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Trial record 38 of 87 for:    NIDDK endocrine and diabetes | Recruiting, Not yet recruiting, Available Studies

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

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ClinicalTrials.gov Identifier: NCT03977207
Recruitment Status : Not yet recruiting
First Posted : June 6, 2019
Last Update Posted : June 6, 2019
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) and 2) cardiovascular (e.g., 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 138 hemodialysis patients with high-normal or subclinical hypothyroid range serum TSH levels to determine the effects of 36 weeks (i.e., 9 months) of levothyroxine vs. placebo on 1) HRQOL Short Form 36 (SF36) Physical Component Score and 2) physical performance measured by the Short Physical Performance Battery (co-primary endpoints).

As secondary endpoints, we will also example 1) HRQOL measured by the ThyPRO survey, 2) muscle strength measured by dynamometry of the knee extensors/flexors, 3) systolic function measured by echocardiogram, 4) total body fat measured by Dual-Energy X-Ray Absorptiometry, and 5) resting energy expenditure measured by indirect calorimetry.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 138 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
Estimated 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 36 weeks. Patients will undergo up to four subsequent dose titrations after 8-, 16-, 24-, and 32-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 36 weeks. Patients in the placebo arm will undergo an equivalent titration in placebo pills (as that of the experimental arm) after 8-, 16-, 24-, and 32-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. Health-Related Quality of Life (HRQOL) - Short Form 36 Physical Component Score [ Time Frame: Week 36 ]
    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.

  5. Physical Performance - Short Physical Performance Battery (SPPB) [ Time Frame: Week 0 (pre-trial/baseline) ]
    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).

  6. Physical Performance - Short Physical Performance Battery (SPPB) [ Time Frame: Week 12 ]
    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).

  7. Physical Performance - Short Physical Performance Battery (SPPB) [ Time Frame: Week 24 ]
    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).

  8. Physical Performance - Short Physical Performance Battery (SPPB) [ Time Frame: Week 36 ]
    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).


Secondary Outcome Measures :
  1. Thyroid-Specific HRQOL - ThyPRO Hypothyroid Symptoms and Tiredness Domain Scores [ Time Frame: Weeks 0 (pre-trial/baseline) and 36 (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. Muscle Strength - Isometric Dynamometry [ Time Frame: Weeks 0 (pre-trial/baseline) and 36 (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.

  3. Systolic Function - Global Longitudinal Strain [ Time Frame: Weeks 0 (pre-trial/baseline) and 36 (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).

  4. Total Body Fat Percentage [ Time Frame: Weeks 0 (pre-trial/baseline) and 36 (post-randomization) ]
    We will assess total body fat percentage using Dual Energy X-Ray absorptiometry.

  5. Resting Energy Expenditure (REE) - Indirect Calorimetry [ Time Frame: Weeks 0 (pre-trial/baseline) and 36 (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

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     History of Changes
Other Study ID Numbers: HS# 2019-5142
First Posted: June 6, 2019    Key Record Dates
Last Update Posted: June 6, 2019
Last Verified: June 2019
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
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs