Clinical Trial Results:
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
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Summary
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EudraCT number |
2015-004553-41 |
Trial protocol |
BG |
Global end of trial date |
10 Jan 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
28 Mar 2019
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First version publication date |
23 Jan 2019
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
UX001-CL203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02731690 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ultragenyx Pharmaceutical Inc.
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Sponsor organisation address |
60 Leveroni Court, Novato, United States, California 94949
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Public contact |
Medical Information, Ultragenyx Pharmaceutical Inc., 1 888-756-8657, medinfo@ultragenyx.com
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Scientific contact |
Medical Information, Ultragenyx Pharmaceutical Inc., 1 888-756-8657, medinfo@ultragenyx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Jan 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jan 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Apr 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 17
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Country: Number of subjects enrolled |
United States: 22
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Country: Number of subjects enrolled |
Canada: 3
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Worldwide total number of subjects |
42
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EEA total number of subjects |
17
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
38
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||
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Pre-assignment
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Screening details |
Subjects were screened up to 28 days before the Baseline Visit. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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UX001 6g/Day | ||||||||||||||
Arm description |
Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Aceneuramic Acid Extended-Release
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Investigational medicinal product code |
UX001
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Other name |
Ace-ER, Sialic Acid Extended Release
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
all subjects with a baseline measurement and at least 1 postbaseline measurement.
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
all enrolled subjects who received at least 1 dose of study drug.
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End points reporting groups
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Reporting group title |
UX001 6g/Day
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Reporting group description |
Open-label UX001 6000 mg (6 g) total daily dose administered orally divided into a 3-times-daily regimen. | ||
Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
all subjects with a baseline measurement and at least 1 postbaseline measurement.
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
all enrolled subjects who received at least 1 dose of study drug.
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation [1] | ||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Subjects Taking Prior and Concomitant Medications | ||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
48 weeks
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Clinically Significant Changes From Baseline In Physical Examinations | ||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
48 weeks
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Clinically Significant Changes From Baseline In Vital Signs | ||||||
End point description |
Vital signs included seated systolic blood pressure and diastolic blood pressure, heart rate, respiration rate, and temperature.
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End point type |
Secondary
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End point timeframe |
48 weeks
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Clinically Significant Changes From Baseline In Clinical Laboratory Results | ||||||||||||
End point description |
The clinical laboratory evaluations performed included serum chemistry, complete blood count (hematology), and urinalysis.
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End point type |
Secondary
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End point timeframe |
48 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Overall Suicidal Behaviors and/or Ideation at Baseline and Post-Baseline | ||||||||||||||||||||
End point 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).
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End point type |
Secondary
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End point timeframe |
48 weeks
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change From Baseline in GNEM-FAS Expanded Version Mobility Domain Subscale Scores Over Time | ||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| Notes [2] - P-values: Week 12=0.5303; Week 24=0.1646; Week 36=0.1189; Week 48=0.0706 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in GNEM-FAS Expanded Version Upper Extremity Domain Subscale Scores Over Time | ||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| Notes [3] - P-values: Week 12=0.0715; Week 24=0.1697; Week 36=0.3428; Week 48=0.0642 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in GNEM-FAS Expanded Version Self-Care Domain Subscale Scores Over Time | ||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| Notes [4] - P-values: Week 12=0.0568; Week 24=0.0533; Week 36=0.0459; Week 48=0.5678 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in GNEM-FAS Expanded Version Total Scores Over Time | ||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| Notes [5] - P-values: Week 12=0.5810; Week 24=0.0465; Week 36=0.1047; Week 48=0.0661 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in HHD Raw Strength (Grip) Over Time | ||||||||||||||||
End point description |
The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in HHD Raw Strength (Shoulder Abductors) Over Time | ||||||||||||||||
End point description |
The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in HHD Raw Strength (Wrist Extensors) Over Time | ||||||||||||||||
End point description |
The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in HHD Muscle Strength in Knee Extensors Over Time | ||||||||||||||||
End point description |
The highest force value collected using hand held dynamometer for each muscle group was used for data analysis. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in HHD Raw Strength (Key Pinch) Over Time | ||||||||||||||||
End point description |
The highest force value collected using hand held dynamometer for each muscle group was used for data analysis.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
48 Weeks (plus 30 [+5] days for participants not enrolling in extension study)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Ace-ER 6 g/day
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Reporting group description |
PLACEHOLDER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Mar 2017 |
The UX0001-CL203 Original Protocol (dated 04 December 2015) has been modified by Amendment 1 to: a) increase the planned number of enrolled subjects; b) clarify the timing and conduct of the Safety Follow-up Period for all subjects; c) clarify that study assessments for a subject should be performed in a consistent order at each visit; d) add urine microscopic examination if abnormal urinalysis results are observed; e) update information regarding safety laboratory blood and urine sample collection and the analytes to be assessed in the samples; f) instruct that the Short Form Health Survey-36 (SF-36) will only be completed for subjects when a validated version is available in the subject’s native language; g) remove the requirement for urine collection for assessment of sialic acid (SA), h) update the requirement for urine collection for N-acetyl-D-mannosamine (ManNAc); i) clarify safety reporting requirements; j) more clearly define the various study period/visits and the associated assessments; k) remove reference to the Study Reference Manual; l) clarify what will be done with leftover blood and urine samples from this study; m) correct the volume of blood to be drawn from subjects; n) correct inconsistencies between sections; o) update the retention requirement for subject identifiers, subject files, and other source data; p) update the Sponsor’s Responsible Medical Officer information; q) add the designated Coordinating Investigator. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
