Mechanistic Study of Subclinical Hypothyroidism In the Elderly

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02399475
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 56.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Subclinical Hypothyroidism	Drug: Levothyroxine; Drug: Liothyronine; Drug: Thyrotropin-Releasing Hormone	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: The Thyroid Axis in Older Individuals With Persistent Subclinical Hypothyroidism: a Mechanistic, Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Sep 30, 2019
• Actual Study Completion Date: Sep 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Levothyroxine First Participants will start on the thyroid hormone Levothyroxine prior to crossing over to Liothyronine	Drug: 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; Other Names: Synthroid ; Drug: 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; Other Names: Cytomel ; Drug: 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).
Experimental: Liothyronine First Participants will start on the thyroid hormone Liothyronine prior to crossing over to Levothyroxine	Drug: 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; Other Names: Synthroid ; Drug: 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; Other Names: Cytomel ; Drug: 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).

Outcome Measures

Primary Outcome Measures

1. 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

2. TSH Max [Between 0 and 180 min after TRH stimulation]

   The maximum concentration of TSH after TRH stimulation when TSH is at goal

3. Free T4 Level [An average of 7 months after initiating therapy]

   Free thyroxine level when TSH level is at goal on therapy.

4. Total T3 Level [An average of 7 months]

   Total triiodothyronine level when TSH is at goal on therapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Anne R Cappola, MD, ScM, The University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 18, 2018

More Information

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02399475
• Other Study ID Numbers: 821564; K24AG042765-01A1
• First Posted: Mar 26, 2015
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by University of Pennsylvania: Levothyroxine; Liothyronine; Thyrotropin Releasing Hormone; Aging; Hypothyroidism; Thyroid diseases
• Additional relevant MeSH terms: Hypothyroidism; Hormones; Thyrotropin-Releasing Hormone

Study Results

Participant Flow

Arm/Group Title	Levothyroxine First	Liothyronine First
Arm/Group Description	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).	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).
Period Title: Overall Study
STARTED	7	7
COMPLETED	6	7
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Levothyroxine First	Liothyronine First	Total
Arm/Group Description	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).	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).	Total of all reporting groups
Overall Participants	6	7	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	77 (5)	77 (4)	77 (5)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	2 28.6%	4 30.8%
Male	4 66.7%	5 71.4%	9 69.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	6 100%	7 100%	13 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	7 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	TSH Area Under the Curve
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levothyroxine	Liothyronine
Arm/Group Description	While taking levothyroxine	While taking liothyronine
Measure Participants	13	13
Mean (Standard Deviation) [μIU*min/mL]	267.8 (137.3)	266.2 (140.2)

2. Primary Outcome

Title	TSH Max
Description	The maximum concentration of TSH after TRH stimulation when TSH is at goal
Time Frame	Between 0 and 180 min after TRH stimulation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levothyroxine	Liothyronine
Arm/Group Description	While taking levothyroxine	While taking liothyronine
Measure Participants	13	13
Mean (Standard Deviation) [mIU/L]	5.5 (3.0)	5.4 (2.9)

3. Primary Outcome

Title	Free T4 Level
Description	Free thyroxine level when TSH level is at goal on therapy.
Time Frame	An average of 7 months after initiating therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levothyroxine	Liothyronine
Arm/Group Description	While taking levothyroxine	While taking liothyronine
Measure Participants	13	13
Mean (Standard Deviation) [ng/dL]	1.65 (0.11)	0.46 (0.19)

4. Primary Outcome

Title	Total T3 Level
Description	Total triiodothyronine level when TSH is at goal on therapy
Time Frame	An average of 7 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Levothyroxine	Liothyronine
Arm/Group Description	While taking levothyroxine	While taking liothyronine
Measure Participants	13	13
Mean (Standard Deviation) [ng/mL]	1.12 (0.24)	1.98 (0.51)

Adverse Events

Time Frame	Through study completion, an average of 7 months in each arm
Arm/Group Title	Levothyroxine		Liothyronine
Arm/Group Description	While taking levothyroxine		While taking liothyronine
All Cause Mortality
	Levothyroxine		Liothyronine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Serious Adverse Events
	Levothyroxine		Liothyronine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Levothyroxine		Liothyronine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.