A Phase 3, Randomized, Double-blind, Placebo-controlled, Crossover Study to Assess the Efficacy and Safety of UX007 in the Treatment of Movement Disorders Associated With Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 44
- 试验地点
- 12
- 主要终点
- Maintenance Phase Movement Disorder Frequency
研究概览
简要总结
The primary objective of the study was to evaluate the efficacy and safety of UX007 in the treatment of disabling paroxysmal movement disorders associated with Glut1 DS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of Glut1 DS confirmed by SLC2A1 mutation
- •Males and females, aged ≥6 years old at the time of informed consent
- •At least 8 disabling paroxysmal movement disorder events in the 12 weeks prior to the Screening, by subject or caregiver report or At least 6 disabling paroxysmal movement disorder events in any 6 consecutive week period, over the last 12 week period prior to the Screening, by subject or caregiver report
- •At least 4 disabling paroxysmal movement disorder events in 6 week Run-in Period, reported in the daily electronic Glut1 DS symptom diary
- •≥80% compliance with daily electronic Glut1 DS symptom diary completion during the Run in Period
- •Not on ketogenic diet (KD), modified KD, or ketosis-inducing modified-fat diet for at least 3 months prior to Screening
- •Plasma level of beta-hydroxybutyrate (BHB) ≤ 1 mmol/L (non-fasting) at Screening
- •Provide written or verbal assent (if possible) and written informed consent by the patient(if an adult), or by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
- •Must, in the opinion of the Investigator, be willing and able to complete key aspects of the study and be likely to complete the 22-week, placebo-controlled, treatment period
- •Patient (or caregiver) must, in the opinion of the Investigator, be able to comply with accurate completion of the study daily electronic Glut1 DS symptom diary
- •Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of child-bearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
- •Participants of child-bearing potential or fertile males with partners of child-bearing potential who are sexually active must consent to use a highly effective method of contraception as determined by the site Investigator from the period following the signing of the informed consent through 30 days after last dose of study drug
排除标准
- •Any known hypersensitivity to triheptanoin or safflower oil that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
- •Prior use of triheptanoin within 30 days prior to Screening
- •History of, or current suicidal ideation, behavior and/or attempts per Columbia Suicide Severity Rating Scale (C-SSRS) at Screening or Baseline
- •Pregnant and/or breastfeeding an infant at Screening or Baseline
- •Participants unwilling or unable to discontinue use of a prohibited medication or other substance that may confound study objectives (medium chain triglyceride [MCT] oil, barbiturates, pancreatic lipase inhibitors, KetoCal or other KD supplements, and/or KD])
- •Glut1 DS treatment regimen, including antiepileptic drugs (AEDs), should be stable for at least 30 days prior to Screening
- •Use of any investigational product (drug, medical food, or supplement, including MCT oil, including coconut oil) within 30 days prior to Screening
- •Has a concurrent disease or condition, or laboratory abnormality 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 introduces additional safety concerns
- •Feeding or nutrition that, in the opinion of the dietitian, potentially affects consistent administration of study drug
研究组 & 干预措施
Double-Blind UX007 Followed by Placebo
Participants will first receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks. After a washout period of 2 weeks, they will then receive placebo for 10 weeks.
Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years.
干预措施: UX007 (Drug)
Double-Blind UX007 Followed by Placebo
Participants will first receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks. After a washout period of 2 weeks, they will then receive placebo for 10 weeks.
Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years.
干预措施: Placebo (Drug)
Double Blind Placebo Followed by UX007
Participants will first receive Placebo for 10 weeks. After a washout period of 2 weeks, they will then receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.
Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years.
干预措施: UX007 (Drug)
Double Blind Placebo Followed by UX007
Participants will first receive Placebo for 10 weeks. After a washout period of 2 weeks, they will then receive UX007 (dosed according to an age- and weight-based strategy, up to a maximum daily administration of 130 g) for 10 weeks.
Participants will have the option of rolling into the open label Extension Period, to continue UX007 treatment for up to 3 years.
干预措施: Placebo (Drug)
结局指标
主要结局
Maintenance Phase Movement Disorder Frequency
时间窗: Maintenance Phase (up to Week 22)
The frequency of paroxysmal movement disorders captured as disabling movement disorder events (normalized to a 4-week rate) observed during the Maintenance Phase in participants treated with UX007 versus placebo, as recorded by the subject/caregiver in an event-based daily Glut1 DS symptom diary.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs
时间窗: From first dose of study drug through 30-35 days after final dose. Mean (SD) treatment duration was 65.7 (12.06) and 68.3 (7.04) days for double-blind UX007 and placebo, and 305.0 (122.71) days for open-label UX007.
An Adverse Event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. Serious adverse events (SAE) was defined as an AE 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); a congenital anomaly/birth defect; other important medical event. All reported AEs with with a start date that occurred or worsened in severity on or after the first dose of study drug in the corresponding treatment period and before the first dose of study drug in the next treatment period were defined as TEAEs. AEs were graded as 1=mild, 2=moderate, 3=severe, 4=life=threatening, 5=death.
Baseline and Post-Baseline Columbia Suicide Severity Rating Scale (C-SSRS) Responses During Double-Blind Treatment Period
时间窗: Baseline, up to Week 22
The C-SSRS is a participant-rated questionnaire to assess suicidal ideation, suicidal behavior, and self-injurious behavior with no suicidal intent (yes or no responses). Positive responses (i.e., 'Yes') to C-SSRS questions correspond to events in these categories with the exception of the category 'No events'. Suicidal ideation includes the following subcategories: passive; active-nonspecific; active-method/no intent/no plan; active-intent/with or without method/no plan; active-method/intent/plan. Suicidal behavior includes the following subcategories: suicide attempt; interrupted attempt; aborted attempt; preparatory actions toward immanent suicidal behaviors; completed suicide. Suicidal ideation and/or suicidal behavior category includes participants with positive responses in the category suicidal ideation and/or suicidal behavior.
次要结局
- Change From Period Baseline in 12 Minute Walk Test (12MWT) Distance at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Health Assessment Questionnaire (Adult Form) Physical Function Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in CANTAB, Spatial Working Memory Between Errors (SWMBE) Scores at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Baseline in CANTAB, Paired Associates Learning Total Errors (PALTEA) at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Pain Interference Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Anxiety Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Upper Extremity Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Pain Interference Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Fatigue Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Sleep Disturbance Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Cognitive Function Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Fatigue Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in CANTAB, Spatial Working Memory Strategy (SWMS) Scores at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Adult Form) Social Roles and Activities Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Mobility Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Clinical Global Impression - Improvement (CGI-I) at Treatment Week 10(Week 10)
- Change From Period Baseline in PROMIS Health Assessment Questionnaire (Pediatric/Parent-Proxy Form) Peer Relationships Score at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Duration of Movement Disorder Events During Maintenance Phase(Maintenance Phase (up to 22 weeks))
- Change From Period Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB), Spatial Span (SSP) Span Length Scores at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)
- Change From Baseline in CANTAB, Paired Associates Learning First Trial Memory Score (PALFTMS) at Treatment Week 10(Period Baseline (defined as the last non-missing assessment prior to or on the date of the first dose of study drug for each double-blind Treatment Period), Week 10)