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

Erasmus University

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Neurofibromatosis Type 1

Treatments: Drug: Lamotrigine; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02256124

MEC-2013-460

NL 44912.078.13 (Other Identifier)

113303003 (Other Grant/Funding Number)

2013-003405-26 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.

Full 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.

Enrollment: 41 patients

Sex: All

Ages: 12 to 18 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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41 participants in 2 patient groups, including a placebo group

Lamotrigine

Experimental group

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.

Treatment:

Drug: Lamotrigine

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo