Download Protocol Title: Neurocognitive effects of subclinical hypothyroidism

Protocol Title: Neurocognitive effects of subclinical hypothyroidism
Investigators:
Name
Department
Affiliation
Phone
E-Mail
Principal
Investigator:
Jane Doe, M.D.
Medicine/Endocrine
1-4444
[email protected]
Co-Investigators:
Jason Smith, Ph.D.
Tammie Ruff, M.D.
Neurology
Medicine/Endocrine
7-7777
5-5555
[email protected]
[email protected]
Contact Person:
Phyllis Carello
OCTRI
4-0164
[email protected]
Other Protocol
Personnel:
Phyllis Carello
OCTRI
4-0164
[email protected]
Scientific Abstract:
The effects of disordered thyroid function on the developing brain are well-known. However, less is
understood about the effects of thyroid dysfunction on cognition in the mature brain, particularly regarding
effects of mild thyroid disease, which is common in the aging population. The goal of this study is to identify
which neural systems and cognitive domains are affected by subclinical hypothyroidism (SCH) in adulthood.
Our hypothesis is that SCH causes specific defects in long-term memory, which are worse with aging. The
study will recruit healthy subjects receiving l-thyroxine for hypothyroidism who have normal TSH levels. In
order to assess the effect of aging, subjects with a broad range of ages (20 to 80 years) will be studied. In a
placebo-controlled, blinded, cross-over fashion, subjects will receive either their usual dose of l-thyroxine or a
lower dose calculated to induce SCH for 3 months. Subjects will undergo specific neurocognitive tests chosen
to detect subtle deficits in short- and long- term memory, and compare those to tests that are not expected to be
affected.
Lay Abstract:
Mild hypothyroidism is common in adults, especially in older women. It is known that severe
hypothyroidism interferes with memory, but the effects of mild hypothyroidism on memory are not known. To
study this question, healthy people (men and women) with well-treated hypothyroidism will be given either their
usual thyroid hormone dose, or a slightly lower dose, for three months, and then the treatments will be switched.
Tests of memory and thinking will be done on the full thyroid hormone dose, and on the lower dose, to see
whether the lower dose leads to impairments in memory. Both young and old subjects will be studied, in order
to see whether age plays a role in making memory impairment induced by hypothyroidism worse.
a. Specific Aims:
Hypothesis #1: Subclinical hypothyroidism is associated with specific deficits in long-term memory.
Specific aim #1: To compare neurocognitive tests of short-term and long-term memory in subjects with
hypothyroidism during full replacement dose of L-thyroxine vs. treatment with doses of L-thyroxine that lead to
subclinical hypothyroidism
Hypothesis #2: The deficits in long-term memory associated with subclinical hypothyroidism are worse in older
subjects.
Specific aim #2: To compare neurocognitive deficits induced by lower L-thyroxine doses in young vs. older
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hypothyroid subjects.
b. Background and Significance:
The effects of congenital hypothyroidism on the developing brain and the resulting cognitive defects
(cretinism) are well-known, and include profound mental retardation, hearing impairment, expressive language
deficits, loss of information processing, and decreased visual perception (see 1 for recent review). However,
less is understood about the effects of hypothyroidism on cognition and specific brain systems in the mature
brain. Clinical observations dating back many years suggest that overt hypothyroidism interferes with a number
of brain functions, and several studies have documented deficits in intelligence, attention and concentration,
memory, perceptual and visuospatial function, language, executive function, and/or psychomotor speed in
patients with adult-onset hypothyroidism (2-5a). However, these studies have a number of limitations: Some
were performed a number of years ago, and utilized now-obsolete techniques of cognitive testing. Others used
only selected cognitive tests to measure limited or nonspecific aspects of cognitive domains. Many did not
control for severity or duration of hypothyroidism, and/or tested patients after various amounts of thyroid
hormone replacement for variable time periods. Many included patients with disorders of mood that can occur
with hypothyroidism, and that would confound measures of cognition. Therefore, although there is some
existing clinical literature on neurocognitive effects of hypothyroidism, it is nonconclusive, and the specific
neural and cognitive defects have not been completely delineated using modern neuroscience methods.
Recently, a great deal of interest has arisen regarding “subclinical” hypothyroidism (SCH), which is
defined as an isolated elevated TSH level, with normal thyroid hormone (T4 and T3) levels. This is a much
more common condition than overt hypothyroidism, affecting 5-6% of young women and up to 20% of older
women (men have age-invariate rates of approximately 5%) (see 6 for recent review). It is usually due to
autoimmune thyroid disease, although any cause of overt hypothyroidism can also cause SCH It was initially
thought to be purely a laboratory abnormality, associated with an increased risk of the eventual development of
overt hypothyroidism, but not associated with any relevant clinical consequences per se. However, a number of
studies over the past ten years have shown deleterious effects of SCH on cardiac function and lipid levels,
although not all studies agree on this issue (reviewed in 6). There is now a trend to treat SCH, but this is not a
universal recommendation among thyroid specialists.
Recently, effects of SCH on neurocognitive function have been reported, although the literature is far
from conclusive, and not all studies report positive findings (4,7-10b). These studies tended to show deficits in
long-term (or “declarative”) memory in subjects, with improvements following treatment with L-thyroxine (LT4). However, some of the same limitations exist for these studies, including heterogeneous subject groups and
nonspecific or limited cognitive domains tested. If specific neurocognitive deficits were present in SCH, this
could provide an important indication for treatment. This is especially pertinent for the increasing number of
older subjects, in whom SCH is common, and who often have incipient defects in cognition at baseline. The
addition of cognitive defects due to SCH in the elderly may cause significant functional impairment.
In addition to the limited clinical data on neurocognitive effects of hypothyroidism, there is a large body
of evidence from animal studies that support our hypotheses (see 11 for recent review). The adult rat brain
contains significant amounts of T4 and T3, with autoradiographs showing dense labeling of the hippocampus.
Peripherally injected T4 or T3 enter the brain rapidly and efficiently. All three known types of iodothyronine
deiodinase (which mediate the metabolism of T4) are present in the adult brain, and chronic hypothyroidism
results in up-regulation of the deiodinase that converts T4 to the active hormone T3. Nuclear T3 receptors are
present in a distinct cellular and regional distribution in the brain, with the highest concentrations in the cerebral
cortex, the amygdala, and the hippocampus. On a morphologic level, hypothyroidism results in a significant
increase in nuclear T3 binding capacity in these brain areas. Adult-onset hypothyroidism in rats reduces the
numbers of granule cells of the dentate gyrus and pyramidal cells of the hippocampal CA1 region, and decreases
the apical dendritic spine density of the hippocampal CA1 pyramidal neurons. This could be the anatomic
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substrate for memory impairments caused by hypothyroidism. On a biochemical level, the activities of RNA
polymerase I and mitochondrial enzymes are reduced in the brains of adult hypothyroid animals. In terms of
neurotransmitter function, the numbers of cerebrocortical alpha and beta adrenergic receptors and hippocampal
adenosine kinase are reduced in hypothyroidism. Taken together, these data show that thyroid hormones are
active in the brain regions that control cognition, and specifically memory functions.
