<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02256124</url>
  </required_header>
  <id_info>
    <org_study_id>MEC-2013-460</org_study_id>
    <secondary_id>2013-003405-26</secondary_id>
    <secondary_id>NL 44912.078.13</secondary_id>
    <secondary_id>113303003</secondary_id>
    <nct_id>NCT02256124</nct_id>
  </id_info>
  <brief_title>Effect of Lamotrigine on Cognition in NF1</brief_title>
  <acronym>NF1-EXCEL</acronym>
  <official_title>The Effect of Lamotrigine on Cognitive Deficits Associated With Neurofibromatosis Type 1: a Phase II Randomized Controlled Multi-centre Trial (NF1-EXCEL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Sant Joan de Deu</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Erasmus Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether lamotrigine can improve cognitive and&#xD;
      neurophysiological deficits in adolescents with Neurofibromatosis type 1.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cognitive deficits in the autosomal dominant disorder Neurofibromatosis type 1 (NF1)&#xD;
      typically consist of a lower than average IQ, impaired visual-spatial learning, attention&#xD;
      problems and impaired executive functioning. These deficits have a substantial influence on&#xD;
      the daily life of pediatric and adolescent individuals with NF1. One of the key underlying&#xD;
      mechanisms of these deficits is an increased gamma-aminobutyric acid (GABA)-ergic inhibition&#xD;
      and a subsequent decrease in synaptic plasticity. The ENCORE laboratory has recently shown&#xD;
      that loss of the NF1-gene is associated with attenuated function of the&#xD;
      hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). These channels,&#xD;
      enriched in membranes of inhibitory interneurons, play an important role in the&#xD;
      pathophysiology underlying the cognitive deficits in NF1. Lamotrigine, an HCN-agonist,&#xD;
      restored function of HCN1, together with the electrophysiological and visual-spatial learning&#xD;
      deficits in Nf1-mice. Thus, lamotrigine is a novel candidate drug for treating cognitive&#xD;
      deficits associated with NF1.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to our experience, the small number of new inclusions, and the uncertainty regarding the&#xD;
    COVID-19 outbreak, we have decided to discontinue the study.&#xD;
  </why_stopped>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">April 2020</completion_date>
  <primary_completion_date type="Actual">April 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Performance intelligence quotient (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Visual-spatial working memory (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual perception (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sustained attention (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual-motor integration (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fine motor coordination (change from baseline)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Assessed by the Grooved Pegboard Test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Attention problems (change from baseline)</measure>
    <time_frame>Baseline, 10 weeks, 26 weeks and 52 weeks</time_frame>
    <description>Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Executive functioning (change from baseline)</measure>
    <time_frame>Baseline, 26 weeks and 52 weeks</time_frame>
    <description>Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short intracortical inhibition (SICI) (change from baseline)</measure>
    <time_frame>Baseline and 10 weeks</time_frame>
    <description>Assessed by paired pulse transcranial magnetic stimulation (ppTMS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long-term potentiation-like plasticity (change from baseline)</measure>
    <time_frame>Baseline and 10 weeks</time_frame>
    <description>Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Full IQ (Intelligence Quotient)</measure>
    <time_frame>Baseline</time_frame>
    <description>Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).</description>
  </other_outcome>
  <other_outcome>
    <measure>Adverse event registration</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>NF1 disease severity</measure>
    <time_frame>Baseline</time_frame>
    <description>Assessed by the Riccardi scale.</description>
  </other_outcome>
  <other_outcome>
    <measure>Physical examination</measure>
    <time_frame>Baseline, 10 weeks and 26 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacokinetics: Area under the curve (AUC) and average steady state concentration.</measure>
    <time_frame>10 weeks, 18 weeks and 26 weeks</time_frame>
    <description>Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose.</description>
  </other_outcome>
  <other_outcome>
    <measure>Kidney function</measure>
    <time_frame>Baseline and 10 weeks</time_frame>
    <description>Urea, creatinine</description>
  </other_outcome>
  <other_outcome>
    <measure>Hepatic enzymes</measure>
    <time_frame>Baseline and 10 weeks</time_frame>
    <description>ALAT, ASAT, GGT</description>
  </other_outcome>
  <other_outcome>
    <measure>Full blood count</measure>
    <time_frame>Baseline and 10 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Parental education</measure>
    <time_frame>Baseline</time_frame>
    <description>Determined by highest educational grade as measured with the &quot;Standaard Onderwijsindeling (SOI)&quot; classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)</description>
  </other_outcome>
  <other_outcome>
    <measure>Parental occupation</measure>
    <time_frame>Baseline</time_frame>
    <description>Determined by the most appropriate level of education for the particular occupation</description>
  </other_outcome>
  <other_outcome>
    <measure>Educational level</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Determined using the ISCED (International Standard Classification of Education) 2011 levels</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Neurofibromatosis Type 1</condition>
  <arm_group>
    <arm_group_label>Lamotrigine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lamotrigine during 28 consecutive weeks:&#xD;
8 weeks dose-increase phase: from 25mg once daily to 100mg twice daily&#xD;
18 weeks target-dose phase: 100mg twice daily&#xD;
2 weeks decline-phase: 100mg once daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lamotrigine</intervention_name>
    <arm_group_label>Lamotrigine</arm_group_label>
    <other_name>Lamictal</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  NF1 patients with a genetically confirmed diagnosis&#xD;
&#xD;
