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，通常在受伤后持续存在。TBI也可能产生注意力重新缺陷（继发性ADHD [SADHD]）。当结合TBI前ADHD和SADHD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甲酯，但哌甲酯用于儿童TBI后的注意力问题是高度可变的。只有两个临床试验评价哌甲酯对儿童创伤性脑损伤后注意力问题的疗效，结果还没有定论。不确定的结果可能是由于样本量小、剂量滴定不充分以及对潜在介导和调节因素评价不充分的限制。本提案将开始填补这些知识空白。本研究的目的是（1）确定哌甲酯治疗儿童TBI后注意力问题的疗效和剂量反应，（2）更好地了解ADHD既往史、TBI后ADHD亚型、执行功能和注意力控制与治疗疗效的关系。拟议的临床试验将招募50名6-17岁的儿童，在中度至重度TBI后12-48个月出现注意力问题，进入一项随机、双盲、安慰剂对照、交叉设计试验，有3种剂量条件（低、中、高）。该研究将描述儿童TBI后对哌甲酯的注意力问题的反应（主要分析），并评估治疗反应的潜在中介和调节因素（次要分析）。该研究将为儿科TBI文献增加新的和创新的信息。它将提供一个更好地了解哌甲酯的疗效 用于治疗儿童TBI后的注意力问题，并将阐明可能影响治疗反应的临床特征。这些发现有可能直接影响临床管理。研究结果还将为更大规模研究的发展提供信息，这将有助于制定针对儿童TBI后注意力问题管理的个性化方案。该研究还建立在候选人先前的研究基础上，该研究评估了儿童TBI后认知和行为结果的预测因子和调节因子。这将为他提供新的技能和知识，使他能够超越评估结果的主持人。该提案将为候选人提供临床试验开发，实施和分析方面的新专业知识，提高他对神经药理学的知识，并进一步发展他对儿科TBI后认知和行为结果评估的知识。候选人在这些领域的专业知识将通过一个培训计划，其中包括教学课程的工作，指导辅导，并从他的指导团队的指导手稿和未来的赠款准备促进。在项目完成后，候选人将准备开发临床试验，以个性化的儿童TBI的神经行为和认知后遗症的管理。

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.