Comparative effectiveness of strategies to improve iron chelation in thalassemia

改善地中海贫血铁螯合策略的有效性比较

• 批准号: 8144713
• 负责人: Janet L Kwiatkowski
• 金额: $ 43.46万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144713
• 关键词: Adherence; Adopted; Adverse effects; Affect; Asians; Canada; Cardiac; Cause of Death; Chelating Agents; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Combined Modality Therapy; Cooley' s anemia; Country; Data; Data Coordinating Center; Data Set; Deferoxamine; Developed Countries; Development; Dose; Evaluation; Feasibility Studies; Feedback; Funding; Future; Goals; Grant; Hemosiderosis; Hereditary Disease; International; Iron; Iron Chelation; Iron Overload; Knowledge; Lead; Life Expectancy; Liver; Liver diseases; Logistics; London; Longevity; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Methods; National Heart, Lung, and Blood Institute; Observational Study; Oral; Organ; Outcome; Outcome Measure; Patients; Plant Roots; Process; Process Measure; Quality of life; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Refractory; Regimen; Relative (related person); Reporting; Research; Research Infrastructure; Research Methodology; Research Personnel; Research Project Grants; Siderosis; Site; Structure; Syndrome; Testing; Thailand; Thalassemia; Transfusion; Work; Workplace; Writing; arm; base; chelation; clinical research site; cohort; comparative effectiveness; design; effectiveness research; improved; meetings; mortality; research study; standard of care; symposium; young adult

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.

描述(由申请人提供)：本提案是一项针对未来比较有效性研究(CER)项目的多中心计划拨款，旨在改善输血依赖型地中海贫血患者的铁负担。在世界范围内，对(非移植的)重型地中海贫血患者的护理标准是持续输血治疗加终身铁螯合治疗。在过去的三十年里，这种疗法已经延长了地中海贫血患者的寿命，但螯合充分性是可变的，死亡的主要原因仍然是心脏铁超载。通过核磁共振测量铁可以简化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。影响螯合充分性的因素很多，包括输血负担和依从性。选择螯合剂(S)和剂量方案(S)也是至关重要的因素，但目前尚不清楚“最佳”策略。这种知识的缺乏不符合随机临床试验的要求，原因有很多，例如(A)当有口服螯合剂可用时，患者不愿随机接受非肠道治疗；(B)不同国家对螯合剂的监管批准状况不同；(C)在支持不同品牌和/或不同品牌的螯合剂之间采用随机联合治疗方法方面存在后勤、财务和企业方面的障碍。这项建议的工作假设是，地中海贫血纵向队列(TLC)是一个正在进行的NHLBI资助的项目，它捕获了约400名患者的螯合疗法、铁状态、输血负担以及依从性和末端器官功能的测量，可以形成一项观察性研究的框架，该研究将在美国、加拿大、英国和泰国计划中的TLC地点进行CER研究。该项目将在两个具体目标中完成：目标1是为多中心、国际CER关于地中海贫血患者铁络合作用的研究开发框架和基础设施。目标2是为计划中的R01应用提供可行性信息和对螯合剂策略的探索性分析。AIM 2的初步分析反馈将反复用于改善AIM 1的后勤，以期在2012年应用R01。 公共卫生相关性该项目旨在确定对长期输血的重型地中海贫血患者进行铁螯合治疗的最有效策略。尽管在过去的30年里，螯合剂极大地延长了地中海贫血患者的预期寿命，但许多患者的心脏和全身铁负荷并不令人满意，心脏铁质沉着症仍然是发达国家地中海贫血年轻人的主要死亡原因。这个问题对于随机临床试验的方法来说是棘手的，不仅是出于后勤和经济原因，而且由于口服螯合剂在世界各地都可以买到，所以不可能使用非肠道去铁胺作为随机对照臂。因此，我们提出了一种比较有效性研究方法，该方法将以正在进行的地中海贫血纵向队列研究为基础，在目前的多站点、多国观察队列中增加一个大型国际站点。R34项目将为全面的CER试验建立基础设施，并提供关于可行性和分析方法本身的试验数据。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全球研究合作的改善和个性化治疗的改进。