NF1-EXCEL: Effect of Lamotrigine on Cognition in NF1

Sponsor

Erasmus Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT02256124

Collaborator

Universitaire Ziekenhuizen Leuven (Other), ZonMw: The Netherlands Organisation for Health Research and Development (Other), Hospital Sant Joan de Deu (Other)

Enrollment

Locations

Arms

Duration (Months)

13.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis Type 1	Drug: Lamotrigine Drug: Placebo	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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 Start Date :

Oct 1, 2014

Actual Primary Completion Date :

Apr 1, 2020

Actual Study Completion Date :

Apr 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lamotrigine 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 Other Names: Lamictal
Placebo Comparator: Placebo Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.	Drug: Placebo

Arm

Intervention/Treatment

Experimental: Lamotrigine

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

Other Names:

Lamictal

Placebo Comparator: Placebo

Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Performance intelligence quotient (change from baseline) [Baseline and 26 weeks]
Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).

Secondary Outcome Measures

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).
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.
Attention problems (change from baseline) [Baseline, 10 weeks, 26 weeks and 52 weeks]
Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).
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).

Other Outcome Measures

Full IQ (Intelligence Quotient) [Baseline]
Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).
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
Educational level [Baseline and 26 weeks]
Determined using the ISCED (International Standard Classification of Education) 2011 levels

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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