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)是儿童脑外伤的危险因素，通常在受伤后持续存在。脑外伤还可能产生新的注意力缺陷(继发性ADHD[SADHD])。将伤前ADHD和SADHD的患病率结合起来，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，但在儿童颅脑损伤后注意力问题的使用上，哌醋甲酯的使用是高度可变的。只有两项临床试验评估了哌醋甲酯对儿童脑外伤后注意问题的疗效，结果尚不确定。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的中介和调节因素评估不足所致。这项提议将开始解决这些知识差距。本研究的目的是(1)确定哌甲酯治疗儿童颅脑损伤后注意问题的有效性和剂量-反应关系；(2)更好地了解既往ADHD病史、脑损伤后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6-17岁的儿童，他们在中到重度脑外伤后12-48个月出现注意力问题，参加随机、双盲、安慰剂对照、交叉设计试验，包括3种剂量条件(低、中、高)。这项研究将描述儿童脑外伤后注意力问题对哌醋甲酯的反应(初级分析)，并评估潜在的调节和调节治疗反应的因素(次级分析)。这项研究将为儿童脑外伤文献增加新的和创新的信息。这将使我们更好地了解哌甲酸甲酯的疗效 用于治疗儿童颅脑损伤后的注意问题，它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。研究结果还将有助于开展更大规模的研究，以促进儿科脑外伤后注意力问题管理的个体化方案的开发。这项研究还建立在候选人先前的研究基础上，该研究评估了儿童脑外伤后认知和行为结果的预测因素和调节因素。它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。这项建议将为候选人在临床试验的开发、实施和分析方面提供新的专业知识，提高他的神经药理学知识，并进一步发展他对儿科脑外伤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得到促进，该培训计划包括授课课程工作、指导指导以及他的指导团队对手稿和未来拨款准备的指导。在该项目完成后，候选人将准备开发临床试验，以个体化处理儿童脑外伤的神经行为和认知后遗症。

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.