Preventing Epilepsy using Vigabatrin in Infants with Tuberous Sclerosis Complex

使用氨己烯酸预防患有结节性硬化症婴儿的癫痫

• 批准号: 9920232
• 负责人: Martina Bebin
• 金额: $ 113.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920232
• 关键词: Adverse event; Affect; Age; Age-Months; Anticonvulsants; Antiepileptogenic; Behavioral; Biological Markers; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Communication; Data; Development; Diagnosis; Double-Blind Method; Drug resistance; Early Diagnosis; Early identification; Early treatment; Effectiveness; Electroencephalography; Epilepsy; Epileptogenesis; Evaluation; Impairment; Individual; Infant; Infantile spasms; Intellectual functioning disability; Intractable Epilepsy; Life; Measures; Medical; Mental Health; Mental disorders; Motor Skills; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Phase; Population; Prevalence; Prevention; Prevention trial; Preventive treatment; Primary Prevention; Randomized; Refractory; Risk; Safety; Seizures; Sensitivity and Specificity; Serious Adverse Event; Severity of illness; Syndrome; Technology; Testing; Time; Toddler; Tuberous sclerosis protein complex; Ultrasonography; United States; Vigabatrin; Vocabulary Test; adverse event risk; arm; autism spectrum disorder; base; cognitive testing; comorbidity; disability; double-blind placebo controlled trial; drug development; improved; infancy; phase III trial; placebo controlled study; prenatal; prevent; preventable epilepsy; primary outcome; prospective; public health relevance; secondary outcome; side effect; study population; symptom treatment; treatment group; visual-motor integration

 DESCRIPTION (provided by applicant): The PREVeNT Trial is a phase IIb randomized double-blind placebo-controlled trial with vigabatrin in infants with Tuberous Sclerosis Complex (TSC). The primary objective of the study is the developmental impact of early versus delayed treatment with vigabatrin at 24 months of age based on the cognitive assessment score of the Bayley-III. The secondary study objectives will focus on the effectiveness of early versus delayed treatment with vigabatrin in clinical seizure prevention and the prevalence of drug resistant epilepsy by the age of 24 months. Also, the impact of early versus delayed vigabatrin treatment on receptive communication, expressive communication, fine and gross motor skills, and risk of autism spectrum disorders (ASD). The outcome measures for this secondary objective will be subdomain scores of the Bayley-III, Vineland-II, Beery Visual Motor Integration (VMI), Peabody Picture Vocabulary Test (PPVT), Differential Ability Scales-II (DAS-II) and ADOS2 at 24 months. Additional exploratory analysis will be completed at 36 months to access changes observed at 24 months are consistent with those seen at 36 months and indicative of long-term outcome. In addition, analysis will be done to determine the safety of vigabatrin as a preventative treatment for seizures in this TSC study population. The study will also confirm the feasibility of using EEG biomarkers to identify TSC infants at risk for developing epilepsy. The early diagnosis of TSC is possible because of the advances in technology such as prenatal ultrasound and often the diagnosis is now made prenatally or in early infancy before the onset of epilepsy due to non- neurological findings [Datta et al. 2008]. As a result there is an appropriate window of opportunity to identify at- risk patients and initiate potential antiepileptogenic treatment prior to the onset of clinical seizures and subsequent epilepsy. The prevalence of medically-refractory epilepsy and associated intellectual impairment, autism spectrum disorders, and mental health disabilities in this population is well documented, [Chu-Shore et al 2010], justifying the initiation of therapy with potential side effects in a presymptomatic stage in TSC patients. The central hypothesis of this proposal is that early identification of EEG biomarkers and presymptomatic treatment with vigabatrin in infants with TSC can prevent or lower the risk of developing infantile spasms and/or refractory seizures. This preventative approach would promote more favorable cognitive, behavioral, developmental, and psychiatric outcomes.

 描述（由申请人提供）：PREVeNT试验是一项在患有多发性硬化症（TSC）的婴儿中进行的氨己烯酸IIb期随机、双盲、安慰剂对照试验。该研究的主要目的是根据Bayley-III的认知评估评分，在24个月龄时早期与延迟氨己烯酸治疗对发育的影响。次要研究目的将侧重于氨己烯酸早期与延迟治疗在临床癫痫发作预防中的有效性以及24个月龄时耐药性癫痫的患病率。此外，早期与延迟氨己烯酸治疗对接受性沟通，表达性沟通，精细和粗大运动技能以及自闭症谱系障碍（ASD）风险的影响。该次要目的的结局指标为24个月时Bayley-III、Vineland-II、Beery视觉运动整合（VMI）、Peabody图片词汇测试（PPVT）、区分能力量表-II（DAS-II）和ADOS 2的子域评分。将在36个月时完成额外的探索性分析，以获得24个月时观察到的变化与36个月时观察到的变化一致，并指示长期结局。此外，将进行分析，以确定氨己烯酸作为TSC研究人群中癫痫发作预防性治疗的安全性。该研究还将证实使用EEG生物标志物识别有癫痫风险的TSC婴儿的可行性。由于产前超声等技术的进步，TSC的早期诊断是可能的，并且由于非神经学发现，现在通常在产前或婴儿早期癫痫发作前进行诊断[Datta et al. 2008]。因此，有一个适当的 在临床癫痫发作和随后的癫痫发作之前，识别风险患者并开始潜在的抗癫痫治疗的机会窗口。该人群中难治性癫痫和相关智力障碍、自闭症谱系障碍和精神健康残疾的患病率已得到充分记录[Chu-Shore et al 2010]，证明在TSC患者的症状前阶段开始治疗具有潜在副作用是合理的。该建议的中心假设是，早期识别EEG生物标志物和用氨己烯酸对TSC婴儿进行症状前治疗可以预防或降低婴儿痉挛和/或难治性癫痫发作的风险。这种预防方法将促进更有利的认知，行为，发展和精神病学的结果。

项目成果

Two different genetic etiologies for tuberous sclerosis complex (TSC) in a single family.

一个家族中有两种不同的结节性硬化症 (TSC) 遗传病因。

• DOI: 10.1002/mgg3.1296
• 发表时间: 2020
• 期刊: Molecular genetics & genomic medicine
• 影响因子: 2
• 作者: Mowrey,Kate;Koenig,MaryKay;Szabo,CharlesA;Samuels,Joshua;Mulligan,Shannon;Pearson,DeborahA;Northrup,Hope
• 通讯作者: Northrup,Hope

Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

早期用氨己烯酸治疗不会减少结节性硬化症的局灶性癫痫发作或改善认知能力：预防试验。

• DOI: 10.1002/ana.26778
• 发表时间: 2023
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Bebin,ElizabethMartina;Peters,JurriaanM;Porter,BrendaE;McPherson,TarrantO;O'Kelley,Sarah;Sahin,Mustafa;Taub,KatherineS;Rajaraman,Rajsekar;Randle,StephanieC;McClintock,WilliamM;Koenig,MaryKay;Frost,MikeD;Northrup,HopeA;W
• 通讯作者: W

Reply to "Chance Bias Arising from TSC2 Mutation Imbalance in the PREVeNT Trial".

回复“预防试验中 TSC2 突变不平衡引起的机会偏差”。

• DOI: 10.1002/ana.26857
• 发表时间: 2024
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Bebin,EMartina