Neurocognitive and Metabolic Effects of Mild Hypothyroidism

NCT00565864 | Completed Phase 4 Results

• 1 other identifier: IRB00002265
• Study Type: interventional
• Target: 173
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with hypothyroidism are routinely treated with thyroid hormone (l-thyroxine) for replacement therapy. Physicians monitor the thyroid hormone dose by measuring a thyroid stimulating hormone (TSH) level in the blood, with the goal of a normal level. However, recent data suggest that the "normal" TSH range is too broad, and that patients may still have symptoms if their TSH levels are at the top or bottom part of the normal range. To study this issue, it is useful to address issues such as general health status, psychological symptoms, mood, memory, and metabolic status, since thyroid hormone has major effects on the brain and metabolism, and since patients with treated hypothyroidism often have symptoms related to these areas. In the present study, otherwise healthy subjects with treated hypothyroidism, ages 20-75 years, will be enrolled in a 7-11month study. At baseline, they will have tests of health status, psychological symptoms, mood, memory, body composition, and energy expenditure performed. Following these baseline measurements, subjects will receive either their usual doses of l-thyroxine, or a slightly higher or lower dose. The doses will be chosen to try to achieve either a low-normal TSH level, a high-normal TSH level, or a mildly elevated TSH level. Which target TSH the patient is assigned will be determined randomly, and neither the subject nor the study contacts will know which dose the patient is receiving. Subjects will be seen every 6 weeks during the study for brief visits to make sure they are not having any side effects, and to adjust the l-thyroxine doses if the TSH has not yet reached the target range. At the 24-week visit (end of study), the subjects will undergo the same tests that they had on the baseline visit. Results from the study will be examined to see if minor changes in TSH or other thyroid hormone levels cause changes in any of the outcomes, and if the degree of TSH change correlates with the degree of outcome changes. These results may help physicians caring for patients with thyroid disease better determine the optimal dose of thyroid hormone for each patient.

Conditions

Hypothyroidism

Keywords

Hypothyroidism; Cognition; Metabolism

Outcome Measures

Primary Outcomes (2)

• Executive Function

  Iowa Gambling Task Net-5. Four decks of cards are shown face down on a computer screen. The subject chooses cards from any deck, resulting in the gain or loss of money. The subject is unaware that 2 decks are advantageous (small gains, smaller losses), while 2 are disadvantageous (large gains, larger losses). The subject's choices are classified as advantageous (X) or disadvantageous (Y), with a net score of X-Y, over 5 trials of 100 cards each. The outcome reported here is the score on the fifth trial, which is generally the best trial due to practice effects. The minimum score is -20 and the maximum score is +20. Higher scores indicate a better outcome.

  24 weeks

• Resting Energy Expenditure

  Measurement of resting energy expenditure (REE) by indirect calorimetry, corrected for lean body mass. Indirect calorimetry is performed at 21.1° C after the participant has fasted for 12h and abstains from significant physical activity for 24h. The indirect calorimeter (VMax Encore 29N Indirect Calorimeter, SensorMedics Viasys Healthcare, Yorba Linda, CA) samples expired air and analyzes it for the volume of oxygen consumed (VO2) and the volume of carbon dioxide produced (VCO2) each minute for 30mins. REE is then calculated using the modified Weir equation. Minimum REE is 23 kcal/kg LBM/day and maximum REE is 39 kcal/kg LBM/day. Within that range, higher levels are considered better for the purposes of this study.

  24 weeks

Other Outcomes (12)

• Quality of Life by SF-36 Survey

  24 weeks

• Mood

  24 weeks

• Working Memory

  24 weeks

Study Arms (3)

1 (Low-normal TSH target)

EXPERIMENTAL

Treatment arm 1 targets a thyroid stimulating hormone (TSH) of 0.28 -2.49 milliunits/liter (mU/L) (the theoretical optimal range). The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses.

Drug: L-thyroxine (L-T4)

2 (High-normal TSH target)

EXPERIMENTAL

Treatment arm 2 targeting a TSH of 2.5 - 5.0 mU/L. The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses.

Drug: L-thyroxine (L-T4)

3 (Mildly elevated TSH target)

EXPERIMENTAL

Treatment arm 3 is targeting a TSH level o f 5.1-12.0 mU/L. The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses.

