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NCT Number: NCT06018519

Relevant Outcome Measures for Creatine Transporter Deficiency Patient

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.

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Key information

Conditions

Creatine Transporter Defect Creatine deficiency, X-linked

Age range

2 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Woman, mother and child hospital, Hospices Civils de Lyon

Bron, 69500, France

Location status: Recruiting

Location contact

Aurore CURIE, MD,PhD

CONTACT

[email protected]

06 70 62 69 76 ext. +33

Aurore CURIE, MD,PhD

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

Clinical endpoints

Other
  • 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

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)

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)

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)

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).

Motor assessments

Other

29- Kinematic task (specifically designed),

30- Purdue-Pegboard test,

31- Renzi test

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)

3T MRI

Other

37- Structural, metabolic and functional data

Cardiac assessments

Other

38- ECG

39- Ultrasound

Biological collection

Other

40- Blood sample

41- Urinary sample

42- Superficial skin biopsy

Primary outcomes

  1. Clinical endpoints : number of epileptic seizures

    Time frame: Up to 90 Days

    Number of epileptic seizures

  2. Clinical endpoints : antiepileptic treatment

    Time frame: 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)

  3. Clinical endpoints : Visual analogical scale

    Time frame: Up to 90 Days

    Visual analogical scale on a target symptom defined with the parents,

  4. Clinical endpoints : actimetry

    Time frame: Up to 90 Days

    Actimetry data over 48 hours

  5. Clinical endpoints : podometry

    Time frame: Up to 90 Days

    Podometry data over 24 hours

  6. Clinical endpoints : walk test

    Time frame: Up to 90 Days

    6 minutes' walk test

  7. Clinical endpoints : Clinical examination

    Time frame: 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

  8. Clinical endpoints :Feasibility of performing an MRI

    Time frame: 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

  9. Parental questionnaires : Vineland Adaptive Behavior scale II

    Time frame: 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

  10. Parental questionnaires : Mac Arthur questionnaire

    Time frame: 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

  11. Parental questionnaires : PDD-MRS

    Time frame: 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)

  12. Parental questionnaires : Dunn sensory profile

    Time frame: 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

  13. Parental questionnaires : Aberrant Behavior Checklist

    Time frame: 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

  14. Parental questionnaires : Nisonger Child Behavior Rating form

    Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

    Nisonger Child Behavior Rating form

  15. Parental questionnaires : Social Responsiveness Scale 2

    Time frame: For all 24 CTD patients: at V1 (Day1/Day2), For 9 out 24 CTD patients: repeated at V7 (Day90).

    Social Responsiveness Scale 2

  16. Parental questionnaires : impact on primary caregiver

    Time frame: 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)

  17. Quality of life scale

    Time frame: 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)

  18. Cognitive assessments : Leiter 3 scale

    Time frame: 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

  19. Cognitive assessments : CPM-BF

    Time frame: 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

  20. Cognitive assessments : reasoning task

    Time frame: 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)

  21. Cognitive assessments : Implicit rules learning

    Time frame: 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),

  22. Cognitive assessments : WPPSI-IV

    Time frame: 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"),

  23. Cognitive assessments : Attention assessment

    Time frame: 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),

  24. Cognitive assessments : Elementary visuo-spatial perception

    Time frame: 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)

  25. Language assessments : EXALANG 3-6

    Time frame: 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

  26. Language assessments : vocabulary

    Time frame: 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,

  27. Language assessments : Automatic language analysis

    Time frame: 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).

  28. Motor assessments : Kinematic task

    Time frame: CTD patients : performed at V1 (Day1/Day2). Controls: Motor assessment at V1 (Day 1)

    Kinematic task (specifically designed)

  29. Motor assessments : Purdue-Pegboard test

    Time frame: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)

    Purdue-Pegboard test

  30. Motor assessments : Renzi test

    Time frame: CTD patients : performed at V1 (Day1/Day2), V3(Day30), and V7 (Day90). Controls: Motor assessment at V1 (Day 1)

    Renzi test

  31. Social assessments : Eye-tracking

    Time frame: 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)

  32. Social assessments : Theory of mind assessment

    Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

    Theory of mind assessment

  33. Social assessments : ADOS scale (Autism Diagnostic Observation Scale)

    Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

    ADOS scale (Autism Spectrum Disorder)

  34. Social assessments : Sensitivity to inequality

    Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

    Sensitivity to inequality

  35. Social assessments : Pro-social behaviors (help of the psychologist)

    Time frame: CTD patients : performed at V1 (Day1/Day2). Controls : Social assessment at V1(Day1)

    Pro-social behaviors (help of the psychologist)

Secondary outcomes

  1. Neuroimaging (MRI)

    Time frame: V1 (Day1/Day2)

    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

  2. Cardiac assessments : Electrocardiogram

    Time frame: CTD patients: V1 (Day1/Day2)

    Electrocardiogram (ECG) will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)

  3. Cardiac assessments : Ultrasound

    Time frame: CTD patients: V1 (Day1/Day2)

    Cardiac Ultrasound will be performed to describe CTD patients cardiac profile (especially the risk of increased QTC and/or cardiac echography abnormality)

  4. Biological collection : Blood sample

    Time frame: CTD patients: V1 (Day1/Day2)

    Blood sample (plasma and peripheral blood mononuclear cells)

  5. Biological collection : Urine sample

    Time frame: CTD patients: V1 (Day1/Day2)

    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.

  6. Biological collection : Superficial skin biopsy

    Time frame: CTD patients: V1 (Day1/Day2)

    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.

  7. Biological collection : biological profile of DTC patients compared to sex- and chronological age-matched controls

    Time frame: Up to 12 months

    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.

Study contacts

Contact information is provided by the study sponsor or research team.

Aurore CURIE, MD,PhD

CONTACT

[email protected]

06 70 62 69 76 ext. +33

Sponsors and collaborators

Lead sponsor

Hospices Civils de Lyon

Other

Registry information

Official study title

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

Acronym: CREAT_criteria

Important dates

Study start
2023
Primary completion
2028
Study completion
2028
First posted
Aug 30, 2023
Registry last updated
May 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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