Over the past ten years, the field of cognitive neuroscience has made tremendous advances in the ability
to detect specific deficits, utilizing targeted neurocognitive tests that have an established neural basis and for
which underlying cognitive processes are known. Application of these tests to healthy subjects and patients
with various cognitive deficits has led to the development of the following structural paradigm for memory
processes (see 12-14 for recent reviews):
Memory
Working memory
(short-term memory)
Declarative Memory
(long term memory)
Prefrontal cortex
Hippocampus,
medial temporal
lobe)
Nondeclarative memory
(skill learning, priming,
simple conditioning,
adaptation)
Cerebellum, basal ganglia
Ex. motor learning
Specific tests exist for each of these memory functions that have been validated with imaging and/or
autopsy studies in healthy subjects and in patients with neurological disorders. It is important to use these
specific tests to study a process such as SCH, which may have subtle effects that are only apparent in
combination with another process such as aging. We propose to apply these tools to the study of cognition in
SCH. In order to avoid subject and disease heterogeneity that has limited past studies, we plan to prospectively
study a group of otherwise healthy subjects with stable, treated hypothyroidism, performing neurocognitive
testing while they are treated with a replacement dose of L-thyroxine, and again while they are treated with a
sub-replacement dose of L-thyroxine that will cause temporary SCH. We will carefully control for age, gender,
degree of subclinical hypothyroidism, mood effects, and other potentially confounding variables.
c. Preliminary Studies / Progress Report:
In support of hypothesis #1, the PI has undertaken a preliminary analysis of two large existing local
databases (Dr. Jeri Janowsky=s study of sex hormones and cognition, and the Oregon Brain Aging Study) that
were designed to measure cognitive functioning during healthy aging. TSH levels were measured in 206
healthy, nondemented subjects, and the PI has performed multivariate analysis of neurocognitive tests in
subjects with normal TSH levels (n=185) vs. those with mildly elevated TSH levels (n=21). After controlling
for age, gender, estrogen status, and education, subjects with subclinical hypothyroidism had decreased
performance on tests of long- term memory (delayed word list and paragraph recall, digit span backwards), as
well as decreased performance on one test of short-term memory (subject ordered pointing). Although
intriguing, these data cannot be considered conclusive, since the study was not designed to measure thyroid
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function, and did not include young subjects for analysis of additive effects of age and thyroid dysfunction.
d. Research Design and Methods:
Experimental Design:
Subjects. Two groups of subjects will be recruited for this study:
1. 60 subjects (ages 20-80) with primary hypothyroidism, receiving replacement doses of L-T4. Subjects will
be hypothyroid as a result of adult-onset disease, either autoimmune, or status post definitive treatment for
hyperthyroidism (radioactive iodine or surgery). The diagnosis of hypothyroidism must include a documented
elevated TSH prior to treatment. Subjects with juvenile onset of disease, or who cannot date the onset of
hypothyroidism, will be ineligible. Subjects must be receiving stable doses of L-T4 as the sole treatment for
hypothyroidism for at least three months, with documented normal TSH levels during this time. Subjects must
not have any acute or chronic illnesses that might affect thyroid function or cognition, and must not be receiving
any medications known to affect thyroid hormone levels, mood, or cognition. Oral contraceptives and
postmenopausal hormone replacement therapy will be allowed, as long as the type and dose have been stable for
at least 3 months. Women will be studied in the follicular phase of the menstrual cycle or in the first week of an
oral contraceptive or hormone replacement cycle. Women who are in the perimenopausal state (defined by
irregular menses for the past year) will not be studied until menopausal status has stabilized, in order to avoid
effects of changing sex steroid levels on cognition. The lower age range was chosen to avoid the neurocognitive
and educational changes common during adolescence and immediate post-high school years .
The upper age range was chosen to sample a relatively healthy group of older subjects (avoiding the oldest old,
who have high rates of incipient dementia and medical conditions).
3. 30 healthy young subjects (ages 20-45) with no thyroid disease. Subjects must not have any acute or chronic
illnesses that might affect thyroid function or cognition, and must not be receiving any medications known to
affect thyroid hormone levels, mood, or cognition. Women receiving cyclic hormone therapy will be studied
during the first week of a cycle. This group will undergo screening and neurocognitive studies only (see below
for details), in order to provide internal normative data for thyroid hormone levels, mood assessments, and
cognitive tests, especially the potential effects of repeated testing. Some of the control subjects will complete
only the screening and baseline visits, while others will complete the screening, baseline, 12-week and 24-week
visits, to assess effects of repeated testing.
Study design:
L-thyroxine is manufactured by a number of pharmaceutical companies under brand names (Synthroid,
Levothroid, Levoxyl, Unithroid) as well as under generic labels. Pharmacokinetic data and sample analysis
show that the branded types of L-thyroxine have adequate amounts of L-T4 per pill, absorption kinetics and lotto-lot stability. However, they cannot be interchanged, since up to half of subjects switched from one brand to
another develop abnormal TSH levels. This is not acceptable for the current study. Therefore, subjects will be
maintained on their usual brand of l-thyroxine for the duration of the study, which will include the usual dose
arm and the lower dose arm. Studies have also shown that some generic types of l-thyroxine are inadequate in
terms of amounts of l-T4 per pill and lot-to-lot stability, and most thyroid specialists do not prescribe generic LT4. For this reason, any subject who is on generic L-T4 will be switched to Levoxyl (the OHSU formulary
brand) at the same dose before beginning the study. A TSH will be checked after 6 weeks of Levoxyl, and the
dose will be adjusted as needed to maintain a normal TSH. The subject will enter the active part of the study
when his/her TSH is normal on Levoxyl. The Levoxyl will be supplied free of charge during this run-in period.
1. Screening visit (week -3 to -2). Each subject (hypothyroid and control) will come to the CTRC
outpatient clinic for a visit to screen for general health, thyroid status, and mood or cognitive disorders. The
subject will be asked to refrain from eating that morning, in order to obtain fasting blood samples, and will be
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asked to delay taking his/her usual L-T4 dose until after the visit. The informed consent document will be
reviewed, and any questions answered. A history and physical examination will be done, with specific attention
to medical conditions, medications, and other exclusionary issues. Subjects will screened for alcohol or drug
abuse by standard questioning. The following laboratories will be done: CBC (to exclude anemia or abnormal
WBC counts), chemistry battery (to exclude metabolic disorders), fasting LDL cholesterol and triglyceride
levels (to exclude significant hyperlipidemia that might make the induction of SCH inadvisable), TSH (to
ensure that the subject=s dose of L-T4 is appropriate), and an ECG (to screen for underlying cardiac disease that
might make the induction of subclinical hypothyroidism inadvisable). Total blood volume is approximately 10
cc. Women of childbearing potential will also have a urine pregnancy test performed prior to entering the study.
Control subjects (group 3 - no thyroid disease) will have CBC, chemistry battery, and TSH only, since the
other tests are for safety monitoring on thyroid hormone.
