Relevant Outcome Measures for Creatine Transporter Deficiency Patient (CREAT_criteria)

A Prospective Study in Creatine Transporter Deficiency (SLC6A8) Patients to Determine the Most Relevant Outcome Measures

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.

Study Overview

• Status: Recruiting
• Conditions: Creatine Transporter Defect
• Intervention / Treatment: Other: Clinical endpoints; Other: Parental questionnaires; Other: Quality of life scale; Other: Cognitive assessments; Other: Language assessments; Other: Motor assessments; Other: Social assessments; Other: 3T MRI; Other: Cardiac assessments; Other: Biological collection

• Study Type: Interventional
• Enrollment (Estimated): 197
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aurore CURIE, MD,PhD; Phone Number: +33 06 70 62 69 76; Email: aurore.curie@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69500
    • Recruiting
    • Woman, mother and child hospital, Hospices Civils de Lyon
    • Contact: Aurore CURIE, MD,PhD; Phone Number: +33 06 70 62 69 76; Email: aurore.curie@chu-lyon.fr
    • Principal Investigator: Aurore CURIE, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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)

• Male
• 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)

• female,
• 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)

• History of neurological or psychiatric disorder,
• Repetition of a grade,
• Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: CTD male patients; Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged > 5 to < 35 years.	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Parental questionnaires; 10- Adaptive assessment with Vineland Adaptive Behavior scale II, 11- Mac Arthur questionnaire regarding language, 12- Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS), 13- Dunn sensory profile, 14- Aberrant Behavior Checklist, 15- Nisonger Child Behavior Rating form, 16- Social Responsiveness Scale 2, 17- Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL); Other: Quality of life scale; 18- Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18); Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist); Other: 3T MRI; 37- Structural, metabolic and functional data; Other: Cardiac assessments; 38- ECG 39- Ultrasound; Other: Biological collection; 40- Blood sample 41- Urinary sample 42- Superficial skin biopsy
Other: Sex and chronological age matched male controls; Control group 24 male, sex and chronological age matched controls, aged > 5 to < 35 years	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist); Other: 3T MRI; 37- Structural, metabolic and functional data; Other: Biological collection; 40- Blood sample 41- Urinary sample 42- Superficial skin biopsy
Other: Sex and mental age matched male controls; Control group 24 male, sex and mental age matched controls, aged > 2 to < 8 years	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist)
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.	Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist)
Other: CTD female patients; 15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged >5 to < 60 years	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Parental questionnaires; 10- Adaptive assessment with Vineland Adaptive Behavior scale II, 11- Mac Arthur questionnaire regarding language, 12- Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS), 13- Dunn sensory profile, 14- Aberrant Behavior Checklist, 15- Nisonger Child Behavior Rating form, 16- Social Responsiveness Scale 2, 17- Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL); Other: Quality of life scale; 18- Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18); Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist); Other: 3T MRI; 37- Structural, metabolic and functional data; Other: Cardiac assessments; 38- ECG 39- Ultrasound; Other: Biological collection; 40- Blood sample 41- Urinary sample 42- Superficial skin biopsy
Other: Sex and mental age matched female controls; Control group 15 female, sex and mental age matched controls, aged > 2 to < 8 years	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist)
Other: Sex and chronological age matched female controls; Control group 15 female, sex and chronological age matched controls, aged > 5 to < 60 years	Other: Clinical endpoints; Number of epileptic seizures; Change in antiepileptic treatment (increase or decrease); Visual analogical scale on a target symptom defined with the parents,; CGI,; Actimetry data over 24 hours,; Podometry data over 24 hours,; 6 minutes' walk test,; Clinical examination; Feasibility of performing an MRI without any anesthesia on a mock scanner; Other: Cognitive assessments; 19- 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 20- CPM-BF 21- Simple reasoning task on tablet (match-to-sample task) 22- Implicit rules learning (modified Brixton), 23- 4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"), 24- Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention), 25- Elementary visuo-spatial perception (on tablets); Other: Language assessments; 26- EXALANG 3-6 (10 sub-tests testing for expressive and receptive language assessments), 27- PPVT-5 (receptive vocabulary), EVT-3 (expressive vocabulary), 28- Automatic language analysis (during a 10 minutes interaction, play).; Other: Motor assessments; 29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test; Other: Social assessments; 32- Eye-tracking analysis of social visual scenes and social preference index (movies), 33- theory of mind assessment, 34- ADOS scale (Autism Spectrum Disorder), 35- sensitivity to inequality, 36- pro-social behaviors (help of the psychologist); Other: 3T MRI; 37- Structural, metabolic and functional data; Other: Biological collection; 40- Blood sample 41- Urinary sample 42- Superficial skin biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical endpoints : number of epileptic seizures	Number of epileptic seizures	Up to 90 Days
Clinical endpoints : antiepileptic treatment	Change in antiepileptic treatment (increase or decrease)	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 endpoints : Visual analogical scale	Visual analogical scale on a target symptom defined with the parents,	Up to 90 Days
Clinical endpoints : actimetry	Actimetry data over 48 hours	Up to 90 Days
Clinical endpoints : podometry	Podometry data over 24 hours	Up to 90 Days
Clinical endpoints : walk test	6 minutes' walk test	Up to 90 Days
Clinical endpoints : Clinical examination	Clinical examination	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 endpoints :Feasibility of performing an MRI	Feasibility of performing an MRI without any anesthesia on a mock scanner	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).
