Distal Myopathy, Nonaka Type, Distal Myopathy With Rimmed Vacuoles, GNE Myopathy, Hereditary Inclusion Body Myopathy, Quadriceps Sparing Myopathy
Conditions
Keywords
GNE Myopathy, GNEM, Nonaka, Hereditary Inclusion Body Myopathy, HIBM, DMRV, QSM
Brief summary
The objective of this study is to evaluate the long-term safety and efficacy of Ace-ER treatment in subjects with GNEM.
Detailed description
This Phase 3b extension study will assess the long-term safety of Ace-ER in patients who participated in and completed study UX001-CL301 (NCT02377921), study UX001-CL202 (NCT01830972), and study UX001-CL203 (NCT02731690).
Interventions
DRUGAceneuramic Acid Extended-Release Tablets
Sponsors
Ultragenyx Pharmaceutical Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have completed UX001-CL202, UX001-CL301 or UX001-CL203 study * 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 * Willing to comply with all study procedures * Female participants of child-bearing potential or male participants with female partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use a 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
Individuals who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | 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. | 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. |
| Change From Baseline in HHD UEC Score Over Time | Baseline, Weeks 8, 16, 24, 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. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Baseline, Weeks 8, 16, 24, 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. 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. |
| Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Baseline, Weeks 8, 16, 24, and 48 | 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. |
| Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Baseline, Weeks 8, 16, 24, and 48 | 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. |
| Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Baseline, Weeks 8, 16, 24, 48 | 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. |
| Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Baseline, Weeks 8, 16, 24, and 48 | 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. |
| Change From Baseline in Total Force in Knee Extensors Over Time | Baseline, Weeks 8, 16, 24, 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. 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. |
| Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Baseline, Weeks 8, 16, 24, and 48 | 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. |
| Change From Baseline in Meters Walked in 6MWT Over Time | Baseline, Weeks 8, 16, 24, and 48 | 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. |
| Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Baseline, Weeks 8, 16, 24, 48 | 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. |
Countries
Bulgaria, Canada, France, Israel, Italy, United Kingdom, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Ace-ER 6 g/Day 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day | 142 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Discontinuation of Study by Sponsor | 134 |
| Overall Study | Other | 6 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ace-ER 6 g/Day |
|---|---|
| 30-second Weighted Arm Lift Test | 30.93 lifts STANDARD_DEVIATION 13.171 |
| Age, Continuous | 74 years STANDARD_DEVIATION 68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy Functional Activities Scale(GNEM-FAS) Mobility Score | 24.17 score on a scale STANDARD_DEVIATION 7.772 |
| GNEM-FAS Expanded Version Upper Extremity Score | 27.53 score on a scale STANDARD_DEVIATION 4.938 |
| Hand Held Dynamometry (HHD) Upper Extremity Composite Score (UEC) | 52.98 kgf STANDARD_DEVIATION 28.814 |
| HHD Lower Extremity Composite (LEC) Score | 51.91 kgf STANDARD_DEVIATION 37.474 |
| Percent of Predicted Total Force in Knee Extensors | 13.69 percent of predicted total force STANDARD_DEVIATION 15.323 |
| Percent Predicted Meters Walked in 6MWT | 49.52 percentage of predicted meters STANDARD_DEVIATION 16.962 |
| Race/Ethnicity, Customized Asian | 19 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 12 Participants |
| Race/Ethnicity, Customized White | 111 Participants |
| Sex: Female, Male Female | 74 Participants |
| Sex: Female, Male Male | 68 Participants |
| Sit-to-Stand Test | 12.75 stands STANDARD_DEVIATION 4.977 |
| Six-Minute Walk Test (6MWT) | 359.4 meters STANDARD_DEVIATION 123.94 |
| Total Force in Knee Extensors | 26.60 kgf STANDARD_DEVIATION 9.746 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 142 |
| other Total, other adverse events | 66 / 142 |
| serious Total, serious adverse events | 7 / 142 |
Outcome results
Primary
Change From Baseline in HHD UEC Score Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in HHD UEC Score Over Time | Week 8 | 0.88 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD UEC Score Over Time | Week 16 | 0.10 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD UEC Score Over Time | Week 24 | -1.40 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD UEC Score Over Time | Week 48 | -2.24 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD UEC Score Over Time | Week 48 | -2.18 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD UEC Score Over Time | Week 8 | 0.09 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD UEC Score Over Time | Week 24 | -0.49 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD UEC Score Over Time | Week 16 | -0.26 kgf |
Comparison: Week 8p-value: 0.428795% CI: [-1.17, 2.77]generalized estimating equation (GEE)
Comparison: Week 16p-value: 0.703195% CI: [-1.49, 2.21]GEE model
Comparison: Week 24p-value: 0.425395% CI: [-3.14, 1.32]GEE model
Comparison: Week 48p-value: 0.974795% CI: [-3.49, 3.38]GEE model
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs
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.
