Relevant Outcome Measures for Creatine Transporter Deficiency Patient

NCT06018519 | Recruiting

• 2 other identifiers: 69HCL21_06552022-A02063-40
• Study Type: interventional
• Target: 197
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Creatine Transporter Defect

Keywords

Creatine Transporter Deficiency (SLC6A8); Outcome measures; Therapeutics; Feasibility; Relevance

Outcome Measures

Primary Outcomes (35)

• 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 Outcomes (7)

• 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)

Study Arms (7)

CTD male patients

OTHER

Case group 24 male CTD patients having a confirmed mutation in the SLC6A8 gene, aged \> 5 to \< 35 years.

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

Sex and chronological age matched male controls

OTHER

Control group 24 male, sex and chronological age matched controls, aged \> 5 to \< 35 years

Other: Clinical endpoints; Other: Cognitive assessments; Other: Language assessments; Other: Motor assessments; Other: Social assessments; Other: 3T MRI; Other: Biological collection

Sex and mental age matched male controls

OTHER

Control group 24 male, sex and mental age matched controls, aged \> 2 to \< 8 years

Other: Clinical endpoints; Other: Cognitive assessments; Other: Language assessments; Other: Motor assessments; Other: Social assessments

Typically developed children

OTHER

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; Other: Language assessments; Other: Motor assessments; Other: Social assessments

CTD female patients

OTHER

15 female CTD patients having a confirmed mutation in the SLC6A8 gene, aged \>5 to \< 60 years

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

Sex and mental age matched female controls

OTHER

Control group 15 female, sex and mental age matched controls, aged \> 2 to \< 8 years

Other: Clinical endpoints; Other: Cognitive assessments; Other: Language assessments; Other: Motor assessments; Other: Social assessments

Sex and chronological age matched female controls

OTHER

Control group 15 female, sex and chronological age matched controls, aged \> 5 to \< 60 years

Other: Clinical endpoints; Other: Cognitive assessments; Other: Language assessments; Other: Motor assessments; Other: Social assessments; Other: 3T MRI; Other: Biological collection

Interventions

Clinical endpoints OTHER

1. Number of epileptic seizures 2. Change in antiepileptic treatment (increase or decrease) 3. Visual analogical scale on a target symptom defined with the parents, 4. CGI, 5. Actimetry data over 24 hours, 6. Podometry data over 24 hours, 7. 6 minutes' walk test, 8. Clinical examination 9. Feasibility of performing an MRI without any anesthesia on a mock scanner

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls; Sex and mental age matched female controls; Sex and mental age matched male controls

Parental questionnaires OTHER

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)

CTD female patients; CTD male patients

Quality of life scale OTHER

18- Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)

CTD female patients; CTD male patients

Cognitive assessments OTHER

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)

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls; Sex and mental age matched female controls; Sex and mental age matched male controls; Typically developed children

Language assessments OTHER

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).

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls; Sex and mental age matched female controls; Sex and mental age matched male controls; Typically developed children

Motor assessments OTHER

29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls; Sex and mental age matched female controls; Sex and mental age matched male controls; Typically developed children

Social assessments OTHER

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)

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls; Sex and mental age matched female controls; Sex and mental age matched male controls; Typically developed children

3T MRI OTHER

37- Structural, metabolic and functional data

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls

Cardiac assessments OTHER

38- ECG 39- Ultrasound

CTD female patients; CTD male patients

Biological collection OTHER

40- Blood sample 41- Urinary sample 42- Superficial skin biopsy

CTD female patients; CTD male patients; Sex and chronological age matched female controls; Sex and chronological age matched male controls

Eligibility Criteria

• Age: 2 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Woman, mother and child hospital, Hospices Civils de Lyon

Bron, 69500, France

RECRUITING

MeSH Terms

Conditions

Creatine deficiency, X-linked

Central Study Contacts

Aurore CURIE, MD,PhD

CONTACT

06 70 62 69 76; aurore.curie@chu-lyon.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2022
• First Posted: August 30, 2023
• Study Start: March 13, 2023
• Primary Completion (Estimated): December 13, 2026
• Study Completion (Estimated): December 13, 2026
• Last Updated: December 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)