Clinical trial NCT02256124: Effect of Lamotrigine on Cognition in 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Neurofibromatosis Type 1
Keywords: Neurofibromatosis type 1
NF1
Cognition
Learning problems
Lamotrigine
Transcranial magnetic stimulation
TMS
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Universitaire Ziekenhuizen KU Leuven
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Hospital Sant Joan de Deu
First posted: 2014-10-03
Enrollment: 41
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Performance intelligence quotient (change from baseline)
timeFrame: Baseline and 26 weeks
Secondary outcomes:
measure: Visual-spatial working memory (change from baseline)
timeFrame: Baseline and 26 weeks
measure: Visual perception (change from baseline)
timeFrame: Baseline and 26 weeks
measure: Sustained attention (change from baseline)
timeFrame: Baseline and 26 weeks
measure: Visual-motor integration (change from baseline)
timeFrame: Baseline and 26 weeks
measure: Fine motor coordination (change from baseline)
timeFrame: Baseline and 26 weeks
measure: Attention problems (change from baseline)
timeFrame: Baseline, 10 weeks, 26 weeks and 52 weeks
measure: Executive functioning (change from baseline)
timeFrame: Baseline, 26 weeks and 52 weeks
measure: Short intracortical inhibition (SICI) (change from baseline)
timeFrame: Baseline and 10 weeks
measure: Long-term potentiation-like plasticity (change from baseline)
timeFrame: Baseline and 10 weeks
Other outcomes:
measure: Full IQ (Intelligence Quotient)
timeFrame: Baseline
measure: Adverse event registration
timeFrame: Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication
measure: NF1 disease severity
timeFrame: Baseline
measure: Physical examination
timeFrame: Baseline, 10 weeks and 26 weeks
measure: Pharmacokinetics: Area under the curve (AUC) and average steady state concentration.
timeFrame: 10 weeks, 18 weeks and 26 weeks
measure: Kidney function
timeFrame: Baseline and 10 weeks
measure: Hepatic enzymes
timeFrame: Baseline and 10 weeks
measure: Full blood count
timeFrame: Baseline and 10 weeks
measure: Parental education
timeFrame: Baseline
measure: Parental occupation
timeFrame: Baseline
measure: Educational level
timeFrame: Baseline and 26 weeks
Locations:
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: South Holland
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
Study officials:
affiliation: Erasmus Medical Center
name: Ype Elgersma, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Henriette A Moll, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: