Clinical Trial Results:
An Open-label Extension Study to Assess the Long-term Safety and Efficacy of UX007 in Subjects with Glucose Transporter Type 1 Deficiency Syndrome
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Summary
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EudraCT number |
2015-000389-69 |
Trial protocol |
GB ES DK |
Global end of trial date |
22 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
03 May 2020
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First version publication date |
03 May 2020
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Other versions |
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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 |
UX007G-CL202
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02599961 | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
EMA/190573: Unique Product Identifier (UPI) | ||
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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 8887568657, medinfo@ultragenyx.com
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Scientific contact |
Medical Information, Ultragenyx Pharmaceutical Inc., +1 8887568657, 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 |
22 Oct 2019
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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 |
22 Oct 2019
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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 the study is to evaluate the long-term safety of UX007 in glucose transporter type 1 deficiency syndrome (Glut1 DS) subjects.
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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 |
10 Sep 2015
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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 |
United States: 9
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Australia: 2
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
Denmark: 1
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Worldwide total number of subjects |
15
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EEA total number of subjects |
4
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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) |
5
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
5
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study enrolled pediatric, adolescent, and adult Glut1 DS subjects who completed the UX007G-CL201 study (2013-003771-35; rollover subjects). No non-rollover subjects (subjects from other clinical studies, investigator sponsored trials, or expanded access/compassionate use treatment) enrolled. | ||||||||||||||||
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Pre-assignment
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Screening details |
For continuing UX007G-CL201 subjects, the Week 52 visit of that study may have been conducted in conjunction with the Baseline visit for this study to avoid duplication of assessments. | ||||||||||||||||
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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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UX007 (Triheptanoin) | ||||||||||||||||
Arm description |
UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
triheptanoin
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Investigational medicinal product code |
UX007
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Other name |
C7 oil, glycerol triheptanoate, glycerol trienanthate, 1, 2, 3- trienanthoylglycerol, trienanthin, 2,3-di(heptanoyloxy)propyl heptanoate
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
Treatment was mixed with food (or formula, if appropriate) and administered orally (PO) or by gastrostomy tube at least four times per day (breakfast, lunch, dinner, and before bed).
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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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End points reporting groups
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Reporting group title |
UX007 (Triheptanoin)
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Reporting group description |
UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake. | ||
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Discontinuations Due to TEAEs, and Deaths [1] | ||||||||||||||||||||||||
End point description |
An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. Serious adverse events (SAEs) are AEs that at any dose, in the view of either the investigator or sponsor, 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; a congenital anomaly/birth defect; other important medical event. An AE was considered a TEAE if it occurred on or after the first dose in this study, and was not present prior to the first dose in this study, or it was present at the first dose in this study but increased in severity during the study. Severity was based on Common Terminology Criteria for Adverse Events (CTCAE): 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = death related to AE.
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End point type |
Primary
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End point timeframe |
From first dose of study drug up to 36 months. The mean (SD) treatment duration was 667.9 (357) days.
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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 |
Change From Baseline Over Time in Overall Seizure Frequency Per 4 Weeks | ||||||||||||||||||||||||
End point description |
The number of observable seizures were recorded by the subject or caregiver via diary throughout the study. Observable seizures were defined as: generalized tonic-clonic; generalized tonic; generalized clonic; generalized atonic; partial/focal with secondary generalization; myoclonic, myoclonic (astatic) atonic, myoclonic tonic; complex partial/focal; simple partial/focal motor; absence.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0-3, Month 4-6, Month 7-9, Month 10-12, Month 13-18, Month 19-24, Month 25-30, Month 31-36
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Attachments |
Untitled (Filename: Statistical Analysis for Change From Baseline Over Time in Overall Seizure Frequency Per 4 Weeks.docx) |
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| Notes [2] - n=subjects with a baseline (BL) and postbaseline (PBL) assessment at given time point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline Over Time in CNS Total Score | ||||||||||||||||||
End point description |
The CNS evaluates measures of neurological function and development delay, and is the sum of scores for the following domains: Weight, Height, Head Circumference, General Medical Exam, Funduscopic Exam, Cranial Nerves, Stance & Gait, Involuntary Movements, Sensation, Cerebellar Function, Muscle Bulk, Tone & Strength, Myotatic Reflexes, Toe Sign, Other Findings. The CNS is only scored when all domains are measured and ranges from 0 (abnormal exam) to 76 (normal exam). Higher scores are associated with higher neurological function.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 24, Month 36
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| Notes [3] - n=subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject). |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline Over Time in SF-10 Health Survey for Children Physical Summary Score | ||||||||||||||||||||
End point description |
The SF-10 Health Survey for Children was administered to caregivers of participants aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18, Month 24, Month 30
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| Notes [4] - n=pediatric subjects with a BL and PBL assessment at given time point. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change From Baseline Over Time in SF-10 Health Survey for Children Psychosocial Summary Score | ||||||||||||||||||||
End point description |
The SF-10 Health Survey for Children was administered to caregivers of participants aged 5-17 years. Responses are used to generate 2 component summary scores: Physical Summary Score and the Psychosocial Summary Score. The T-score based scale scores were centered so that a score of 50 corresponds to the average score in a comprehensive 2006 sample (a combination of general population and supplemental disability and chronic condition samples). Higher scores are associated with better quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18, Month 24, Month 30
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| Notes [5] - n=pediatric subjects with a BL and PBL assessment at given time point. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change From Baseline Over Time in SF-12v2 Health Survey PCS Score | ||||||||||||||||
End point description |
SF-12v2 was assessed for adults 18 years of age and older. Eight domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). The PCS and MCS scores have mean of 50 and SD of 10. The T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general population T-score and scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18
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| Notes [6] - n=adult subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject). |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline Over Time in SF-12v2 Health Survey MCS Score | ||||||||||||||||
End point description |
SF-12v2 was assessed for adults 18 years of age and older. Eight domain scores were used to generate 2 component summary scores: physical health (PCS) and mental health (MCS). The PCS and MCS scores have mean of 50 and SD of 10. The T-score based scoring method scores the data in relation to U.S. general population T-scores. Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general population T-score and scores above 50 can be interpreted as above the U.S. general population T-score. Higher global scores are associated with better quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (2013-003771-35), Month 0, Month 6, Month 12, Month 18
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| Notes [7] - n=adult subjects with a BL and PBL assessment at given time point. 99999=not applicable (1 subject). |
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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 |
From first dose of study drug up to 36 months. The mean (SD) treatment duration was 667.9 (357) days.
