The TRUST Study - CardioVascular Imaging IMT

Study Overview
=================
Brief Summary
-----------------
Coronary heart disease (CHD) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes. The goals of this proposal are to address the impact of thyroid replacement on subclinical atherosclerosis. The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline. The main outcome will be CV imaging modalities measured by carotid ultrasound at the close-out visit. Assessment of the impact of thyroid replacement on subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo.

Detailed Description
-----------------
Background: Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Subclinical hypothyroidism (SHypo), defined as elevated serum TSH levels with normal thyroxine values, is common in older adults (5-10%). Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes (largest trial to date: 45 participants). Imaging endpoints are especially well-suited for early trials with investigational therapies for HF treatment and prevention, as well as validated and strong surrogate markers of clinical outcomes. Specific Aims: The goals of this proposal are to address the impact of thyroid replacement on subclinical atherosclerosis. Methods: The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline (4 death and 17 withdrawal). The main outcome will be CV imaging modalities measured by carotid ultrasound at the close-out visit. Ultrasound of carotid intima media thickness (CIMT) will be used to assess subclinical atherosclerosis and plaque burden. All images will be centralized at the core lab for a blinded and standardized interpretation. Expected value of the proposed project: Controversies persist regarding the indications for screening and treatment of SHypo due to the lack of an appropriately powered RCT addressing the impact of thyroid replacement on CV outcomes. Assessment of the impact of thyroid replacement on subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo. The strengths of this study include the combination of: 1) High feasibility of the project in collaboration with the largest RCT on SHypo making it possible to investigate the mechanisms of associations with CV disease; 2) Innovative project with combined CV imaging to assess subclinical atherosclerosis with thyroid replacement therapy vs. placebo; 3) Excellent power given the large sample size and participants' older age. The sample size for this proposal will be 5-fold higher than previous small trials of thyroid replacement on CV outcomes and is comparable to statin trials showing a positive impact on CIMT. The collaboration of CV imaging modalities expertise with the ongoing largest trial on SHypo, is a unique opportunity to address the clinical and scientific issue of the impact of SHypo on the CV system.

Official Title
-----------------
Impact of Thyroid Hormone Replacement on Progression of Atherosclerosis : a Randomized Placebo-Controlled Trial in Older Adults With Subclinical Hypothyroidism.

Conditions
-----------------
Thyroid Dysfunction, Atherosclerosis, Heart Failure

Intervention / Treatment
-----------------
* Drug: Levothyroxine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Community-dwelling patients aged >= 65 years with subclinical hypothyroidism Written informed consent Exclusion Criteria: Subjects currently under levothyroxine or antithyroid drugs (amiodarone, lithium) Recent thyroid surgery or radio-iodine (within 12 months) Grade IV NYHA heart failure Prior clinical diagnosis of dementia Recent hospitalization for major illness or elective surgery (within 4 weeks) Terminal illness Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Subjects who are participating in ongoing RCTs of therapeutic interventions (including CTIMPs) Plan to move out of the region in which the trial is being conducted within the next 2 years (proposed minimum follow-up period)

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>The intervention will start with Levothyroxine 50 mcg daily (reduced to 25 mcg in subjects <50 kg of body weight or if known coronary heart disease - previous myocardial infarction or symptoms of angina pectoris) vs. matching placebo; at 3 months, if the serum TSH level is <0.4 mU/L, dose will be reduced by 25 mcg; TSH >=0.4 and <4.6 mU/L, no change to dose; TSH >=4.6 mU/L, additional 25 mcg. The process will be repeated at 12 months, then annually; mock titration will be performed in the placebo group. The maximum possible dose of Levothyroxine which will be prescribed is 150 mcg (after 4 increments of 25 mcg at 3 months, 1, 2, 3 years; from the starting dose of 50 mcg). | Drug: Levothyroxine<br>* The intervention will start with Levothyroxine 50 mcg daily (reduced to 25 mcg in subjects <50 kg of body weight or if known coronary heart disease - previous myocardial infarction or symptoms of angina pectoris) vs. matching placebo; at 3 months, if the serum TSH level is <0.4 mU/L, dose will be reduced by 25 mcg; TSH >=0.4 and <4.6 mU/L, no change to dose; TSH >=4.6 mU/L, additional 25 mcg. The process will be repeated at 12 months, then annually; mock titration will be performed in the placebo group. The maximum possible dose of Levothyroxine which will be prescribed is 150 mcg (after 4 increments of 25 mcg at 3 months, 1, 2, 3 years; from the starting dose of 50 mcg).<br>|
| Placebo Comparator: 2<br>Control patients will obtain a placebo pill of the same characteristics as the intervention drug, and mock titration will be carried out identically to the intervention drug. Pharmaceutical composition of placebo (100 mg): Lactose monohydrate 66 mg, Maize starch 25 mg, Gelatin 5 mg, Croscarmellose sodium 3.5 mg, Magnesium stearate (vegetable source) 0.5 mg. | Drug: Placebo<br>* Control patients will obtain a placebo pill of the same characteristics as the intervention drug, and mock titration will be carried out identically to the intervention drug. Pharmaceutical composition of placebo (100 mg): Lactose monohydrate 66 mg, Maize starch 25 mg, Gelatin 5 mg, Croscarmellose sodium 3.5 mg, Magnesium stearate (vegetable source) 0.5 mg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carotid Intima Media Thickness as measured by carotid ultrasound |  | one year follow up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thyroid Dysfunction, Atherosclerosis, Heart Failure, Cardiovascular Imaging, Randomized Controlled Trial