Parental questionnaires : Vineland Adaptive Behavior scale II	Adaptive assessment with Vineland Adaptive Behavior scale II	For all 24 CTD patients: V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Parental questionnaires : Mac Arthur questionnaire	Mac Arthur questionnaire regarding language	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Parental questionnaires : PDD-MRS	Pervasive Development Disorder in Mentally Retarded persons Scale (PDD-MRS)	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Parental questionnaires : Dunn sensory profile	Dunn sensory profile	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Parental questionnaires : Aberrant Behavior Checklist	Aberrant Behavior Checklist	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).
Parental questionnaires : Nisonger Child Behavior Rating form	Nisonger Child Behavior Rating form	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Parental questionnaires : Social Responsiveness Scale 2	Social Responsiveness Scale 2	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).
Parental questionnaires : impact on primary caregiver	Scales assessing the impact on primary caregiver (CBI-M/ Beach Center Family QOL)	For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V3 (Day30) and V7 (Day90).
Quality of life scale	Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)	For all 24 CTD patients: At V1 (Day1/Day2) For 9 out of 24 CTD patients: Repeated at V3 (Day30) and V7 (Day90).
Cognitive assessments : Leiter 3 scale	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	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)
Cognitive assessments : CPM-BF	CPM-BF : Raven's coloured Progressive Matrices	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)
Cognitive assessments : reasoning task	Simple reasoning task on tablet (match-to-sample task)	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)
Cognitive assessments : Implicit rules learning	Implicit rules learning (modified Brixton),	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)
Cognitive assessments : WPPSI-IV	4 sub-tests from the WPPSI-IV ("zoo location" to assess spatial memory, "block design" to assess visuo-constructive abilities, "bug search" , "cancellation"),	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)
Cognitive assessments : Attention assessment	Attention assessment (4 sub-tests from KITTAP: alert, go/no go, flexibility, divided attention),	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)
Cognitive assessments : Elementary visuo-spatial perception	Elementary visuo-spatial perception (on tablets)	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)
Language assessments : EXALANG 3-6	EXALANG 3-6 - Computerized battery for the evaluation of oral and written language : 10 sub-tests testing for expressive and receptive language assessments	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)
Language assessments : vocabulary	PPVT-5 : Peabody Picture Vocabulary Test Fifth Edition = receptive vocabulary, EVT-3 : Expressive Vocabulary Test third edition,	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)
Language assessments : Automatic language analysis	Automatic language analysis (during a 10 minutes interaction, play).	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)
Motor assessments : Kinematic task	Kinematic task (specifically designed)	CTD patients : performed at V1 (Day1/Day2). Controls: Motor assessment at V1 (Day 1)
Motor assessments : Purdue-Pegboard test	Purdue-Pegboard test	CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)
Motor assessments : Renzi test	Renzi test	CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)
Social assessments : Eye-tracking	Eye-tracking analysis of social visual scenes and social preference index (movies)	CTD patients : performed at V1 (Day1/Day2), V3 (Day30) and V7 (Day90). Controls : Social assessment at V1(Day1)
Social assessments : Theory of mind assessment	Theory of mind assessment	CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Social assessments : ADOS scale (Autism Diagnostic Observation Scale)	ADOS scale (Autism Spectrum Disorder)	CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Social assessments : Sensitivity to inequality	Sensitivity to inequality	CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)
Social assessments : Pro-social behaviors (help of the psychologist)	Pro-social behaviors (help of the psychologist)	CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroimaging (MRI)	The MRI will be performed to describe structural and functional neuroanatomical profile of CTD patient in comparison to chronological age-matched controls and variability in creatine peak assessment using MR spectroscopy	V1 (Day1/Day2)
Cardiac assessments : Electrocardiogram	Electrocardiogram (ECG) will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)	CTD patients: V1 (Day1/Day2)
Cardiac assessments : Ultrasound	Cardiac Ultrasound will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)	CTD patients: V1 (Day1/Day2)
Biological collection : Blood sample	Blood sample (plasma and peripheral blood mononuclear cells)	CTD patients: V1 (Day1/Day2)
Biological collection : Urine sample	Urine sample will be collected to create a collection of biological samples associated with clinical and genomic data from CTD patients. In the future this will be usefull for research labs to investigate new biomarkers (not identified yet) or to test for the efficiency of new therapeutic approaches in vitro (on cultivated fibroblasts or after the development of iPS cells or organoïds) in this rare disease.	CTD patients: V1 (Day1/Day2)
Biological collection : Superficial skin biopsy	Superficial skin biopsy will be performed to get cultivated fibroblasts to create a collection of biological samples associated with clinical and genomic data from CTD patients. In the future this will be usefull for research labs to investigate new biomarkers (not identified yet) or to test for the efficiency of new therapeutic approaches in vitro (on cultivated fibroblasts or after the development of iPS cells or organoïds) in this rare disease.	CTD patients: V1 (Day1/Day2)
Biological collection : biological profile of DTC patients compared to sex- and chronological age-matched controls	To describe the biological profile of DTC patients compared to sex- and chronological age-matched controls. Biological profile will be performed for CTD patients and the sex- and chronological age- matched controls who agreed on participating to the biological collection.	Up to 12 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2023
• Primary Completion (Estimated): December 13, 2028
• Study Completion (Estimated): December 13, 2028

Study Registration Dates

• First Submitted: November 3, 2022
• First Submitted That Met QC Criteria: August 25, 2023
• First Posted (Actual): August 30, 2023

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Feasibility; Outcome measures; Therapeutics; Relevance; Creatine Transporter Deficiency (SLC6A8)
• Additional Relevant MeSH Terms: Creatine deficiency, X-linked
• Other Study ID Numbers: 69HCL21_0655; 2022-A02063-40 (Other Identifier: ID-RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No