The subjects’ degree of schooling will be recorded (probable range 12-18 years), and they will complete
the vocabulary subtest of the WAIS-R. These measures will allow us to assess and match subject groups for
general intellectual level. The WAIS-R Vocabulary subtest is standardized measure of general intellectual
functioning that does not decline with normal aging within our age range (15). It is a better matching variable
among groups for functional status than education, since older subjects may have left school early due to family
circumstances but have had a lifetime of non-academic education. Finally, to screen for underlying mood or
cognitive disorders that would exclude a subject, the SCL-90-R (Symptom Checklist-90-revised) and MMSE
(Mini Mental State Examination) will be administered (16,17). The older subjects (over age 60 years) will also
complete the GDS (Geriatric Depression Survey), a short questionnaire specifically designed to screen for
depression in the elderly (18). Subjects will be disqualified from the study and referred to their physicians for
further evaluation if they score < 8 on the WAIS-R Vocabulary Subtest, > 10 on the GDS, < 26 on the MMSE,
or have a psychiatric disorder diagnosed by the SCL-90-R. The entire screening visit will take one hour or less.
Older and younger subjects will be matched for overall intelligence and education equivalence using the WAISR.
It is possible that the occasional subject will not have a normal TSH on the screening visit, despite
previous documented normal TSH levels on the same dose and brand of L-T4. In this case, compliance will be
carefully checked. If compliance is an issue, the subject will be encouraged to improve compliance, and a
repeat TSH will be checked after 6 weeks. If compliance is not thought to be an issue, the subject’s L-T4 dose
will be adjusted as appropriate, and a repeat TSH will be checked after 6 weeks. Once the subject’s TSH is
normal, s/he will proceed to the first study visit.
2. First study visit (week 0). If the subject qualifies for the study (hypothyroid and control), s/he will be
asked to return to the CTRC within 3 weeks of the screening visit. The hypothyroid subjects will be asked to
refrain from taking their L-T4 dose until after the morning’s visit (at which time they will be given study drug to
take instead of their usual L-T4). TSH, free T4, and total T3 levels will be obtained as baseline levels (for this
blood sample, and all subsequent samples, the sample will be sent to the OHSU/Kaiser lab, but extra serum and
plasma will also be saved in the CTRC core laboratory in case of lab accident or need to remeasure any thyroid
hormone or thyroid hormone-dependent laboratory levels. In addition, the subject will be asked to provide a
second-morning void spot urine specimen, which will be stored in the core lab. The purpose of this specimen is
to provide a urine sample for measures of bone resporption in the future, if this experimental design proves
salutory for the measurement of bone turnover in subclincal hypothyroidism. Any future planned analysis of
these samples will be submitted to the CTRC for approval, and will be funded by the investigator). Total blood
volume is 20 cc for this and subsequent blood samples. The subject will be asked to report in the fasting state at
this an subsequent visits, to exclude any possible effects of variations in caloric intake on neurocognitive tests or
other parameters.
At this visit, baseline neurocognitive tests will be performed. The specific cognitive measures to be used
are described below. Also at this visit, the physician will complete the Billewicz Scale, a 14-point rating scale
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that screens for the presence or absence of typical hypothyroid symptoms (19). The subject will complete the
SF-36 health survey, a validated questionnaire about general health and well-being. The subject will also
complete the POMS (Profile of Mood States), a short questionnaire about mood (20). The Billewicz Scale, SF36 and POMS will be repeated at subsequent visits to measure possible changes in general health, hypothyroid
symptoms, and affect that could play roles as co-variants in cognitive outcomes. This visit will take 2 hours.
After neurocognitive testing is completed, the subject (hypothyroid only) will be randomized to continue
to receive his/her usual L-T4 dose (euthyroid arm), or will be given a slightly lower dose, calculated to increase
serum TSH levels to 10-40 mU/L, which corresponds to the range of TSH levels commonly reported in the
literature on SCH (SCH arm). During the second arm of the study (see below), the subject will receive the
alternate L-T4 dose (full dose if s/he were initially on the SCH arm, reduced dose if s/he were initially on the
euthyroid arm).
It is difficult to determine what L-T4 dose reduction will lead to a TSH level within the desired SCH
range, given inter-subject variations in L-T4 starting doses, absorption rates, and metabolism. In addition, many
subjects continue to have some endogenous l-thyroxine secretion, and this can blunt the desired TSH responses
to exogenous l-thyroxine dose changes. A literature review reveals only two studies where L-T4 doses were
decreased in this range. Carr et al reported 11 patients with TSH levels in the low-normal to normal range, who
had their L-T4 doses decreased by 25-100 ug (starting doses 100-200 ug) (21). In 7 subjects whose L-T4 doses
were decreased by 20-25%, resulting TSH levels were less than 10 mU/L. In 4 subjects whose L-T4 doses were
decreased by 25-50%, 3 had resulting TSH levels in the target range (11-22 mU/L). Guimaraes and DeGroot
studied 15 patients on replacement or suppressive doses of L-T4 for thyroid cancer, decreasing their L-T4 doses
by 50% for 4-6 weeks in preparation for I-131 scanning (22). Initial L-T4 doses and TSH levels were not given,
but TSH levels on “half-dose” L-T4 were 16-221 mU/L. Only 4 were in the target TSH range (16-28 mU/L).
From these studies, we conclude that a 50% decrease from full replacement doses is likely too much, while a
25% decrease will often be too little, to obtain TSH levels of 10-40 mU/L in subjects with no endogenous Lthyroxine secretion. Based on these data, as well as clinical experience, we propose to utilize the following
algorithm for l-thyroxine dose adjustments:
In subjects with a documented history of near-total dependence on exogenous l-thyroxine (markedly
elevated TSH levels prior to treatment), as an initial estimate, the subject=s replacement dose will be decreased
by 30%, or as close to that level as possible using available L-T4 doses. The specific dose adjustments are listed
in the table below (see below for explanation of 2nd dose adjustments). The usual replacement dose range of LT4 is 75-175 ug/day; if a subject is on a dose outside this range, a similar calculation will be made to adjust
his/her dose for the study.
Usual
Initial SCH dose (new dose
2nd adjustment if TSH too low 2nd adjustment if TSH too high
dose
as percentage of usual dose)
after 6 weeks
after 6 weeks (or if free T4 is low)
75 ug
50 ug (67%)
37.5 ug (50%)
62.5 ug (83%)
88 ug
62.5 ug (71%)
50 ug (57%)
75 ug (85%)
100 ug 62.5 ug (63%)
50 ug (50%)
75 ug (25%)
112 ug 75 ug (67%)
62.5 ug (56%)
88 ug (79%)
125 ug 88 ug (70%)
75 ug (60%)
100 ug (80%)
137 ug 88 ug (64%)
75 ug (55%)
100 ug (73%)
150 ug 100 ug (67%)
88 ug (59%)
112 ug (75%)
175 ug 125 ug (71%)
100 ug (57%)
137 ug (78%)
In subjects who are not totally dependent on exogenous l-thyroxine (ie. subjects with more mild TSH
elevations prior to treatment), the above doses will be adjusted based on the patient=s past laboratory values and
clinical experience. For example, if a subject is known to have had a TSH level of 15 mU/L on 75 ug of l6
thyroxine, then that dose will be chosen as the SCH dose, and will be compared to the euthyroid dose with
appropriate placebo pills for matching. All subjects will have close follow-up with TSH measurements to
ensure that the SCH dose is appropriate, and the above algorithm will be modified as subjects are studied and
more experience is gained in this degree of dose adjustment.
