Therapeutic Response Evaluation and Adherence Trial: A Prospective Study of Hydroxyurea for Children with Sickle Cell Anemia

 描述（由申请人提供）：简介：镰状细胞性贫血（SCA）是一种严重的和破坏性的血液系统疾病，影响近10万人在美国和数百万世界各地。现在有充分的临床证据表明，每日一次口服药物羟基脲对SCA成人和儿童都是安全有效的。2014年美国国家心脏、肺和血液研究所的SCA循证指南建议，无论临床严重程度如何，现在都应向所有受影响的9个月大的儿童提供羟基脲。尽管有压倒性的证据证明了其安全性和有效性，但由于各种原因，羟基脲仍未得到充分利用。两个最重要的障碍是确定最有效的羟基脲剂量和准确客观地监测羟基脲的依从性。在这项转化试验中，McGann博士旨在利用几种新颖和创新的方法来解决这些障碍。候选人和职业发展计划：McGann博士是辛辛那提儿童医疗中心（CCHMC）血液学部的儿科助理教授。他的研究重点是改善SCA儿童的预后。他的短期目标是通过全面的培训计划和亚历山大文克斯博士的密切指导，发展儿科临床药理学和药理学建模方面的专业知识。他还旨在为SCA儿童的临床研究开发进一步的专业知识。他的长期导师Russell Ware博士将继续为SCA儿童的儿科血液学和临床研究领域提供密切的指导，并支持他的持续职业发展。McGann博士的长期目标是成为一名独立的研究人员，专注于美国和撒哈拉以南非洲地区SCA儿童的研究。非洲SCA的临床负担与缺乏 资源和临床研究。McGann博士的目标是利用他在儿科血液学和药理学方面的培训，通过创新的临床研究来改善SCA儿童的治疗和结局。研究环境：CCHMC的研究环境为McGann博士发展成为独立资助的临床研究者提供了特殊的环境。CCHMC在初级研究人员方面有着悠久的投资历史，McGann博士得到了儿科和血液科的全力支持。他在整个机构中培养了一支强大的导师队伍，并获得了广泛的机构资源，这将使他能够实现自己的职业目标。研究策略：本研究建议的中心假设是，可以通过使用新的基于药物计量学的剂量和创新的实验室技术来测量依从性和对治疗的反应来改善羟基脲治疗SCA的有效性。该研究包括以下具体目的：1）使用新型群体药代动力学/药效学（PK/PD）模型，缩短SCA儿童达到最大耐受剂量（MTD）的时间; 2）确定来自羟基脲暴露的独特尿液代谢组学特征，可用于监测依从性; 3）进行药物基因组学分析以鉴定与羟基脲MTD相关的遗传标记。总结：在K23申请中，McGann博士正在寻求正式的指导，培训和研究支持，使他能够发展成为一名独立资助的临床研究人员，特别关注SCA儿童的改善和个性化治疗。

 DESCRIPTION (provided by applicant): Introduction: Sickle cell anemia (SCA) is a severe and devastating hematological disorder that affects nearly 100,000 persons in the United States and millions more worldwide. There is now ample clinical evidence that hydroxyurea, a once-daily oral medication, is safe and effective for both adults and children with SCA. The 2014 National Heart, Lung, and Blood Institute's evidence-based guidelines for SCA, recommend that hydroxyurea now be offered to all affected children as young as nine months of age, regardless of clinical severity. Despite the overwhelming evidence demonstrating safety and efficacy, hydroxyurea remains underutilized for a variety of reasons. Two of the most significant barriers are the identification of the most effective hydroxyurea dose and the accurate and objective monitoring of hydroxyurea adherence. In this translational trial, Dr. McGann aims to utilize several novel and innovative methods to address these barriers. Candidate and Career Development Plan: Dr. McGann is an Assistant Professor of Pediatrics at Cincinnati Children's Medical Center (CCHMC) in the Division of Hematology. His research focuses on improving outcomes for children with SCA. His short-term goal is to develop an expertise in pediatric clinical pharmacology and pharmacometric modeling through a comprehensive training program and the close mentorship of Dr. Alexander Vinks. He also aims to develop further expertise in clinical research for children with SCA. His long-time mentor, Dr. Russell Ware, will continue to provide close mentorship in the area of pediatric hematology and clinical research for children with SCA and support his continued career development. Dr. McGann's long-term goal is to become an independent investigator with research focused on children with SCA both in the US and in sub-Saharan Africa. The clinical burden of SCA in Africa is in sharp contrast to the lack of resources and clinical research. Dr. McGann aims to use his training in pediateri hematology and pharmacology to improve the therapies and outcomes for children with SCA through innovative clinical research. Research Environment: The research environment at CCHMC provides an exceptional setting for Dr. McGann to develop into an independently funded clinical investigator. CCHMC has a long-history of investment in junior investigators and Dr. McGann has the full support of the Department of Pediatrics and the Division of Hematology. He has developed a strong cadre of mentors across the institution, and has access to a wide range of institutional resources that will allow him to achieve his career goals. Research Strategy: The central hypothesis of this research proposal is that the effectiveness of hydroxyurea treatment for SCA can be improved by using novel pharmacometrics-based dosing and innovative laboratory techniques to measure adherence and response to therapy. The study includes the following Specific Aims: 1) Reduce the time it takes to reach maximum tolerated dose (MTD) of hydroxyurea for children with SCA using a novel population pharmacokinetic/pharmacodynamic (PK/PD) model; 2) To identify a unique urine metabolomics signature from hydroxyurea exposure, that can be used to monitor adherence; 3) Perform pharmacogenomics analyses to identify genetic markers that are associated with the hydroxyurea MTD. Summary: In this K23 application, Dr. McGann is seeking the formal mentorship, training and research support that will allow him to develop into an independently funded clinical investigator with a special focus of improving and personalizing therapy for children with SCA.