          -  Age 12-17.5 years at inclusion&#xD;
&#xD;
          -  Oral and written informed consent by parents and assent from participants&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Segmental NF1&#xD;
&#xD;
          -  Severe hearing problems or deafness&#xD;
&#xD;
          -  Severe visual problems or blindness&#xD;
&#xD;
          -  Use of the following medication, as of interaction with lamotrigine: phenytoin,&#xD;
             carbamazepine, phenobarbital, primidon, rifampicin, atazanavir/ritonavir,&#xD;
             lopinavir/ritonavir, oxcarbazepine, topiramate, oral contraceptive pill including&#xD;
             stop-week (estrogen and progesterone) and valproic acid during 3 months before&#xD;
             inclusion.&#xD;
&#xD;
          -  Use of psycho-active medication other than methylphenidate&#xD;
&#xD;
          -  Previous allergic reactions to anti-epileptic drugs&#xD;
&#xD;
          -  Epilepsy or epilepsy in the past&#xD;
&#xD;
          -  Suicidal thoughts or behaviour&#xD;
&#xD;
          -  Renal insufficiency&#xD;
&#xD;
          -  Liver insufficiency&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Brain tumour or other brain pathology potentially influencing the outcome measures&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ype Elgersma, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Henriette A Moll, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Leuven</name>
      <address>
        <city>Leuven</city>
        <zip>B-3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <state>South Holland</state>
        <zip>3015CN</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Joan de Deu</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>https://www.erasmusmc.nl/nl-nl/sophia/patientenzorg/centra/encore</url>
    <description>ENCORE expertise center</description>
  </link>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>September 17, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 3, 2014</study_first_posted>
  <last_update_submitted>April 10, 2020</last_update_submitted>
  <last_update_submitted_qc>April 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Erasmus Medical Center</investigator_affiliation>
    <investigator_full_name>M.J. Ottenhoff, MD</investigator_full_name>
    <investigator_title>MD, MSc</investigator_title>
  </responsible_party>
  <keyword>Neurofibromatosis type 1</keyword>
  <keyword>NF1</keyword>
  <keyword>Cognition</keyword>
  <keyword>Learning problems</keyword>
  <keyword>Lamotrigine</keyword>
  <keyword>Transcranial magnetic stimulation</keyword>
  <keyword>TMS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lamotrigine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02256124
org study id: MEC-2013-460
secondary id: 2013-003405-26
secondary id: NL 44912.078.13
secondary id: 113303003
nct id: NCT02256124
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine whether lamotrigine can improve cognitive and
      neurophysiological deficits in adolescents with Neurofibromatosis type 1.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Performance intelligence quotient (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).
measure: Visual-spatial working memory (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).
measure: Visual perception (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).
measure: Sustained attention (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).
measure: Visual-motor integration (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6).
measure: Fine motor coordination (change from baseline)
time frame: Baseline and 26 weeks
description: Assessed by the Grooved Pegboard Test.
measure: Attention problems (change from baseline)
time frame: Baseline, 10 weeks, 26 weeks and 52 weeks
description: Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).
measure: Executive functioning (change from baseline)
time frame: Baseline, 26 weeks and 52 weeks
description: Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).
measure: Short intracortical inhibition (SICI) (change from baseline)
time frame: Baseline and 10 weeks
description: Assessed by paired pulse transcranial magnetic stimulation (ppTMS).
measure: Long-term potentiation-like plasticity (change from baseline)
time frame: Baseline and 10 weeks
description: Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).
measure: Full IQ (Intelligence Quotient)
time frame: Baseline
description: Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).
measure: Adverse event registration
time frame: Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication
measure: NF1 disease severity
time frame: Baseline
description: Assessed by the Riccardi scale.
measure: Physical examination
time frame: Baseline, 10 weeks and 26 weeks
measure: Pharmacokinetics: Area under the curve (AUC) and average steady state concentration.
time frame: 10 weeks, 18 weeks and 26 weeks
description: Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose.
measure: Kidney function
time frame: Baseline and 10 weeks
description: Urea, creatinine
measure: Hepatic enzymes
time frame: Baseline and 10 weeks
description: ALAT, ASAT, GGT
measure: Full blood count
time frame: Baseline and 10 weeks
measure: Parental education
time frame: Baseline
description: Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)
measure: Parental occupation
time frame: Baseline
description: Determined by the most appropriate level of education for the particular occupation
measure: Educational level
time frame: Baseline and 26 weeks
description: Determined using the ISCED (International Standard Classification of Education) 2011 levels
arm group label: Lamotrigine
arm group type: Experimental
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 group label: Placebo
arm group type: Placebo Comparator
description: Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.
intervention type: Drug
intervention name: Lamotrigine
arm group label: Lamotrigine
other name: Lamictal
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 12 Years
maximum age: 18 Years
healthy volunteers: No
last name: Ype Elgersma, PhD
role: Principal Investigator
affiliation: Erasmus Medical Center
last name: Henriette A Moll, MD, PhD
role: Principal Investigator
affiliation: Erasmus Medical Center
facility: 
facility: 
facility: 
country: Belgium
country: Netherlands
country: Spain
url: https://www.erasmusmc.nl/nl-nl/sophia/patientenzorg/centra/encore
description: ENCORE expertise center
responsible party type: Principal Investigator
investigator affiliation: Erasmus Medical Center
investigator full name: M.J. Ottenhoff, MD
investigator title: MD, MSc
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Lamotrigine