IEMO 80-plus thyroid trial.

Background of the study:

Subclinical hypothyroidism is a common condition (8-18%)
among older men and women. Although by definition
subclinical hypothyroidism comprises biochemically mild
thyroid hormone deficiency, it is a possible contributor to
multiple problems in older age. Thyroid hormone has effects

on numerous physiological systems, including the vascular
tree, heart, skeletal muscle and brain. Therefore, thyroxine
substitution to overcome thyroid hormone deficiency has the
potential to give multisystem benefits to older people with
subclinical hypothyroidism. Small studies have reported
reduced atherosclerosis and improved heart function with
thyroxine replacement, but no large clinical trials have been
performed. Therefore the available evidence is limited,
leading to major variations in guidelines and clinical practice,
with uncertainty regarding the indications for screening and
treatment. This is especially the case for the oldest old,
because observational studies are conflicting and very few
oldest old are included in clinical trials, although they have
the highest prevalence of subclinical hypothyroidism and its
potentially related symptoms and diseases.

 

Objective of the study:

1. Does Levothyroxine treatment for subclinical
hypothyroidism give multi-modal benefits for the oldest old
people with subclinical hypothyroidism?


2. Are benefits seen across a wide range of outcomes,
including prevention of cardiovascular disease, and
improving health- related quality of life, muscle function and
cognition?


3. Are benefits seen in specific subgroups of oldest old
people with SCH, including women, and those with mild
degrees of subclinical hypothyroidism (TSH 4.6-10 mU/L)?


4. Are any benefits offset by adverse effects, such as atrial
fibrillation or heart failure? 

5. To store study blood samples in a repository of blood
samples from which potential biomarkers and/or genes may
be identified that better predict those older people with SCH
who are at risk of dying or developing ill-health, including
cardiovascular and cerebrovascular disease.



Study design:

Randomised double-blind placebo-controlled parallel group
trial. The IEMO 80-plus thyroid trial was set up as a an
independent randomised double-blind placebo-controlled
parallel group trial of levothyroxine for oldest old persons
with subclinical hypothyroidism. From the outset the study
was designed jointly and in parallel with the TRUST trial and
both trials share a near identical design and infrastructure
including study protocols, standard operating procedures,
independent data monitoring and endpoint committees,
databases, statisticians and study nurses.



Study population:

145 community-dwelling patients aged >80 years with
subclinical hypothyroidism, diagnosed on the basis of
persistently elevated TSH levels, measured on a minimum of
two occasions at least 3 months apart, over 2 years. 



Intervention:

Oral Levothyroxine 50 μg daily (reduced to 25 mcg daily in
subjects < 50 kg body weight or if known coronary heart
disease) versus matching placebo. 



Primary study parameters/outcome of the study:

The main study endpoint is change in thyroid-specific quality
of life and symptom burden assessed using the hypothyroid
symptoms scale score and tiredness symptoms scale score
on the thyroid-specific quality of life (ThyPRO) questionnaire
at baseline, six to eight weeks and 12 months after
recruitment and at the close-out visit are included.



Secundary study parameters/outcome of the study:

1. General quality of life
;

2. Handgrip strength
;

3. Cognitive function, particularly executive function;

4. Total mortality and cardiovascular mortality;

5. Functional ability (basic Activities of Daily Living (ADL);

extended activities of daily living);

6. Gait speed;

7. Haemoglobin;

8. Depressive symptoms ;

9. Fatal and non-fatal cardiovascular events (this will include
acute myocardial infarction; stroke; amputations for
peripheral vascular disease; revascularisations for
atherosclerotic vascular disease, including for acute coronary
syndrome and heart failure hospitalisations). 



Nature and extent of the burden and risks associated with
participation, benefit and group relatedness:

Adverse events (atrial fibrillation, heart failure and fractures
in particular) are likely to occur only in the context of over
replacement of Levothyroxine. Our dose titration scheme and
study processes of careful monitoring of thyroid function
tests are designed to ensure we avoid prolonged periods of
thyroid hormone excess.
For the group allocated to placebo,
there is risk of developing overt clinical hypothyroidism;
however, our study processes of careful monitoring of
thyroid function tests are designed to avoid this scenario.



Statistical analysis:

The participants of the present project will be included in a
pre-planned combined analysis with the international TRUST
consortium, of which the LUMC is the Dutch member
(protocol number P12.203), who includes a total number of
738 participants over the age of 65 years. The present
project adds 145 80-plus year old participants to perform an
adequately powered sub-group analysis in the over eighties
age group. The main analysis will be the association between
thyroid specific quality of life and treatment in the combined
study population of IEMO and the 80-plus participants of
TRUST. Treatment effects will be assessed using analysis of
covariance (ANCOVA) adjusting for gender and baseline
levels of the same variable. To assess for associations with
cardiovascular events, time to first event Cox regression
analysis are used stratified by gender in models containing
the randomised treatment allocation as a covariate
(intention-to- treat). Tests of treatment effect will be based
on the Wald test and corresponding point estimates and 95%
confidence intervals for the hazard ratio for treatment will be
calculated. The assumption of proportionality of hazards will
be tested. Additional end points relevant to older people will
be assessed for the present study alone and in combination
with the 80-plus participants in TRUST.

1. Does Levothyroxine treatment for subclinical hypothyroidism give multi-modal benefits for the oldest old people with subclinical hypothyroidism?

2. Are benefits seen across a wide range of outcomes, including prevention of cardiovascular disease, and improving health-related quality of life, muscle function and cognition?

3. Are benefits seen in specific subgroups of oldest old people with subclinical hypothyroidism, including women, and those with mild degrees of subclinical hypothyroidism (TSH 4.6-10 mU/L)?

4. Are any benefits offset by adverse effects, such as atrial fibrillation or heart failure?

5. To store study blood samples in a repository of blood
samples from which potential biomarkers and/or genes may
be identified that better predict those older people with SCH
who are at risk of dying or developing ill-health, including
cardiovascular and cerebrovascular disease.

The primary outcome will be assessed at baseline, six to eight weeks and 12 months after recruitment and eventually at 24 and 36 months.

Oral Levothyroxine 50 µg daily (reduced to 25 mcg daily in subjects < 50 kg body weight or if known coronary heart disease) versus matching placebo. The intervention will have a maximum of 3 years.