The Effect of Lamotrigine on Cognitive Deficits Associated With Neurofibromatosis Type 1: a Phase II Randomized Controlled Multi-centre Trial (NF1-EXCEL)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 41
- 试验地点
- 3
- 主要终点
- Performance intelligence quotient (change from baseline)
研究概览
简要总结
The purpose of this study is to determine whether lamotrigine can improve cognitive and neurophysiological deficits in adolescents with Neurofibromatosis type 1.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Lamotrigine (Drug)
Placebo
Placebo tablets during 28 consecutive weeks, with identical appearance to lamotrigine tablets, mimicking the lamotrigine dosing schedule.
干预措施: Placebo (Drug)
结局指标
主要结局
Performance intelligence quotient (change from baseline)
时间窗: Baseline and 26 weeks
Assessed by the Wechsler Intelligence Scales for Children - third edition (WISC-III).
次要结局
- Attention problems (change from baseline)(Baseline, 10 weeks, 26 weeks and 52 weeks)
- Executive functioning (change from baseline)(Baseline, 26 weeks and 52 weeks)
- Short intracortical inhibition (SICI) (change from baseline)(Baseline and 10 weeks)
- Long-term potentiation-like plasticity (change from baseline)(Baseline and 10 weeks)
- Visual-spatial working memory (change from baseline)(Baseline and 26 weeks)
- Visual perception (change from baseline)(Baseline and 26 weeks)
- Sustained attention (change from baseline)(Baseline and 26 weeks)
- Visual-motor integration (change from baseline)(Baseline and 26 weeks)
- Fine motor coordination (change from baseline)(Baseline and 26 weeks)
研究者
M.J. Ottenhoff, MD
MD, MSc
Erasmus Medical Center