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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-003405-26 | EudraCT Number | ||
| NL 44912.078.13 | Other Identifier | The Central Committee on Research Involving Human Subjects (CCMO) | |
| 113303003 | Other Grant/Funding Number | ZonMw, Netherlands Organisation for Health Research and Development |
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Due to our experience, the small number of new inclusions, and the uncertainty regarding the COVID-19 outbreak, we have decided to discontinue the study.
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| Name | Class |
|---|---|
| Universitaire Ziekenhuizen KU Leuven | OTHER |
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
| Hospital Sant Joan de Deu | OTHER |
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The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lamotrigine | Experimental | Lamotrigine during 28 consecutive weeks:
|
|
| Placebo | Placebo Comparator | Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lamotrigine | Drug |
|
| |
| Placebo |
| 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 |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Full IQ (Intelligence Quotient) | Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III). | Baseline |
| Adverse event registration | Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ype Elgersma, PhD | Erasmus Medical Center | Principal Investigator |
| Henriette A Moll, MD, PhD | Erasmus Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Leuven | Leuven | B-3000 | Belgium | |||
| Erasmus Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40121838 | Derived | Ottenhoff MJ, Heuvelmans A, Castricum J, Tulen JH, Rens G, Fujiyama H, Levin O, Swinnen SP, Moll HA, Wit MY, Elgersma Y. The effect of lamotrigine on cortical inhibition and plasticity in Neurofibromatosis type 1: Exploratory analysis of a randomized controlled trial (NF1-EXCEL). Clin Neurophysiol. 2025 May;173:150-162. doi: 10.1016/j.clinph.2025.02.270. Epub 2025 Mar 10. | |
| 39340758 |
| Label | URL |
|---|---|
| ENCORE expertise center | View source |
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| ID | Term |
|---|---|
| D009456 | Neurofibromatosis 1 |
| ID | Term |
|---|---|
| D017253 | Neurofibromatoses |
| D009455 | Neurofibroma |
| D018317 | Nerve Sheath Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
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| ID | Term |
|---|---|
| D000077213 | Lamotrigine |
| ID | Term |
|---|---|
| D014227 | Triazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Drug |
|
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 |
| NF1 disease severity | Assessed by the Riccardi scale. | Baseline |
| Physical examination | Baseline, 10 weeks and 26 weeks |
| Pharmacokinetics: Area under the curve (AUC) and average steady state concentration. | Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose. | 10 weeks, 18 weeks and 26 weeks |
| Kidney function | Urea, creatinine | Baseline and 10 weeks |
| Hepatic enzymes | ALAT, ASAT, GGT | Baseline and 10 weeks |
| Full blood count | Baseline and 10 weeks |
| Parental education | Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS) | Baseline |
| Parental occupation | Determined by the most appropriate level of education for the particular occupation | Baseline |
| Educational level | Determined using the ISCED (International Standard Classification of Education) 2011 levels | Baseline and 26 weeks |
| Rotterdam |
| South Holland |
| 3015CN |
| Netherlands |
| Hospital Sant Joan de Deu | Barcelona | Spain |
| Derived |
| Ottenhoff MJ, Mous SE, Castricum J, Rietman AB, Oostenbrink R, van der Vaart T, Tulen JHM, Parra A, Ramos FJ, Legius E, Moll HA, Elgersma Y, de Wit MY; ENCORE Expertise Center for NF1. Lamotrigine for cognitive deficits associated with neurofibromatosis type 1: A phase II randomized placebo-controlled trial. Dev Med Child Neurol. 2025 Apr;67(4):537-549. doi: 10.1111/dmcn.16094. Epub 2024 Sep 28. |
| D009370 |
| Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009386 | Neoplastic Syndromes, Hereditary |
| D020752 | Neurocutaneous Syndromes |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |