Effect of Lamotrigine on Cognition in NF1

Neurofibromatosis Type 1 Clinical Trial

— NF1-EXCEL  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02256124
• Other study ID #: MEC-2013-460
• Secondary ID: 2013-003405-26NL
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: October 2014
• Est. completion date: April 2020

Study information

• Verified date: April 2020
• Source: Erasmus Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 41
• Est. completion date: April 2020
• Est. primary completion date: April 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Neurofibroma
• Neurofibromatoses
• Neurofibromatosis 1
• Neurofibromatosis Type 1

Intervention

Drug:
• Lamotrigine

• Placebo

Locations

Country	Name	City	State
Belgium	University Hospital Leuven	Leuven
Netherlands	Erasmus Medical Center	Rotterdam	South Holland
Spain	Hospital Sant Joan de Deu	Barcelona

Sponsors (4)

Lead Sponsor	Collaborator
Erasmus Medical Center	Hospital Sant Joan de Deu, Universitaire Ziekenhuizen Leuven, ZonMw: The Netherlands Organisation for Health Research and Development

Countries where clinical trial is conducted

Belgium,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Full IQ (Intelligence Quotient)	Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).	Baseline
Other	Adverse event registration		Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication
Other	NF1 disease severity	Assessed by the Riccardi scale.	Baseline
Other	Physical examination		Baseline, 10 weeks and 26 weeks
Other	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
Other	Kidney function	Urea, creatinine	Baseline and 10 weeks
Other	Hepatic enzymes	ALAT, ASAT, GGT	Baseline and 10 weeks
Other	Full blood count		Baseline and 10 weeks
Other	Parental education	Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)	Baseline
Other	Parental occupation	Determined by the most appropriate level of education for the particular occupation	Baseline
Other	Educational level	Determined using the ISCED (International Standard Classification of Education) 2011 levels	Baseline and 26 weeks
Primary	Performance intelligence quotient (change from baseline)	Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).	Baseline and 26 weeks
Secondary	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
Secondary	Visual perception (change from baseline)	Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).	Baseline and 26 weeks
Secondary	Sustained attention (change from baseline)	Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).	Baseline and 26 weeks
Secondary	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
Secondary	Fine motor coordination (change from baseline)	Assessed by the Grooved Pegboard Test.	Baseline and 26 weeks
Secondary	Attention problems (change from baseline)	Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).	Baseline, 10 weeks, 26 weeks and 52 weeks
Secondary	Executive functioning (change from baseline)	Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).	Baseline, 26 weeks and 52 weeks
Secondary	Short intracortical inhibition (SICI) (change from baseline)	Assessed by paired pulse transcranial magnetic stimulation (ppTMS).	Baseline and 10 weeks
Secondary	Long-term potentiation-like plasticity (change from baseline)	Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).	Baseline and 10 weeks

External Links

•   ENCORE expertise center