L-T4 pills are available in numerous doses, each dose manufactured as a different colored pill. Therefore,
subjects would be aware of dose changes if different colored or number of pills were substituted for their usual
L-T4 prescriptions. In order to avoid this and maintain subject blinding, the pills will be placed in gel capsules
for administration to subjects. These gel capsules have been used in many previous studies over many years for
this purpose. They are approved for administration to humans, nonexperimental, metabolically inert,
nonallergenic, and dissolve rapidly in the stomach. They do not change drug absorption kinetics. However, to
completely ensure that the gel capsules have no effect on the data, the following preliminary study will be done
initially with the gel capsules:
Gel capsule substudy. Up to 10 study subjects who currently take a branded L-T4 product with a normal
TSH level will be asked to participate in a 6-week substudy. For the 6 weeks, they will continue to receive their
usual dose of L-T4, but it will be placed inside a gel capsule. After 6 weeks, a TSH level will be drawn. Mean
TSH levels before and after the 6 week substudy will be compared by paired t-test to ensure that there is no
significant change, and that no TSH levels are out of the normal range.
Note that, in some cases, pills will have to be cut in half, since pills in some of the doses listed in the
table do not exist. The pills are scored, and are cut in the research pharmacy, to minimize any effects on cutting
on doses. L-T4 pills are sometimes prescribed for clinical indications in half-pill amounts, with no effect on
dosing. In addition, the investigator has not found any effects of cutting pills in half in previous studies.
The examining physician (MHS) and the technician in charge of neurocognitive testing will be unaware
of which arm of the study the subject enters first. The randomization and determination of doses will be carried
out by the prescribing co-investigator (KGS), who will not be involved in patient contact.
3. Second study visit (week 6) - interim visit. Six weeks after starting the L-T4 combination, subjects
(hypothyroid only) will be seen for a brief (30 min) visit, to assess safety and adequacy of the L-T4 dose in
achieving SCH. The physician will assess any possible effects of a lower L-T4 dose (fatigue, weight gain,
edema, cold intolerance, constipation) by history and examination, and by the Billewicz scale. The physician
and subject will determine whether the subject can comfortably continue the study at this point, without
knowledge of the subject=s L-T4 dose or TSH level. TSH and free T4 levels will be measured at this visit,
since a minimum of 4-6 weeks is required after changing L-T4 doses for thyroid hormone levels to stabilize. A
fasting LDL and TG will be measured, to make sure that hyperlipidemia has not occurred due to induction of
SCH. Subjects who develop hyperlipidemia at this point will be discontinued from the study and restarted on
their usual doses of L-T4. We do not expect this to happen, since subjects will be pre-screened for
hyperlipidemia, but include it as an additional safety measure. In order to maintain physician blinding, the
thyroid hormone levels from this interim visit will be reviewed by the prescribing physician (KEG), as follows:
1) If the subject is on the SCH arm, the target TSH is 10-40 mU/L. If this TSH level has been achieved, no
changes will be made in the dose. If the TSH is too low, the L-T4 dose will be decreased to the dose listed in
the second column of the L-T4 dose table above. If the TSH is too high, the L-T4 dose will be increased to the
dose listed in the third column of the table above. As an additional safeguard against causing an unacceptable
level of hypothyroidism, the L-T4 dose will be adjusted upward according to the third column in the table if the
free T4 level is low, regardless of the TSH level. We expect that these minor changes in dose, combined with
the original decrease in dose at the first study visit, will be sufficient to bring the TSH within the target range by
the time of the second neurocognitive testing, six weeks from this interim visit (see below).
2) If a subject is on the euthyroid arm, it is expected that the original L-T4 dose will maintain a normal TSH,
since this was confirmed at the screening visit. However, it is possible that we will occasionally see mildly
lowered or suppressed TSH levels in the euthyroid arm at the 6-week visit, due to previous slight
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noncompliance, or to changing the brand or L-T4 from the subject=s usual brand (previous studies have shown
that minor changes in TSH levels can occur when changing L-T4 brands). In this case, the prescribing physician
(KGS) will make minor dose adjustments to the subject=s L-T4 dose according to clinical judgement, with the
goal of maintaining the TSH within the normal range.
To maintain blinding, subjects will be told that they may need to return to the CTRC to pick up new
bottles of pills, regardless of whether their doses have changed. For each subject on the SCH arm who is
required to make an interim minor dose adjustment, a subject on the euthyroid arm will also be called back and
given new pills, either with or without changing the overall dose, depending on the TSH. Any minor changes in
dose will be done within one week of this interim visit.
4. Third study visit (week 12). 12 weeks after starting the L-T4 combination (and possibly 5-6 weeks
after the additional minor dose adjustment), hypothyroid subjects will return to the CTRC for an extended (2
hour) visit. Control subjects will return 12 weeks after their baseline visits, with no interventions prior to this
visit. The physician will perform a history and physician examination focused on the thyroid axis, and will
compete the Billewicz scale. The subject will complete the SF-36 questionnaire and the POMS survey to assess
general health and affective changes. TSH, free T4, and total T3 levels will be measured, and extra serum,
plasma and second-void urine samples will be collected and stored as in the first study visit. The neurocognitive
tests detailed above for the first study visit will be repeated.
The time course of 12 weeks was chosen based on the following data: One well-controlled study of 19
women with SCH reported improvements in logical memory, numeric span, visual memory, and total memory
quotient (all part of the Wechsler Memory Scale) after 3 months of treatment with L-T4 that normalized TSH
levels, with no changes in affective measures or visuo-spatial perception (10). One case report of a woman with
long-standing overt hypothyroidism documented numerous deficits on memory testing, some of which improved
within 2-6 weeks of L-thyroxine treatment initiation (5). Another study reported cognitive changes after short
term thyroid hormone withdrawal (10 days to 2 weeks) for thyroid cancer screening (3). Other studies that
reported cognitive changes with SCH included variable time periods of hypothyroidism, or only measured
cognitive parameters after 6 months or more of treatment (2,4,7-9). Finally, Smith and Ain reported that
subjects taken off of thyroid hormone for thyroid cancer screening (off T4 for six weeks and off T3 for two
weeks) developed changes in cerebral metabolism as measured by 31-P NMR spectroscopy. These changes
improved 7-8 weeks after reinstating L-T4 therapy (23). Therefore, there is not a large body of literature to guide
the selection of time course for the proposed study. Given that the serum half-life of L-T4 is 7 days, at least 4-5
weeks are required to reach a new steady-state. Therefore, the initial 6 week period was chosen to allow
accurate assessment of adequacy of dose adjustment, with a second 6 week period to allow equilibration at the
new steady state or minor dose adjustment if needed. It would maximize the chances of finding neurocognitive
changes to allow a longer period of SCH, but this was thought to be burdensome for the subjects, who might
develop side effects of a lowered L-T4 dose over a longer period of time. In addition, compliance would likely
decrease and drop-out rates would increase over a longer time period. Therefore, the choice of 12 weeks was a
compromise between optimizing expected outcomes and minimizing subject discomfort and drop-out rates.
After the neurocognitive tests are completed at week 12, the subject will be crossed over to the second
study arm (euthyroid arm for those subjects originally on the SCH arm, SCH arm for those subjects originally
on the euthyroid arm). L-T4 doses will be calculated and dispensed in an identical fashion as described above
for the first study arm.
