Rubinstein-Taybi Syndrome: Functional Imaging and Therapeutic Trial

Study Overview
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Brief Summary
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An exploratory phase 2 therapeutic trial in children from 6 to 21, RTS carriers, randomized to be treated either with sodium valproate with the usual pediatric dosage (30 mg/kg/j), or by placebo for one year. The investigator would like to include children because they could best profit from it due to their neuronal plasticity as CBP and EP300 take effect through neuronal and synaptic plasticity. The therapeutic effect of sodium valproate in RTS patients will be assessed thanks to a clinical approach (learning and memory neuropsychological evaluation, fine motor skills assessment by pointing), to a biological approach (histone acetylation functional tests), and to imaging (morphological and functional MRI).

Detailed Description
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Such a multidisciplinary approach has never been presented for this syndrome; it should enable us identifying specific cognitive and motor deficits and their association thanks to imaging markers. Assessing the various aspects of motor skills, i.e. primary (movements, standing at ease position, immobility) and complex motor skills (actions and behaviours, motor aspects of feelings and language expressions) is an integral part of the clinical examination in psychiatrics. The main interest of a functional capacity analysis is to be used as an index allowing the assessment of the nervous system's global capacities and the study of the connections between cognitive functions and motor skills Main objective: Evaluate long term memory with subtest point location - CMS and image recognition RBMT A patient is said to be responder if after one year his or her test result increase for one point at least one of the two tests : a increase of one point to point location or image recognition. Double-blind phase 2 clinical trial, designed as a one-step Fleming design but with a control group. Rubival is a two-parallel group randomized trial: a placebo group of 20 patients a group of 40 patients taking sodium valproate (HDAC inhibitor) with an oral dosage of 30 mg/kg/jour

Official Title
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Rubinstein-Taybi Syndrome: Functional Imaging and Therapeutic Trial

Conditions
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Rubinstein-Taybi Syndrome

Intervention / Treatment
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* Drug: sodium valproate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children over 6 and under 21 RTS confirmed by a genetic study with a CBP gene or EP300 gene mutation Sufficient cognitive capacities for neuropsychological evaluation Free and informed consent of the parents or guardians Children affiliated to or benefiting of the French social welfare system Exclusion Criteria: Contraindication to sodium valproate Women of reproductive age without effective contraception means Case history of sodium valproate treatment Monotherapy treatment for epilepsy with Lamictal with a dosage superior to 5 mg/kg/j Family history of severe hepatitis including drug Acute or chronic hepatitis Pregnancy

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Valproate<br>Group of 40 patients receiving one year of sodium valproate | Drug: sodium valproate<br>* sodium valproate (HDAC inhibitor) with an oral dosage of 30 mg/kg/jour<br>|
| Placebo Comparator: Placebo<br>Group of 20 patients receiving one year of placebo | Drug: Placebo<br>* Placebo with an oral dosage of 30 mg/kg/jour<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory tests (assessing memory learning) | The main outcome measure was to evaluate long term memory with two subtests : point location, subtest of CMS (children memory scale). The score ranges from 0 to 6 image recognition, subtest of RBMT (Rivermead Behavioural Memory Test). The score range from 0 to 10. One point for each image recognized A patient is said to be responder if after one year of treatment , his or her test result increase for one point at least one of the two tests | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Special brain imaging profile and motor skills (posturology and motor coordination in a visio-manual pointing task) | For motor skills, the profile was based on 3 tasks : posturology, motor coordination in a visuo-manual pointing task and in mobile interception task.. For brain imaging, a variety of outcome measures will be used for example, brain volume, anisotropy fraction, diffusion coefficient for structural magnetic imaging and the signal intensity for functional Magnetic Resonance Imaging | 1 year | 
| Cognitive and developmental profile | Based on the results of several battery test and evaluation scale, VABS II (Vineland Adaptative Behaviour Scale II), Leiter R, EVIP, ECOSSE, NEPSY : fluency verbal sutest, CMS : 2 subtests, RBMT : 1 subtest | 1 year | 
| Histone acetylation profile |  | 1 year | 
| Global acetylation level |  | 1 year | 
| Acetylation level of selected gene |  | 1 year | 
| Measurement of selected gene expression |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rubinstein Taybi, explorative phase 2, clinical approach, biological approach, motor skills, RTS