Health system based clinical trial recruitment

基于卫生系统的临床试验招募

• 批准号: 8251498
• 负责人: TREVOR J. ORCHARD
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251498
• 关键词: Accounting; Acute-Phase Proteins; Address; Albuminuria; Antioxidants; Atherosclerosis; Authorization documentation; Binding; Cardiovascular system; Cessation of life; Clinical Trials; Complications of Diabetes Mellitus; Controlled Clinical Trials; Coronary Arteriosclerosis; Death Rate; Development; Diabetes Mellitus; Diabetic Angiopathies; Double-Blind Method; Eligibility Determination; End stage renal failure; Enrollment; Epidemiology; Etiology; Evaluation Studies; Event; Functional disorder; Future; General Population; Genotype; Grant; Haptoglobins; Health system; Healthcare Systems; Heart; Hemoglobin; High Density Lipoproteins; Hyperglycemia; Hyperlipidemia; Hypertension; Incidence; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Kidney Failure; Left; Longitudinal Studies; Medical center; Modification; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Ohio; Outcome; Pathogenesis; Patient Care; Pennsylvania; Pharmacogenetics; Physicians; Placebo Control; Population; Prevention; Protein Binding; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Recruitment Activity; Registries; Renal function; Research; Residencies; Risk; Risk Factors; Source; Subgroup; Supplementation; Testing; Tissues; Tocopherols; United States National Institutes of Health; Universities; Vitamin E; West Virginia; antioxidant therapy; base; cohort; diabetic; disorder risk; neglect; oxidative damage; premature; prevention evaluation; prospective; protective effect; success; willingness

DESCRIPTION (provided by applicant): Reactive oxygen species have been implicated in the etiology and progression of diabetes complications, although clinical trials generally have not supported a protective effect of 1-tocopherol supplementation on CVD outcomes. It has recently been proposed that the success of antioxidant therapy may be limited to susceptible subgroups, such as individuals with diabetes and the Haptoglobin (Hp) 2-2 genotype. Hp binds to free hemoglobin, thereby inhibiting hemoglobin-induced oxidative damage to tissues. It has been shown that the Hp 2-2 genotype is less effective as an antioxidant, interacting with the diabetic state to promote HDL oxidative modification and dysfunction. Indeed, longitudinal studies in type 2 diabetes have shown increased CVD risk in those with the Hp 2-2 genotype and retrospective analyses of the HOPE trial showed a reduction in MI and CVD death rates with vitamin E only in the group with diabetes and the Hp 2-2 genotype. Importantly, daily supplementation with 400 IU vitamin E significantly reduced CVD events by 53% within 18 months in a prospective randomized double-blinded clinical trial in those with type 2 diabetes and the Hp 2-2 genotype. Dual therapy with vitamin E and statins provided superior cardiovascular protection compared to statin therapy alone. The Pittsburgh Epidemiology of Diabetes Complications study has also shown a twofold increased coronary artery disease risk in those with the Hp 2-2 compared to the Hp 1-1 genotype in type 1 diabetes. In this type 1 diabetes cohort, Hp predicted early renal function decline and end-stage renal disease (ESRD) but not albuminuria per se. To date, beyond intensive insulin therapy, limited direct trial evidence exists for CVD prevention in type 1 diabetes and physicians caring for these patients have been left having to infer from type 2 diabetes studies. Unfortunately, this strategy may have contributed to a smaller decline in the incidence of CVD in type 1 diabetes than seen for other complications (e.g. renal disease). Thus, evaluating the potential of vitamin E to reduce rates of diabetic vascular disease in type 1 diabetes provides a unique opportunity to address both this inequity and a major neglected need for those with type 1 diabetes. Our long term plan is therefore to conduct a randomized (within Hp genotype), double-blind, placebo controlled clinical trial of daily supplementation with 400 IU 1-tocopherol on CVD events in type 1 diabetes. A U34 planning grant has already been submitted to NIDDK. However, the major concern is the feasibility to raise the needed number of subjects (>3,000) with type 1 diabetes at sufficient risk for a 5 year trial to be conducted. Thus, our aim for this R03 application is to develop a registry of individuals with diabetes treate within one of the largest U.S. health care systems, the University of Pittsburgh Medical Center (UPMC) and thus assess the feasibility of recruiting for such a clinical trial in the type 1 diabets population. PUBLIC HEALTH RELEVANCE: A prospective clinical trial in type 2 diabetes showed a 53% reduction in CVD risk with daily vitamin E supplementation in those with the Hp 2-2 genotype, a subgroup at increased CVD risk in diabetes. Whether trial results can be extrapolated to type 1 diabetes is currently unknown. The proposed study therefore offers a unique opportunity for CVD prevention with a simple and inexpensive treatment with vitamin E supplementation in a large proportion of individuals with type 1 diabetes as 44% of individuals have this genotype.

