Subclinical Hypothyroidism
Conditions
Brief summary
The investigators propose the following hypothesis: discontinuation of levothyroxine (LT4) for veterans with subclinical hypothyroidism (SCH) will be feasible, acceptable, and safe and will not negatively affect their Quality of Life (QoL). The investigators aim to evaluate the feasibility of LT4 discontinuation among veterans with SCH and determine the changes in QoL measures, lipids, and adverse events.
Detailed description
This is a pilot, randomized, double-blind, placebo-controlled trial. Methodology: The investigators will conduct a double-blind, placebo-controlled clinical trial where eligible veterans diagnosed with SCH and on LT4 will be 1:1 randomized to either continue LT4 or change to placebo. The primary outcome is intervention feasibility (willingness to enter the trial, recruitment rate, and completion rate). Secondary outcomes are: 1) changes in QoL measures (Hypothyroid Symptom \[HSS\] and Tiredness scale scores of the Thyroid-Specific Patient-Related Outcome Measure \[ThyPRO\], EuroQoL 5-Dimension Self-Report Questionnaire) measured at baseline, 6-8 weeks and 6 months and 2) changes in lipids assessed at baseline and 6 months, and 3) incidence of adverse events (overt hypothyroidism, hyperthyroidism, atrial fibrillation, fractures, acute myocardial infarction, stroke, acute coronary syndrome, heart failure, mortality).
Interventions
DRUGLevothyroxine
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.
OTHERPlacebo
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.
Sponsors
Central Arkansas Veterans Healthcare System
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Veterans * diagnosis of SCH
Exclusion criteria
* thyroid-stimulating hormone (TSH) \> 10 milli-international units per liter (mlU/L) (at any point) * Levothyroxine (LT4) dose more than 75 mcg daily * use of antithyroid medications, amiodarone, tyrosine kinase inhibitors or lithium * history of thyroidectomy or radioactive iodine therapy * LT4 suppressive therapy for thyroid cancer, goiter, or inflammation * pregnancy or plans for pregnancy in the next 6 months * an unstable medical condition that would jeopardize safety or interfere with study participation * severe hypothyroidism-related symptoms * strong family history of hypothyroidism * severe dyslipidemia * hospitalization for major illness within the previous 4 weeks * acute coronary artery syndrome, acute myocarditis, or pancarditis with the previous 12 months * grade IV New York Heart Association heart failure * receiving services from hospice * lack of decision-making capacity * terminal medical condition for which life expectancy would be less than 6 months * not willing to stop LT4 * self-reported non-adherence to LT4 therapy * abnormal TSH at time of screening for participation (assessed during Baseline Visit)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants' Willingness to Enter the Trial | The time from first consent signed to last consent signed. March 2021 to April 2022. | Percent of eligible participants approached who consented to participate during the recruitment phase. |
| Recruitment Rate | The time from first consent signed to last consent signed. March 2021 to April 2022. 13 months. | The number of enrolled (consented) participants divided by the length of the recruitment period. |
| Completion Rate | 6 months | Percentage of randomized participants who completed the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | Baseline, 6 weeks and 6 months | The Hypothyroid Symptoms score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more symptoms. |
| Lipid Levels | 6 months | Differences in mean 6-month lipid levels after adjusting for gender and baseline lipid level. |
| Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | Baseline, 6 weeks and 6 months | The Tiredness score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more tiredness. |
| Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | 6 weeks and 6 months | The EuroQoL \[EQ\] Group 5-Dimension Self-Report Questionnaire (EQ-5D) scores include the EQ-5D descriptive index, on a scale from -0.59 to 1.00. Higher scores indicate better quality of life. The EQ-5D scores include the score on the EQ visual-analogue scale (EQ-5D VAS), on a scale from 0 to 100. Higher scores indicate better quality of life. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on opt-in/opt-out letter at 1 VA medical center between March 2021 and April 2022. The first participant was enrolled on March 24, 2021 and the last participant was enrolled in April 2022.
Pre-assignment details
Of 52 enrolled participants, 50 were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Levothyroxine Group (Sham Discontinuation) Continue the current dose of levothyroxine. The brand of levothyroxine to be used in this study will be Synthroid tablets of 25 mcg, 50 mcg, and 75 mcg (AbbVie Inc).
