A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients

NCT03977207 | Recruiting DMC

• 1 other identifier: 20195142
• Study Type: interventional
• Target: 336
• Locations: 1 country
• Sites: 1

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.

Conditions

Thyroid; Functional Disturbance; Hypothyroidism; Hemodialysis

Outcome Measures

Primary Outcomes (5)

• Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score

  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.

  Week 0 (pre-trial/baseline)

• Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score

  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.

  Week 12

• Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score

  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.

  Week 24

• Coronary Artery Calcification (CAC) - Volume Score

  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).

  Week 0 (pre-trial/baseline)

• Coronary Artery Calcification (CAC) - Volume Score

  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).

  Week 24

Secondary Outcomes (8)

• 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)

Study Arms (2)

Levothyroxine

EXPERIMENTAL

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.

Drug: Levothyroxine Sodium

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebos

Interventions

Levothyroxine Sodium DRUG

Thyroid hormone supplement

Levothyroxine

Placebos DRUG

Placebo oral capsule

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Irvine: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of California Irvine

Orange, California, 92868, United States

RECRUITING

Related Publications (6)

• 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.

  PMID: 28705886 BACKGROUND

• 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.

  PMID: 28324018 BACKGROUND

• 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.

  PMID: 25632971 BACKGROUND

• 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.

  PMID: 23258793 BACKGROUND

• 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.

  PMID: 27525529 BACKGROUND

• 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.

  PMID: 29728200 BACKGROUND

MeSH Terms

Conditions

Thyroid Diseases; Hypothyroidism

Interventions

Thyroxine

Condition Hierarchy (Ancestors)

Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Central Study Contacts

Connie Rhee, MD, MSc

CONTACT

714-456-5142; crhee1@uci.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine and Public Health; Division of Nephrology and Hypertension, Department of Medicine

Study Record Dates

• First Submitted: May 28, 2019
• First Posted: June 6, 2019
• Study Start: July 20, 2020
• Primary Completion: November 30, 2025
• Study Completion: November 30, 2025
• Last Updated: September 8, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)