5. Fourth study visit (week 18). This is an interim visit for hypothyroid subjects only, identical to the
week 6 interim visit described above, with subjects now on the alternate study arm.
6. Fifth study visit (week 24). This visit is identical to the week 12 study visit described above, with
subjects now on the alternate study arm. Following this visit, subjects will be returned to their original L-T4
dose as continued treatment. Control subjects are studied 24 weeks after their baseline visit with no
intervention.
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7. Sixth study visit (week 30). This brief (30 min) follow-up visit is to ensure that subjects are now
receiving their usual L-T4 dose without any sequellae from the study, and to assess whether they perceived any
difference between the two study arms and could predict which arm contained the lower dose of L-T4. A history
and physical examination will be performed, blood will be drawn for storage in the core laboratory, and any further
follow-up deemed necessary will be prescribed. If subjects are doing well, we may contact them by phone instead
of having them come to the clinic for this visit.
Specific Cognitive Measures:
The tasks and cognitive processes chosen for this study are based on the memory paradigm presented in
the background section (see figure). They meet several criteria that address shortcomings of previous studies:
1. We focus on tasks that we suspect, based on previous studies, clinical experience, and preliminary data from
our two large local databases, will be specifically affected by mild hypothyroidism (tests of long-term or
declarative memory). These neural systems have been mapped to the hippocampus, which is known to take up
thyroid hormone to a greater extent than other brain areas, contains high densities of thyroid hormone receptors,
and undergoes morphologic changes in animal models of adult hypothyroidism (11).
2. We include tasks that we suspect, based on clinical experience, past studies, and preliminary data, will not be
affected by mild hypothyroidism (tests of working memory), as a control for global cognitive impairment.
3. We include measures of motor learning and motor speed, tasks that are known to be independent of
hippocampal function, but which serve as a control for motor slowing that can be seen in hypothyroidism and
aging, and provide a measure of nondeclarative memory.
4. We focus on tasks that are particularly affected by aging (working memory, verbal memory), since we
suspect that SCH and aging exert cumulative effects on some of these tasks. This would be especially important
if there were a “threshold” effect for SCH effects on cognition, since younger subjects might be unaffected,
while older subjects may develop clinically significant decrements in memory with the addition of SCH.
5. Finally, we have chosen tasks for which the critical neural systems for performance have been identified
using lesion or neuroimaging studies in animals and humans. They include the prefrontal cortex (working
memory), medial temporal lobe/hippocampus (long-term memory), and basal ganglia/cerebellum
(nondeclarative memory, for example motor learning). This will allow us to design future studies that
investigate the anatomic substrate of effects of thyroid hormones on the brain utilizing functional imaging.
1) Tests of Long-Term (Declarative) Memory:
A. Paragraph Recall (verbal memory). The Paragraph Recall subtest of the Wechsler Memory Scale Revised will be used and administered in the standard manner. On this task, subjects are read two brief stories
and after each story they immediately recall it. The response is scored for number of story elements (maximum
25) recalled, but the order in which the information is recalled is not relevant. The subject is told to try to
remember the stories for a later recall session. After a retention interval of 30 minutes, the subject again recalls
each story and his/her response is scored (24).
B. Complex Figure Test (visual memory). The Rey-Osterrieth Complex Figure Test will be
administered in the standard manner. On this task, subjects are given a standard complex figure and asked to
copy it. The figure is then removed, and the subject is asked to immediately draw it from memory. The
response is scored for accuracy using a standard scoring system. The subject is told to try to draw the figure
again after a retention interval of 30 minutes, and his/her response is scored (25).
2) Test of Short-Term (Working) Memory:
A. N-back test: For the purposes of description, each letter projected is called a “trial.” In the control
condition, the trial consists of a letter presented alone on the screen for 2 seconds (1 sec. interstimulus interval)
during which the subject responds with a key press if a particular letter appears (e.g. “X”) or an alternative
keypress if it is not the target letter. Subjects are then be taught the 1-Back task (“Respond when a letter
appears that you have seen 1-trial back”). The control versus 1-Back blocks of trials are signaled by a visual
9
title on the screen a the beginning of the block telling the subject which type of task they are doing, and in the
control condition, which is the target letter (“X” or “1-Back”) . The number of possible responses to the 1-Back
and control conditions are equated (approximately 1/7 trials). The task is then repeated at increasing levels of
difficulty, 2-Back and 3-Back (26). In addition, the 0-back subtest of the N-back test provides a measure of
reaction time, which could be affected by hypothyroidism. If affected, this would be included in the data
analysis as a co-variant. The N-back test measures the updating and storage functions of working memory.
B. Subject Ordered Pointing (SOP): The SOP will be administered in the standard manner. Briefly, the
subjects are presented with stacks of cards (6,8,10 or 12 cards per set). Each card shows a regular array of
abstract drawings, but the drawings are in a different spatial arrangement on each card. The subject is instructed
to touch one drawing on each card in any order, but not to touch the same drawing on subsequent cards in the
set. Subjects err when they touch a drawing that had been touched on a previous card in the set. Therefore, the
subject has to remember previous drawings touched while planning future responses. Subjects repeat each card
set three times. The total number of errors across all card sets is the measure of interest. Subjects are instructed
to do the task at their own pace, and to try not to go too quickly or too slowly. The SOP measures the updating
and storage functions of working memory (27).
C. Digit Span Backwards: The examiner reads number sequences of increasing length, and after each
sequence the subject is asked to repeat the sequence backwards. Subjects err when they cannot successfully
repeat two sequences at a specific length. The Digit Span Backwards test measures the updating, storage, and
manipulating functions of working memory (28).
3) Tests of Motor Learning:
A. Pursuit Rotor Motor Learning test. The Pursuit Rotor test is performed on a photoelectric pursuit
Rotor (Model 30014, Lafayette Instrument Company, Lafayette, IN). Subjects hold a photosensitive wand to
pursue and 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 min. The speed at which the subject remains ontarget nearest to 5 sec is the rate at which remaining trials are performed. After the baseline is established for
each subject, three blocks of eight 2-second trials are administered, with a 20-sec rest after each trial, and a 60sec rest period after each 4 trials (29).
The total amount of time to complete the above tests is approximately one hour, so the two visits that
include cognitive testing will last approximately 2 hours.
The strengths of the above study design include the strict randomization and blinding of subjects and
investigators to the L-T4 dose, which is essential for unbiased neurocognitive testing, and which was not
accomplished in most previous studies. In addition, this scheme minimizes the heterogeneity of SCH that has
compromised previous studies, by strictly controlling the length of time and degree of SCH. The cross-over
design also allows us to utilize each subject as his/her own control, and to assess the effect of reinstating
treatment in subjects who had SCH during the first arm; reversibility of neurocognitive alterations would
provide added proof that the alterations were specific to the thyroid state. Finally, this study design minimizes
the effects of repeated neurocognitive testing, which can lead to improvement in test results simply due to
practice, rather than to therapeutic interventions.