Levothyroxine: Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day. | 21 |
| Placebo Group (Real Discontinuation) Stop the current dose of levothyroxine and take study placebo
Placebo: Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day. | 24 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pre-study SCH diagnosis could not be confirmed per study entry criteria | 3 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Levothyroxine Group (Sham Discontinuation) | Placebo Group (Real Discontinuation) | Total |
|---|---|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 7.9 | 65.7 years STANDARD_DEVIATION 10.6 | 68.2 years STANDARD_DEVIATION 9.7 |
| Body mass index | 32.5 kg/m^2 STANDARD_DEVIATION 7.7 | 29.7 kg/m^2 STANDARD_DEVIATION 7.8 | 31.0 kg/m^2 STANDARD_DEVIATION 7.8 |
| Diastolic Blood Pressure (DBP) | 80.1 mm Hg STANDARD_DEVIATION 8.7 | 80.2 mm Hg STANDARD_DEVIATION 11.7 | 80.1 mm Hg STANDARD_DEVIATION 10.3 |
| EQ-5D Descriptive score | 0.758 scores on scale STANDARD_DEVIATION 0.193 | 0.746 scores on scale STANDARD_DEVIATION 0.229 | 0.752 scores on scale STANDARD_DEVIATION 0.21 |
| EQ-5D VAS score | 72.0 scores on scale STANDARD_DEVIATION 15 | 77.3 scores on scale STANDARD_DEVIATION 14.4 | 74.8 scores on scale STANDARD_DEVIATION 14.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 23 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| free thyroxine (FT4) | 0.9 ng/dL STANDARD_DEVIATION 0.1 | 0.9 ng/dL STANDARD_DEVIATION 0.1 | 0.9 ng/dL STANDARD_DEVIATION 0.1 |
| HDL | 42.4 mg/dL STANDARD_DEVIATION 11.5 | 53.3 mg/dL STANDARD_DEVIATION 19.8 | 48.2 mg/dL STANDARD_DEVIATION 17.2 |
| Hypothyroid Symptoms score | 21.1 scores on scale STANDARD_DEVIATION 18.4 | 27.1 scores on scale STANDARD_DEVIATION 20.4 | 24.3 scores on scale STANDARD_DEVIATION 19.5 |
| LDL | 77.5 mg/dL STANDARD_DEVIATION 34.5 | 104.2 mg/dL STANDARD_DEVIATION 28.4 | 91.7 mg/dL STANDARD_DEVIATION 33.9 |
| Levothyroxine (LT4) dose prior to enrollment, 25mcg | 7 Participants | 7 Participants | 14 Participants |
| LT4 dose prior to enrollment, 50mcg | 10 Participants | 13 Participants | 23 Participants |
| LT4 dose prior to enrollment, 75mcg | 4 Participants | 4 Participants | 8 Participants |
| LT4 duration, 2 to 7 yrs | 10 Participants | 12 Participants | 22 Participants |
| LT4 duration, < 2 yrs | 6 Participants | 6 Participants | 12 Participants |
| LT4 duration, > 7 yrs | 5 Participants | 6 Participants | 11 Participants |
| Pulse | 68.3 beats/min STANDARD_DEVIATION 15.7 | 66.8 beats/min STANDARD_DEVIATION 9.4 | 67.5 beats/min STANDARD_DEVIATION 12.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 21 Participants | 39 Participants |
| Region of Enrollment United States | 21 Participants | 24 Participants | 45 Participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 9 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 36 Participants |
| Systolic Blood Pressure (SBP) | 141.1 mm Hg STANDARD_DEVIATION 19.7 | 137.5 mm Hg STANDARD_DEVIATION 16.8 | 139.2 mm Hg STANDARD_DEVIATION 18.1 |
| ThyPRO-39 score | 20.5 scores on scale STANDARD_DEVIATION 14.8 | 18.4 scores on scale STANDARD_DEVIATION 11.2 | 19.4 scores on scale STANDARD_DEVIATION 12.9 |
| thyroid peroxidase (TPO) positivity | 4 Participants | 4 Participants | 8 Participants |
| thyroid-stimulating hormone (TSH) | 3.19 mIU/L STANDARD_DEVIATION 1.42 | 3.08 mIU/L STANDARD_DEVIATION 0.99 | 3.1 mIU/L STANDARD_DEVIATION 1.2 |
| Tiredness score | 31.1 scores on scale STANDARD_DEVIATION 23.9 | 33.2 scores on scale STANDARD_DEVIATION 23.7 | 32.2 scores on scale STANDARD_DEVIATION 23.5 |
| Total Cholesterol | 148.1 mg/dL STANDARD_DEVIATION 41.9 | 179.8 mg/dL STANDARD_DEVIATION 31.3 | 165.0 mg/dL STANDARD_DEVIATION 39.6 |
| Triglycerides | 141.5 mg/dL STANDARD_DEVIATION 68 | 111.4 mg/dL STANDARD_DEVIATION 48 | 125.4 mg/dL STANDARD_DEVIATION 59.5 |
| Weight | 220.4 pounds STANDARD_DEVIATION 58.4 | 201.0 pounds STANDARD_DEVIATION 61.5 | 210.1 pounds STANDARD_DEVIATION 60.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 23 |
| other Total, other adverse events | 9 / 21 | 15 / 23 |
| serious Total, serious adverse events | 3 / 21 | 1 / 23 |
Outcome results
Primary
Completion Rate
Percentage of randomized participants who completed the trial.
