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

• Sponsor: Ultragenyx Pharmaceutical Inc (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02731690
• Collaborator: (none)
• Enrollment: 42
• Locations: 5
• Arm: 1
• Actual Duration (Months): 20.4
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary objective of this Phase 2 study is to evaluate the safety of open-label 6 g/day Ace-ER in GNEM participants with severe ambulatory impairment.

Condition or Disease	Intervention/Treatment	Phase
Hereditary Inclusion Body Myopathy; Distal Myopathy With Rimmed Vacuoles; Distal Myopathy, Nonaka Type; GNE Myopathy; Quadriceps Sparing Myopathy; Inclusion Body Myopathy 2	Drug: Aceneuramic Acid Extended-Release	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Open-label Study to Evaluate the Safety of Aceneuramic Acid Extended Release (Ace-ER) Tablets in GNE Myopathy (GNEM) (Also Known as Hereditary Inclusion Body Myopathy (HIBM)) Patients With Severe Ambulatory Impairment
• Actual Study Start Date: Apr 29, 2016
• Actual Primary Completion Date: Jan 10, 2018
• Actual Study Completion Date: Jan 10, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open Label UX001, 6g/day	Drug: Aceneuramic Acid Extended-Release; oral tablets; Other Names: Ace-ER Sialic Acid Extended Release UX001

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)]

   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.

Secondary Outcome Measures

1. Number of Participants Taking Prior and Concomitant Medications [48 weeks]

   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.

2. Number of Participants With Clinically Significant Changes From Baseline In Physical Examinations [48 weeks]

   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.

3. Number of Participants With Clinically Significant Changes From Baseline In Vital Signs [48 weeks]

   Vital signs included seated systolic blood pressure and diastolic blood pressure, heart rate, respiration rate, and temperature.

4. Number of Participants With Clinically Significant Changes From Baseline In Clinical Laboratory Results [48 weeks]

   The clinical laboratory evaluations performed included serum chemistry, complete blood count (hematology), and urinalysis.

5. Number of Participants With Overall Suicidal Behaviors and/or Ideation at Baseline and Post-Baseline [48 weeks]

   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).

6. Change From Baseline in GNEM-FAS Expanded Version Mobility Domain Subscale Scores Over Time [Baseline, Weeks 12, 24, 36, and 48]

   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.

7. Change From Baseline in GNEM-FAS Expanded Version Upper Extremity Domain Subscale Scores Over Time [Baseline, Weeks 12, 24, 36, and 48]

   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.

8. Change From Baseline in GNEM-FAS Expanded Version Self-Care Domain Subscale Scores Over Time [Baseline, Weeks 12, 24, 36, and 48]

   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.

9. Change From Baseline in GNEM-FAS Expanded Version Total Scores Over Time [Baseline, Weeks 12, 24, 36, and 48]

   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.

10. Change From Baseline in HHD Raw Strength (Grip) Over Time [Baseline, Weeks 12, 24, 36, and 48]

    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.

11. Change From Baseline in HHD Raw Strength (Shoulder Abductors) Over Time [Baseline, Weeks 12, 24, 36, and 48]

    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.

12. Change From Baseline in HHD Raw Strength (Wrist Extensors) Over Time [Baseline, Weeks 12, 24, 36, and 48]

    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.

13. Change From Baseline in HHD Muscle Strength in Knee Extensors Over Time [Baseline, Weeks 12, 24, 36, and 48]

    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.

14. Change From Baseline in HHD Raw Strength (Key Pinch) Over Time [Baseline, Weeks 12, 24, 36, and 48]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female, aged ≥ 18 years old

• Willing and able to provide written, signed informed consent after the nature of the study has been explained, and before any research-related procedures are conducted

• Have a documented diagnosis of GNEM, HIBM, distal myopathy with rimmed vacuoles (DMRV), or Nonaka disease due to previously demonstrated mutations in the gene encoding the GNE/N-acetylmannosamine kinase (MNK) enzyme (genotyping will not be conducted in this study).

• Should meet the criteria for severe ambulatory impairment defined below:

• Unable to rise from a seated position to standing without help from another person, assistive device(s), stationary object, or other support AND

• Unable to walk without the assistance of another person OR if able to walk (use of assistive device(s) permitted), requires at least 2 minutes to walk 40 meters (one full lap of the 6-minute walk test [6MWT] course) AND

• Use of wheelchair or scooter for activities outside of the home or unable to leave the home independently

• Willing and able to comply with all study procedures

• Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use highly effective method of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation or true abstinence (when this is in line with the preferred and usual lifestyle of the subject) which means not having sex because the subject chooses not to), from the period following the signing of the informed consent through 30 days after last dose of study drug

• Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause for at least two years, have had tubal ligation at least one year prior to Screening, or who have had a total hysterectomy or bilateral salpingo-oophorectomy

Exclusion Criteria:

• Ingestion of N-acetyl-D-mannosamine (ManNAc), SA, or related metabolites; intravenous immunoglobulin (IVIG); or anything that can be metabolized to produce SA in the body within 60 days prior to the Screening Visit

• Prior participation in a clinical trial involving treatment with Ace-ER/placebo and/or Sialic Acid immediate release (SA-IR) in the past year

• Has had any hypersensitivity to aceneuramic acid or its excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects

• Has serum transaminase (i.e. aspartate aminotransferase [AST] or gamma-glutamyl transpeptidase [GGT]) levels greater than 3X the upper limit of normal (ULN) for age/gender, or serum creatinine of greater than 2X ULN at Screening

• Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study

• Use of any investigational product or investigational medical device within 30 days prior to Screening, or anticipated requirement for any investigational agent prior to completion of all scheduled study assessments

• Has a condition of such severity and acuity, in the opinion of the investigator, that it warrants immediate surgical intervention or other treatment or may not allow safe participation in the study

• Has a concurrent disease, active suicidal ideation, or other condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study, or would interfere with study participation or would affect safety

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Irvine	Orange	California	United States	92868
2	Washington University, St. Louis	Saint Louis	Missouri	United States	63110
3	NYU Langone Medical Center	New York	New York	United States	10016
4	University Alexandrovska, Bulgaria	Sofia		Bulgaria	1431
5	McMaster University	Hamilton	Ontario	Canada	L8N 3Z5

Sponsors and Collaborators

• Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 29, 2017
• Study Protocol - Mar 15, 2017

More Information

Publications

None provided.

