The goal of this clinical trial is to learn whether low-dose levothyroxine can be safely discontinued in adults aged 65 years or older who are taking levothyroxine for subclinical hypothyroidism. The study will also evaluate the cost-effectiveness of discontinuing levothyroxine. The main questions it aims to answer are: * Does discontinuing levothyroxine result in no clinically meaningful worsening of thyroid-related symptoms compared with continuing levothyroxine? * What are the effects of discontinuing levothyroxine on quality of life, tiredness, cognition, thyroid hormone levels, lipid levels, weight, and adverse events? * Is discontinuing levothyroxine cost-effective compared with continuing treatment? Researchers will compare participants who discontinue levothyroxine and receive placebo with participants who continue their current dose of levothyroxine to determine the effects of levothyroxine discontinuation. Participants will: * Complete a 2-week run-in period during which they continue their usual levothyroxine and record their medication use. * Eligible participants will be randomly assigned to either continue their current dose of levothyroxine or receive a matching placebo for 6 months. Participants, their clinicians, and study investigators will not know which treatment they are receiving during the study. * Complete study assessments at baseline, approximately 2 months, and 6 months. Assessments will include blood tests, measurements such as body weight, questionnaires about thyroid-related symptoms and quality of life, and assessments of cognition and other health outcomes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
138
Participants assigned to the levothyroxine continuation arm will continue levothyroxine at their pre-study dose (≤50 mcg/day) for 6 months. Levothyroxine will be administered orally once daily as over-encapsulated study medication matched in appearance to placebo to maintain blinding.
Participants assigned to the levothyroxine discontinuation arm will discontinue levothyroxine and receive matching placebo orally once daily for 6 months. Placebo will be over-encapsulated and matched in appearance to the active study medication to maintain blinding.
Central Arkansas Veterans Healthcare System
Little Rock, Arkansas, United States
University of Florida Clinical Research Center
Gainesville, Florida, United States
Mayo Clinic
Rochester, Minnesota, United States
Mean ThyPRO Hypothyroid Symptoms Scale Score at 6 Months
Thyroid-related symptoms will be assessed using the 4-item Thyroid-specific Patient Reported Outcome (ThyPRO) Hypothyroid Symptoms Scale. Scores are transformed to a 0-100 scale, with higher scores indicating more severe hypothyroid symptoms. The mean 6-month score will be compared between the levothyroxine discontinuation (placebo) group and the levothyroxine continuation group. The prespecified noninferiority margin is 9 points.
Time frame: 6 months
Mean ThyPRO Hypothyroid Symptoms Scale Score Over Time
Mean score on the 4-item ThyPRO Hypothyroid Symptoms Score. Scores range from 0 to 100, with higher scores indicating more severe hypothyroid symptoms. Longitudinal changes will be evaluated between treatment groups.
Time frame: Baseline, 2 months, 6 months
Mean ThyPRO Tiredness Scale Score
Tiredness will be assessed using the 7-item ThyPRO Tiredness Scale. Scores range from 0 to 100, with higher scores indicating greater tiredness. Mean scores and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 month, and 6 months
Mean Brief Fatigue Inventory Score
Fatigue will be assessed during the 9-item Brief Fatigue Inventory (BFI). Items are scored from 0 to 10 and the mean item score will be calculated, with higher scores indicating greater fatigue severity or interference. Mean scores and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Patient-Generated Index Visual Analogue Scale Score
Participant-identified symptoms considered important and related to subclinical hypothyroidism will be assessed using the Patient-Generated Index (PGI) visual analogue scale. Scores range from 0-100, with higher scores indicating less severe symptoms. Mean scores and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean ThyPRO-39 Quality-of-Life Score
Thyroid-specific quality of life will be assessed using the 39-item ThyPRO-39 questionnaire. Scores range from 0 to 100, with higher scores indicating worse thyroid-related quality of life. Mean scores will be compared between treatment groups.
Time frame: Baseline and 6 months
Mean EQ-5D Descriptive Index Score
General health-related quality of life will be assessed using the EQ-5D descriptive index. Scores range from -0.59 to 1.00, with higher scores indicating better health-related quality of life. Mean scores and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean EQ Visual Analogue Scale Score
Self-rated health will be assessed using the EQ visual analogue scale (EQ VAS). Scores range from 0 to 100, with higher scores indicating better self-rated health. Mean scores and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Number of Participants Preferring Study Treatment Versus Pre-Study Treatment
Participants will report whether they prefer the treatment they are currently receiving during the study or their pre-study levothyroxine treatment. The number and percentage of participants reporting each preference will be summarized by treatment group.
Time frame: 2 months and 6 months
Mean Modified Telephone Interview for Cognitive Status Score
Cognitive function will be assessed using the Modified Telephone Interview for Cognitive Status (TICS-M), a 13-item cognitive assessment evaluating orientation, concentration, memory, naming, calculation, comprehension, and reasoning. Total scores range from 0 to 39, with higher scores indicating better cognitive performance. Mean scores will be compared between treatment groups.
Time frame: Baseline and 6 months
Mean Body Weight
Body weight will be measured in kilograms. Mean body weight and change in body weight will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Thyroid-Stimulating Hormone Level
Serum thyroid-stimulating hormone (TSH) will be measured in mIU/L to assess thyroid function. Mean TSH levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Free Thyroxine Level
Serum free thyroxine (free T4) will be measured in ng/dL to assess thyroid function. Mean free T4 levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Total Cholesterol Level
Serum total cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Low-Density Lipoprotein Cholesterol Level
Serum low-density lipoprotein (LDL) cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean High-Density Lipoprotein Cholesterol Level
Serum high-density lipoprotein (HDL) cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Mean Triglyceride Level
Serum triglycerides will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups.
Time frame: Baseline, 2 months, and 6 months
Incidence of All-Cause Mortality
Number and proportion of participants who die from any cause during study participation, assessed through medical record review and/or family report.
Time frame: From enrollment to the end of the study at 6 months
Incidence of Cardiovascular Events
Number and proportion of participants experiencing one or more cardiovascular events, including acute myocardial infarction, atrial fibrillation, stroke, acute coronary syndrome, or heart failure, assessed through medical record review and participant report.
Time frame: From enrollment to the end of the study at 6 months
Incidence of Falls and Fractures
Number and proportion of participants experiencing one or more falls or fractures, assessed through medical record review and participant report.
Time frame: From enrollment to the end of the study at 6 months
Incidence of Overt Hypothyroidism
Number and proportion of participants who develop overt hypothyroidism based on protocol-defined thyroid hormone criteria.
Time frame: 2 months and 6 months
Incidence of Hyperthyroidism
Number and proportion of participants who develop hyperthyroidism based on protocol-defined thyroid hormone criteria.
Time frame: 2 months and 6 months
Proportion of Participants Maintaining Euthyroid Status After Levothyroxine Discontinuation
Among participants randomized to levothyroxine discontinuation/placebo, the number and proportion who remain euthyroid based on protocol-defined thyroid hormone criteria will be assessed.
Time frame: 2 months and 6 months
Number of Participants with Adverse Events
Number and proportion of participants experiencing one or more adverse events during study participation. Adverse events will be assessed and classified according to the protocol-defined criteria for severity, expectedness, and relationship to study intervention.
Time frame: From enrollment to 30 days after Month 6
Number of Participants with Serious Adverse Events
Number and proportion of participants experiencing one or more serious adverse events as defined in the study protocol.
Time frame: From enrollment to 30 days after Month 6
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