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

治疗反应评估和依从性试验：羟基脲治疗镰状细胞性贫血儿童的前瞻性研究

• 批准号: 9130250
• 负责人: Patrick Thomas McGann
• 金额: $ 18.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130250
• 关键词: Address; Adherence; Adult; Affect; Africa; Africa South of the Sahara; Age-Months; Area; Biological Markers; Child; Childhood; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Research; Data; Development Plans; Disease; Dose; Drug Kinetics; Effectiveness; Environment; Evaluation; Funding; Genetic; Genetic Markers; Goals; Guidelines; Health; Hematological Disease; Hematology; Inherited; Institution; Investments; Laboratories; Life; Marrow; Maximum Tolerated Dose; Measurement; Measures; Medical center; Mentors; Mentorship; Methods; Modeling; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Oral; Pain; Patients; Pediatric Hematologist; Pediatric Hematology; Pediatrics; Persons; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Population; Prospective Studies; Recording of previous events; Reporting; Research; Research Personnel; Research Proposals; Research Support; Resources; Safety; Severities; Sickle Cell Anemia; Techniques; Time; Training; Training Programs; Training Support; Translational trial; United States; Urine; base; career; career development; evidence based guidelines; experience; hydroxyurea; improved; improved outcome; innovation; interest; interpatient variability; medication compliance; metabolomics; novel; open label; pediatric department; pediatric pharmacology; personalized approach; personalized medicine; pharmacodynamic model; professor; prospective; research study; response; therapy outcome; treatment response; urinary

 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.

 描述（适用提供）：简介：镰状细胞贫血（SCA）是一种严重而毁灭性的血液学疾病，影响了美国近100,000人，在全球范围内影响了数百万。现在有足够的临床证据表明，羟基脲是一种每日一次的口服药物，对成人和SCA儿童都是安全有效的。 2014年国家心脏，肺部和血液研究所的SCA循证指南建议现在向所有9个月大的受影响的儿童提供羟基脲，无论临床严重程度如何。尽管有大量的证据表明安全性和有效性，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鉴定最有效的羟基脲剂量以及对羟基脲依从性的准确和客观监测。在这项翻译试验中，麦甘博士旨在利用几种新颖的创新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）的儿科助理教授，曾在血液学系中。他的研究重点是改善SCA儿童的结果。他的短期目标是通过全面的培训计划和亚历山大·维克斯（Alexander Vinks）博士的仔细思想来开发儿科临床药理学和药物建模方面的专业知识。他还旨在为患有SCA儿童的临床研究发展进一步的专家。他的长期心态，罗素·韦尔（Russell Ware）博士，将继续在儿童血液学和SCA儿童的临床研究领域提供仔细的心态，并支持他持续的职业发展。 McGann博士的长期目标是成为一名独立研究者，研究专注于美国和撒哈拉以南非洲的SCA儿童的研究。非洲SCA的临床燃烧与缺乏 资源和临床研究。 McGann博士的目标是利用他在Pediater血液学和药理学方面的培训来通过创新的临床研究来改善SCA儿童的疗法和结果。研究环境：CCHMC的研究环境为McGann博士提供了一个杰出的环境，使其发展为独立资助的临床研究者。 CCHMC对初级研究人员有长期的投资，麦加恩博士得到了儿科和血液学部门的全部支持。他在整个机构中建立了强大的导师干部，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：这项研究建议的核心假设是，通过使用新型的基于药物计量的剂量和创新的实验室技术来衡量治疗的依从性和反应，可以改善羟基脲处理对SCA的有效性。该研究包括以下具体目的：1）减少使用新型种群药代动力学/药物动力学（PK/PD）模型为患有SCA儿童达到最大耐受剂量（MTD）所需的时间； 2）从羟基脲暴露中确定独特的尿液代谢组学特征，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。摘要：在此K23申请中，麦甘博士正在寻求正式的心态，培训和研究支持，这将使他能够发展成为一名独立资助的临床研究者，特别是针对SCA儿童改善和个性化治疗。