A Prospective Study in Creatine Transporter Deficiency (SLC6A8) Patients to Determine the Most Relevant Outcome Measures
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 197
- 试验地点
- 2
- 主要终点
- Clinical endpoints : Visual analogical scale
研究概览
简要总结
Creatine transport deficiency (CTD) is a rare genetic disorder related to pathogenic variants in the SLC6A8 gene, located on chromosome Xq28. Clinical diagnosis of CTD is based on clinical presentation, an increased urinary creatine/creatinine ratio and a severe decreased creatine peak on 1H-MRS magnetic resonance spectroscopy.
A retrospective study with questionnaires identified that most CTD patients had moderate to severe intellectual disability. Less than one third of patients were able to speak in sentences. Seizures were present in 59% of the patients. 41% had autistic features. Motor dysfunction was mentioned in 58%, and gastrointestinal symptoms were reported in 35% of the patients.
Several new therapeutic avenues are currently emerging in this disease for which no treatment has been available until now : cyclocreatine (interesting but unfortunately with very little clinical applicability due to its toxicity; dodecyl creatine ester incorporated into lipid nanocapsules with intranasal administration; pharmaco-chaperoning (for the folding-deficient creatine transporter variants, Ultragenyx pharmaceuticals new prodrug designed to deliver creatine to the brain (UX068). These new pharmacological treatment options may offer future opportunities to improve cognition in CTD patients.
A key issue is to determine outcome measures that are accessible to these patients, despite the importance of their cognitive deficit. In a preliminary study (on 31 CTD patients), investigators showed for example, that 75% of patients were unable to perform a Wechsler scale, which is one of the most used neuropsychological test to determine patient IQ (intelligence quotient). Most of the existing cognitive tests were developed to distinguish typically developing persons and ID (intellectual disability) patients, leading to a floor effect in the latter who systematically fail these tests. Therefore, these tests are not adapted to capture the potential effect of a drug in ID patient group. The identification of reliable and sensitive outcome measures for use in clinical trials in ID patients was recognized as a priority in a meeting convened by the NIH. N-of-1 trials (also called Single-Case Experimental Designs or SCEDs) appear of great interest for rare diseases, statistical power coming from the number of repeated measures, which leads to choose outcome measures that can be repeated multiple times.
This innovative study will allow to efficiently preparing future therapeutic trials, by specifying the phenotype of the patients, and by determining the most adapted outcome measures taking into account their cognitive deficiency and the type of experimental design to be used in the context of rare diseases.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male CTD patients (n=24)
- •Male CTD patients having a confirmed mutation in the SLC6A8 gene,
- •Aged > 5 to < 35 years
- •Whose maternal language is French,
- •Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent,
- •Affiliated to national Health Insurance system or parents/legal guardian affiliated to national health insurance system.
- •Female CTD patients (n=15)
- •Female CTD patients having a confirmed mutation in the SLC6A8 gene,
- •Aged > 5 to < 60 years,
- •Whose maternal language is French,
- •Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent.
- •Affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system
- •Sex- and chronological age-matched controls (n=24)
- •Aged > 5 to < 35 years
- •Whose maternal language is French,
- •Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent,
- •Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system.
- •Sex- and chronological age-matched female controls (n=15)
- •Aged > 5 to < 60 years,
- •Whose maternal language is French,
- •Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent
- •Affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system
- •Sex- and mental age-matched controls (n=39)
- •Male and female
- •Aged > 2 to < 8 years
- •Whose maternal language is French,
- •For whom parents/legal guardian have signed the informed consent,
- •Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system.
- •Typically developed children (n=80)
- •Male and female
- •Aged > 2 to < 8 years
- •Whose maternal language is French,
- •For whom parents/legal guardian have signed the informed consent,
- •Affiliated to national health insurance system or parents/legal guardian affiliated to national health insurance system.
- •Sex- and chronological age-matched controls and Sex- and mental age-matched controls, aged < 8 years, could also be included in the Typically developed children group, as the data from the Typically developed children are only necessary to complete the developmental trajectory of the new tasks.
- •Non-inclusion Criteria:
- •CTD patients (n=39):
- •Having a contraindication to the MRI examination (people using a pacemaker or an insulin pump, people wearing a metal prosthesis or an intracerebral clip, and claustrophobic subjects),
- •Refusal of the subject and/or the subject's parents to be informed of possible abnormalities detected by MRI,
- •Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the cardiac assessment.
- •Sex- and chronological age-matched controls (n=39)
- •History of neurological or psychiatric disorder,
- •Repetition of a grade,
- •Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy),
- •For participants agreeing on performing the MRI examination, having a contraindication to the MRI examination (use of a pacemaker or an insulin pump, people wearing a metal prosthesis or an intracerebral clip, and claustrophobic subjects) and refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected by MRI.
