Subclinical Hypothyroidism
Conditions
Keywords
Levothyroxine, Liothyronine, Thyrotropin Releasing Hormone, Aging, Hypothyroidism, Thyroid diseases
Brief summary
Subclinical hypothyroidism, defined as an elevated TSH in the setting of normal thyroid hormone levels, is a common diagnosis in the elderly. The purpose of this study is to examine the hypothalamic-pituitary-thyroid axis in men and women aged 70 years and older with persistent subclinical hypothyroidism. To evaluate the mechanism behind this condition, participants will undergo thyrotropin releasing hormone stimulation testing at 3 visits: baseline and while taking two different thyroid hormone preparations, levothyroxine and liothyronine. The investigators will also assess physiologic responses to these two different thyroid hormone medications to help us understand how the thyroid works in advanced age.
Interventions
DRUGLevothyroxine
Oral levothyroxine with a total starting dose of 0.7mcg/kg/day split into three daily doses will be titrated to a target TSH level of 0.5 -1.5mU/L
DRUGLiothyronine
Oral liothyronine with a starting dose of 1/3 of the weight-based LT4 dose divided into three daily doses titrated to a target TSH level of 0.5 -1.5mU/L
200 µg intravenous TRH will be given at study visit 1 (baseline), study visit 2 (on first thyroid treatment), and study visit 3 (on second thyroid treatment).
Sponsors
National Institute on Aging (NIA)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. men and women aged 70 and older 2. TSH between 4.5 and 19.9 mU/L as an outpatient 3. ability to provide informed consent
Exclusion criteria
Laboratory Tests: 1. TSH \<4.5 mU/L or \>20 mU/L on repeat testing at least four weeks later or free T4 level outside the reference range 2. thyroid peroxidase (TPO) antibody positive 3. abnormal liver function tests (LFTs \>3 x upper limit of normal) 4. hemoglobin \<11 g/dL Surgeries or Procedures: 1. thyroid surgery 2. pituitary surgery 3. bariatric surgery 4. bowel resection involving the jejunum and upper ileum 5. radioactive iodine therapy 6. radiation treatments to head or neck Medical Conditions: 1. diagnosis of pituitary disease 2. diagnosis of amyloidosis, sarcoidosis, hemochromatosis 3. diagnosis of adrenal insufficiency 4. obesity with BMI \> 35 mg/kg2 5. history of stroke 6. chronic or ongoing angina, Class II or higher congestive heart failure, or uncontrolled hypertension with current blood pressure greater than 160/100 7. diabetes mellitus with hemoglobin A1C level greater than 8.0% in the past six months 8. celiac sprue, Crohn's disease, ulcerative colitis, Zollinger-Ellison syndrome 9. renal insufficiency with calculated glomerular filtration rate \<45 cc/min 10. cognitive impairment with Mini Mental State Exam\[30\] \<24/30 11. history of any seizures 12. unstable medical or psychological condition in the judgment of the principal investigator Medications: 1. thyroid hormone preparations 2. antithyroid drugs 3. medications that interfere with the absorption or metabolism of thyroid hormone 4. medications that interfere with the TRH stimulation test 5. proton pump inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| TSH Area Under the Curve | 0, 5, 10, 15, 20, 30, and 60 min post TRH | TSH area under the curve within 60 minutes of TRH stimulation when TSH is at goal |
| TSH Max | Between 0 and 180 min after TRH stimulation | The maximum concentration of TSH after TRH stimulation when TSH is at goal |
| Free T4 Level | An average of 7 months after initiating therapy | Free thyroxine level when TSH level is at goal on therapy. |
| Total T3 Level | An average of 7 months | Total triiodothyronine level when TSH is at goal on therapy |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levothyroxine First Participants will start on the thyroid hormone Levothyroxine prior to crossing over to Liothyronine
Levothyroxine: Oral levothyroxine with a total starting dose of 0.7mcg/kg/day split into three daily doses will be titrated to a target TSH level of 0.5 -1.5mU/L
Liothyronine: Oral liothyronine with a starting dose of 1/3 of the weight-based LT4 dose divided into three daily doses titrated to a target TSH level of 0.5 -1.5mU/L
Thyrotropin-Releasing Hormone: 200 µg intravenous TRH will be given at study visit 1 (baseline), study visit 2 (on first thyroid treatment), and study visit 3 (on second thyroid treatment). | 6 |
| Liothyronine First Participants will start on the thyroid hormone Liothyronine prior to crossing over to Levothyroxine
Levothyroxine: Oral levothyroxine with a total starting dose of 0.7mcg/kg/day split into three daily doses will be titrated to a target TSH level of 0.5 -1.5mU/L
Liothyronine: Oral liothyronine with a starting dose of 1/3 of the weight-based LT4 dose divided into three daily doses titrated to a target TSH level of 0.5 -1.5mU/L
Thyrotropin-Releasing Hormone: 200 µg intravenous TRH will be given at study visit 1 (baseline), study visit 2 (on first thyroid treatment), and study visit 3 (on second thyroid treatment). | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Levothyroxine First | Total | Liothyronine First |
|---|---|---|---|
| Age, Continuous | 77 years STANDARD_DEVIATION 5 | 77 years STANDARD_DEVIATION 5 | 77 years STANDARD_DEVIATION 4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 6 Participants | 13 Participants | 7 Participants |
| Region of Enrollment United States | 6 participants | 13 participants | 7 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Free T4 Level
Free thyroxine level when TSH level is at goal on therapy.
Time frame: An average of 7 months after initiating therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine | Free T4 Level | 1.65 ng/dL | Standard Deviation 0.11 |
| Liothyronine | Free T4 Level | 0.46 ng/dL | Standard Deviation 0.19 |
Primary
Total T3 Level
Total triiodothyronine level when TSH is at goal on therapy
Time frame: An average of 7 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine | Total T3 Level | 1.12 ng/mL | Standard Deviation 0.24 |
| Liothyronine | Total T3 Level | 1.98 ng/mL | Standard Deviation 0.51 |
Primary
TSH Area Under the Curve
TSH area under the curve within 60 minutes of TRH stimulation when TSH is at goal
Time frame: 0, 5, 10, 15, 20, 30, and 60 min post TRH
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine | TSH Area Under the Curve | 267.8 μIU*min/mL | Standard Deviation 137.3 |
| Liothyronine | TSH Area Under the Curve | 266.2 μIU*min/mL | Standard Deviation 140.2 |
Primary
TSH Max
The maximum concentration of TSH after TRH stimulation when TSH is at goal
Time frame: Between 0 and 180 min after TRH stimulation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levothyroxine | TSH Max | 5.5 mIU/L | Standard Deviation 3 |
| Liothyronine | TSH Max | 5.4 mIU/L | Standard Deviation 2.9 |