A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 336
- 试验地点
- 1
- 主要终点
- Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
研究概览
简要总结
Hypothyroidism, defined by elevated thyrotropin (TSH) levels, is a common endocrine complication in chronic kidney disease patients, and prior evidence shows that higher TSH levels, even within the normal laboratory range, are strongly associated with impaired quality of life and cardiovascular disease in this population. Levothyroxine is one of the most frequently prescribed medications in chronic kidney disease, yet its efficacy and safety in these patients have not been well-studied. Hence, this study will investigate 1) whether levothyroxine improves patient-centered (e.g., health-related quality of life, physical performance, strength) and 2) cardiovascular (e.g., coronary artery calcification, endothelial function, systolic function) outcomes in dialysis patients, and 3) if thyroid hormone replacement exerts classic metabolic effects (i.e., changes in body fat and resting energy expenditure) in this population.
详细描述
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 impaired health-related quality of life (HRQOL) and cardiovascular (CV) morbidity and mortality, but until recently there was a paucity of data regarding its prognostic implications in CKD. Our research has been 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). Our studies have also advanced the field by showing that elevated TSH levels even within the "normal" range (>3.0mIU/L) are associated with heightened risk of CV disease and death across multiple dialysis cohorts. 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. While levothyroxine is one of the most commonly prescribed medications in CKD, little is known about its efficacy in this population.
To address these knowledge gaps, we propose to conduct a randomized double-blind placebo-controlled trial among 336 hemodialysis patients with high-normal or subclinical hypothyroid range serum TSH levels to determine the effects of 24 weeks (i.e., 6 months) of levothyroxine vs. placebo on 1) HRQOL Short Form 36 (SF36) Physical Component Score and 2) coronary artery calcifcation (CAC) progression (co-primary endpoints).
As secondary endpoints, we will also examine 1) HRQOL measured by the ThyPRO survey, 2) physical performance, 3) endothelial function, 4) vascular calcification inhibitor levels, and 5) total body fat percentage. In a sub-study of 108 hemodialysis patients, we will also examine exploratory secondary endpoints of 1) muscle strength, 2) systolic function, and 3) resting energy expenditure.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 years old
- •Received hemodialysis at least four weeks
- •Have two consecutive thyrotropin (TSH) levels >3.0-10.0mIU/L during the screening period
- •Have normal free thyroxine (FT4) levels
- •Have ability to provide written informed consent
排除标准
- •Active treatment with thyroid hormone supplementation or anti-thyroid medications
- •Active receipt of dialysis
- •Prior kidney transplantation
- •Life expectancy less than six months
- •Active malignancy or prior thyroid malignancy
- •Active pregnancy or planning a pregnancy
- •Active coronary ischemia or atrial fibrillation (evaluated by EKG)
- •Active congestive heart failure exacerbation
- •Osteoporosis
- •Weight in excess of 450 lbs.
- •Hyperthyroidism as determined by TSH <0.5mIU/L during the screening period, anti-thyroid medication use, or hyperthyroidism diagnosis
研究组 & 干预措施
Levothyroxine
Patients will be randomized to levothyroxine or placebo (similar in size, shape, and color to levothyroxine) via permuted blocks stratified by two TSH levels (>3.0-5.0 and 5.0-10.0mIU/L) to ensure treatment balance across TSH levels. The study medications will be prepared in pill form. In the treatment arm, initial L-T4 doses will be 25mcg vs. 50mcg among patients whose TSH is >3.0-5.0mIU/L vs. 5.0-10.0mIU/L, respectively. Patients in the placebo arm will receive an equivalent number of placebo pills daily depending upon TSH level.
The intervention period is 24 weeks. Patients will undergo up to two subsequent dose titrations after 8- and 16-weeks of treatment, based on interim TSH measurements at these time points. Patients whose TSH levels are higher or lower than the therapeutic TSH target of 0.5-3.0mIU/L will undergo a dose adjustment (+/- 25mcg), while those whose TSH levels are in target range will continue the prior dose.
干预措施: Levothyroxine Sodium (Drug)
Placebo
Patients will be randomized to levothyroxine or placebo (similar in size, shape, and color to levothyroxine) via permuted blocks stratified by two TSH levels (>3.0-5.0 and 5.0-10.0mIU/L) to ensure treatment balance across TSH levels. The study medications will be prepared in pill form. In the treatment arm, initial L-T4 doses will be 25mcg vs. 50mcg among patients whose TSH is >3.0-5.0mIU/L vs. 5.0-10.0mIU/L, respectively. Patients in the placebo arm will receive an equivalent number of placebo pills daily depending upon TSH level.
The intervention period is 24 weeks. Patients in the placebo arm will undergo an equivalent titration in placebo pills (as that of the experimental arm) after 8- and 16-weeks of treatment, based on interim TSH measurements at these time points.
干预措施: Placebos (Drug)
结局指标
主要结局
Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
时间窗: Week 24
We will assess HRQOL using the Short Form 36, which consists of 36 questions grouped into eight subscales (score 0-100 for each subscale; higher scores indicate better states of health) that will be used to derive a summary Physical Component Score.
Coronary Artery Calcification (CAC) - Volume Score
时间窗: Week 24
We will assess CAC Volume Score using a 256-multidetector CT test. Volume score will be calculated by multiplying the number of voxels with calcification by the volume of each voxel for each calcified lesion, and summing individual lesion scores from the four main coronary arteries (left main, left anterior descending, circumflex, and right coronary artery).
次要结局
- Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Physical Performance - Short Physical Performance Battery (SPPB)(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Endothelial Function - Digital Thermal Monitor(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Vascular Calcification Inhibitor - Matrix Gla Protein Levels(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Total Body Fat Percentage(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Muscle Strength - Isometric Dynamometry(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Systolic Function - Global Longitudinal Strain(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
- Resting Energy Expenditure (REE) - Indirect Calorimetry(Weeks 0 (pre-trial/baseline) and 24 (post-randomization))
研究者
Connie Rhee
Assistant Professor of Medicine and Public Health; Division of Nephrology and Hypertension, Department of Medicine
University of California, Irvine