Neurocognitive and Metabolic Effects of Mild Hypothyroidism
Condition: Hypothyroidism
MeSH terms: Hypothyroidism
Study type: Interventional
Phase: Phase 4

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.
    

Detailed 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.
    

Intervention name(s): L-thyroxine (L-T4)
Intervention type(s): Drug
Intervention description(s): 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
Other intervention name(s): Subjects will remain on their usual brand of L-T4.; Subjects on generic L-T4 will be switched to Levoxyl.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Hypothyroidism; Cognition; Metabolism