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: 10438772
• 负责人: Connie Meeyoung Rhee
• 金额: $ 68.01万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438772
• 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; Drug Prescriptions; 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; 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 repository; 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.

项目概要/摘要 三十多年来的数据表明，甲状腺功能减退症在慢性肾病中非常普遍 慢性肾病 (CKD) 人群，影响 25% 接受透析治疗的人群。 甲状腺功能减退症，即促甲状腺素 (TSH) 水平升高，与心血管 (CV) 相关 发病率和死亡率以及健康相关生活质量 (HRQOL) 受损，但直到最近， 缺乏关于其对 CKD 预后影响的数据。我们的开创性研究得到了 PI 的 NIH 的支持。 F32、K23 和 R03 奖项表明促甲状腺素 (TSH) 水平升高甚至可以促进该领域的发展 “正常”范围内 (>3.0mIU/L) 与 CV 疾病（例如冠状动脉 在一位美国人的支持下，多个透析队列中的钙化、内皮功能障碍）和死亡。 甲状腺协会资助，我们的研究也是第一个显示高正常 TSH 水平与 透析患者的 HRQOL Short Form 36 得分较差，特别是在以身体为中心的子量表中 健康（例如身体机能、精力/疲劳）然而，对于 1) 仍存在相当大的争议。 甲状腺功能障碍是否与以患者为中心的不良结局和心血管结局存在因果关系，2) 如果 TSH 水平升高代表 CKD 中的甲状腺功能性疾病与非甲状腺疾病。 各州肾脏数据系统分析表明，左旋甲状腺素 (L-T4) 是最常用的处方药之一 终末期肾病患者的药物治疗，迫切需要进行随机对照试验 （随机对照试验）将确定 L-T4 在该人群中的有效性和安全性。 本着我们最近的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 其中一名早期研究人员，辅以一支独特的高素质多学科团队 专家们将对L-T4进行严格设计且可行的随机、双盲、平行双臂试验 与安慰剂相比，336 名血液透析患者的 TSH 水平处于正常高值或亚临床甲状腺功能减退症 (>3.0-5.0 和 >5.0-10.0mIU/L，分别）。我们的主要目标是确定 L-T4 六个月的效果。 HRQOL（目标 1）和冠状动脉钙化（目标 2）的共同主要结果。 目标是确定 L-T4 对身体机能（目标 1）、血管 在来自母体试验的 108 名 HD 患者的子队列中，我们将进行健康（目标 2）和身体成分（目标 3）。 还检查了 L-T4 对三个新的探索性次要终点（肌肉力量、心脏）的影响。 功能和静息能量消耗，这将为未来多中心推论随机对照试验的框架提供信息。 成功完成此 R01 提案将通过确定甲状腺是否 功能障碍是 CKD 中 HRQOL 和 CV 疾病受损的一个新的、可改变的危险因素； 甲状腺功能障碍对 CKD 的影响；确定 L-T4 在该人群中的有效性和安全性； 通过二次子研究生成数据存储库，为未来 L-T4 在 CKD 中的试验提供信息。