Hypothyroidism
Conditions
Keywords
subclinical hypothyroidism, levothyroxine, deprescribing, thyroid-related symptoms, older adults
Brief summary
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.
Interventions
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.
DRUGPlacebo
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.
Sponsors
Spyridoula Maraka
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥65 years. 2. Euthyroid at the time of enrollment, defined as thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels within the reference range. 3. Receiving levothyroxine treatment for subclinical hypothyroidism for at least 6 months. 4. Receiving levothyroxine at a dose ≤50 mcg/day, or ≤25 mcg/day for participants weighing \<50 kg. 5. Receiving outpatient care at the participating study site for at least 12 months. Subclinical hypothyroidism is defined as a TSH level above the normal reference range but \<10 mIU/L, with a normal fT4 level, prior to initiation of levothyroxine therapy.
Exclusion criteria
1. TSH \>10 mIU/L at any time documented in the institutional electronic health record. 2. Levothyroxine therapy initiated less than 6 months before enrollment. 3. Abnormal thyroid function at the time of enrollment. 4. Current use of medications that affect thyroid hormone levels, such as antithyroid medications, amiodarone, or lithium. 5. History of thyroid cancer or goiter with compressive symptoms. 6. History of partial or total thyroidectomy or radioactive iodine therapy. 7. New York Heart Association (NYHA) Class IV heart failure. 8. Hospitalization for a major illness or elective surgery within the previous 4 weeks, including acute coronary syndrome, acute myocarditis, pancarditis, or stroke. 9. Unstable medical condition that, in the investigator's judgment, would jeopardize participant safety or interfere with study participation. 10. Terminal illness with a life expectancy of less than 6 months. 11. Lack of decision-making capacity. 12. Severe dyslipidemia, defined as LDL cholesterol \>190 mg/dL. 13. Untreated depression. 14. Uncontrolled psychiatric disorder. 15. Uncontrolled chronic fatigue syndrome. 16. Uncontrolled pain.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean ThyPRO Hypothyroid Symptoms Scale Score at 6 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean ThyPRO Hypothyroid Symptoms Scale Score Over Time | Baseline, 2 months, 6 months | 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. |
| Mean ThyPRO Tiredness Scale Score | Baseline, 2 month, and 6 months | 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. |
| Mean Brief Fatigue Inventory Score | Baseline, 2 months, and 6 months | 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. |
| Mean Patient-Generated Index Visual Analogue Scale Score | Baseline, 2 months, and 6 months | 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. |
| Mean ThyPRO-39 Quality-of-Life Score | Baseline and 6 months | 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. |
| Mean EQ-5D Descriptive Index Score | Baseline, 2 months, and 6 months | 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. |
| Mean EQ Visual Analogue Scale Score | Baseline, 2 months, and 6 months | 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. |
| Number of Participants Preferring Study Treatment Versus Pre-Study Treatment | 2 months and 6 months | 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. |
| Mean Modified Telephone Interview for Cognitive Status Score | Baseline and 6 months | 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. |
| Mean Body Weight | Baseline, 2 months, and 6 months | Body weight will be measured in kilograms. Mean body weight and change in body weight will be compared between treatment groups. |
| Mean Thyroid-Stimulating Hormone Level | Baseline, 2 months, and 6 months | 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. |
| Mean Free Thyroxine Level | Baseline, 2 months, and 6 months | 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. |
| Mean Total Cholesterol Level | Baseline, 2 months, and 6 months | Serum total cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups. |
| Mean Low-Density Lipoprotein Cholesterol Level | Baseline, 2 months, and 6 months | Serum low-density lipoprotein (LDL) cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups. |
| Mean High-Density Lipoprotein Cholesterol Level | Baseline, 2 months, and 6 months | Serum high-density lipoprotein (HDL) cholesterol will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups. |
| Mean Triglyceride Level | Baseline, 2 months, and 6 months | Serum triglycerides will be measured in mg/dL. Mean levels and longitudinal changes will be compared between treatment groups. |
| Incidence of All-Cause Mortality | From enrollment to the end of the study at 6 months | Number and proportion of participants who die from any cause during study participation, assessed through medical record review and/or family report. |
| Incidence of Cardiovascular Events | From enrollment to the end of the study at 6 months | 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. |
| Incidence of Falls and Fractures | From enrollment to the end of the study at 6 months | Number and proportion of participants experiencing one or more falls or fractures, assessed through medical record review and participant report. |
| Incidence of Overt Hypothyroidism | 2 months and 6 months | Number and proportion of participants who develop overt hypothyroidism based on protocol-defined thyroid hormone criteria. |
| Incidence of Hyperthyroidism | 2 months and 6 months | Number and proportion of participants who develop hyperthyroidism based on protocol-defined thyroid hormone criteria. |
| Proportion of Participants Maintaining Euthyroid Status After Levothyroxine Discontinuation | 2 months and 6 months | Among participants randomized to levothyroxine discontinuation/placebo, the number and proportion who remain euthyroid based on protocol-defined thyroid hormone criteria will be assessed. |
| Number of Participants with Adverse Events | From enrollment to 30 days after Month 6 | 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. |
| Number of Participants with Serious Adverse Events | From enrollment to 30 days after Month 6 | Number and proportion of participants experiencing one or more serious adverse events as defined in the study protocol. |
Countries
United States
Contacts
CONTACTSpyridoula Maraka, M.D., M.S.
CONTACTKatherine Dishongh
STUDY_DIRECTORSpyridoula Maraka, M.D., M.S.
Central Arkansas Veterans Healthcare System
Outcome results
None listed