However, this study design also contains some weaknesses that are inescapable when one tries to design
a prospective, blinded, cross-over study. First, the length of time subjects will have SCH is limited to 12 weeks,
which we expect will be long enough to see neurocognitive changes, based on previous studies as discussed
above. We did not feel that subjects should receive subtherapeutic doses of L-T4 for longer than 12 weeks, so
this decision was a compromise between ensuring optimal results and subject safety and comfort. Another
weakness is the likelihood that not all subjects will achieve the target SCH TSH level after the first L-T4 dose
change, due to variability in pill absorption and metabolism, and will require the interim dose change detailed
for the 6 and 18 week visits. Therefore, there will be some heterogeneity in the length of time at the target TSH
levels prior to testing. This is an unavoidable consequence of the prospective nature of the study, and in our
10
opinion is preferable to recruiting untreated subjects with SCH, who are even more heterogeneous, and which
would greatly extend the time course of subject enrollment. Finally, the cross-over nature of the study means
that carry-over effects are possible between the two treatment arms. We have no data to suggest that this will
occur, but this is admittedly an assumption. We did not include a wash-out period between the two treatments,
since the time lapse between the two treatments is already 12 weeks, but we will test for sequence effects in our
data analysis. We considered a parallel-group, rather than a cross-over study, but the sample size calculations
revealed a prohibitively large sample size for a parallel study design.
Analytic Methods:
All thyroid hormone levels will be measured through the OHSU/Kaiser laboratories. The types of assays
and performance characteristics in the OHSU/Kaiser lab are as follows: Serum TSH levels will be measured by
two-site chemiluminescent assay (Nichols Institute, San Juan Capistrano, CA). The functional sensitivity of the
TSH assay is 0.01 mU/L, and the analytical sensitivity is 0.003 mU/L. Intraassay CV is 9.5% at 0.03 mU/L, and
4.7% at 11.6 mU/L. Interassay CV is 17% at 0.02 mU/L and 4.6% at 14 mU/L. Serum Free T4 levels will be
measured by Nichols chemiluminescent method, with a sensitivity of 0.08 ng/dL, an intraassay CV of 5.7% at
0.27 ng/dL and 1% at 4.6 ng/dL, and an interassay CV of 6.8% at 0.3 ng/dL and 1.6% at 3.8 ng/dL. Total T3
levels will be measured by Abbott Axsym MEIA, with a sensitivity of 30 ng/dL, an intraassay CV of 8% at 60
ng/dL and 3% at 350 ng/dL, and an interassay CV of 10% at 60 ng/dL and 4% at 350 ng/dL.
Data Analysis:
In both the younger and older groups hypothyroid subjects will be recruited in groups of four that are
homogeneous with respect to educational level, scores on WAIS-R, gender and estrogen status. Having formed
a group of similar patients, each patient will be randomized to a treatment sequence based on a computer
generated randomization scheme. The assessing physician will be blinded as to the treatment assignment of each
patient. Control subjects will be recruited in groups of four to match educational level, WAIS-R scores, gender
and estrogen status.
The outcome for each variable will be summarized by computing mean values, standard deviations,
standard errors and 95% confidence intervals at each assessment point for each treatment sequence. Baseline
assessment scores (including WAIS-R vocabulary, educational level, and POMS) will be compared for the
control and hypothyroid groups to assess comparibility, and between the two treatment groups to ascertain the
baseline comparability of the two treatment sequences. In the unlikely event that the baseline mean scores for
the two treatment sequences are not the same for an important variable characteristic variable, that variable will
be used as a covariate when comparing the end of treatment values for the two sequences. The comparison of
baseline values will be based on a two sample t-test. The primary analysis will be based on repeated measures
analysis of variance and paired (low dose vs usual dose) t-test (with covariates if necessary) as appropirate in
each age group. The significance level of tests of hypothesis will be 0.05.
Given that there will be a 3-month interval between the two L-T4 doses, we do not expect a carry-over
effect. However, this is an assumption, since there are no data to address this issue. In any case, we do not
anticipate a differential carry-over effect, since the order of treatments is randomized. However, we will test for
sequence effects.
It is possible that mood or affect changes will occur due to the induction of SCH, which might
secondarily change cognitive measures. If this occurs, changes in the POMS variables should occur, and will be
used as a covariate in the end of treatment values.
In order to determine if the difference between low- and usual-dose responses is greater in the older
subjects than in the younger subjects, we need to test for an age-group by dose interaction. This will be done
using a two way repeated measures ANOVA with repeated measures on treatment.
11
Sample Size Calculations:
We have based our estimates of statistical power on data found in the literature and augmented our
assumptions with preliminary data obtained from elderly women participating in the Oregon Brain Aging Study
described earlier. We have focused our estimates on the outcome logical memory, since this is the measure of
long-term memory most commonly reported in the literature and the OBAS study. We have found two reports
that seem suitable for estimating statistical power. The first (8) reported a change in the mean logical memory
post treatment scores of 2.3 in 14 patients (p< 0.01) while the second (10) reported an average change in the
score of 1.1 in 19 patients (p< 0.05) . From these data we have been able to construct estimates of the standard
deviation within subjects. These estimates range between 2.25 and 2.75. It should be noted that the two
referenced articles both studied younger women (Average age 39 +/- 9 in (8), age range of 28 - 68 in (10)). We
expect the older women to have somewhat more variability than the women reported in the literature. We have
therefore extended the table to include values for sigma from 2.25 to 3.0.
Assuming a significance level of 0.05 we have constructed a table indicating sample size when statistical
power is set at 80% for several values of the within subject standard deviation and several treatment differences.
Difference in logical
memory score ( approximate
% change )
1.1
1.5
1.9
( 25% )
( 35% )
( 50% )
2.25
Sigma
2.50
2.75
3.0
N = 35
N = 15
N = 14
N = 43
N = 24
N = 16
N = 52
N = 29
N = 19
N = 61
N = 34
N = 22
From this table we can see that the crossover will have 80% power to detect treatment differences of
approximately 35% using group sizes of 15 to 29 people when σ is within the range found in the literature.
When considering older subjects, σ is expected to be one of the larger values, so we will need 29 to 34 older
subjects to permit an analysis of age effects. Accordingly we are proposing to study 60 hypothyroid subjects
total. We also propose to study 30 healthy euthyroid subjects, for a total proposed number of 90 subjects
completing the study. We anticipate that some subjects will screen out, while approximately 10% will drop out
during the study, so we anticipate enrolling approximately 120 subjects. Further sample size refinements will be
based on data accumulated in the first phases of this study, including data from the healthy control group.
