TRUST: Thyroid Hormone Replacement for Subclinical Hypothyroidism

Sponsor

NHS Greater Glasgow and Clyde (Other)

Overall Status

Completed

CT.gov ID

NCT01660126

Collaborator

University of Glasgow (Other), University College Cork (Other), University of Bern (Other), Leiden University Medical Center (Other)

737

Enrollment

Location

Arms

30.6

Duration (Months)

24.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Subclinical Hypothyroidism	Drug: Levothyroxine Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

737 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2014

Actual Primary Completion Date :

Nov 18, 2016

Actual Study Completion Date :

Nov 18, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Levothyroxine Oral Levothyroxine, starting dose 25 or 50 micrograms increased to a maximum of 150 micrograms once daily.	Drug: Levothyroxine 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. Other Names: Thyroxine
Placebo Comparator: Placebo Matched placebo	Drug: Placebo

Arm

Intervention/Treatment

Active Comparator: Levothyroxine

Oral Levothyroxine, starting dose 25 or 50 micrograms increased to a maximum of 150 micrograms once daily.

Drug: Levothyroxine

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.

Other Names:

Thyroxine

Placebo Comparator: Placebo

Matched placebo

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Thyroid-specific quality of life - Hypothyroid symptoms and Fatigue symptoms (co-primary outcomes) [Measured at baseline and 12 months]
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).

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde	Glasgow		United Kingdom	G31 2ER

Sponsors and Collaborators

NHS Greater Glasgow and Clyde
University of Glasgow
University College Cork
University of Bern
Leiden University Medical Center

Investigators

Principal Investigator: David J Stott, MBChB MD, University of Glasgow
Principal Investigator: Jacobijn Gussekloo, MD, Leiden University Medical Center
Principal Investigator: Nicolas Rodondi, MD, University of Bern
Principal Investigator: Patricia Kearney, MD, University College Cork
Principal Investigator: Rudi JG Westendorp, MD, University of Copenhagen