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A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients (THYROID-HD)

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ClinicalTrials.gov Identifier: NCT03977207
Recruitment Status : Recruiting
First Posted : June 6, 2019
Last Update Posted : June 5, 2020
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of California, Irvine

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.

Condition or disease Intervention/treatment Phase
Thyroid; Functional Disturbance Hypothyroidism Hemodialysis Drug: Levothyroxine Sodium Drug: Placebos Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 336 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.

Drug: Levothyroxine Sodium
Thyroid hormone supplement

Placebo Comparator: 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.

Drug: Placebos
Placebo oral capsule




Primary Outcome Measures :
  1. Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score [ Time Frame: Week 0 (pre-trial/baseline) ]
    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.

  2. Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score [ Time Frame: Week 12 ]
    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.

  3. Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score [ Time Frame: 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.

  4. Coronary Artery Calcification (CAC) - Volume Score [ Time Frame: Week 0 (pre-trial/baseline) ]
    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).

  5. Coronary Artery Calcification (CAC) - Volume Score [ Time Frame: 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).


Secondary Outcome Measures :
  1. Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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).

  2. Physical Performance - Short Physical Performance Battery (SPPB) [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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).

  3. Endothelial Function - Digital Thermal Monitor [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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.

  4. Vascular Calcification Inhibitor - Matrix Gla Protein Levels [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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.

  5. Total Body Fat Percentage [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    We will assess total body fat percentage using Dual Energy X-Ray absorptiometry.

  6. Muscle Strength - Isometric Dynamometry [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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.

  7. Systolic Function - Global Longitudinal Strain [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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).

  8. Resting Energy Expenditure (REE) - Indirect Calorimetry [ Time Frame: Weeks 0 (pre-trial/baseline) and 24 (post-randomization) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03977207


Contacts
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Contact: Connie Rhee, MD, MSc 714-456-5142 crhee1@uci.edu

Locations
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United States, California
University of California Irvine Recruiting
Orange, California, United States, 92868
Contact: Kamyar Kalantar-Zadeh    714-456-5142    kkz@uci.edu   
Sponsors and Collaborators
University of California, Irvine
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Publications:

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Responsible Party: University of California, Irvine
ClinicalTrials.gov Identifier: NCT03977207    
Other Study ID Numbers: HS# 2019-5142
First Posted: June 6, 2019    Key Record Dates
Last Update Posted: June 5, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thyroid Diseases
Hypothyroidism
Endocrine System Diseases