Efficacy of Methylphenidate for Management of Long-term Attention Problems inTBI

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是儿童TBI的危险因素，通常在损伤后持续存在。创伤性脑损伤也可能产生新生注意力缺陷（继发性注意力缺陷多动症[SADHD]）。当合并tbi前ADHD和SADHD发生率时，损伤后ADHD的患病率接近40-45%。原发性ADHD的一线药物治疗是哌醋甲酯，但使用哌醋甲酯治疗儿童脑外伤后的注意力问题是高度可变的。只有两项临床试验评估哌甲酯对儿童脑外伤后注意力问题的疗效，结果尚无定论。不确定的结果可能是由于样本量小、剂量滴定不足以及对潜在中介和调节因素的评估不充分所致。本提案将着手解决这些知识差距。本研究的目的是：(1)确定哌醋甲酯治疗儿童TBI后注意问题的疗效和剂量反应，(2)更好地了解ADHD病史、TBI后ADHD亚型、执行功能和注意控制与治疗效果的关系。拟议的临床试验将招募50名年龄在6-17岁，在中度至重度脑外伤后12-48个月出现注意力问题的儿童，进行随机、双盲、安慰剂对照、交叉设计试验，试验有3种剂量条件（低、中、高）。本研究将描述儿童脑外伤后注意问题对哌醋甲酯的反应（初步分析），并评估治疗反应的潜在中介和调节因素（二次分析）。该研究将为儿童创伤性脑损伤文献增加新的和创新的信息。这将有助于更好地了解哌甲酯的疗效

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a risk factor for pediatric TBI and often persists post-injury. TBI may also produce attention deficis de novo (secondary ADHD [SADHD]). When combining pre-TBI ADHD and SADHD rates, the prevalence of post-injury ADHD is near 40-45%. First line medication treatment for primary ADHD is methylphenidate, but the use of methylphenidate for attention problems after pediatric TBI is highly variable. Only two clinical trials evaluating the efficacy of methylphenidate on attention problems after pediatric TBI have been performed and the results have been inconclusive. The inconclusive results may be due to limitations of small sample sizes, inadequate dose titration, and inadequate evaluation of potential mediating and moderating factors. This proposal will begin to address these knowledge gaps. The objectives of the study are to (1) determine the efficacy and dose-response of methylphenidate treatment of attention problems after pediatric TBI and (2) provide a better understanding of the relationship of a prior history of ADHD, ADHD subtypes after TBI, executive function, and attentional control to treatment efficacy. The proposed clinical trial will enroll 50 children, age 6-17 years, with attention problems 12-48 months after moderate to severe TBI into a randomized, double-blind, placebo-controlled, cross-over design trial with 3 dose conditions (low, medium, and high). The study will characterize the response of attention problems after pediatric TBI to methylphenidate (primary analysis) and evaluate potential mediating and moderating factors of treatment response (secondary analyses). The study will add new and innovative information to the pediatric TBI literature. It will provide a better understanding of the efficacy of methylphenidate for treatment of attention problems after pediatric TBI and it will elucidate clinical profiles tha may influence response to treatment. The findings have the potential to directly impact clinical management. Findings will also inform the development of larger studies that will facilitate the development of individualized protocols for management of attention problems after pediatric TBI. The study also builds on the candidate's prior research that has evaluated predictors and moderators of cognitive and behavioral outcomes after pediatric TBI. It will provide him with new skills and knowledge that will allow him to move beyond evaluating moderators of outcomes. This proposal will provide the candidate with new expertise in the development, conduct and analysis of clinical trials, improve his knowledge of neuropharmacology, and further develop his knowledge of the assessment of cognitive and behavioral outcomes after pediatric TBI. The candidate's expertise in these areas will be facilitated through a training plan that incorporates didactic course work, directed mentoring, and guidance from his mentoring team on manuscript and future grant preparation. At completion of the project, the candidate will be poised to develop clinical trials to individualize the management of neurobehavioral and cognitive sequelae of pediatric TBI.