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RUBIVAL Clinical Trial

This clinical trial investigates the effectiveness of sodium valproate treatment on long-term memory in children with Rubinstein-Taybi syndrome (RTS). The study also evaluates brain imaging profiles, motor skills, cognitive and developmental profiles, and histone acetylation profiles. The trial follows a double-blind, randomized design with a control group and includes cognitive assessments, motor skill tasks, MRI scans, and biological analyses.

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RUBIVAL Clinical Trial

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  1. RUBIVAL Clinical Trial Functional Imaging and Therapeutic Trial in RTS children Pr. Didier Lacombe Genetic Dept., University Hospital, Bordeaux This biomedical research received funding under the program hospitalier of clinical research in 2011 with the support of Rubinstein Taybi syndrome Fondation under the aegis of Fondation de France

  2. Eric KANDEL, Nobel price 2000

  3. RTS mice

  4. SRT Clinical Trial • HDAC inhibitors : • Trichostatine A • Sodium Valproate : Marketed Anti-epileptictreatment (30 mg/kg), crosses the blood-brainbarrier

  5. An exploratory phase 2 therapeutic trial («proof of concept ») • Primaryendpoint : To estimate the efficiencyafter one year of sodium valproatetreatment (30 mg/kg/j) on long term memory in RTS children. • SecondaryOutcomes : - Special brain imaging profile and motor skills (posturology and motor coordination in a visuo-manual pointing task) - Cognitive and developmental profile - Histone acetylation profile

  6. Study design • Monocentric,double-blind phase 2 clinical trial, designed as a one-step Fleming with a control group. Rubival is a two-parallel group randomized trial: - Placebo group of 20 RTS patients - Group of 40 RTS patients taking sodium valproate (HDAC inhibitor) with an oral dosage of 30 mg/kg/jour

  7. Inclusion Criteria: • Children over 6 and under 21 • RTS confirmed by a CREBBP or EP300 genes identified 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

  8. 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

  9. TREATMENT PERIOD V0 = Screening-baseline assesment battery test and evaluation scale Motor skill tasks MRI Randomization sodium valproate group 2 per day in morning and evening 1 day to 12 months after randomization Biologilical analysis after 1 month, 2 months, and 3 months of treatment for survey After 6 mouth of treatment, V1 : Battery test only for primary outcome After 12 month of treatment, V2 : battery test and evaluation scale Motor skill tasks MRI 15 days after V2, treatment stopped with decreased dose Placebo group 2 per day in morning and evening 1 day to 12 months after randomization Biologilical analysis after 1 month, 2 months, and 3 months of treatment for survey After 6 mouth of treatment, V1 : Battery test only for primary outcome After 12 month of treatment, V2 : battery test and evaluation scale Motor skill tasks MRI 15 days after V2, treatment stopped with decreased dose

  10. Inclusions Number of patients expected : 60, number of patients enrolled : 41 Enrollement have been stopped at 41 patients with the Scientific Committee agreement

  11. RTS clinical trial • Number of patients included : 41 • 1 First inclusion : April 03 2012 • Last inclusion : September 17 2013 • Last Follow up visit : September 02 2014 • Freezing of data base : January 22 2016

  12. Population caracteristic at V0 More girls in placebo group

  13. Assesments tools • IMAGING • MOTOR SKILLS • NEUROSPYCHOLOGICAL BATTERY TEST AND EVALUATION SCALE • HISTONE ACETYLATION PROFILE

  14. NEUROSPYCHOLOGICAL BATTERY TEST AND EVALUATION SCALE • VO: mémory + langage tests, rater : speech therapist ; parents interview and cognitive overall assesments, rater Psychologist • V1 : mémory + langage tests, rater : speech therapist • V2: mémory + langage tests, rater : speech therapist ; parents interview and cognitive overall assesments, rater Psychologist

  15. NEUROSPYCHOLOGICAL BATTERY TEST AND EVALUATION SCALEMémory tests • Subtests of battery test adapted to cognitive capacities of RTS children and for all children in this study • Subtests of neuropsychological battery test design especially for memory evaluation ( CMS (Chidren Memory Scale), RBMT( Rivermead Behavourial Memory Test) • Tests for long term memory and also for short-term memory • Tests for chidren with or without speech

  16. Primary outcome measure Memory tests • 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 recognized image. • 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.

