A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients

血液透析患者补充甲状腺激素的随机对照试验

• 批准号: 9975160
• 负责人: Connie Meeyoung Rhee
• 金额: $ 68.77万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975160
• 关键词: Address; Affect; American; Atherosclerosis; Award; Blood Vessels; Body Composition; Body fat; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Clinical Management; Complement; Complication; Data; Dialysis patients; Dialysis procedure; Disease; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Echocardiography; End stage renal failure; Endocrine; Endothelium; Energy Metabolism; Fatigue; Functional disorder; Future; General Population; Grant; Health; Heart failure; Hemodialysis; Hypothyroidism; Impaired health; Impairment; Indirect Calorimetry; Information Systems; Isometric Exercise; Isotonic Exercise; Kidney; Kidney Diseases; Knowledge; Laboratories; Link; Measurable; Measures; Metabolic; Monitor; Morbidity - disease rate; Normal Range; Observational Study; Outcome; Parents; Pathway interactions; Patient Self-Report; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Physical Function; Physical Performance; Placebos; Population; Population Study; Precipitation; Prospective cohort; Proteins; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Reference Values; Research; Research Personnel; Rest; Risk; Risk Factors; Safety; Scanning; Serum; Supplementation; Surveys; Systems Analysis; Therapeutic; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; United States; United States National Institutes of Health; Vascular calcification; adverse outcome; bone turnover; calcification inhibitor; cardiovascular disorder risk; cohort; coronary artery calcification; data warehouse; design; digital; double-blind placebo controlled trial; endothelial dysfunction; health related quality of life; heart function; improved; insight; modifiable risk; mortality; multidisciplinary; muscle strength; novel; overtreatment; patient oriented; physical conditioning; pilot trial; primary endpoint; primary outcome; prognostic; secondary endpoint; two-arm trial

PROJECT SUMMARY/ABSTRACT Data spanning over three decades show that hypothyroidism is highly prevalent in the chronic kidney disease (CKD) population, affecting 25% of those receiving dialysis therapy. In the general population hypothyroidism, defined by elevated thyrotropin (TSH) levels, has been associated with cardiovascular (CV) morbidity and mortality and impaired health-related quality of life (HRQOL), but until recently there was a paucity of data regarding its prognostic implications in CKD. Our pioneering studies supported by the PI’s NIH F32, K23, and R03 awards have advanced the field by showing that elevated thyrotropin (TSH) levels even within the “normal” range (>3.0mIU/L) are associated with heightened risk of CV disease (e.g., coronary artery calcification, endothelial dysfunction) and death across multiple dialysis cohorts. With support of an American Thyroid Association grant, our research was also the first to show a link between high-normal TSH levels and worse HRQOL Short Form 36 scores in dialysis patients, particularly among subscales centered on physical health (e.g., physical function, energy/fatigue). However, there remains considerable controversy as to 1) whether thyroid dysfunction is causally associated with adverse patient-centered and CV outcomes, and 2) if elevated TSH levels represent thyroid functional disease vs. non-thyroidal illness in CKD. Moreover, as United States Renal Data System analyses show that levothyroxine (L-T4) is one of the most commonly prescribed medications in end-stage renal disease patients, there is pressing urgency for a randomized controlled trial (RCT) that will determine the efficacy and safety of L-T4 in this population. In the spirit of our recent discoveries and supportive findings by others, we propose this R01 study in which an Early-Stage Investigator, complemented by a uniquely well-qualified multi-disciplinary team of experts, will conduct a rigorously-designed and feasible randomized, double-blind, parallel two-arm trial of L-T4 vs. placebo among 336 hemodialysis patients with high-normal or subclinical hypothyroid TSH levels (>3.0-5.0 and >5.0-10.0mIU/L, respectively). Our primary objective will be to determine the effects of six months of L-T4 on the co-primary outcomes of HRQOL (Aim 1) and coronary artery calcification (Aim 2). Our main secondary objectives will be to determine the effects of L-T4 on the domains of physical performance (Aim 1), vascular health (Aim 2), and body composition (Aim 3). In a subcohort of 108 HD patients from the parent trial, we will also examine the effects of L-T4 on three novel exploratory secondary endpoints of muscle strength, cardiac function, and resting energy expenditure that will inform the framework of future multi-center corollary RCT’s. Successful completion of this R01 proposal will address major knowledge gaps by determining whether thyroid dysfunction is a novel, modifiable risk factor for impaired HRQOL and CV disease in CKD; defining the causal implications of thyroid dysfunction in CKD; establishing the efficacy and safety of L-T4 in this population; and generating a repository of data through a secondary substudy that will inform future trials of L-T4 in CKD.

项目摘要/摘要 超过三十年的数据表明，甲状腺功能减退症在慢性肾脏中非常普遍 疾病（CKD）人群，影响接受透析治疗的人中有25％。在一般人口 甲状腺功能减退，由甲状腺激素（TSH）水平升高，与心血管（CV）有关 发病率和死亡率以及与健康相关的生活质量受损（HRQOL），但直到最近才有 与CKD有关其预后含义的数据差。我们的开拓性研究由PI的NIH支持 F32，K23和R03奖项通过表明甲状腺激素（TSH）级别甚至是 在“正常”范围内（> 3.0miU/L）与CV疾病的风险增加有关（例如，冠状动脉 钙化，内皮功能障碍）和多个透析队列的死亡。在美国人的支持下 甲状腺协会赠款，我们的研究也是第一个显示高正常TSH级别和 透析患者中​​的HRQOL短形式为36个得分，尤其是在物理上的分量表中 健康（例如身体功能，能量/疲劳）。但是，关于1的争议仍然存在很大的争议 甲状腺功能障碍有时是否与以患者为中心和CV结果相关，以及2） TSH水平升高代表CKD中甲状腺功能疾病与非甲状腺疾病。而且，作为联合 各州肾脏数据系统分析表明，左甲状腺素（L-T4）是最常见的规定之一 末期肾脏疾病患者的药物，紧迫的随机对照试验紧迫 （RCT）将确定L-T4在该人群中的效率和安全性。 本着我们最近发现和其他人的支持性发现的精神，我们提出了这项R01研究 这是一个由一个独特合格的多学科团队完成的早期调查员 专家将进行严格设计和可行的随机，双盲，平行的双臂试验 在336例高正常或亚甲基甲状腺功能低下TSH水平的血液透析患者中​​与安慰剂相比（> 3.0-5.0 和> 5.0-10.0miu/l，分别为）。我们的主要目标是确定L-T4六个月的影响 关于HRQOL（AIM 1）和冠状动脉计算的共同结果（AIM 2）。我们的主要次要 目标将是确定L-T4对身体性能领域的影响（AIM 1），血管 健康（AIM 2）和身体成分（AIM 3）。在父母试验中的108名HD患者的子病毒中，我们将 还要检查L-T4对肌肉力量，心脏强度的三个新型探索性次要终点的影响 功能和休息能量消耗，将为未来多中心推论RCT的框架提供依据。 成功完成此R01提案将通过确定是否甲状腺来解决重大知识差距 功能障碍是CKD中HRQOL和CV疾病受损的新型，可改变的危险因素。定义因果关系 CKD中甲状腺功能障碍的含义；确定L-T4在该人群中的效率和安全性；和 通过二级属性生成数据存储库，该二级将为CKD中L-T4的未来试验提供信息。