Drug: L-thyroxine (L-T4)

Interventions

L-thyroxine (L-T4) DRUG

L-thyroxine (L-T4) is the intervention for each arm/group. In each arm/group, the dose of L-T4 is adjusted to achieve TSH levels in the randomly assigned arm. L-thyroxine at doses appropriate to attain target TSH levels for the different arms for 24 weeks

Also known as: Subjects will remain on their usual brand of L-T4., Subjects on generic L-T4 will be switched to Levoxyl.

1 (Low-normal TSH target); 2 (High-normal TSH target); 3 (Mildly elevated TSH target)

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ages 20-75
• Primary hypothyroidism on stable dose of L-T4 for \> 3 months
• Documented elevated TSH off L-T4
• Normal TSH level on usual dose of L-T4
• No acute or chronic medical or psychiatric illnesses that affect thyroid function, mood or cognition
• No medication use that affects thyroid function, mood or cognition (oral contraceptives or estrogen therapy allowed)
• Normal score on screening Mini-Mental State Exam (MMSE) (to test for dementia)
• Normal vision by screening examination
• Normal hearing by screening examination
• Non smoker

You may not qualify if:

• Inability to speak and comprehend English
• A history of coronary artery disease
• Screening hgb \<10
• Screening wbc \> 10,000
• Clinically significant abnormalities on screening metabolic set
• Screening LDL cholesterol \> 160
• Screening triglyceride \> 300
• Significant abnormalities on screening ECG
• Pregnancy or intent to become pregnant in next 6 months
• Present or recent use of medications that affect thyroid hormone levels or interfere with thyroid hormone effects, including beta-blockers, lithium, glucocorticoids, or iodine containing agents
• MMSE score \< 26

Sponsors & Collaborators

• Oregon Health and Science University: lead

Study Sites (1)

Oregon Health and Science University

Portland, Oregon, 97201, United States

Location

Related Publications (6)

• Samuels MH, Kolobova I, Niederhausen M, Purnell JQ, Schuff KG. Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4163-4175. doi: 10.1210/jc.2018-01203.

  PMID: 30165520 DERIVED

• Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG. Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. J Clin Endocrinol Metab. 2018 May 1;103(5):1997-2008. doi: 10.1210/jc.2017-02668.

  PMID: 29509918 DERIVED

• Samuels MH, Kolobova I, Antosik M, Niederhausen M, Purnell JQ, Schuff KG. Thyroid Function Variation in the Normal Range, Energy Expenditure, and Body Composition in L-T4-Treated Subjects. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2533-2542. doi: 10.1210/jc.2017-00224.

  PMID: 28460140 DERIVED

• Samuels MH, Kolobova I, Smeraglio A, Niederhausen M, Janowsky JS, Schuff KG. Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects. Thyroid. 2016 Sep;26(9):1173-84. doi: 10.1089/thy.2016.0141. Epub 2016 Jul 25.

  PMID: 27338133 DERIVED

• Samuels MH, Kolobova I, Smeraglio A, Peters D, Purnell JQ, Schuff KG. Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition. Thyroid. 2016 Mar;26(3):347-55. doi: 10.1089/thy.2015.0345. Epub 2016 Feb 3.

  PMID: 26700485 DERIVED

• Samuels MH, Kolobova I, Smeraglio A, Peters D, Janowsky JS, Schuff KG. The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition. J Clin Endocrinol Metab. 2014 Mar;99(3):843-51. doi: 10.1210/jc.2013-3686. Epub 2014 Jan 13.

  PMID: 24423358 DERIVED

MeSH Terms

Conditions

Hypothyroidism

Interventions

Thyroxine

Condition Hierarchy (Ancestors)

Thyroid Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Mary Samuels
• Organization: Oregon Health & Science University

samuelsm@ohsu.edu

5034945242

Study Officials

• Mary Samuels, MD

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: November 28, 2007
• First Posted: November 30, 2007
• Study Start: August 1, 2008
• Primary Completion: August 1, 2013
• Study Completion: August 1, 2013
• Last Updated: August 22, 2018
• Results First Posted: August 22, 2018

Record last verified: 2018-08

Locations

US (1)