3.56)	-0.08 (-2.28 to 2.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1502
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95% -0.41 to 2.69
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8188
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) -1.89% -1.89 to 1.49
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5122
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% -1.58 to 3.17
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7022
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95% -2.96 to 4.40
	Estimation Comments	[Not Specified]

11.Secondary Outcome


Title	Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time
Description	The percent predicted total force value of lower extremity muscle stre...
Description	The percent predicted total force value of lower extremity muscle strength in the knee extensors was determined based on reference equations adjusting for age, gender, height, and weight. Analyzed using a repeated measure GEE model, which includes the baseline value as a covariate.
Time Frame	Baseline, Weeks 8, 16, 24, and 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants in parent study UX001-CL301 (NCT02377921) with a UX001-CL302 baseline measurement and at least one post-baseline measurement in UX001-CL302.


Arm/Group Title	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day)	Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2...	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description:	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took Ace-ER in study UX001-CL301 (NCT02377921)	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day in participants who took placebo in study UX001-CL301 (NCT02377921)
Overall Number of Participants Analyzed	44	43
Least Squares Mean (95% Confidence Interval) Unit of Measure: percent of predicted total force (kgf)
Week 8	-0.98 (-1.78 to -0.19)	-1.17 (-2.44 to 0.09)
Week 16	-0.59 (-1.48 to 0.31)	-1.25 (-2.43 to -0.07)
Week 24	-0.70 (-1.92 to 0.53)	-0.85 (-2.53 to 0.83)
Week 48	-1.02 (-2.17 to 0.13)	-3.10 (-4.40 to -1.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7906
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95% -1.22 to 1.60
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3531
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95% -0.74 to 2.07
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8846
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95% -1.92 to 2.23
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ace-ER 6 g/Day (Parent Study Treatment: Ace-ER 6 g/Day), Ace-ER 6 g/Day (Parent Study Treatment: Placebo)
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0168
	Comments	Baseline is fit into the model as a covariate.
	Method	GEE model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in LS means
	Estimated Value	2.08
	Confidence Interval	(2-Sided) 95% 0.38 to 3.79
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug through the end of treatment plus 30 days (+5 days). Mean (SD) duration of treatment was 256.3 (101.54) days.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Ace-ER 6 g/Day
Arm/Group Description	4 tablets (500 mg Ace-ER each for 2...
Arm/Group Description	4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day
All-Cause Mortality
	Ace-ER 6 g/Day
	Affected / at Risk (%)
Total	0/142 (0.00%)
Serious Adverse Events Serious Adverse Events
	Ace-ER 6 g/Day
	Affected / at Risk (%)
Total	7/142 (4.93%)
Gastrointestinal disorders
Abdominal pain ^† 1	1/142 (0.70%)
Hepatobiliary disorders
Cholecystitis acute ^† 1	1/142 (0.70%)
Infections and infestations
Atypical pneumonia ^† 1	1/142 (0.70%)
Investigations
Biopsy kidney ^† 1	1/142 (0.70%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma ^† 1	1/142 (0.70%)
Malignant melanoma in situ ^† 1	1/142 (0.70%)
Renal and urinary disorders
Renal pain ^† 1	1/142 (0.70%)
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	66/142 (46.48%)
Gastrointestinal disorders
Diarrhoea ^† 1	10/142 (7.04%)
Flatulence ^† 1	9/142 (6.34%)
General disorders
Fatigue ^† 1	8/142 (5.63%)
Infections and infestations
Nasopharyngitis ^† 1	8/142 (5.63%)
Injury, poisoning and procedural complications
Fall ^† 1	30/142 (21.13%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	17/142 (11.97%)
Back pain ^† 1	13/142 (9.15%)
Musculoskeletal pain ^† 1	11/142 (7.75%)
Pain in extremity ^† 1	10/142 (7.04%)
Nervous system disorders
Headache ^† 1	8/142 (5.63%)
1 Term from vocabulary, MedDRA 17.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

No efficacy result summaries or analyses were performed for participants rolling over from UX001-CL202 or UX001-CL203 because of the limited data from those participants due to the early study closure.

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

Layout table for Results Point of Contact information

Name/Title:	Medical Information
Organization:	Ultragenyx Pharmaceutical Inc
Phone:	1-888-756-8657
EMail:	medinfo@ultragenyx.com

Layout table for additonal information

Responsible Party:	Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier:	NCT02736188
Other Study ID Numbers:	UX001-CL302
First Submitted:	April 4, 2016
First Posted:	April 13, 2016
Results First Submitted:	January 7, 2019
Results First Posted:	February 19, 2019
Last Update Posted:	March 24, 2023

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