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

Primary Purpose

Thyroid; Functional Disturbance, Hypothyroidism, Hemodialysis

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Levothyroxine Sodium
Placebos
Sponsored by
University of California, Irvine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thyroid; Functional Disturbance

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California IrvineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Levothyroxine

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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).
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).

Secondary Outcome Measures

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).
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).
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.
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.
Total Body Fat Percentage
We will assess total body fat percentage using Dual Energy X-Ray absorptiometry.
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.
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).
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.

Full Information

First Posted
May 28, 2019
Last Updated
December 16, 2020
Sponsor
University of California, Irvine
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT03977207
Brief Title
A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
Acronym
THYROID-HD
Official Title
A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2019 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, Irvine
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thyroid; Functional Disturbance, Hypothyroidism, Hemodialysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
336 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Levothyroxine
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Levothyroxine Sodium
Intervention Description
Thyroid hormone supplement
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
Placebo oral capsule
Primary Outcome Measure Information:
Title
Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
Description
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.
Time Frame
Week 0 (pre-trial/baseline)
Title
Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
Description
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.
Time Frame
Week 12
Title
Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score
Description
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.
Time Frame
Week 24
Title
Coronary Artery Calcification (CAC) - Volume Score
Description
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).
Time Frame
Week 0 (pre-trial/baseline)
Title
Coronary Artery Calcification (CAC) - Volume Score
Description
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).
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores
Description
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).
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Physical Performance - Short Physical Performance Battery (SPPB)
Description
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).
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Endothelial Function - Digital Thermal Monitor
Description
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.
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Vascular Calcification Inhibitor - Matrix Gla Protein Levels
Description
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.
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Total Body Fat Percentage
Description
We will assess total body fat percentage using Dual Energy X-Ray absorptiometry.
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Muscle Strength - Isometric Dynamometry
Description
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.
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Systolic Function - Global Longitudinal Strain
Description
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).
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)
Title
Resting Energy Expenditure (REE) - Indirect Calorimetry
Description
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.
Time Frame
Weeks 0 (pre-trial/baseline) and 24 (post-randomization)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Connie Rhee, MD, MSc
Phone
714-456-5142
Email
crhee1@uci.edu
Facility Information:
Facility Name
University of California Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kamyar Kalantar-Zadeh
Phone
714-456-5142
Email
kkz@uci.edu

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28705886
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.
Results Reference
background
PubMed Identifier
28324018
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.
Results Reference
background
PubMed Identifier
25632971
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.
Results Reference
background
PubMed Identifier
23258793
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.
Results Reference
background
PubMed Identifier
27525529
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.
Results Reference
background
PubMed Identifier
29728200
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.
Results Reference
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A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients

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