Effect of Lamotrigine on Cognition in NF1

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.

Detailed Description
-----------------
Cognitive deficits in the autosomal dominant disorder Neurofibromatosis type 1 (NF1) typically consist of a lower than average IQ, impaired visual-spatial learning, attention problems and impaired executive functioning. These deficits have a substantial influence on the daily life of pediatric and adolescent individuals with NF1. One of the key underlying mechanisms of these deficits is an increased gamma-aminobutyric acid (GABA)-ergic inhibition and a subsequent decrease in synaptic plasticity. The ENCORE laboratory has recently shown that loss of the NF1-gene is associated with attenuated function of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). These channels, enriched in membranes of inhibitory interneurons, play an important role in the pathophysiology underlying the cognitive deficits in NF1. Lamotrigine, an HCN-agonist, restored function of HCN1, together with the electrophysiological and visual-spatial learning deficits in Nf1-mice. Thus, lamotrigine is a novel candidate drug for treating cognitive deficits associated with NF1.

Official Title
-----------------
The Effect of Lamotrigine on Cognitive Deficits Associated With Neurofibromatosis Type 1: a Phase II Randomized Controlled Multi-centre Trial (NF1-EXCEL)

Conditions
-----------------
Neurofibromatosis Type 1

Intervention / Treatment
-----------------
* Drug: Lamotrigine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: NF1 patients with a genetically confirmed diagnosis Age 12-17.5 years at inclusion Oral and written informed consent by parents and assent from participants Exclusion Criteria: Segmental NF1 Severe hearing problems or deafness Severe visual problems or blindness Use of the following medication, as of interaction with lamotrigine: phenytoin, carbamazepine, phenobarbital, primidon, rifampicin, atazanavir/ritonavir, lopinavir/ritonavir, oxcarbazepine, topiramate, oral contraceptive pill including stop-week (estrogen and progesterone) and valproic acid during 3 months before inclusion. Use of psycho-active medication other than methylphenidate Previous allergic reactions to anti-epileptic drugs Epilepsy or epilepsy in the past Suicidal thoughts or behaviour Renal insufficiency Liver insufficiency Pregnancy Brain tumour or other brain pathology potentially influencing the outcome measures

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamotrigine<br>Lamotrigine during 28 consecutive weeks: 8 weeks dose-increase phase: from 25mg once daily to 100mg twice daily 18 weeks target-dose phase: 100mg twice daily 2 weeks decline-phase: 100mg once daily. | Drug: Lamotrigine<br> <br> * Other names: Lamictal;|
| Placebo Comparator: Placebo<br>Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule. | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance intelligence quotient (change from baseline) | Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III). | Baseline and 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual-spatial working memory (change from baseline) | Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). | Baseline and 26 weeks | 
| Visual perception (change from baseline) | Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3). | Baseline and 26 weeks | 
| Sustained attention (change from baseline) | Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT). | Baseline and 26 weeks | 
| Visual-motor integration (change from baseline) | Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6). | Baseline and 26 weeks | 
| Fine motor coordination (change from baseline) | Assessed by the Grooved Pegboard Test. | Baseline and 26 weeks | 
| Attention problems (change from baseline) | Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL). | Baseline, 10 weeks, 26 weeks and 52 weeks | 
| Executive functioning (change from baseline) | Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF). | Baseline, 26 weeks and 52 weeks | 
| Short intracortical inhibition (SICI) (change from baseline) | Assessed by paired pulse transcranial magnetic stimulation (ppTMS). | Baseline and 10 weeks | 
| Long-term potentiation-like plasticity (change from baseline) | Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS). | Baseline and 10 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neurofibromatosis type 1, NF1, Cognition, Learning problems, Lamotrigine, Transcranial magnetic stimulation, TMS