Neurocognitive and Metabolic Effects of Mild Hypothyroidism

Hypothyroidism Clinical Trial

Official title:

Neurocognitive and Metabolic Effects of Mild Hypothyroidism

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00565864
• Other study ID #: IRB00002265
• Status: Completed
• Phase: Phase 4
• Start date: August 2008
• Est. completion date: August 2013

Study information

• Verified date: August 2018
• Source: Oregon Health and Science University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Thyroid hormone is essential for neurocognitive and metabolic function, and patients with overt thyroid dysfunction have well-described alterations in mood, cognition, energy expenditure, and body composition. However, it is not clear that patients with more mild degrees of thyroid dysfunction have clinically significant alterations in these parameters.

In addition, recent data suggest that variations in thyroid function within the laboratory reference range may also affect these parameters.

Patients with hypothyroidism are routinely treated with levothyroxine (L-T4) as replacement therapy. Physicians monitor the L-T4 dose by measuring serum thyroid stimulating hormone (TSH) levels, with the goal of a normal level. However, many patients with normal TSH levels continue to report symptoms, primarily in neurocognitive and metabolic areas. For this reason, patients with hypothyroidism often request higher L-T4 doses, but the clinical consequences of this are unknown.

In the present study, otherwise healthy subjects with treated hypothyroidism and normal TSH levels, ages 20-75 years, will be enrolled in a 7-11 month study. At baseline, the following tests will be performed to measure health status, psychological symptoms, mood, memory, body composition, and energy expenditure: the Short Form Health Survey-36 (SF-36), Profile of Mood States (POMS), Affective Lability Scale (ALS), Letter Cancellation Test (LCT), Trail Making Test, Iowa Gambling Task (IGT), N-Back Test, Subject-Ordered Pointing, Paragraph Recall, Pursuit Rotor, Motor Sequence Learning Test, resting energy expenditure (REE) and thermic effect of food (TEF) by indirect calorimetry, total energy expenditure (TEE) by doubly labelled water, physical activity energy expenditure (PAEE) by accelerometry, diet intake by 24-hour diet recalls, and body composition by dual energy x-ray absorptiometry (DEXA). Following these baseline measurements, subjects will receive either their usual doses of L-T4, 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 L-T4 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 173
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• Failure to meet any of the above inclusion criteria

