Effect of Lamotrigine on Cognition in NF1 (NF1-EXCEL)

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

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

Study Overview

• Status: Terminated
• Conditions: Neurofibromatosis Type 1
• Intervention / Treatment: Drug: Placebo; Drug: Lamotrigine

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 Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, B-3000
    • University Hospital Leuven
• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015CN
      • Erasmus Medical Center
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Deu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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)	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

Other Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Universitaire Ziekenhuizen KU Leuven; ZonMw: The Netherlands Organisation for Health Research and Development; Hospital Sant Joan de Deu
• Investigators: Principal Investigator: Ype Elgersma, PhD, Erasmus Medical Center; Principal Investigator: Henriette A Moll, MD, PhD, Erasmus Medical Center

Publications and helpful links

Helpful Links

• ENCORE expertise center

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): April 1, 2020

Study Registration Dates

• First Submitted: September 17, 2014
• First Submitted That Met QC Criteria: October 1, 2014
• First Posted (Estimate): October 3, 2014

Study Record Updates

• Last Update Posted (Actual): April 14, 2020
• Last Update Submitted That Met QC Criteria: April 10, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Cognition; Transcranial magnetic stimulation; Lamotrigine; TMS; NF1; Learning problems; Neurofibromatosis type 1
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anticonvulsants; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Lamotrigine
• Other Study ID Numbers: MEC-2013-460; 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)