描述（由申请人提供）：活性氧与糖尿病并发症的病因和进展有关，尽管临床试验通常不支持1-生育酚补充剂对CVD结局的保护作用。最近有人提出，抗氧化治疗的成功可能仅限于易感亚组，如糖尿病患者和结合珠蛋白（Hp）2-2基因型。Hp与游离血红蛋白结合，从而抑制血红蛋白诱导的组织氧化损伤。已经表明，Hp 2-2基因型作为抗氧化剂不太有效，与糖尿病状态相互作用以促进HDL氧化修饰和功能障碍。事实上，2型糖尿病的纵向研究显示，Hp 2-2基因型患者的心血管疾病风险增加，HOPE试验的回顾性分析显示，维生素E仅在糖尿病和Hp 2-2基因型组中降低MI和心血管疾病死亡率。重要的是，在2型糖尿病和Hp 2-2基因型患者中进行的一项前瞻性随机双盲临床试验中，每日补充400 IU维生素E可在18个月内显著降低53%的CVD事件。与他汀类药物单独治疗相比，维生素E和他汀类药物双重治疗提供了上级心血管保护。匹兹堡糖尿病并发症流行病学研究也表明，与1型糖尿病中的Hp 1-1基因型相比，Hp 2-2基因型患者的冠状动脉疾病风险增加了两倍。在这个1型糖尿病队列中，Hp可预测早期肾功能下降和终末期肾病（ESRD），但不能预测蛋白尿本身。到目前为止，除了强化胰岛素治疗外，1型糖尿病患者CVD预防的直接试验证据有限。 糖尿病和照顾这些患者的医生不得不从2型糖尿病研究中推断。不幸的是，这种策略可能导致1型糖尿病CVD发病率的下降幅度小于其他并发症（例如肾脏疾病）。因此，评估维生素E降低1型糖尿病患者糖尿病血管疾病发生率的潜力，为解决这种不平等和1型糖尿病患者被忽视的主要需求提供了独特的机会。因此，我们的长期计划是进行一项随机（在Hp基因型内）、双盲、安慰剂对照的临床试验， 400 IU 1-生育酚对1型糖尿病CVD事件的影响已经向NIDDK提交了一份U34规划赠款。然而，主要的问题是增加所需数量的1型糖尿病受试者（> 3，000）的可行性，这些受试者具有足够的风险进行5年试验。因此，我们的R 03申请的目的是在美国最大的医疗保健系统之一匹兹堡大学医学中心（UPMC）内开发糖尿病治疗个体的登记，从而评估在1型糖尿病人群中招募此类临床试验的可行性。 公共卫生关系：一项2型糖尿病的前瞻性临床试验显示，在Hp 2-2基因型人群中，每日补充维生素E可使心血管疾病风险降低53%，这是糖尿病心血管疾病风险增加的一个亚组。试验结果是否可以外推到1型糖尿病目前尚不清楚。因此，拟议的研究为大部分1型糖尿病患者提供了一个独特的机会，通过简单而廉价的维生素E补充治疗来预防CVD，因为44%的人患有这种基因型。