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02731690
• Other Study ID Numbers: UX001-CL203
• First Posted: Apr 7, 2016
• Last Update Posted: Feb 19, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Ultragenyx Pharmaceutical Inc: GNE Myopathy; Nonaka; GNEM; Hereditary Inclusion Body Myopathy; HIBM; DMRV; QSM
• Additional relevant MeSH terms: Muscular Diseases; Distal Myopathies

Study Results

Participant Flow

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

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 Participants	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.0 (13.97)
Sex: Female, Male (Count of Participants)
Female	25 59.5%
Male	17 40.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	42 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	31 73.8%
Asian	2 4.8%
Other (Not Specified)	9 21.4%
Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	10.63 (7.816)
GNEM-FAS Upper Extremity Domain Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.20 (8.897)
GNEM-FAS Self-Care Domain Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	13.00 (7.413)
GNEM-FAS Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	38.83 (23.116)
Hand-Held Dynamometry (HHD) Raw Strength: Average Grip (kgf) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kgf]	5.535 (7.6778)
HHD Raw Strength: Average Shoulder Abduction (kgf) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kgf]	3.880 (4.4583)
HHD Raw Strength: Average Wrist Extension (kgf) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kgf]	3.532 (3.5177)
HHD Lower Extremity Muscle Strength: Average Knee Extension (kgf) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kgf]	10.50 (8.001)
HHD Raw Strength: Key Pinch (kgf) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kgf]	1.790 (2.1614)

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.
Measure Participants	42
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.
Measure Participants	42
Prior Medications	31 73.8%
Concomitant Medications	33 78.6%

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.
Measure Participants	42
Number [participants]	0 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.
Measure Participants	42
Number [participants]	0 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.
Measure Participants	42
Hematology	0 0%
Clinical Chemistry	2 4.8%
Urinalysis	0 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.
Measure Participants	42
Overall Suicidal Behaviors: Baseline	1 2.4%
Overall Suicidal Behaviors: Post-Baseline	0 0%
Non-Suicide Self-Injurious Behavior: Baseline	0 0%
Non-Suicide Self-Injurious Behavior: Post-Baseline	0 0%
Completed Suicide: Post-Baseline	0 0%
Overall Suicidal Ideation: Baseline	7 16.7%
Overall Suicidal Ideation: Post-Baseline	1 2.4%

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.
Measure Participants	41
Week 12	0.16
Week 24	-0.65
Week 36	-0.69
Week 48	-1.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.57
Week 24	-0.62
Week 36	-0.51
Week 48	-1.91

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	-0.39
Week 24	-0.71
Week 36	-0.83
Week 48	-0.40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.35
Week 24	-1.95
Week 36	-2.02
Week 48	-3.34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.258
Week 24	0.128
Week 36	0.038
Week 48	-0.261

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.339
Week 24	0.379
Week 36	0.437
Week 48	-0.277

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.235
Week 24	0.152
Week 36	0.358
Week 48	-0.123

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

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

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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.80
Week 24	1.35
Week 36	2.05
Week 48	2.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 24
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 36
	Type of Statistical Test	Superiority
	Comments
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

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	UX001 6g/Day
	Comments	Week 48
	Type of Statistical Test	Superiority
	Comments
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

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.
Measure Participants	41
Week 12	0.110 (0.7083)
Week 24	0.112 (0.6534)
Week 36	0.049 (0.8090)
Week 48	0.318 (0.9509)

Adverse Events

Time Frame	48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
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 (%)	# Events
Total	0/42 (0%)
Serious Adverse Events
	Ace-ER 6 g/Day
	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)
Infections and infestations
Pyelonephritis	1/42 (2.4%)
Sepsis	1/42 (2.4%)
Renal and urinary disorders
Nephrolithiasis	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Ace-ER 6 g/Day
	Affected / at Risk (%)	# Events
Total	26/42 (61.9%)
Gastrointestinal disorders
Abdominal distension	7/42 (16.7%)
Abdominal pain upper	6/42 (14.3%)
Dyspepsia	3/42 (7.1%)
Dysphagia	3/42 (7.1%)
Flatulence	7/42 (16.7%)
Nausea	3/42 (7.1%)
General disorders
Fatigue	3/42 (7.1%)
Oedema peripheral	3/42 (7.1%)
Infections and infestations
Upper respiratory tract infection	7/42 (16.7%)
Urinary tract infection	3/42 (7.1%)
Injury, poisoning and procedural complications
Fall	4/42 (9.5%)
Metabolism and nutrition disorders
Diabetes mellitus	3/42 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/42 (7.1%)
Back pain	3/42 (7.1%)
Muscular weakness	4/42 (9.5%)
Pain in extremity	4/42 (9.5%)
Nervous system disorders
Headache	3/42 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	3/42 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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