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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 |
20.0
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Reporting groups
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Reporting group title |
UX007 (Triheptanoin)
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Reporting group description |
UX007 dosing was targeted and/or maintained at 35% of total daily caloric intake. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 Jun 2016 |
• The number of study sites was changed from ‘approximately 12’ to ‘up to 16.’ The number of subjects planned was approximated at 40 subjects from the UX007 CL201 study and additional subjects who participated in qualified ISTs.
• Updated inclusion criteria to state that all subjects at least 1 year of age at time of informed consent are eligible for participation in this study.
• Modified inclusion criteria to remove the 3 month window following completion of the feeder study, to allow more flexibility.
• The inclusion criterion regarding pregnancy testing and contraception was split into 2 separate inclusion criteria for clarity.
• The exclusion criterion regarding serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was removed, as it was not considered a likely safety concern.
• Removed specific requirements regarding percent of daily fat intake from the exclusion criteria, to allow investigators to manage subject diet.
• Removed diabetes mellitus as an exclusionary condition.
• The first secondary objective was changed to ‘Evaluate the long-term effect of UX007 efficacy on seizures associated with Glut1 DS’. This change affects multiple sections of the protocol related to statistical evaluations and analyses.
• Stopping rules were modified to correct notification procedures should unexpected and study drug-related SAEs occur, or if the study was restarted.
• The Investigational Product section was modified to specify UX007 should be mixed with food; the requirement to never administer directly as the oil was removed. In addition, the language around dose level was modified to recognize and allow the subject to remain on current dose, which may be different (ie, lower or higher) than 35% of total daily caloric intake.
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02 Jun 2016 |
(continued)
• Study Duration section was modified to state “The planned duration of treatment in this study is 3 years, or until one of the following occurs: the subject withdraws consent or is discontinued from the study at the discretion of the Investigator or Ultragenyx; the study is terminated, or until commercial availability of study drug in a subject’s region, whichever occurs first.”. Due to this change, specific references to a “3-year Treatment Extension” were changed to “Treatment Extension Period” throughout the protocol.
• Updated Prohibited Medications section to remove valproate, MCT oil, KetoCal, or other KD supplements, or other prescribed diet plan as prohibited medications; pancreatic lipase inhibitors was added to the list of prohibited medications.
• The frequency of overnight EEG assessments was increased. Interictal epileptiform discharges will not be examined as an efficacy variable.
• Efficacy assessments including Cambridge Neuropsychological Test Automated Battery Six Minute Walk Test and associated paroxysmal exertional dyskinesia (6MWT/PED), the Clinical Global Impression Scales (CGI), and the Pediatric Evaluation of Disability Inventory – Computer Adaptive Test (PEDI-CAT) were removed from the study. Study objectives and endpoints were updated to reflect this change. The Short Form Health Surveys (SF-10 and SF-12v2) will not be performed if no pre-treatment baseline data was available from feeder study.
• Beta-ketopentanoic acid (BKP) will no longer be assayed.
• Physical examination of the genitourinary system was no longer specified.
• Dietitian Consultation and Diet Assessment Section was modified to remove the requirement for a 3-day diet diary prior to the Baseline Visit. Daily caloric intake and UX007 dose determined by interview with the dietitian at the Baseline Visit.
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02 Jun 2016 |
(continued)
• Separate safety analysis and intent-to-treat populations were replaced with 1 analysis set to include all subjects who receive at least 1 dose of UX007 during the study.
• Reduction in frequency of seizures was removed as an efficacy analysis and replaced with a list of efficacy measures to be assessed.
• A coordinating investigator will be named for this multicenter study.
• The Record Retention section was updated to state that all study records must be retained for at least 25 years after the end of the clinical trial or in accordance with national law.
• The Adverse Event Reporting section was updated to match Sponsor’s current safety reporting procedures.
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28 Jul 2016 |
The main purpose of Amendment 2 was to update the list of examples of highly effective contraception methods, to add a Safety Follow-up Phone Call to standardize how AE information was collected 30 days following the last dose of UX007, and to clarify that the end of study was the last subject’s Safety Follow-up Phone Call, per Regulatory Authorities’ request for end of study clarification. |
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20 Sep 2017 |
• Phone calls were added 3 months between study site visits during Years 2 and 3.
• Optional study site visits were added 3 months between study site visits during Years 2 and 3.
• Additional language was added throughout the protocol and within the Study Schema to specify that, at the discretion of the Sponsor, additional subjects who participated in other clinical studies, ISTs, or expanded access/compassionate use treatment programs may be eligible for inclusion in UX007G-CL202.
• The window of time to draw blood for UX007 metabolites was expanded from 90 min (± 5 min) to 90 min (± 10 min) following consumption of food and study drug, as specified within Footnote 6 in the Schedule of Events.
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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 | |||
