Comparative effectiveness of strategies to improve iron chelation in thalassemia

描述（由申请人提供）：该提案是一项多中心计划资助，旨在改善输血依赖性地中海贫血患者的铁负荷，用于未来的比较有效性研究（CER）项目。在世界范围内，（非移植）重型地中海贫血患者的标准治疗是持续输血治疗加终身铁螯合。在过去的三十年里，这种疗法提高了地中海贫血患者的寿命，但螯合作用的充分性是可变的，死亡的主要原因仍然是心脏铁过载。通过MRI进行铁测量简化了全身和心脏铁负荷的评估，但许多患者的螯合状态并不理想。许多因素影响螯合的充分性，包括输血负担和依从性。螯合剂和剂量方案的选择也是至关重要的因素，但“最佳”策略目前尚不清楚。由于许多原因，这种知识的缺乏不适合随机临床试验，例如（a）当口服螯合剂可用时，患者不愿意随机接受胃肠外治疗，（B）不同国家中螯合剂的不同监管批准状态，和（c）支持螯合剂品牌之间和/或之中的随机组合治疗方法的后勤、财务和公司障碍。该提案的工作假设是，地中海贫血纵向队列（TLC）是一项正在进行的NHLBI资助的项目，该项目采集了约400例患者的螯合剂方案、铁状态、输血负担以及依从性和终末器官功能指标，可以形成一项观察性研究的框架，该研究将成为美国、加拿大、英国TLC研究中心和泰国新计划研究中心的计划CER研究的基础。该项目将完成两个具体目标：目标1是制定一个多中心，国际CER研究铁螯合在地中海贫血严重的框架和基础设施。目的2是为计划的R 01应用提供螯合剂策略的可行性信息和探索性分析。目标2初步分析的反馈将反复用于改进目标1的后勤工作，以期待2012年R 01的应用。 公共卫生相关性该项目的目的是确定最有效的策略，铁螯合在慢性输血地中海贫血患者。尽管在过去三十年中螯合剂极大地提高了地中海贫血的预期寿命，但许多患者的心脏和全身铁负荷并不令人满意，并且心脏铁质沉着症仍然是发达国家中患有地中海贫血的年轻成人的主要死因。这个问题是难治的随机临床试验的方法，不仅后勤和财政的原因，而且不可能使用肠外去铁胺作为一个随机对照组，现在口服螯合剂是世界各地。因此，我们提出了一种比较有效性研究方法，该方法将基于正在进行的地中海贫血纵向队列研究，并在目前的多中心、多国观察性队列中增加一个大型国际研究中心。R34项目将为全面的CER试验建立基础设施，并提供可行性和分析方法本身的试点数据。地中海贫血仍然是世界上最普遍的遗传疾病之一，该项目的结果将直接导致改善全球研究合作和改善个性化治疗。

DESCRIPTION (provided by applicant): This proposal is a multicenter planning grant toward a future comparative effectiveness research (CER) project aimed at improving the iron burden of transfusion-dependent thalassemia patients. Worldwide, the standard of care for (non-transplanted) thalassemia major patients is ongoing transfusion therapy plus lifelong iron chelation. This therapy has improved lifespan in thalassemia over the last three decades, but chelation adequacy is variable, and the leading cause of death remains cardiac iron overload. Iron measurements by MRI have simplified assessment of total-body and cardiac iron burden, yet chelation status of many patients is suboptimal. Many factors affect adequacy of chelation, including transfusion burden and adherence. Choice of chelator(s) and dose regimen(s) are also vital factors, but the "optimal" strategy is unclear presently. This lack of knowledge is not amenable to randomized clinical trials for many reasons, e.g. (a) unwillingness of patients to be randomized to parenteral therapy when oral chelators are available, (b) varying regulatory approval status of the chelators in different countries, and (c) logistical, financial and corporate impediments for supporting randomized combination therapy approaches between and/or among chelator brands. The working hypothesis for this proposal is that the Thalassemia Longitudinal Cohort (TLC), an ongoing NHLBI-funded project which captures chelator regimens, iron status, transfusion burden, and measures of adherence and end-organ function for ~400 patients, can form the framework of an observational study that will underlie the planned CER study at TLC sites in the US, Canada, the UK and a new planned site in Thailand. The project will be accomplished in two specific aims: Aim 1 is to develop the framework and infrastructure for a multicenter, international CER study of iron chelation in thalassemia major. Aim 2 is to provide both feasibility information and exploratory analyses of chelator strategies for the planned R01 application. Feedback from initial analyses in aim 2 will be used iteratively to improve Aim 1 logistics in anticipation of an R01 application in 2012. PUBLIC HEALTH RELEVANCE The project aims to determine the most effective strategies for iron chelation in chronically transfused thalassemia major patients. Although chelators have greatly improved life- expectancy in thalassemia over the last three decades, many patients have unsatisfactory cardiac and whole-body iron burdens, and cardiac siderosis remains the leading cause of death in young adults with thalassemia in developed countries. The problem is refractory to approaches by randomized clinical trials not only for logistical and financial reasons, but also the impossibility of using parenteral deferoxamine as a randomized comparator arm, now that oral chelators are available worldwide. We therefore propose a Comparative Effectiveness Research approach, which will be based on the ongoing Thalassemia Longitudinal Cohort study, with addition of a large international site to the current multi-site, multinational observational cohort. The R34 project will establish the infrastructure for a full CER trial, and provide pilot data on feasibility and the analysis methods themselves. Thalassemia remains one of the most prevalent genetic conditions worldwide, and the results of this project will lead directly to improved global research collaboration and improved individualized therapies.