We updated the design of this site on September 25th. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified June 2017 by M.J. Ottenhoff, MD, Erasmus Medical Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT02256124
First Posted: October 3, 2014
Last Update Posted: June 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Universitaire Ziekenhuizen Leuven
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
M.J. Ottenhoff, MD, Erasmus Medical Center
  Purpose
The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.

Condition Intervention Phase
Neurofibromatosis Type 1 Drug: Lamotrigine Drug: Placebo Phase 2 Phase 3

Study Type: Interventional
Study Design: 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)

Resource links provided by NLM:


Further study details as provided by M.J. Ottenhoff, MD, Erasmus Medical Center:

Primary Outcome Measures:
  • Performance intelligence quotient (change from baseline) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Baseline and 26 weeks ]
    Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).

  • Sustained attention (change from baseline) [ Time Frame: Baseline and 26 weeks ]
    Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).

  • Visual-motor integration (change from baseline) [ Time Frame: 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) [ Time Frame: Baseline and 26 weeks ]
    Assessed by the Grooved Pegboard Test.

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

  • Executive functioning (change from baseline) [ Time Frame: 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) [ Time Frame: Baseline and 10 weeks ]
    Assessed by paired pulse transcranial magnetic stimulation (ppTMS).

  • Long-term potentiation-like plasticity (change from baseline) [ Time Frame: Baseline and 10 weeks ]
    Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).


Other Outcome Measures:
  • Full IQ (Intelligence Quotient) [ Time Frame: Baseline ]
    Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).

  • Adverse event registration [ Time Frame: Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication ]
  • NF1 disease severity [ Time Frame: Baseline ]
    Assessed by the Riccardi scale.

  • Physical examination [ Time Frame: Baseline, 10 weeks and 26 weeks ]
  • Pharmacokinetics: Area under the curve (AUC) and average steady state concentration. [ Time Frame: 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 [ Time Frame: Baseline and 10 weeks ]
    Urea, creatinine

  • Hepatic enzymes [ Time Frame: Baseline and 10 weeks ]
    ALAT, ASAT, GGT

  • Full blood count [ Time Frame: Baseline and 10 weeks ]
  • Parental education [ Time Frame: Baseline ]
    Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)

  • Parental occupation [ Time Frame: Baseline ]
    Determined by the most appropriate level of education for the particular occupation

  • Educational level [ Time Frame: Baseline and 26 weeks ]
    Determined using the ISCED (International Standard Classification of Education) 2011 levels


Estimated Enrollment: 60
Study Start Date: October 2014
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Lamictal
Placebo Comparator: Placebo
Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.
Drug: Placebo

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   12 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02256124


Contacts
Contact: Marie-Claire Y de Wit, MD, PhD +31107036956 m.c.y.dewit@erasmusmc.nl
Contact: Myrthe J Ottenhoff, MD, MSc +31107036148 m.ottenhoff@erasmusmc.nl

Locations
Belgium
University Hospital Leuven Recruiting
Leuven, Belgium, B-3000
Contact: Eric Legius, MD, PhD    +3216345903    eric.legius@uzleuven.be   
Contact: Ellen Plasschaert, MSc    +3216345903    ellen.plasschaert@uzleuven.be   
Sub-Investigator: Ellen Plasschaert, MSc         
Principal Investigator: Eric Legius, MD, PhD         
Netherlands
Erasmus Medical Center Recruiting
Rotterdam, South Holland, Netherlands, 3015CN
Principal Investigator: Marie-Claire Y de Wit, MD, PhD         
Sub-Investigator: Myrthe Ottenhoff, MD, MSc         
Sponsors and Collaborators
Erasmus Medical Center
Universitaire Ziekenhuizen Leuven
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Ype Elgersma, PhD Erasmus Medical Center
Principal Investigator: Henriette A Moll, MD, PhD Erasmus Medical Center
  More Information

Additional Information:
Responsible Party: M.J. Ottenhoff, MD, MD, MSc, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT02256124     History of Changes
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 )
First Submitted: September 17, 2014
First Posted: October 3, 2014
Last Update Posted: June 23, 2017
Last Verified: June 2017

Keywords provided by M.J. Ottenhoff, MD, Erasmus Medical Center:
Neurofibromatosis type 1
NF1
Cognition
Learning problems
Lamotrigine
Transcranial magnetic stimulation
TMS

Additional relevant MeSH terms:
Neurofibromatosis 1
Neurofibromatoses
Neurofibroma
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Lamotrigine
Anticonvulsants
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers