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Thyroid; Functional DisturbanceTHYROID-HDNCT03977207

A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients

A study testing Levothyroxine Sodium in people with Thyroid; Functional Disturbance and Hypothyroidism, run by University of California, Irvine at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Levothyroxine Sodium
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
336 participants
Where
1 siteUnited States
Study dates
20 Jul 2020to 30 Nov 2025
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Connie Rhee, MD, MSc contact

714-456-5142

crhee1@uci.edu

United States1 site, 1 recruiting
  • University of California Irvine

    Orange, California, 92868

    Kamyar Kalantar-Zadeh, 7144565142, kkz@uci.edu

    Recruiting

Other trials in United States

About this study

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.

Read the 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.

Being tested
Levothyroxine Sodium, Placebos
Medical subject headings
Thyroid Diseases, Hypothyroidism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Levothyroxine SodiumDrug

    Thyroid hormone supplement

  • PlacebosDrug

    Placebo oral capsule

Study groups in NCT03977207
Study groupRoleWhat they receive
LevothyroxineExperimentalPatients 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.
Receives: Drug: Levothyroxine Sodium
PlaceboPlacebo comparatorPatients 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.
Receives: Drug: Placebos

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Week 0 (pre-trial/baseline)

  2. 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.

    Measured: Week 12

  3. 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.

    Measured: Week 24

  4. 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).

    Measured: Week 0 (pre-trial/baseline)

  5. 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).

    Measured: Week 24

Secondary outcomes (8)
  1. Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores

    We will administer the thyroid-specific quality of life patient-reported outcome (ThyPRO) measure, which is comprised of 84 items categorized into 13 domains, plus a general quality of life question (this is a composite measure).

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  2. Physical Performance - Short Physical Performance Battery (SPPB)

    We will measure physical performance using the Short Physical Performance Battery (SPPB), which tests 1) gait speed (faster of two timed, usual pace 15-foot walks), 2) balance (balance test measuring ability to stand with feet in side-by-side, semi-tandem, and tandem positions for 10 seconds), and 3) chair raises (timed series of five attempts to arise from a chair unassisted without use of arms), with each component ranging from 0 to 4 (score 0-12; higher score indicates better performance).

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  3. Endothelial Function - Digital Thermal Monitor

    We will measure endothelial function using digital thermal monitor (DTM) testing, which is based on the principle that changes in fingertip temperature during and after an ischemic stimulus (blood pressure [BP] cuff occlusion) reflect changes in blood flow. In normal endothelial function, cuff inflation results in a 1-3 degree Celsius temperature decline, followed by rapid temperature rise to above baseline during cuff deflation due to compensatory vasodilation. Temperature (temp) will be measured before, during, and after a 2-minute BP cuff inflation in the non-vascular access arm in order to measure Area Under the Temp Curve (TMP-AUC), defined as area under the curve between the maximum and minimum temp.

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  4. Vascular Calcification Inhibitor - Matrix Gla Protein Levels

    We will use plasma collected during hemodialysis treatments to measure total uncarboxylated matrix Gla protein levels. Assays will be conducted in the University of California Irvine Institute of Clinical Translational Science Bioassay Core.

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  5. Total Body Fat Percentage

    We will assess total body fat percentage using Dual Energy X-Ray absorptiometry.

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  6. Muscle Strength - Isometric Dynamometry

    We will assess muscle strength using BioDex dynamometry, which will be used to measure Isometric Quadriceps Maximal Strength (Peak Torque, Newton-meters), in which patients will perform three maximal knee-extension efforts at a knee angle of 60 degrees using the dominant leg; each trial consists of a repetition of five seconds of concentric quadriceps contraction, followed by at least 90-seconds of resting recovery.

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  7. Systolic Function - Global Longitudinal Strain

    We will measure systolic function using Global Longitudinal Strain (GLS) using speckle-tracking 2D-echocardiography, which measures the contraction/deformation of myocardium during systole and is represented by a negative value (i.e., more negative GLS indicates better function).

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

  8. Resting Energy Expenditure (REE) - Indirect Calorimetry

    We will measure REE using indirect calorimetry, in which following an overnight fast, patients will undergo a 20-minute resting period, after which oxygen consumption and carbon dioxide expiration will be recorded for 20-minutes while remaining under resting conditions, which will be used to calculate REE using the Weir formula.

    Measured: Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jun 2019
  2. Study start20 Jul 2020
  3. Primary completion30 Nov 2025 (estimated)
  4. Study completion30 Nov 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
336 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03977207
Sponsor's protocol ID
20195142
Acronym
THYROID-HD
Status last verified
Aug 2025
First submitted
28 May 2019
Last updated
8 Sep 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 28705886
  • 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.

    PubMed 28324018
  • 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.

    PubMed 25632971
  • 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.

    PubMed 23258793
  • 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.

    PubMed 27525529
  • 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.

    PubMed 29728200

Questions about this trial

What is this clinical trial studying?

A study testing Levothyroxine Sodium in people with Thyroid; Functional Disturbance and Hypothyroidism, run by University of California, Irvine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 8 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Connie Rhee, MD, MSc (714-456-5142, crhee1@uci.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score (time frame: Week 0 (pre-trial/baseline)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03977207, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Sep 2025.

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