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)

Study Overview
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Brief Summary
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The objective of this study is to evaluate the long-term safety and efficacy of Ace-ER treatment in subjects with GNEM.

Detailed Description
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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).

Official Title
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Phase 3B Open-Label Extension Study to Evaluate the Safety and Efficacy of Aceneuramic Acid Extended-Release (Ace-ER) Tablets in Patients With GNE Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)

Conditions
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Hereditary Inclusion Body Myopathy, Distal Myopathy With Rimmed Vacuoles, Distal Myopathy, Nonaka Type, GNE Myopathy, Quadriceps Sparing Myopathy

Intervention / Treatment
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* Drug: Aceneuramic Acid Extended-Release Tablets


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria will not be eligible to participate in the study: Ingestion of N-acetyl-D-mannosamine (ManNAc) 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 Has had any hypersensitivity to sialic acid (SA) or its excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: Aceneuramic Acid Extended-Release Tablets<br>Participants will take 4 tablets (500 mg Ace-ER each for 2 g per dose) orally 3 times per day (TID). | Drug: Aceneuramic Acid Extended-Release Tablets<br> <br> * Other names: Ace-ER;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | Baseline, Weeks 8, 16, 24, 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Weeks 8, 16, 24, 48 | 
| 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. | Baseline, Weeks 8, 16, 24, 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 
| 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. | Baseline, Weeks 8, 16, 24, and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GNE Myopathy, GNEM, Nonaka, Hereditary Inclusion Body Myopathy, HIBM, DMRV, QSM