  17. NEUROSPYCHOLOGICAL BATTERY TEST AND EVALUATION SCALE Tests for primaryoutcome ( visual long term memory): • « dot location » CMS subtest • « image recognition » RBMT subtest

  18. NEUROSPYCHOLOGICAL BATTERY TESTAND EVALUATION SCALE Tests for secondaryoutcome: No speech test -  « Images location » CMS (visual short-term memory) • «  faces recognition » RBMT (visual long term memory) • EVIP et morphosyntaxic ECOSSE. • LEITER evaluationscale Speech tests -  «wordrecall » CMS (auditive long term memory). - Subtest of NEPSY

  19. Imaging Whole-brain imaging: • Conventional morphological MRI T1 (macroscopic) • Difusion tenseur Imaging (DTI)(microscopic) • Fonctionnal imaging, T2

  20. Imagingfonctionnal imaging • To look for possible links between identified anatomical anomalies and motor deficit or/and cognitive disorder highlighted during psychological and behavioural explorations in order to have a better understanding of observed disorder physiopathology and in a long term, to suggest more appropriate patient management. • To explore fonctionning of neural network at rest.

  21. IRM

  22. Motor skills Severaltasks : • Visuo-manualpointingtask • Mobile interception task (Mesurementswithadhesive markers and cameras) • Posturometry : to stand on a platformstilleyes open and aftereyesclosed

  23. Tête Bras: Epaules, coudes et mains Pieds Centre de pression, forces Plateforme de force au sol

  24. HISTONE ACETYLATION PROFILE Studying histone acétylation isuseful : • To be sure thanvalproatetreatment have an effect on histone acétylation 2) To look for an effect of valproate dose taken by patients on histone acétylation level 3) To look for a corrélation betweenimprovementlevel of phénotype and the histone acétylation level.

  25. Tests fonctionnels d’acétylation des histones Sang des patients V0 V1 V2 T0 6 mois 12 mois Isolement des lymphocytes Fixation de la chromatine Immunoprécipitation Chromatine (mesure du niveau d’acétylation au niveau de gènes cibles de CREBBP) Extraction ARN RT-PCR quantitative (mesure du niveau d’expression de gènes cibles de CREBBP) Extraction protéique (Histones) Western Blot (mesure du degré d’acétylation des Histones) NR4A1 NR4A2 GLI3 acH2B/H2B acH3/H3 acH4/H4 NR4A2

  26. STUDY DESIGN PATIENTS SELECTION RTS carriers confirmed by a genetic study with a CREBBP gene or EP300 gene mutation Children over 6 and under 21 60 patients SELECTION PERIOD : 18 months Randomization Drug usualy used in epilepsy treatment Study time frame: 30 months Sodium valproate 30 mgr/kg/j, 2 times a day Morning and evening 40 patients Placebo 30 mgr/kg/j 2 times a day Morning and evening 20 patients Treatment PERIOD : 12 months Double-blind phase 2 clinical trial, randomized in two parallèle group Double blind : nobody knows if child takes sodium valproate or placebo, neither the medical team, nor the child family

  27. Secondary Outcome Measures •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 •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 •Histone acetylation profile -Global acetylation level -Acetylation level of selected gene -Measurement of selected gene expression

  28. Description of inclusions Number of patients randomised (n = 41 ) Randomised in treatment group : sodium valproate (n = 28) Randomised in placebo group ( n = 13) • Lost to follow-up ( n = 0) • Treatment discontinuation (n = 3 ) : • -somnolence, slow réactions,weigthincrease (4kgs in 4 months) ( n = 1) • SAE : lowerlimbsedema ( n = 1) • weigthincrease and no periodduring a long time (n = 1) Lost to follow-up ( n = 0) Patient wronglyincluded (n = 1 ) : - no compliance with the following inclusion criteria : sufficient cognitive capacities for neuropsychological evaluation Analysed (n=28) Analysed (n=12)

  29. ANALYSIS OF PRINCIPAL ENDPOINT

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