Clinical trial NCT03977207: A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
Official title: A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Thyroid; Functional Disturbance
Hypothyroidism
Hemodialysis
Lead sponsor: University of California, Irvine
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2019-06-06
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
timeFrame: Week 0 (pre-trial/baseline)
measure: Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
timeFrame: Week 12
measure: Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
timeFrame: Week 24
measure: Coronary Artery Calcification (CAC) - Volume Score
timeFrame: Week 0 (pre-trial/baseline)
measure: Coronary Artery Calcification (CAC) - Volume Score
timeFrame: Week 24
Secondary outcomes:
measure: Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Physical Performance - Short Physical Performance Battery (SPPB)
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Endothelial Function - Digital Thermal Monitor
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Vascular Calcification Inhibitor - Matrix Gla Protein Levels
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Total Body Fat Percentage
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Muscle Strength - Isometric Dynamometry
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Systolic Function - Global Longitudinal Strain
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
measure: Resting Energy Expenditure (REE) - Indirect Calorimetry
timeFrame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California Irvine
state: California
Study officials:
References:
citation: Rhee CM, Chen Y, You AS, Brunelli SM, Kovesdy CP, Budoff MJ, Brent GA, Kalantar-Zadeh K, Nguyen DV. Thyroid Status, Quality of Life, and Mental Health in Patients on Hemodialysis. Clin J Am Soc Nephrol. 2017 Aug 7;12(8):1274-1283. doi: 10.2215/CJN.13211216. Epub 2017 Jul 13.
citation: Rhee CM, You AS, Nguyen DV, Brunelli SM, Budoff MJ, Streja E, Nakata T, Kovesdy CP, Brent GA, Kalantar-Zadeh K. Thyroid Status and Mortality in a Prospective Hemodialysis Cohort. J Clin Endocrinol Metab. 2017 May 1;102(5):1568-1577. doi: 10.1210/jc.2016-3616.
citation: Rhee CM, Kim S, Gillen DL, Oztan T, Wang J, Mehrotra R, Kuttykrishnan S, Nguyen DV, Brunelli SM, Kovesdy CP, Brent GA, Kalantar-Zadeh K. Association of thyroid functional disease with mortality in a national cohort of incident hemodialysis patients. J Clin Endocrinol Metab. 2015 Apr;100(4):1386-95. doi: 10.1210/jc.2014-4311. Epub 2015 Jan 29.
citation: Rhee CM, Alexander EK, Bhan I, Brunelli SM. Hypothyroidism and mortality among dialysis patients. Clin J Am Soc Nephrol. 2013 Apr;8(4):593-601. doi: 10.2215/CJN.06920712. Epub 2012 Dec 20.
citation: Rhee CM, Ravel VA, Streja E, Mehrotra R, Kim S, Wang J, Nguyen DV, Kovesdy CP, Brent GA, Kalantar-Zadeh K. Thyroid Functional Disease and Mortality in a National Peritoneal Dialysis Cohort. J Clin Endocrinol Metab. 2016 Nov;101(11):4054-4061. doi: 10.1210/jc.2016-1691. Epub 2016 Aug 15.
citation: Rhee CM, Kalantar-Zadeh K, Ravel V, Streja E, You AS, Brunelli SM, Nguyen DV, Brent GA, Kovesdy CP. Thyroid Status and Death Risk in US Veterans With Chronic Kidney Disease. Mayo Clin Proc. 2018 May;93(5):573-585. doi: 10.1016/j.mayocp.2018.01.024.