Transcript Prof Didier Lacombe – Clinical Trial of Effect of Sodium Valproate on

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
Eric KANDEL, Nobel price 2000
RTS mice
SRT Clinical Trial
• HDAC inhibitors :
• Trichostatine A
• Sodium Valproate :
Marketed Anti-epileptic treatment (30 mg/kg),
crosses the blood-brain barrier
An exploratory phase 2 therapeutic trial
(«proof of concept »)
• Primary endpoint : To estimate the efficiency
after one year of sodium valproate treatment (30
mg/kg/j) on long term memory in RTS children.
• Secondary Outcomes :
- Special brain imaging profile and motor skills
(posturology and motor coordination in a
visuo-manual pointing task)
- Cognitive and developmental profile
- Histone acetylation profile
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
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
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
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
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
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 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
After 12 month of treatment, V2 :
battery test and evaluation scale
Motor skill tasks
MRI
15 days after V2,
treatment stopped with decreased dose
Inclusions
Number of patients expected : 60, number of patients enrolled : 41
Enrollement have been stopped at 41 patients with the Scientific Committee agreement
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
Population caracteristic at V0
More girls
in placebo
group
Assesments tools
• IMAGING
• MOTOR SKILLS
• NEUROSPYCHOLOGICAL BATTERY
TEST AND EVALUATION SCALE
• HISTONE ACETYLATION PROFILE
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
NEUROSPYCHOLOGICAL BATTERY TEST AND
EVALUATION SCALE
Mémory 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 shortterm memory
• Tests for chidren with or without speech
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.
NEUROSPYCHOLOGICAL BATTERY TEST
AND EVALUATION SCALE
Tests for primary outcome
( visual long term memory):
- « dot location » CMS subtest
- « image recognition » RBMT subtest
NEUROSPYCHOLOGICAL BATTERY TEST
AND EVALUATION SCALE
Tests for secondary outcome:
No speech test
- « Images location » CMS (visual short-term memory)
- « faces recognition » RBMT (visual long term memory)
- EVIP et morphosyntaxic ECOSSE.
- LEITER evaluation scale
Speech tests
- « word recall » CMS (auditive long term memory).
- Subtest of NEPSY
Imaging
Whole-brain imaging:
• Conventional morphological MRI T1
(macroscopic)
• Difusion tenseur Imaging
(DTI)(microscopic)
• Fonctionnal imaging, T2
Imaging
fonctionnal 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.
IRM
41 Participants
17 participants had a
MRI at V0
13 participants
refused
6 participants do
contain
contraindications for
MRI
1 wrongly included
11 participants had MRI
at V0 and V2
6 participants can not
have MRI at V2 because
MRI was not available
5 participants can not
have MRI at V0 because
MRI was not available
Motor skills
Several tasks :
• Visuo-manual pointing task
• Mobile interception task
(Mesurements with adhesive markers and
cameras)
• Posturometry : to stand on a platform still
eyes open and after eyes closed
Tête
Bras:
Epaules,
coudes
et mains
Pieds
Centre de
pression,
forces
Plateforme de
force au sol
HISTONE ACETYLATION PROFILE
Studying histone acétylation is useful :
1) To be sure than valproate treatment 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 between improvement level of
phénotype and the histone acétylation level.
Tests fonctionnels d’acétylation des histones
V0
T0
Sang des patients
V1
V2
6 mois
12 mois
Isolement des lymphocytes
Extraction protéique (Histones)
Extraction ARN
Fixation de la chromatine
Western Blot
(mesure du degré d’acétylation des
Histones)
RT-PCR quantitative
(mesure du niveau d’expression de
gènes cibles de CREBBP)
Immunoprécipitation Chromatine
(mesure du niveau d’acétylation
au niveau de gènes cibles
de CREBBP)
acH2B/H2B
acH3/H3
acH4/H4
NR4A1
NR4A2
GLI3
NR4A2
STUDY DESIGN
SELECTION PERIOD :
18 months
Drug usualy used
in epilepsy
treatment
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
Randomization
Study time frame:
30 months
TREATMENT PERIOD :
12 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
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
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
Description of inclusions
Number of patients randomised
(n = 41 )
Randomised in treatment group :
sodium valproate
(n = 28)
Randomised in placebo group
Lost to follow-up ( n = 0)
Lost to follow-up ( n = 0)
Treatment discontinuation (n = 3 ) :
Patient wrongly included (n = 1 ) :
-somnolence, slow réactions,weigth
increase (4kgs in 4 months) ( n = 1)
- SAE : lower limbs edema ( n = 1)
- weigth increase and no period during
a long time (n = 1)
- no compliance with the following
inclusion criteria : sufficient cognitive
capacities for neuropsychological
evaluation
Analysed (n=28)
Analysed (n=12)
( n = 13)
ANALYSIS OF PRINCIPAL ENDPOINT