Neurofibromatosis Type 1
Conditions
Keywords
Neurofibromatosis type 1, NF1, Cognition, Learning problems, Lamotrigine, Transcranial magnetic stimulation, TMS
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.
Interventions
DRUGLamotrigine
DRUGPlacebo
Sponsors
Universitaire Ziekenhuizen KU Leuven
ZonMw: The Netherlands Organisation for Health Research and Development
Hospital Sant Joan de Deu
Erasmus Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Performance intelligence quotient (change from baseline) | Baseline and 26 weeks | Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual perception (change from baseline) | Baseline and 26 weeks | Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3). |
| Sustained attention (change from baseline) | Baseline and 26 weeks | Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT). |
| Visual-motor integration (change from baseline) | Baseline and 26 weeks | Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6). |
| Fine motor coordination (change from baseline) | Baseline and 26 weeks | Assessed by the Grooved Pegboard Test. |
| Visual-spatial working memory (change from baseline) | Baseline and 26 weeks | Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). |
| Executive functioning (change from baseline) | Baseline, 26 weeks and 52 weeks | Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF). |
| Short intracortical inhibition (SICI) (change from baseline) | Baseline and 10 weeks | Assessed by paired pulse transcranial magnetic stimulation (ppTMS). |
| Long-term potentiation-like plasticity (change from baseline) | Baseline and 10 weeks | Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS). |
| Attention problems (change from baseline) | Baseline, 10 weeks, 26 weeks and 52 weeks | Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Full IQ (Intelligence Quotient) | Baseline | Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III). |
| Educational level | Baseline and 26 weeks | Determined using the ISCED (International Standard Classification of Education) 2011 levels |
| Adverse event registration | Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication | — |
| NF1 disease severity | Baseline | Assessed by the Riccardi scale. |
| Physical examination | Baseline, 10 weeks and 26 weeks | — |
| Pharmacokinetics: Area under the curve (AUC) and average steady state concentration. | 10 weeks, 18 weeks and 26 weeks | Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose. |
| Kidney function | Baseline and 10 weeks | Urea, creatinine |
| Hepatic enzymes | Baseline and 10 weeks | ALAT, ASAT, GGT |
| Full blood count | Baseline and 10 weeks | — |
| Parental education | Baseline | Determined by highest educational grade as measured with the Standaard Onderwijsindeling (SOI) classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS) |
| Parental occupation | Baseline | Determined by the most appropriate level of education for the particular occupation |
Countries
Belgium, Netherlands, Spain
Outcome results
None listed