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

• ClinicalTrials.gov Identifier: NCT02256124
• Recruitment Status: Terminated
• First Posted: October 3, 2014
• Last Update Posted: April 14, 2020
• Sponsor: Erasmus Medical Center
• Collaborators: Universitaire Ziekenhuizen KU Leuven; ZonMw: The Netherlands Organisation for Health Research and Development; Hospital Sant Joan de Deu
• Information provided by (Responsible Party): M.J. Ottenhoff, MD, Erasmus Medical Center

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.

Condition or disease	Intervention/treatment	Phase
Neurofibromatosis Type 1	Drug: Lamotrigine; Drug: Placebo	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• 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)
• Study Start Date: October 2014
• Actual Primary Completion Date: April 2020
• Actual Study Completion Date: April 2020

Arms and Interventions

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 Name: Lamictal
Placebo Comparator: Placebo; Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. 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 :

1. 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).
2. Visual perception (change from baseline) [ Time Frame: Baseline and 26 weeks ]
   Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).
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).
4. 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).
5. Fine motor coordination (change from baseline) [ Time Frame: Baseline and 26 weeks ]
   Assessed by the Grooved Pegboard Test.
6. 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).
7. 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).
8. Short intracortical inhibition (SICI) (change from baseline) [ Time Frame: Baseline and 10 weeks ]
   Assessed by paired pulse transcranial magnetic stimulation (ppTMS).
9. 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:

1. Full IQ (Intelligence Quotient) [ Time Frame: Baseline ]
   Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).
2. Adverse event registration [ Time Frame: Baseline, 4 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, 26 weeks, 28 weeks and additionally on indication ]
3. NF1 disease severity [ Time Frame: Baseline ]
   Assessed by the Riccardi scale.
4. Physical examination [ Time Frame: Baseline, 10 weeks and 26 weeks ]
5. 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.
6. Kidney function [ Time Frame: Baseline and 10 weeks ]
   Urea, creatinine
7. Hepatic enzymes [ Time Frame: Baseline and 10 weeks ]
   ALAT, ASAT, GGT
8. Full blood count [ Time Frame: Baseline and 10 weeks ]
9. 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)
10. Parental occupation [ Time Frame: Baseline ]
    Determined by the most appropriate level of education for the particular occupation
11. Educational level [ Time Frame: Baseline and 26 weeks ]
    Determined using the ISCED (International Standard Classification of Education) 2011 levels

Eligibility Criteria

• 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

Locations

Belgium

University Hospital Leuven

Leuven, Belgium, B-3000

Netherlands

Erasmus Medical Center

Rotterdam, South Holland, Netherlands, 3015CN

Spain

Hospital Sant Joan de Deu

Barcelona, Spain

Sponsors and Collaborators

Erasmus Medical Center

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

More Information

Additional Information:

ENCORE expertise center 

• Responsible Party: M.J. Ottenhoff, MD, MD, MSc, Erasmus Medical Center
• ClinicalTrials.gov Identifier: NCT02256124
• 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 Posted: October 3, 2014
• Last Update Posted: April 14, 2020
• Last Verified: April 2020

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:

Neurofibromatoses; Neurofibromatosis 1; 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 Diseases; Neuromuscular Diseases; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Lamotrigine; Anticonvulsants; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Sodium Channel Blockers