Behaviors and Mental Disorders

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Neoplasms

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Autistic Disorder

Sclerosis

Intellectual Disability

Tuberous Sclerosis

Autism Spectrum Disorder

Child Development Disorders, Pervasive

Developmental Disabilities

Neurodevelopmental Disorders

Mental Disorders

Psychotic Disorders

Hamartoma

Neoplasms, Multiple Primary

Syndrome

Neoplastic Syndromes, Hereditary

Congenital Abnormalities

Malformations of Cortical Development

Nervous System Malformations

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Tuberous Sclerosis Complex

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Everolimus once daily for 1 year, titration to trough levels of 5-10 ng/ml

Placebo treatment for 1 year. Tablets will be identical to everolimus tablets.

Everolimus once daily titrated to trough levels of 5-10 ng/ml.

Placebo

M.C.Y. de Wit, MD. PhD.

I.E. Overwater, MSc

Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian target of rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies suggests that mTOR inhibitors improve learning and development in patients with TSC.

Randomized double-blind placebo controlled intervention study in children with TSC between age 4 and 15 years with an intelligence quotient (IQ) estimated \<80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.

Patients are randomised to receive everolimus or placebo during a period of 12 months.

Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex

Assessed by the school CITO (centraal instituut voor toetsontwikkeling) scores or reading and arithmetic scores

Assessed by measuring trough levels of everolimus

Levels of and abnormalities in blood control values

Assessed by Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III NL) and Wechsler Intelligence Scale for Children (WISC-III-NL)

Assessed by Autism Diagnostic Observation Schedule (ADOS)

Assessed by social responsiveness scale (SRS) and Dutch Children's Communication Checklist (CCC-2-NL) questionnaires

Assessed by Cambridge Neuropsychological Test Automated Battery (CANTAB)

Assessed by BEERY Visual-Motor Integration (BEERY VMI), grooved pegboard

Assessed by Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) questionnaires

Assessed by Behavior Rating Inventory of Executive Functioning (BRIEF) questionnaire Dutch version

Assessed by Sleep Disturbance Scale for Children (SDSC) questionnaire

Assessed by Child Health Questionnaire Parent Form (CHQ-PF50) questionnaire

Assessed by Short Sensory Profile (SSP) questionnaire

Comparison of epilepsy frequency during month previous to study start and last month of trial participation.

EEG abnormalities

Utrecht University

Erasmus Medical Center

Pediatric Neurologist

Cognitive Dysfunction

Cognition Disorders

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Neurofibromatosis

Neurofibromatosis Type 1

Dermatologic Agents

Channel Blockers

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

Bone Density Conservation Agents

Chlorhexidine

Chlorhexidine gluconate

Lamotrigine

Calcium

Calcium Channel Blockers

Calcium, Dietary

Hormones

Antipsychotic Agents

Sodium Channel Blockers

Diuretics, Potassium Sparing

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.

Ype Elgersma, PhD

Henriette A Moll, MD, PhD

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.

Effect of Lamotrigine on Cognition in NF1

The Effect of Lamotrigine on Cognitive Deficits Associated With Neurofibromatosis Type 1: a Phase II Randomized Controlled Multi-centre Trial (NF1-EXCEL)

Assessed by the Wechsler Intelligence Scales for children - third edition (WISC-III).

Pharmacokinetic model build with NONMEM analysis of trough level, Tmax level and a level 6 hours post-dose.

Determined by highest educational grade as measured with the "Standaard Onderwijsindeling (SOI)" classification by Statistics Netherlands (Centraal Bureau voor Statistiek; CBS)

Determined by the most appropriate level of education for the particular occupation

Determined using the ISCED (International Standard Classification of Education) 2011 levels

Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).

Assessed by the Paired Associative Learning (PAL) task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Assessed by the Motor Free Visual Perception Test - third edition (MVPT-3).

Assessed by the Sustained Attention DOTS (SA-DOTS) of the Amsterdam Neuropsychological Tasks (ANT).

Assessed by the Beery-Buktenica Developmental Task of Visual Motor Integration - sixth edition (Beery-VMI-6).

Assessed by a parent rated ADHD-questionnaire, the ADHD-vragenlijst (AVL).

Assessed by the Behavior Rating Inventory for Executive Function parent questionnaire (BRIEF).

Assessed by paired pulse transcranial magnetic stimulation (ppTMS).

Assessed by paired associative stimulation (PAS) using transcranial magnetic stimulation (TMS).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex	NCT01730209	Tuberous Sclero... TSC Related Cog... TSC Related Aut... TSC Related Lea...	Everolimus Placebo	4 Years - 15 Years	Erasmus Medical Center
Effect of Lamotrigine on Cognition in NF1	NCT02256124	Neurofibromatos...	Lamotrigine Placebo	12 Years - 18 Years	Erasmus Medical Center

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