Thyroid Hormone Replacement for Subclinical Hypothyroidism

Study Overview
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Brief Summary
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Subclinical hypothyroidism (SCH) is a common condition among older men and women. Although by definition SCH comprises biochemically mild thyroid hormone deficiency without overt symptoms, 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 SCH. 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. The investigators propose a multicentre randomised placebo controlled trial to assess the impact of thyroxine replacement in a minimum of 540 older adults (maximum 750) with persisting SCH (excluding those in whom it is a temporary phenomenon who are unlikely to benefit). The investigators will include older men and women with a wide age range and of varying health status. Outcomes include health related quality of life, muscle strength, executive cognitive function and cardiovascular events, with a minimum of 1 year of follow up. Blood and urine samples will be stored in a biobank, to allow future research on causes of ill health in older people with SCH. The investigators have the support of patient advocacy groups and a consortium with the wide range of expertise and experience required to conduct large scale multicentre clinical trials. The proposal explores the multisystem and quality of life benefits to older people of a tailored approach to management of SCH. This clinical trial should definitively clarify whether thyroxine treatment for SCH provides benefits that are relevant for patients. This trial will provide strong evidence with the potential to improve clinical practice, reduce health care costs and promote healthy ageing of older adults.

Official Title
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Multi-modal Effects of Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism; a Randomised Placebo-controlled Trial

Conditions
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Subclinical Hypothyroidism

Intervention / Treatment
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* Drug: Levothyroxine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Community-dwelling patients aged >=65 years with Subclinical Hypothyroidism (SCH). SCH is defined as elevated TSH levels (>=4.6, <=19.9 mU/L) and free thyroxine (fT4) in reference range measured on a minimum of two occasions at least 3 months apart. Exclusion Criteria: Subjects currently on Levothyroxine or antithyroid drugs, amiodarone or lithium. Recent thyroid surgery or radio-iodine (within 12 months). Grade IV NYHA heart failure. Prior clinical diagnosis of dementia. Recent hospitalisation for major illness or elective surgery (within 4 weeks). Recent acute coronary syndrome, including myocardial infarction or unstable angina (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
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Levothyroxine<br>Oral Levothyroxine, starting dose 25 or 50 micrograms increased to a maximum of 150 micrograms once daily. | Drug: Levothyroxine<br>* The intervention will start with Levothyroxine 50 µg daily (reduced to 25 µg in subjects <50Kg body weight or if known coronary heart disease - previous myocardial infarction or symptoms of angina pectoris) versus matching placebo; at 3 months if the serum TSH level is <0.4 mU/L dose will be reduced by 25 µg; TSH >=0.4 and <4.6 mU/L, no change to dose; TSH >=4.6mUL, additional 25 µg. 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 that will be prescribed is 150μg.<br>* Other names: Thyroxine;|
| Placebo Comparator: Placebo<br>Matched placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thyroid-specific quality of life - Hypothyroid symptoms and Fatigue symptoms (co-primary outcomes) | Change in Hypothyroid Symptoms and Fatigue scores (measured using the Thyroid-specific quality of life Patient Reported Outcome questionnaire - ThyPRO; Hypothyroid symptoms and Fatigue domains). | Measured at baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health-related quality of life | The EuroQol5D | measured at baseline; 3 month; 12 month and final follow up (expected mean follow-up of 18 months). | 
| Handgrip strength | Handgrip strength measured using the Jadaar hand dynamometer. | Measured at baseline; 12 months and final follow up (expected mean follow-up of 18 months). | 
| Executive cognitive function | Letter Digit Coding Test [LDCT). | Measured at baseline and final follow-up (expected mean follow-up of 18 months). | 
| Total mortality | Total mortality | Up to final follow up (expected mean follow-up of 18 months). | 
| Basic Activities of Daily Living | Basic Activities of Daily Living (ADL) measured using the 20-point Barthel Index [BI]. | Measured at baseline and final follow-up (expected mean follow-up of 18 months). | 
| Extended activities of daily living | Extended activities of daily living measured using the older American resources and services [OARS]) questionnaire | Measured at baseline and final follow-up (expected mean follow-up of 18 months). | 
| Haemoglobin | Change in haemoglobin, measured on a full blood count | Measured at baseline and 1 year | 
| Fatal and non-fatal cardiovascular events | This will include fatal and non fatal acute myocardial infarction and stroke; amputations for peripheral vascular disease; revascularisations for atherosclerotic vascular disease, including for acute coronary syndrome; heart failure hospitalisations. | Expected mean follow-up of 18 months. | 
| Generic thyroid specific quality of life | Thyroid-related quality of life Patient-Reported Outcome measure (ThyPRO) 39 | Final follow-up | 
| Thyroid-specific quality of life - Hypothyroid symptoms | Change in hypothyroid symptom burden (measured using the Thyroid-specific quality of life Patient Reported Outcome questionnaire - ThyPRO; Hypothyroid symptoms domain). | Measured at 6-8 weeks and at final review | 
| Thyroid specific quality of life - Fatigue symptoms | Change in fatigue (measured using the Thyroid-specific quality of life Patient Reported Outcome questionnaire - ThyPRO; Fatigue and vitality domain). | Measured at 6-8 weeks and at final review | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aged, Cardiovascular disease, Levothyroxine, Randomised controlled trial, Quality of life, Subclinical hypothyroidism