Population: Safety Analysis Set: all participants who received at least one dose of study drug in UX001-CL302.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | TEAEs | 104 Participants |
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Serious TEAEs (SAEs) | 7 Participants |
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Deaths | 0 Participants |
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | Grade 3 or 4 TEAEs | 11 Participants |
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | TEAEs Leading to Study Drug Discontinuation | 2 Participants |
| Ace-ER 6 g/Day | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), and Discontinuations Due to AEs | TEAEs Leading to Study Discontinuation | 1 Participants |
Secondary
Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 8 | 0.01 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 16 | -1.63 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 24 | -0.60 kgf |
| Ace-ER 6 g/Day | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 48 | -0.32 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 48 | -4.47 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 8 | -0.77 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 24 | -0.10 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in HHD Lower Extremity Composite (LEC) Score Over Time | Week 16 | -0.98 kgf |
Comparison: Week 8p-value: 0.654695% CI: [-2.65, 4.22]GEE model
Comparison: Week 16p-value: 0.705495% CI: [-3.97, 2.69]GEE model
Comparison: Week 24p-value: 0.844195% CI: [-5.45, 4.45]GEE model
Comparison: Week 48p-value: 0.086495% CI: [-0.59, 8.9]GEE model
Secondary
Change From Baseline in Meters Walked in 6MWT Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in Meters Walked in 6MWT Over Time | Week 8 | -1.40 meters |
| Ace-ER 6 g/Day | Change From Baseline in Meters Walked in 6MWT Over Time | Week 16 | -3.91 meters |
| Ace-ER 6 g/Day | Change From Baseline in Meters Walked in 6MWT Over Time | Week 24 | -2.73 meters |
| Ace-ER 6 g/Day | Change From Baseline in Meters Walked in 6MWT Over Time | Week 48 | -13.91 meters |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Meters Walked in 6MWT Over Time | Week 48 | -21.89 meters |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Meters Walked in 6MWT Over Time | Week 8 | -3.41 meters |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Meters Walked in 6MWT Over Time | Week 24 | -6.88 meters |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Meters Walked in 6MWT Over Time | Week 16 | -1.93 meters |
Comparison: Week 8p-value: 0.643495% CI: [-6.48, 10.49]GEE model
Comparison: Week 16p-value: 0.711895% CI: [-12.53, 8.55]GEE model
Comparison: Week 24p-value: 0.439995% CI: [-6.39, 14.69]GEE model
Comparison: Week 48p-value: 0.44395% CI: [-12.41, 28.37]GEE model
Secondary
Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 8 | 0.26 lifts |
| Ace-ER 6 g/Day | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 16 | 0.03 lifts |
| Ace-ER 6 g/Day | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 24 | 0.13 lifts |
| Ace-ER 6 g/Day | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 48 | -1.58 lifts |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 48 | -1.17 lifts |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 8 | -0.19 lifts |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 24 | -0.14 lifts |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Number of Lifts in the 30-Second Weighted Arm Lift Test Over Time | Week 16 | 0.59 lifts |
Comparison: Week 8p-value: 0.544795% CI: [-1, 1.9]GEE model
Comparison: Week 16p-value: 0.505195% CI: [-2.22, 1.09]GEE model
Comparison: Week 24p-value: 0.747895% CI: [-1.36, 1.9]GEE model
Comparison: Week 48p-value: 0.742995% CI: [-2.86, 2.04]GEE model
Secondary
Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 8 | -0.17 percent of predicted distance |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 24 | -0.38 percent of predicted distance |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 48 | -1.94 percent of predicted distance |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 16 | -0.49 percent of predicted distance |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 48 | -2.93 percent of predicted distance |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 8 | -0.45 percent of predicted distance |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 16 | -0.24 percent of predicted distance |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Meters Walked in 6MWT Over Time | Week 24 | -0.96 percent of predicted distance |
Comparison: Week 8p-value: 0.642895% CI: [-0.9, 1.46]GEE model
Comparison: Week 16p-value: 0.733495% CI: [-1.72, 1.21]GEE model
Comparison: Week 24p-value: 0.440995% CI: [-0.89, 2.04]GEE model
Comparison: Week 48p-value: 0.468795% CI: [-1.69, 3.68]GEE model
Secondary
Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 8 | -0.98 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 16 | -0.59 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 24 | -0.70 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 48 | -1.02 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 48 | -3.10 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 8 | -1.17 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 24 | -0.85 percent of predicted total force (kgf) |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Percent Predicted Total Force in Knee Extensors Over Time | Week 16 | -1.25 percent of predicted total force (kgf) |
Comparison: Week 8p-value: 0.790695% CI: [-1.22, 1.6]GEE model
Comparison: Week 16p-value: 0.353195% CI: [-0.74, 2.07]GEE model
Comparison: Week 24p-value: 0.884695% CI: [-1.92, 2.23]GEE model
Comparison: Week 48p-value: 0.016895% CI: [0.38, 3.79]GEE model
Secondary
Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 8 | -0.12 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 16 | -0.30 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 24 | -0.78 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 48 | -0.73 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 48 | -0.45 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 8 | 0.15 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 24 | -0.34 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the GNEM-FAS Expanded Version Mobility Domain Score Over Time | Week 16 | -0.12 score on a scale |
Comparison: Week 8p-value: 0.472195% CI: [-1.01, 0.47]GEE model
Comparison: Week 16p-value: 0.661195% CI: [-1.02, 0.64]GEE model
Comparison: Week 24p-value: 0.27695% CI: [-1.22, 0.35]GEE model
Comparison: Week 48p-value: 0.697795% CI: [-1.69, 1.13]GEE model
Secondary
Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 8 | 0.02 stands |
| Ace-ER 6 g/Day | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 16 | -0.04 stands |
| Ace-ER 6 g/Day | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 24 | 0.06 stands |
| Ace-ER 6 g/Day | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 48 | -0.39 stands |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 48 | -0.36 stands |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 8 | -0.05 stands |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 24 | -0.41 stands |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in the Number of Stands in the Sit-to-Stand Test Over Time | Week 16 | 0.14 stands |
Comparison: Week 8p-value: 0.860395% CI: [-0.65, 0.78]GEE model
Comparison: Week 16p-value: 0.615495% CI: [-0.86, 0.51]GEE model
Comparison: Week 24p-value: 0.199995% CI: [-0.25, 1.2]GEE model
Comparison: Week 48p-value: 0.956895% CI: [-1.25, 1.18]GEE model
Secondary
Change From Baseline in Total Force in Knee Extensors Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline in Total Force in Knee Extensors Over Time | Week 8 | 0.50 kgf |
| Ace-ER 6 g/Day | Change From Baseline in Total Force in Knee Extensors Over Time | Week 16 | -0.95 kgf |
| Ace-ER 6 g/Day | Change From Baseline in Total Force in Knee Extensors Over Time | Week 24 | 0.33 kgf |
| Ace-ER 6 g/Day | Change From Baseline in Total Force in Knee Extensors Over Time | Week 48 | 0.63 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Total Force in Knee Extensors Over Time | Week 48 | -0.08 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Total Force in Knee Extensors Over Time | Week 8 | -0.64 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Total Force in Knee Extensors Over Time | Week 24 | -0.46 kgf |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline in Total Force in Knee Extensors Over Time | Week 16 | -0.75 kgf |
Comparison: Week 8p-value: 0.150295% CI: [-0.41, 2.69]GEE model
Comparison: Week 16p-value: 0.8188-1.89% CI: [-1.89, 1.49]GEE model
Comparison: Week 24p-value: 0.512295% CI: [-1.58, 3.17]GEE model
Comparison: Week 48p-value: 0.702295% CI: [-2.96, 4.4]GEE model
Secondary
Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ace-ER 6 g/Day | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 8 | 0.68 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 24 | 0.26 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 48 | -0.82 score on a scale |
| Ace-ER 6 g/Day | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 16 | 0.34 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 48 | -0.48 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 8 | -0.02 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 16 | -0.40 score on a scale |
| Ace-ER 6 g/Day (Parent Study Treatment: Placebo) | Change From Baseline on the GNEM-FAS Upper Extremity Domain Score Over Time | Week 24 | -0.17 score on a scale |
Comparison: Week 8p-value: 0.064895% CI: [-0.04, 1.45]GEE model
Comparison: Week 16p-value: 0.069295% CI: [-0.06, 1.55]GEE model
Comparison: Week 24p-value: 0.431795% CI: [-0.65, 1.52]GEE model
Comparison: Week 48p-value: 0.641695% CI: [-1.78, 1.1]GEE model