Trial Outcomes & Findings for Neurocognitive and Metabolic Effects of Mild Hypothyroidism (NCT NCT00565864)

NCT ID: NCT00565864

Last Updated: 2018-08-22

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 173 participants
• Primary outcome timeframe: 24 weeks
• Results posted on: 2018-08-22

Participant Flow

Participant milestones

Measure	Arm 1 Normal baseline thyroid stimulating hormone (TSH) Target TSH 0.28 - 2.50 milliunits/liter (mU/L)	Arm 2 Normal baseline thyroid stimulating hormone (TSH) target TSH 2.51 - 5.60 milliunits/liter (mU/L)	Arm 3 Normal baseline thyroid stimulating hormone (TSH) target TSH 5.61 - 12.0 milliunits/liter (mU/L)
Overall Study STARTED	58	59	56
Overall Study COMPLETED	46	47	45
Overall Study NOT COMPLETED	12	12	11

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Neurocognitive and Metabolic Effects of Mild Hypothyroidism

Baseline characteristics by cohort

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L	Total n=138 Participants Total of all reporting groups
Age, Continuous	49.5 years STANDARD_DEVIATION 11.5 • n=5 Participants	50.9 years STANDARD_DEVIATION 12.3 • n=7 Participants	49.3 years STANDARD_DEVIATION 10.7 • n=5 Participants	49.7 years STANDARD_DEVIATION 11.7 • n=4 Participants
Sex: Female, Male Female	41 Participants n=5 Participants	41 Participants n=7 Participants	43 Participants n=5 Participants	125 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	13 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	45 Participants n=5 Participants	44 Participants n=7 Participants	42 Participants n=5 Participants	131 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	44 Participants n=5 Participants	41 Participants n=7 Participants	42 Participants n=5 Participants	127 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants

PRIMARY outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Executive Function	7.9 units on a scale Standard Error 1.6	7.5 units on a scale Standard Error 1.5	8.8 units on a scale Standard Error 1.6

PRIMARY outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Resting Energy Expenditure	30.3 kcal/kg LBM/day Standard Error 0.4	30.0 kcal/kg LBM/day Standard Error 0.4	30.0 kcal/kg LBM/day Standard Error 0.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Quality of Life by SF-36 Survey	41.0 units on a scale Standard Error 0.9	39.8 units on a scale Standard Error 1.1	39.4 units on a scale Standard Error 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Mood	7.4 units on a scale Standard Error 0.8	6.7 units on a scale Standard Error 0.9	6.9 units on a scale Standard Error 0.8

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Working Memory	11.7 units on a scale Standard Error 0.3	11.5 units on a scale Standard Error 0.4	11.5 units on a scale Standard Error 0.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Declarative Memory	11.9 units on a scale Standard Error 0.4	12.1 units on a scale Standard Error 0.5	12.8 units on a scale Standard Error 0.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Motor Learning	41.8 seconds Standard Error 2.3	39.4 seconds Standard Error 1.9	45.0 seconds Standard Error 2.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

Population: The number of participants analyzed is less than the total number of participants due to a nationwide shortage of doubly labelled water during the study. This meant that not all subjects entered into the study were able to receive the doubly labelled water.

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.

Outcome measures

Measure	Arm 1 n=23 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=19 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=23 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Total Energy Expenditure	53.0 kcal/kg LBM/day Standard Error 1.6	51.1 kcal/kg LBM/day Standard Error 1.5	50.6 kcal/kg LBM/day Standard Error 1.1

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

Population: The number of subjects who underwent measurement of thermic effect of food was less than the total number of subjects in the study due to scheduling constraints. TEF measurements take over 5 hours, and some subjects did not have sufficient time to participate in this part of the study, but were still able to conduct the other activities.

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.

Outcome measures

Measure	Arm 1 n=26 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=23 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=31 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Thermic Effect of Food	147 kcal/day Standard Error 28	136 kcal/day Standard Error 13	125 kcal/day Standard Error 12

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

Population: A few subjects did not have data collected due to a technical problem with downloading their data from the Actical device.

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.

Outcome measures

Measure	Arm 1 n=45 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=46 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=43 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Physical Activity Energy Expenditure	11.6 kcal/kg LBM/day Standard Error 0.7	12.6 kcal/kg LBM/day Standard Error 0.6	11.4 kcal/kg LBM/day Standard Error 0.6

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

Population: One subject could not be reached by telephone to conduct the diet recalls.

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=44 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Daily Energy Intake	26.8 kcal/kg/day Standard Error 1.3	28.6 kcal/kg/day Standard Error 1.6	27.4 kcal/kg/day Standard Error 1.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Body Mass Index	28.6 kg/m2 Standard Error 0.8	27.3 kg/m2 Standard Error 0.8	27.6 kg/m2 Standard Error 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Lean Body Mass	46.2 kg Standard Error 1.1	45.0 kg Standard Error 1.4	43.8 kg Standard Error 1.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 24 weeks

% 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.

Outcome measures

Measure	Arm 1 n=46 Participants Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 Participants Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 Participants Normal baseline TSH target TSH 5.61 - 12.0 mU/L
% Fat Mass	38.2 percentage of total mass Standard Error 1.0	36.4 percentage of total mass Standard Error 1.2	38.1 percentage of total mass Standard Error 1.1

Adverse Events

Arm 1

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Arm 2

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Arm 3

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Arm 1 n=46 participants at risk Normal baseline TSH Target TSH 0.28 - 2.50 mU/L	Arm 2 n=47 participants at risk Normal baseline TSH target TSH 2.51 - 5.60 mU/L	Arm 3 n=45 participants at risk Normal baseline TSH target TSH 5.61 - 12.0 mU/L
Product Issues medication error	4.3% 2/46 • Number of events 2	2.1% 1/47 • Number of events 1	4.4% 2/45 • Number of events 2
Endocrine disorders symptoms	0.00% 0/46	2.1% 1/47 • Number of events 1	2.2% 1/45 • Number of events 1

Additional Information

Dr. Mary Samuels

Oregon Health & Science University

Phone: 5034945242

Email: samuelsm@ohsu.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place