- •Sex- and mental age-matched controls (n=39)
- •History of neurological or psychiatric disorder,
- •Repetition of a grade,
- •Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy).
- •Typically developed children (n=80)
- 另有 3 项未显示
排除标准
- 未提供
研究组 & 干预措施
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Biological collection (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: 3T MRI (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: 3T MRI (Other)
Typically developed children
Control group 80 typically developed children aged > 2 to < 8 years, which corresponds to the mental age of CTD patients.
40 children aged > 2 to < 5 years, and 40 children aged > 6 to < 8 years will perform the newly developed outcome measures.
干预措施: Motor assessments (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Clinical endpoints (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Parental questionnaires (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Motor assessments (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Social assessments (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: 3T MRI (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Cardiac assessments (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Biological collection (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Clinical endpoints (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Quality of life scale (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Cognitive assessments (Other)
CTD male patients
Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.
干预措施: Language assessments (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Cognitive assessments (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Language assessments (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Motor assessments (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: Social assessments (Other)
Sex and chronological age matched male controls
Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years
干预措施: 3T MRI (Other)
Sex and mental age matched male controls
Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Clinical endpoints (Other)
Sex and mental age matched male controls
Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Cognitive assessments (Other)
Sex and mental age matched male controls
Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Language assessments (Other)
Sex and mental age matched male controls
Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Motor assessments (Other)
Sex and mental age matched male controls
Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Social assessments (Other)
Typically developed children
Control group 80 typically developed children aged > 2 to < 8 years, which corresponds to the mental age of CTD patients.
40 children aged > 2 to < 5 years, and 40 children aged > 6 to < 8 years will perform the newly developed outcome measures.
干预措施: Cognitive assessments (Other)
Typically developed children
Control group 80 typically developed children aged > 2 to < 8 years, which corresponds to the mental age of CTD patients.
40 children aged > 2 to < 5 years, and 40 children aged > 6 to < 8 years will perform the newly developed outcome measures.
干预措施: Language assessments (Other)
Typically developed children
Control group 80 typically developed children aged > 2 to < 8 years, which corresponds to the mental age of CTD patients.
40 children aged > 2 to < 5 years, and 40 children aged > 6 to < 8 years will perform the newly developed outcome measures.
干预措施: Social assessments (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Cognitive assessments (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Cardiac assessments (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Biological collection (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Clinical endpoints (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Parental questionnaires (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Quality of life scale (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Language assessments (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Motor assessments (Other)
CTD female patients
15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years
干预措施: Social assessments (Other)
Sex and mental age matched female controls
Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Clinical endpoints (Other)
Sex and mental age matched female controls
Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Cognitive assessments (Other)
Sex and mental age matched female controls
Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Language assessments (Other)
Sex and mental age matched female controls
Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Motor assessments (Other)
Sex and mental age matched female controls
Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years
干预措施: Social assessments (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Clinical endpoints (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Cognitive assessments (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Language assessments (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Motor assessments (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Social assessments (Other)
Sex and chronological age matched female controls
Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years
干预措施: Biological collection (Other)
结局指标
主要结局
Clinical endpoints : Visual analogical scale
时间窗: Up to 90 Days
Visual analogical scale on a target symptom defined with the parents,
Clinical endpoints : walk test
时间窗: Up to 90 Days
6 minutes' walk test
Clinical endpoints : antiepileptic treatment
时间窗: For all 24 CTD patients: all examinations at V1 (Day 1/Day2) For 9 out of 24 CTD patients: examinations repeated every two weeks at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).
Change in antiepileptic treatment (increase or decrease)
Clinical endpoints : Clinical examination
时间窗: For all 24 CTD patients: all examinations at V1 (Day 1/Day2) For 9 out of 24 CTD patients: examinations repeated every two weeks at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).
Clinical examination
Clinical endpoints :Feasibility of performing an MRI
时间窗: For all 24 CTD patients: all examinations at V1 (Day 1/Day2) For 9 out of 24 CTD patients: examinations repeated every two weeks at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).
Feasibility of performing an MRI without any anesthesia on a mock scanner
Parental questionnaires : Dunn sensory profile
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Dunn sensory profile
Clinical endpoints : podometry
时间窗: Up to 90 Days
Podometry data over 24 hours
Parental questionnaires : Vineland Adaptive Behavior scale II
时间窗: For all 24 CTD patients: V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Adaptive assessment with Vineland Adaptive Behavior scale II
Parental questionnaires : Nisonger Child Behavior Rating form
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Nisonger Child Behavior Rating form
Quality of life scale
时间窗: For all 24 CTD patients: At V1 (Day1/Day2) For 9 out of 24 CTD patients: Repeated at V3 (Day30) and V7 (Day90).
Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)
Cognitive assessments : reasoning task
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
Simple reasoning task on tablet (match-to-sample task)
Social assessments : Eye-tracking
时间窗: CTD patients : performed at V1 (Day1/Day2), V3 (Day30) and V7 (Day90). Controls : Social assessment at V1(Day1)
Eye-tracking analysis of social visual scenes and social preference index (movies)
Social assessments : ADOS scale (Autism Diagnostic Observation Scale)
时间窗: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
ADOS scale (Autism Spectrum Disorder)
Clinical endpoints : number of epileptic seizures
时间窗: Up to 90 Days
Number of epileptic seizures
Parental questionnaires : Aberrant Behavior Checklist
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90).
Aberrant Behavior Checklist
Cognitive assessments : Leiter 3 scale
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
Leiter 3 scale (4 cognitive sub-tests to be able to compute the non-verbal IQ and 2 non-verbal memory sub-tests) or Bayley 4 if Leiter 3 is not possible
Cognitive assessments : CPM-BF
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
CPM-BF : Raven's coloured Progressive Matrices
Cognitive assessments : Implicit rules learning
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
Implicit rules learning (modified Brixton),
Language assessments : EXALANG 3-6
时间窗: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)
EXALANG 3-6 - Computerized battery for the evaluation of oral and written language : 10 sub-tests testing for expressive and receptive language assessments
Cognitive assessments : WPPSI-IV
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V3 (Day30) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"),
Clinical endpoints : actimetry
时间窗: Up to 90 Days
Actimetry data over 48 hours
Parental questionnaires : Mac Arthur questionnaire
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Mac Arthur questionnaire regarding language
Parental questionnaires : PDD-MRS
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS)
Parental questionnaires : Social Responsiveness Scale 2
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Social Responsiveness Scale 2
Parental questionnaires : impact on primary caregiver
时间窗: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL)
Cognitive assessments : Attention assessment
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V3 (Day30) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention),
Language assessments : Automatic language analysis
时间窗: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)
Automatic language analysis (during a 10 minutes interaction, play).
Motor assessments : Renzi test
时间窗: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)
Renzi test
Motor assessments : Kinematic task
时间窗: CTD patients : performed at V1 (Day1/Day2). Controls: Motor assessment at V1 (Day 1)
Kinematic task (specifically designed)
Motor assessments : Purdue-Pegboard test
时间窗: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)
Purdue-Pegboard test
Social assessments : Sensitivity to inequality
时间窗: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Sensitivity to inequality
Cognitive assessments : Elementary visuo-spatial perception
时间窗: For the 24 CTD patients: at V1 (Day1/Day2), For 9 out of 24 CTD patients: repeated at V2 (Day15), V3 (Day30), V4 (Day45), V5 (Day60), V6 (Day75) and V7 (Day90). Controls: Cognitive assessment at V1(Day 1)
Elementary visuo-spatial perception (on tablets)
Language assessments : vocabulary
时间窗: For all 24 CTD patients: performed at V1 (Day1/Day2). For 9 out of 24 CTD patients: repeated at V3 (Day30), and V7 (Day90). Controls: Language assessment at V1(Day 1)
PPVT-5 : Peabody Picture Vocabulary Test Fifth Edition = receptive vocabulary, EVT-3 : Expressive Vocabulary Test third edition,
Social assessments : Theory of mind assessment
时间窗: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Theory of mind assessment
Social assessments : Pro-social behaviors (help of the psychologist)
时间窗: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Pro-social behaviors (help of the psychologist)
次要结局
- Neuroimaging (MRI)(V1 (Day1/Day2))
- Cardiac assessments : Electrocardiogram(CTD patients: V1 (Day1/Day2))
- Cardiac assessments : Ultrasound(CTD patients: V1 (Day1/Day2))
- Biological collection : Blood sample(CTD patients: V1 (Day1/Day2))
- Biological collection : Urine sample(CTD patients: V1 (Day1/Day2))
- Biological collection : Superficial skin biopsy(CTD patients: V1 (Day1/Day2))
- Neuroimaging (MRI)(V1 (Day1/Day2))
- Cardiac assessments : Electrocardiogram(CTD patients: V1 (Day1/Day2))
- Cardiac assessments : Ultrasound(CTD patients: V1 (Day1/Day2))
- Biological collection : Blood sample(CTD patients: V1 (Day1/Day2))
- Biological collection : Urine sample(CTD patients: V1 (Day1/Day2))
- Biological collection : Superficial skin biopsy(CTD patients: V1 (Day1/Day2))
- Biological collection : biological profile of DTC patients compared to sex- and chronological age-matched controls(Up to 12 months)