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

Primary Purpose

Neurofibromatosis Type 1

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Lamotrigine
Placebo
Sponsored by
Erasmus Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neurofibromatosis Type 1 focused on measuring Neurofibromatosis type 1, NF1, Cognition, Learning problems, Lamotrigine, Transcranial magnetic stimulation, TMS

Eligibility Criteria

12 Years - 18 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

  • University Hospital Leuven
  • Erasmus Medical Center
  • Hospital Sant Joan de Deu

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Lamotrigine

Placebo

Arm Description

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.

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

Outcomes

Primary Outcome Measures

Performance intelligence quotient (change from baseline)
Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).

Secondary Outcome Measures

Visual-spatial working memory (change from baseline)
Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).
Visual perception (change from baseline)
Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).
Sustained attention (change from baseline)
Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).
Visual-motor integration (change from baseline)
Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6).
Fine motor coordination (change from baseline)
Assessed by the Grooved Pegboard Test.
Attention problems (change from baseline)
Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).
Executive functioning (change from baseline)
Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).
Short intracortical inhibition (SICI) (change from baseline)
Assessed by paired pulse transcranial magnetic stimulation (ppTMS).
Long-term potentiation-like plasticity (change from baseline)
Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).

Full Information

First Posted
September 17, 2014
Last Updated
April 10, 2020
Sponsor
Erasmus Medical Center
Collaborators
Universitaire Ziekenhuizen KU Leuven, ZonMw: The Netherlands Organisation for Health Research and Development, Hospital Sant Joan de Deu
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1. Study Identification

Unique Protocol Identification Number
NCT02256124
Brief Title
Effect of Lamotrigine on Cognition in NF1
Acronym
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)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Terminated
Why Stopped
Due to our experience, the small number of new inclusions, and the uncertainty regarding the COVID-19 outbreak, we have decided to discontinue the study.
Study Start Date
October 2014 (undefined)
Primary Completion Date
April 2020 (Actual)
Study Completion Date
April 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Erasmus Medical Center
Collaborators
Universitaire Ziekenhuizen KU Leuven, ZonMw: The Netherlands Organisation for Health Research and Development, Hospital Sant Joan de Deu

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurofibromatosis Type 1
Keywords
Neurofibromatosis type 1, NF1, Cognition, Learning problems, Lamotrigine, Transcranial magnetic stimulation, TMS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lamotrigine
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.
Intervention Type
Drug
Intervention Name(s)
Lamotrigine
Other Intervention Name(s)
Lamictal
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Performance intelligence quotient (change from baseline)
Description
Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).
Time Frame
Baseline and 26 weeks
Secondary Outcome Measure Information:
Title
Visual-spatial working memory (change from baseline)
Description
Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).
Time Frame
Baseline and 26 weeks
Title
Visual perception (change from baseline)
Description
Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).
Time Frame
Baseline and 26 weeks
Title
Sustained attention (change from baseline)
Description
Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).
Time Frame
Baseline and 26 weeks
Title
Visual-motor integration (change from baseline)
Description
Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6).
Time Frame
Baseline and 26 weeks
Title
Fine motor coordination (change from baseline)
Description
Assessed by the Grooved Pegboard Test.
Time Frame
Baseline and 26 weeks
Title
Attention problems (change from baseline)
Description
Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).
Time Frame
Baseline, 10 weeks, 26 weeks and 52 weeks
Title
Executive functioning (change from baseline)
Description
Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).
Time Frame
Baseline, 26 weeks and 52 weeks
Title
Short intracortical inhibition (SICI) (change from baseline)
Description
Assessed by paired pulse transcranial magnetic stimulation (ppTMS).
Time Frame
Baseline and 10 weeks
Title
Long-term potentiation-like plasticity (change from baseline)
Description
Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).
Time Frame
Baseline and 10 weeks
Other Pre-specified Outcome Measures:
Title
Full IQ (Intelligence Quotient)
Description
Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).
Time Frame
Baseline
Title
Adverse event registration
Time Frame
Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication
Title
NF1 disease severity
Description
Assessed by the Riccardi scale.
Time Frame
Baseline
Title
Physical examination
Time Frame
Baseline, 10 weeks and 26 weeks
Title
Pharmacokinetics: Area under the curve (AUC) and average steady state concentration.
Description
Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose.
Time Frame
10 weeks, 18 weeks and 26 weeks
Title
Kidney function
Description
Urea, creatinine
Time Frame
Baseline and 10 weeks
Title
Hepatic enzymes
Description
ALAT, ASAT, GGT
Time Frame
Baseline and 10 weeks
Title
Full blood count
Time Frame
Baseline and 10 weeks
Title
Parental education
Description
Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)
Time Frame
Baseline
Title
Parental occupation
Description
Determined by the most appropriate level of education for the particular occupation
Time Frame
Baseline
Title
Educational level
Description
Determined using the ISCED (International Standard Classification of Education) 2011 levels
Time Frame
Baseline and 26 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ype Elgersma, PhD
Organizational Affiliation
Erasmus Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Henriette A Moll, MD, PhD
Organizational Affiliation
Erasmus Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Leuven
City
Leuven
ZIP/Postal Code
B-3000
Country
Belgium
Facility Name
Erasmus Medical Center
City
Rotterdam
State/Province
South Holland
ZIP/Postal Code
3015CN
Country
Netherlands
Facility Name
Hospital Sant Joan de Deu
City
Barcelona
Country
Spain

12. IPD Sharing Statement

Links:
URL
https://www.erasmusmc.nl/nl-nl/sophia/patientenzorg/centra/encore
Description
ENCORE expertise center

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Effect of Lamotrigine on Cognition in NF1

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