Time frame: 6 months
Population: Number of randomized participants that completed the trial divided by the total number of randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Completion Rate | 44 Participants |
Primary
Participants' Willingness to Enter the Trial
Percent of eligible participants approached who consented to participate during the recruitment phase.
Time frame: The time from first consent signed to last consent signed. March 2021 to April 2022.
Population: The number of patients consented divided by the total number of eligible patients contacted.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Participants' Willingness to Enter the Trial | 52 Participants |
Primary
Recruitment Rate
The number of enrolled (consented) participants divided by the length of the recruitment period.
Time frame: The time from first consent signed to last consent signed. March 2021 to April 2022. 13 months.
Population: The number of participants enrolled divided by the length of recruitment period (13 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Recruitment Rate | 4 participants per month |
Secondary
Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6
The EuroQoL \[EQ\] Group 5-Dimension Self-Report Questionnaire (EQ-5D) scores include the EQ-5D descriptive index, on a scale from -0.59 to 1.00. Higher scores indicate better quality of life. The EQ-5D scores include the score on the EQ visual-analogue scale (EQ-5D VAS), on a scale from 0 to 100. Higher scores indicate better quality of life.
Time frame: 6 weeks and 6 months
Population: All randomized participants who completed 6 months follow-up visit. An intent-to-treat strategy was employed where participants were analyzed into the group they were randomized, regardless of protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D Descriptive Score 6 weeks | 0.759 score on a scale | Standard Deviation 0.19 |
| Percentage of Eligible Patients Willing to Participate. | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D Descriptive Score 6 months | 0.742 score on a scale | Standard Deviation 0.18 |
| Percentage of Eligible Patients Willing to Participate. | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D VAS 6 weeks | 78.0 score on a scale | Standard Deviation 13.8 |
| Percentage of Eligible Patients Willing to Participate. | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D VAS 6 months | 68.4 score on a scale | Standard Deviation 21.2 |
| Placebo Group (Real Discontinuation) | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D VAS 6 months | 79.9 score on a scale | Standard Deviation 12.9 |
| Placebo Group (Real Discontinuation) | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D Descriptive Score 6 weeks | 0.786 score on a scale | Standard Deviation 0.214 |
| Placebo Group (Real Discontinuation) | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D VAS 6 weeks | 77.2 score on a scale | Standard Deviation 19.6 |
| Placebo Group (Real Discontinuation) | Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6 | EQ-5D Descriptive Score 6 months | 0.750 score on a scale | Standard Deviation 0.232 |
Comparison: Analysis of 6-week EQ-5D Descriptive score outcome.p-value: 0.468495% CI: [-0.076, 0.036]ANCOVA
Comparison: Analysis of 6-month EQ-5D Descriptive score outcome.p-value: 0.958595% CI: [-0.102, 0.107]ANCOVA
Comparison: Analysis of 6-week EQ-5D VAS score outcome.p-value: 0.064395% CI: [-0.4, 14.4]ANCOVA
Comparison: Analysis of 6-month EQ-5D VAS score outcome.p-value: 0.174295% CI: [-15.3, 2.9]ANCOVA
Secondary
Lipid Levels
Differences in mean 6-month lipid levels after adjusting for gender and baseline lipid level.
