Relevant Outcome Measures for Creatine Transporter Deficiency Patient
A Prospective Study in Creatine Transporter Deficiency (SLC6A8) Patients to Determine the Most Relevant Outcome Measures
Hospices Civils de Lyon
197 participants
Mar 13, 2023
INTERVENTIONAL
Conditions
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.
Eligibility
Inclusion Criteria54
- 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.
- 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).
Interested in this trial?
Get notified about updates and connect with the research team.
Interventions
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
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)
18- Quality of life scale (PedsQL 4.0 for children or San Martin scale if the patient is older than 18)
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)
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).
29- Kinematic task (specifically designed), 30- Purdue-Pegboard test, 31- Renzi test
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)
37- Structural, metabolic and functional data
38- ECG 39- Ultrasound
40- Blood sample 41- Urinary sample 42- Superficial skin biopsy
Locations(1)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT06018519