We have no preliminary data regarding hypothesis #2 nor is there any in the literature, to our knowledge,
upon which to base reasonable estimates of statistical power. However, since this protocol represents a pilot for
a K-24 application to the NIH, 60 hypothyroid subjects will also allow us to further refine hypothesis 2 so that
we can construct estimates accurately for the K-24 application. All power calculations were made using nQuery
Advisor Release 3.0 Study Planning Software, Statistical Solutions Ltd. Boston, 1999.
e. Human Subjects:
Subject Characteristics (including explicit list of inclusion and exclusion criteria):
Inclusion:
ages 20-80 years
Primary hypothyroidism on stable dose of L-T4 for > 3 months
Hypothyroidism due to autoimmune disease, idiopathic, or s/p treatment of hyperthyroidism
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
12
Exclusion:
Control group:
No medication use that affects thyroid function, mood or cognition (oral contraceptives or
estrogen therapy allowed)
Normal score on screening SCL-90-R (to test for underlying mood disorders)
Normal score on screening MMSE (older subjects only) (to test for dementia)
Normal score on GDS (Geriatric Depression test) (older subjects only)
Normal vision by screening examination
Normal hearing by screening examination
Failure to meet any of the above inclusion criteria
Inability to speak and comprehend English
A history of coronary artery disease
Screening hct < 32%
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 known to affect thyroid hormone levels or to interfere with
thyroid hormone effects, including beta-blockers, lithium, glucocorticoids, or iodine containing
agents
WAIS-R score < 8
GDS score < 10
MMSE score < 26
Psychiatric disorder diagnosed on SCL-90-R
Inclusion and exclusion criteria as above, except for the following:
Age range 20-45
No history of thyroid disease, taking no thyroid medication
Normal TSH level
No LDL, TG, ECG criteria
Source of Research Material:
Research material will consist of clinical measurements, blood samples, and neurocognitive tests
obtained for research purposes only.
Subject Recruitment and Consent:
Potential subjects will be identified by MHS and KEG through the general endocrinology clinic at
OHSU, which is a referral center for thyroid disease. A large number of subjects who would be eligible for this
study are currently under the care of the two physician investigators, and no problems are seen with recruitment.
The study will be explained to interested subjects by MHS, and the consent form will be reviewed prior to
enrollment. Additional subjects may be recruited via review of OHSU medical records. In this case, the OHSU
medical records of patients who have received outpatient treatment with radioactive iodine in the past five years
will be reviewed by MHS for inclusion and exclusion criteria. This is because almost all patients treated with
radioactive iodine develop primary hypothyroidism. If a subject appears to qualify for the study by review of
the medical records, MHS will notify the potential subject with a letter. She will invite the subject to call her
office if s/he is interested in learning more about the study.
Risks:
Potential risks of inducing subclinical hypothyroidism in healthy subjects are minor and reversible.
13
They include changes in mood or cognition, which is the aim of the current proposal. In published studies, such
changes have been mild to moderate in severity. Subjects will be carefully screened for underlying psychiatric
or cognitive disorders, and will be followed with clinical examinations every 6 weeks to minimize the chances
that any subject will develop a clinically significant problem with affect or cognition. Subjects will be free to
discontinue the study at any time if they desire, with no effect on their usual care; if this occurs, the subject will
immediately be given his/her usual dose of L-T4 and will be followed to ensure that symptoms abate. Other
reported effects of subclinical hypothyroidism include increased lipid levels and minor decrements in cardiac
function; subjects will be carefully screened for these conditions prior to and during the study. It is not expected
that such effects would cause any clinical problems during the 12 weeks of the study.
Potential risks of blood drawing include pain, bruising, and infection at the site of blood drawing.
Anemia is not expected to be a problem, since subjects will be screened for anemia, and since the amount of
blood drawn over the 12 week study is only 60 cc.
Potential risks of the neurocognitive and mood tests include fatigue and discomfort or frustration. The
tests will be stopped any time a subject does not wish to continue.
Protection From Risks:
Subjects will be carefully screened to exclude underlying disorders that would make the induction of
subclinical hypothyroidism inadvisable (cardiac disease, psychiatric disease, hyperlipidemia). They will be
screened for anemia. LDL cholesterol and triglyceride levels will be rechecked after 6 weeks, and subjects will
discontinue the study if the LDL has risen to 160 mg/dL or higher, or if the TG has risen to 300 mg/dL or
higher. They will be advised that they may discontinue the study at any time without changing their usual
treatment.
Risk in Relation to Benefits:
The minor risks of this study are far outweighed by the knowledge to be gained. If neurocognitive
changes are seen during subclinical hypothyroidism, this would be an important treatment indication. Since
many subjects with SCH are not currently treated, this would represent a important change in clinical practice.
This is especially important for the large number of older women who have SCH, and who may also have other
mild cognitive disturbances that could add to SCH in leading to functional impairment.
Gender/Minority/Pediatric Inclusion for Research:
What disease/population is being studied?
Subclinical hypothyroidism
Table 1. National Disease Prevalence Demographics
American
Indian or
Alaskan Native
Asian or
Pacific
Islander
Black, NOT of
Hispanic Origin
Hispanic
White, NOT of
Hispanic Origin
Other
Total
Female
0.6
2.2
9.4
7.0
60.6
0
79.8
Male
0.2
0.6
2.4
1.8
15.2
0
20.2
Total
0.8
2.8
11.8
8.8
75.8
0
100
Source:
Approximately 80% of subjects with subclinical hypothyroidism are women. There is no known ethnic
14
predilection, so the ethnic composition of the normal population is used.
Table 2. Local Disease Prevalence Demographics
American
Indian or
Alaskan Native
Asian or
Pacific
Islander
Black, NOT of
Hispanic
Origin
Hispanic
White, NOT of
Hispanic Origin
Other
Total
Female
1.6
1.6
1.6
3.2
71.2
1.6
80.8
Male
0.4
0.4
0.4
0.8
26.8
0.4
19.2
Total
2.0
2.0
2.0
4.0
89.0
2.0
100
Source:
Approximately 80% of subjects with subclinical hypothyroidism are women. There is no known ethnic
predilection, so the ethnic composition of the normal population is used.
Recruitment Strategies and Outreach Activities to Meet National Demographics
The two physician investigators (MHS, KGS) see large numbers of thyroid patients in the OHSU general
endocrinology clinic. We serve as a consultant and referral site for primary care clinics in underserved areas,
including the Multnomah County clinic and the Salud clinic. We will notify the primary care physicians at
these clinics as to the nature of the study, and encourage them to have interested subjects contact us.
Table 3. Expected Enrollment Demographics for this Protocol
American
Indian or
Alaskan Native
Asian or
Pacific
Islander
Black, NOT of
Hispanic Origin
Hispanic
White, NOT of
Hispanic
Origin
Other
Total
Female
2
4
4
6
59
75
Male
0
2
2
2
9
15
Total
2
6
6
8
68
90
Source:
Local demographics and outreach activities. Note that these numbers include the 60 subjects with
hypothyroidism , as well as the 30 control subjects who will be recruited to perform the neurocognitive tests
only.
Exclusion of Children and Justification
Subclinical hypothyroidism could affect children, but its incidence and effects are not known. However, it is
not ethical to decrease the dose of thyroid hormone in a child, given the well-known cognitive effects of
hypothyroidism on the developing brain. In addition, dose titration for L-T4 is quite different in children, and
15
it would be very difficult to precisely titrate the dose to achieve the target TSH levels. Therefore, there would
be a higher risk of inducing overt hypothyroidism in children. Finally, the effects of overt hypothyroidism
have already been extensively studied in children.
f. Protocol Category:
Category A
x
Category B
Category D
Category A and D
g. CTRC Utilization and Requested Resources:
Duration of Project:
2 years
Anticipated study completion date:
7/2002
Total number of subjects to be enrolled for entire project:
Total number of subjects to be screened for entire project:
90
100
Nursing Services:
1. Inpatient services: [ ] Yes [x ] No
2. Outpatient services: [ x] Yes [ ] No
Number of outpatients per year
Number of outpatient visits per patient
Total number of
outpatient visits per year
30 hypothyroid subjects
15 healthy subjects
7 for hypothyroid subjects
4 for healthy subjects
210
60
total = 270
3. Inpatient and/or Outpatient Care Summary:
Please provide precise nursing instructions for protocol accomplishment
a. Special nursing instructions
See below
16
b. If experimental drugs are used, give specific instructions
NA
c. If isotopes are used, give specific instructions
NA
d. Daily schedule - Specify the precise goals of each day with detailed nursing instructions. Be precise as to
fluid administration and blood and urine collection sequences, etc.
