Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST)

March 9, 2017 updated by: Professor David J Stott, NHS Greater Glasgow and Clyde

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

737

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Glasgow, United Kingdom, G31 2ER
        • Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years and older (Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Matched placebo
Drug: Placebo
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Thyroid-specific quality of life - Hypothyroid symptoms and Fatigue symptoms (co-primary outcomes)
Time Frame: 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).
Measured at baseline and 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Health-related quality of life
Time Frame: measured at baseline; 3 month; 12 month and final follow up (expected mean follow-up of 18 months).
The EuroQol5D
measured at baseline; 3 month; 12 month and final follow up (expected mean follow-up of 18 months).
Handgrip strength
Time Frame: Measured at baseline; 12 months and final follow up (expected mean follow-up of 18 months).
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
Time Frame: Measured at baseline and final follow-up (expected mean follow-up of 18 months).
Letter Digit Coding Test [LDCT).
Measured at baseline and final follow-up (expected mean follow-up of 18 months).
Total mortality
Time Frame: Up to final follow up (expected mean follow-up of 18 months).
Total mortality
Up to final follow up (expected mean follow-up of 18 months).
Basic Activities of Daily Living
Time Frame: 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].
Measured at baseline and final follow-up (expected mean follow-up of 18 months).
Extended activities of daily living
Time Frame: 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
Measured at baseline and final follow-up (expected mean follow-up of 18 months).
Haemoglobin
Time Frame: Measured at baseline and 1 year
Change in haemoglobin, measured on a full blood count
Measured at baseline and 1 year
Fatal and non-fatal cardiovascular events
Time Frame: 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.
Expected mean follow-up of 18 months.
Generic thyroid specific quality of life
Time Frame: Final follow-up
Thyroid-related quality of life Patient-Reported Outcome measure (ThyPRO) 39
Final follow-up
Thyroid-specific quality of life - Hypothyroid symptoms
Time Frame: 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).
Measured at 6-8 weeks and at final review
Thyroid specific quality of life - Fatigue symptoms
Time Frame: 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).
Measured at 6-8 weeks and at final review

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NHS Greater Glasgow and Clyde

Collaborators

University of Bern
Leiden University Medical Center
University College Cork
University of Glasgow

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2014

Primary Completion (Actual)

November 18, 2016

Study Completion (Actual)

November 18, 2016

Study Registration Dates

First Submitted

August 6, 2012

First Submitted That Met QC Criteria

August 7, 2012

First Posted (Estimate)

August 8, 2012

Study Record Updates

Last Update Posted (Actual)

March 13, 2017

Last Update Submitted That Met QC Criteria

March 9, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GN11GE272
  • 2011-004554-26 (EudraCT Number: EudraCT)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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