Time frame: 6 months
Population: All participants who completed 6-8 weeks and 6 months follow-up visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Lipid Levels | Total cholesterol 6 months | 145.3 mg/dL | Standard Deviation 32.6 |
| Percentage of Eligible Patients Willing to Participate. | Lipid Levels | LDL 6 months | 76.5 mg/dL | Standard Deviation 28.6 |
| Percentage of Eligible Patients Willing to Participate. | Lipid Levels | HDL 6 months | 42.7 mg/dL | Standard Deviation 16.5 |
| Percentage of Eligible Patients Willing to Participate. | Lipid Levels | Triglycerides 6 months | 137.5 mg/dL | Standard Deviation 66.8 |
| Placebo Group (Real Discontinuation) | Lipid Levels | Triglycerides 6 months | 139.7 mg/dL | Standard Deviation 68.4 |
| Placebo Group (Real Discontinuation) | Lipid Levels | Total cholesterol 6 months | 177.4 mg/dL | Standard Deviation 39.6 |
| Placebo Group (Real Discontinuation) | Lipid Levels | HDL 6 months | 51.5 mg/dL | Standard Deviation 16.2 |
| Placebo Group (Real Discontinuation) | Lipid Levels | LDL 6 months | 100.2 mg/dL | Standard Deviation 32.3 |
Comparison: Analysis of 6-month total cholesterol outcome.p-value: 0.169595% CI: [-29.3, 5.3]ANCOVA
Comparison: Analysis of 6-month LDL outcome.p-value: 0.380595% CI: [-22.2, 8.6]ANCOVA
Comparison: Analysis of 6-month HDL outcome.p-value: 0.572495% CI: [-4.44, 7.9]ANCOVA
Comparison: Analysis of 6-month triglyceride outcome.p-value: 0.393995% CI: [-59.4, 23.9]ANCOVA
Secondary
Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score
The Hypothyroid Symptoms score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more symptoms.
Time frame: Baseline, 6 weeks and 6 months
Population: All randomized participants who completed 6 months follow-up visit. An intent-to-treat strategy was employed where participants were analyzed in the group to which they were randomized, regardless of protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | Baseline | 21.1 score on a scale | Standard Deviation 18.4 |
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | 6 weeks | 22.0 score on a scale | Standard Deviation 17.7 |
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | 6 months | 22.9 score on a scale | Standard Deviation 19.5 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | Baseline | 27.1 score on a scale | Standard Deviation 20.4 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | 6 weeks | 25.3 score on a scale | Standard Deviation 21.9 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score | 6 months | 28.3 score on a scale | Standard Deviation 22.8 |
Comparison: A one-sided t-test will be used to determine whether the mean Hypothyroid Symptoms score for the real discontinuation group is no more than 14 points worse than the score of the sham discontinuation group at 6 months.p-value: 0.091390% CI: [-16.1, 5.4]Welch's two-sample t-test
Comparison: Analysis of 6-week outcomep-value: 0.879395% CI: [-9.4, 10.9]ANCOVA
Comparison: Analysis of 6-month outcomep-value: 0.68695% CI: [-14, 9.3]ANCOVA
Secondary
Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score
The Tiredness score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more tiredness.
Time frame: Baseline, 6 weeks and 6 months
Population: All randomized participants who completed 6 months follow-up visit. An intent-to-treat strategy was employed where participants were analyzed in the group to which they were randomized, regardless of protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | Baseline | 31.1 score on a scale | Standard Deviation 23.9 |
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | 6 weeks | 33.0 score on a scale | Standard Deviation 23.6 |
| Percentage of Eligible Patients Willing to Participate. | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | 6 months | 32.8 score on a scale | Standard Deviation 22.1 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | Baseline | 33.2 score on a scale | Standard Deviation 23.7 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | 6 weeks | 31.1 score on a scale | Standard Deviation 24.3 |
| Placebo Group (Real Discontinuation) | Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score | 6 months | 27.6 score on a scale | Standard Deviation 22.8 |
Comparison: A one-sided t-test will be used to determine whether the mean Tiredness score for the real discontinuation group is no more than 14 points worse than the score of the sham discontinuation group at 6 months.p-value: 0.003690% CI: [-6.2, 16.6]Welch's two-sample t-test
Comparison: Analysis of 6-week outcomep-value: 0.710495% CI: [-10.1, 14.7]ANCOVA
Comparison: Analysis of 6-month outcomep-value: 0.338195% CI: [-5.9, 16.7]ANCOVA