1. Pre-screening Synthroid adjustment. Draw serum TSH level (send to clinical lab).
2. Screening visit. Obtain height and weight. Draw blood samples for screening labs. Obtain urine for
screening pregnancy test, if applicable.
3. First study visit. Obtain height and weight. Draw blood samples for thyroid hormone levels and storage
of serum and plasma. Obtain second-void urine sample and store in core lab.
4. Second study visit. Obtain height and weight. Draw blood samples for thyroid hormone levels and
lipids, and for storage of serum and plasma.
5. Third study visit. Obtain height and weight. Draw blood samples for thyroid hormone levels and
storage of serum and plasma. Obtain second-void urine sample and store in core lab.
6. Fourth study visit. Obtain height and weight. Draw blood samples for thyroid hormone levels and
lipids, and for storage of serum and plasma.
7. Fifth study visit. Obtain height and weight. Draw blood samples for thyroid hormone levels and for
storage of serum and plasma. Obtain second-void urine sample and store in core lab.
8. Sixth study visit. Obtain height and weight. Draw blood samples for storage.
9. Gel capsule substudy. Draw serum TSH level.
Ancillary Expense Table:
Ancillary
Unit Cost
# / Pt.
# Pts.
Total Cost
screening CBC
$7.72
1
70
$540
screening comprehensive metabolic set
$7.81
1
70
$547
screening LDL cholesterol
$10.93
1
70
$765
screening triglyceride
$4.46
1
70
$312
follow-up LDL cholesterol
$10.93
2
60
$1311
follow-up triglyceride
$4.46
2
60
$535
screening TSH
(1 per patient for 70 patients, plus 1 extra per patient
for up to 20 patients who need to switch to Synthroid
prior to the study)
$21.40
1
90
$1926
screening ECG
no charge
1
70
$0
17
screening urine bhCG
TOTAL COST FOR ANCILLARIES
$7.89
2 (one before each
arm of the study)
56
$884
$6820
The CTRC is asked to provide the funds for the screening tests needed to enroll the hypothyroids subjects, and
for the safety monitoring (lipid levels). It is anticipated that 70 hypothyroids subjects will have to be screened in
order to enroll the estimated sample size of 60 subjects. The other costs of the study (drug randomization and
dispensation, thyroid hormone levels, neurocognitive tests) will be paid for by the investigator (MHS). The
laboratory tests for the 30 healthy subjects will be paid for by MHS.
Alias
Org
Fund
Industrial Acct #
Bionutrition Services: [x ] Yes [ ] No
Information about the extensive CTRC bionutrition services is available upon request.
Contact Martha McMurry, [email protected], 494-6232.
1. Will your study subjects need to have meals or snacks during their stay? [ x ]Yes [ ] No
If yes, please estimate usual schedule of meals for typical CRC admissions:
[ ]
Inpatients: describe usual time of day to help us order meals/snacks, if predictable:
Admit at about ___:00 (check one:) am___ or pm___ on day 1
Discharge at about ___:00 (check one) am___ or pm___ (list day:) on day ____
[x ]
Outpatients: The meals required for the study are:
[x ] Complimentary CRC Breakfast at about 10-11 am
[ ] Hospital Lunch Tray or [ ]Hospital Box Lunch at about ______pm
[ ] Hospital dinner tray and/or breakfast trays B these are usually served at 2SE (inpatient unit) unless special
arrangements can be made, list times needed:_______
[ ] Specific snack of _______________ at (give time) _______ am or pm
[ ] Research meal or meals, specified below
2. Will your subjects have diet orders other than Ageneral select diet@? [ ] Yes [ x ] No
Does your study have any special nutritional considerations regarding the composition of the meals, the timing of
food served, or types of foods to include? If so, please describe in detail:
None
4. Do you require consultation with a CRC bionutritionist (the research dietitians)?
[ ]Yes [ x ] No
18
4. Body Energy and Composition Measurements:
[ ] Yes
If yes, please indicate the measurements needed:
[ ] Whole body composition by DEXA
[ ] Site-specific bone density by DEXA
[ ] Indirect calorimetry
[ ] Skin-fold thicknesses
[ ] Percent body fat by Bioimpedence analysis (BIA)
[ ] Abdominal fat by CT or MRI
[ ] Body circumferences (waist, hip)
[ ] Other:
[ x ] No
Core Laboratory Services: [x ] Yes [ ] No
Please list the assays to be run in the CTRC Core Laboratory.
Assay
# Samples / Year
Sample Type
(Blood, Urine, Other)
none
List only other requests (e.g. sample processing, shipping, etc). State how the above listed assays will be
funded (i.e. investigator will purchase kits, provide technician support, etc.)
Sample processing and shipping to OHSU/Kaiser lab. We also request that a duplicate serum and a
plasma specimen be processed at each blood draw and stored in the core lab, in case of OHSU/Kaiser
lab accident or future thyroid hormone measurement needs. In order to optimize possible future assays,
we request that the samples be placed on ice immediately by nursing staff after drawing, and transported
to the Core Lab on ice.
Biostatistical Services: [x ] Yes [ ] No
19
We have already met with Dr. Sexton regarding experimental design and sample size issues. We will
again require his assistance in data analysis as described in the data analysis section.
Computing Services: [x ] Yes [ ] No
Please provide an explanation of the CTRC services requested (e.g. database design, custom software design,
electronic document processing, special software or hardware, etc):
Creation of a database for subject demographics, hormone levels, and cognitive test results. Possible
use of Teleform for forms processing.
Justification for Requested CTRC Resources:
Please mark all that apply:
[]
[x ]
[]
No funding provided in our grant
Resources not available elsewhere
Other (describe below)
h. Literature Cited:
1. Dugbartey AT. Neurocognitive aspects of hypothyroidism. Arch Intern Med 158:1413-8, 1998
2. Whybrow PC, Prange AJ, Treadway CR. Mental changes accompanying thyroid gland dysfunction. A
20
reappraisal using objective psychological measurement. Arch Gen Psychiat 20:48-63, 1969
3. Denicoff KD, Joffe RT, Lakshmanan MC, Robbins J, Rubinow DR. Neuropsychiatric manifestations of
altered thyroid state. Am J Psychiatry 147:94-9, 1990
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i. IRB Approval:
[ x] Yes
[ ] Pending
If Yes, submit the IRB approval letter, IRB Memo of Committee Review, and IRB-dated consent form(s).
j. Category D Protocol:
[ ] Yes
[x ] No
If Yes, submit 1 copy of industry-prepared protocol and budget.
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