• 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

Related Conditions & MeSH terms

• Hypothyroidism

Intervention

Drug:
• L-thyroxine (L-T4)
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

Locations

Country	Name	City	State
United States	Oregon Health and Science University	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Oregon Health and Science University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life by SF-36 Survey	Short Form Survey (SF-36) mental component summary, which combines results from mental component subscales of the SF-36. The SF-36 health survey (SF-36) is a questionnaire about general health and well-being (127). It consists of 8 subscales (bodily pain, general health, mental health, physical functioning, vitality, role physical, social functioning, role emotional) and two summary scales (Mental Component and Physical Component Summaries). The mental component summary is a weighted average of the 8 subscales, with more weight to role emotional and mental health subscales. Minimum score for the SF-36 mental component summary is 14. Maximum score is 50. Higher scores on the SF-36 summary scales and subscales reflect better health status and well-being.	24 weeks
Other	Mood	Profile of Mood States (POMS) fatigue subscale. The POMS consists of survey questions that cover 6 subscales: anxiety, confusion, depression-dejection, fatigue, tension, and vigor. Each subscale score is calculated from weighted averages of individual questions related to the subject's perception of fatigue. Minimum score for the fatigue subscale is 0. Maximum score is 30. Higher scores on the POMS fatigue subscale are worse.	24 weeks
Other	Working Memory	3-Back correct on target. The N-Back test consists of three conditions of increasing load on working memory, the 1-Back, 2-Back and 3-Back. In the 1-Back, letters are presented one at a time on a computer screen for 2 sec (1 sec interstimulus interval) during which the subject responds with a key press if a particular letter appears that had appeared on the previous screen. In the 2-Back, the subject must hold in mind letters and respond when s/he sees a letter that was previously presented two screens back. In the 3-Back, the subject responds when s'he sees a letter that was presented three screens back. N-back test measures the updating and storage functions of working memory. The test is scored as the number of targets correctly identified in each condition. The outcome of interest here is the number correct on target during the 3-Back, which is the most difficult of the three conditions. Minimum score is 0. Maximum score is 16. Higher scores are better.	24 weeks
Other	Declarative Memory	Paragraph Recall - 30 min. Subjects were read a brief story and verbally recalled it immediately and after 30 minutes. The score was the total number of story elements recalled at 30 minutes. Minimum score is 0; Maximum score is 20. Higher scores are better.	24 weeks
Other	Motor Learning	Pursuit Rotor Trial 4. This test is performed on a photoelectric pursuit Rotor (Model 30014, Lafayette Instrument Company, Lafayette, IN). Subjects hold a photosensitive wand to maintain contact with a 2 cm. light disk rotating on a variable speed turntable. An initial block of 4 trials is administered at 15, 30, 45, and 60 revolutions per minute. The speed at which the subject remains on-target is the rate at which remaining trials are performed. Three blocks of eight 20-second trials are then administered, with a 20-sec rest after each trial, and a 60-sec rest period after 4 trials. This sequence is repeated after a retention interval of 30 minutes. The measure of interest here is the time the wand maintains on target during the final trial. Minimum score is 0; maximum score is 80 seconds. Higher numbers are better.	24 weeks
Other	Total Energy Expenditure	Total energy expenditure (TEE) measured by isotopic doubly labelled water (DLW) technique, corrected for lean body mass. A urine sample is collected and analyzed for background enrichment of deuterium and 18-O. The subject then drinks a dose of doubly labeled water at 1.7 gm per kg body weight, Samples are collected 2, 3 and 4 hours and seven days following the DLW dose to determine whole body equilibrium. Samples are measured as a ratio of deuterium to hydrogen in hydrogen gas and 18-O/ 16-O in CO2 using a Europa 20/20 Isotope Ratio Mass Spectrometer (Metabolic Solutions, Inc., Nashau, NH). CO2 production is then used to calculate TEE by Weir's equation. Minimum value is 36 kcal/kg LBM/day. Maximum value is 74 kcal/kg LBM/day. Within this range, higher values are considered to be better for the purposes of this study.	24 weeks
Other	Thermic Effect of Food	Thermic effect of food (TEF)is a measurement of energy expenditure over 5 hours following consumption of a standard test meal by indirect calorimetry. Each subject consumes a liquid mixed meal (Ensure, Ross Laboratories, 14% protein, 31.5% fat, and 54.5% carbohydrate) over 5 minutes and sampling for O2 and CO2 is then done by indirect calorimetry for the last 6 min of every 0.5 h for 5 h. For each metabolic measurement the respiratory exchange ratio (respiratory quotient or RQ = VCO2/VO2) is calculated and results converted to kilocalories by the Weir equation. Minimum value is 5 kcal/day. Maximum value is 730 kcal/day. Within this range, higher values are considered to be better for the purposes of this study.	24 weeks
Other	Physical Activity Energy Expenditure	Physical activity energy expenditure (PAEE) by accelerometry, corrected for lean body mass. The Actical activity monitoring device (Mini Mitter Co Inc, Bend, OR) utilizes a multidirectional accelerometer to monitor the occurrence and intensity of motion, or epoch (137). The Actical device measures 3 cm by 3 cm, weighs 17.0 grams, and is securely attached to a waistband and placed around the waist. The device is worn for 7 days. Data are downloaded from the accelerometer using an ActiReader and converted into total activity counts, average activity (counts per minute), time interval duration (minutes), activity ranges during sedentary, light, moderate, and vigorous activity, and accumulated time within each activity range (minutes). These data are then converted to PAEE by proprietary algorithms. Minimum value is 3 kcal/kg LBM/day. Maximum value is 40 kcal/kg LBM/day. Higher values are better.	24 weeks
Other	Daily Energy Intake	Daily caloric intake is measured by 24-hour diet recalls, corrected for lean body mass (LBM). Three 24h food recall interviews are conducted by telephone within one week of the testing visit by research nutritionists trained in the Nutrition Data System for Research (NDSR), a software application for the collection of dietary recall information in a standardized fashion. Data from the phone interviews are manually entered into the NDSR program, which calculated caloric intake. The average of the three diet recalls is used as the outcome. Minimum value is 10 kcal/kg LBM/day. Maximum value is 72 kcal/kg LBM/day. Lower values are considered better for the purposes of this study.	24 weeks
Other	Body Mass Index	Body mass Index (BMI) is calculated as the weight in kg divided by the (height in meters squared). Minimum value is 18 kg/m2. Maximum value is 50 kg/m2. For the purposes of this study, lower values are considered better.	24 weeks
Other	Lean Body Mass	Lean body mass (LBM) is measured by dual energy X-ray absorptiometry (DEXA). Measurements are made using a Hologic Discovery A Densitometer (Hologic, Inc., Bedford, MA). Proprietary algorithms calculate LBM from DEXA data. Minimum value is 28 kg. Maximum value is 71 kg. For the purposes of this study, higher values are considered better.	24 weeks
Other	% Fat Mass	% fat mass is measured by dual energy X-ray absorptiometry (DEXA). Measurements are made using a Hologic QDR Discovery A Densitometer (Hologic, Inc., Bedford, MA). Proprietary algorithms calculate % fat mass from DEXA data. Minimum value is 20%. Maximum value is 56%. For the purposes of this study, lower values are considered better.	24 weeks
Primary	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
Primary	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