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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

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

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

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Study Type : Interventional  (Clinical Trial)
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 : April 29, 2016
Actual Primary Completion Date : January 10, 2018
Actual Study Completion Date : January 10, 2018


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




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02731690


Locations
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United States, California
University of California, Irvine
Orange, California, United States, 92868
United States, Missouri
Washington University, St. Louis
Saint Louis, Missouri, United States, 63110
United States, New York
NYU Langone Medical Center
New York, New York, United States, 10016
Bulgaria
University Alexandrovska, Bulgaria
Sofia, Bulgaria, 1431
Canada, Ontario
McMaster University
Hamilton, Ontario, Canada, L8N 3Z5
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Investigators
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Study Director: Medical Director Ultragenyx Pharmaceutical Inc
  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:
Statistical Analysis Plan  [PDF] March 29, 2017
Study Protocol  [PDF] March 15, 2017

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Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02731690    
Other Study ID Numbers: UX001-CL203
First Posted: April 7, 2016    Key Record Dates
Results First Posted: February 19, 2019
Last Update Posted: February 19, 2019
Last Verified: February 2019
Keywords provided by Ultragenyx Pharmaceutical Inc:
GNE Myopathy
Nonaka
GNEM
Hereditary Inclusion Body Myopathy
HIBM
DMRV
QSM
Additional relevant MeSH terms:
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Muscular Diseases
Distal Myopathies
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Muscular Dystrophies
Muscular Disorders, Atrophic
Genetic Diseases, Inborn