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

April 10, 2020 updated by: M.J. Ottenhoff, MD, Erasmus Medical Center

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

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
41

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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 Déu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Performance intelligence quotient (change from baseline)
Time Frame: Baseline and 26 weeks
Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).
Baseline and 26 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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).
Baseline and 26 weeks
Visual perception (change from baseline)
Time Frame: Baseline and 26 weeks
Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).
Baseline and 26 weeks
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).
Baseline and 26 weeks
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).
Baseline and 26 weeks
Fine motor coordination (change from baseline)
Time Frame: Baseline and 26 weeks
Assessed by the Grooved Pegboard Test.
Baseline and 26 weeks
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).
Baseline, 10 weeks, 26 weeks and 52 weeks
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).
Baseline, 26 weeks and 52 weeks
Short intracortical inhibition (SICI) (change from baseline)
Time Frame: Baseline and 10 weeks
Assessed by paired pulse transcranial magnetic stimulation (ppTMS).
Baseline and 10 weeks
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).
Baseline and 10 weeks

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Full IQ (Intelligence Quotient)
Time Frame: Baseline
Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).
Baseline
Adverse event registration
Time Frame: Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication
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.
Baseline
Physical examination
Time Frame: Baseline, 10 weeks and 26 weeks
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.
10 weeks, 18 weeks and 26 weeks
Kidney function
Time Frame: Baseline and 10 weeks
Urea, creatinine
Baseline and 10 weeks
Hepatic enzymes
Time Frame: Baseline and 10 weeks
ALAT, ASAT, GGT
Baseline and 10 weeks
Full blood count
Time Frame: Baseline and 10 weeks
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)
Baseline
Parental occupation
Time Frame: Baseline
Determined by the most appropriate level of education for the particular occupation
Baseline
Educational level
Time Frame: Baseline and 26 weeks
Determined using the ISCED (International Standard Classification of Education) 2011 levels
Baseline and 26 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Erasmus Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Universitaire Ziekenhuizen KU Leuven
ZonMw: The Netherlands Organisation for Health Research and Development
Hospital Sant Joan de Deu

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ype Elgersma, PhD, Erasmus Medical Center
  • Principal Investigator: Henriette A Moll, MD, PhD, Erasmus Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 17, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 1, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 3, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 14, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 10, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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