Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST)

David J Stott; Jacobijn Gussekloo; Patricia M Kearney; Nicolas Rodondi; Rudi G J Westendorp; Simon Mooijaart; Sharon Kean; Terence J Quinn; Naveed Sattar; Kirsty Hendry; Robert Du Puy; Wendy P J Den Elzen; Rosalinde K E Poortvliet; Jan W A Smit; J Wouter Jukema; Olaf M Dekkers; Manuel Blum; Tinh-Hai Collet; Vera McCarthy; Caroline Hurley; Stephen Byrne; John Browne; Torquil Watt; Douglas Bauer; Ian Ford

doi:10.1186/s12902-017-0156-8

Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST)

BMC Endocr Disord. 2017 Feb 3;17(1):6. doi: 10.1186/s12902-017-0156-8.

Authors

David J Stott^{1

2}, Jacobijn Gussekloo³, Patricia M Kearney⁴, Nicolas Rodondi^{5

6}, Rudi G J Westendorp^{7

8}, Simon Mooijaart⁹, Sharon Kean¹⁰, Terence J Quinn¹¹, Naveed Sattar¹², Kirsty Hendry¹¹, Robert Du Puy³, Wendy P J Den Elzen¹³, Rosalinde K E Poortvliet³, Jan W A Smit¹⁴, J Wouter Jukema¹⁵, Olaf M Dekkers⁹, Manuel Blum¹⁶, Tinh-Hai Collet¹⁷, Vera McCarthy¹⁸, Caroline Hurley¹⁹, Stephen Byrne²⁰, John Browne⁴, Torquil Watt²¹, Douglas Bauer²², Ian Ford¹⁰

Affiliations

¹ Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. David.J.Stott@glasgow.ac.uk.
² Glasgow Royal Infirmary, Room 2.42, 2nd Floor New Lister Building, G31 2ER, Glasgow, UK. David.J.Stott@glasgow.ac.uk.
³ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.
⁴ Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
⁵ Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
⁶ Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
⁷ Leyden Academy on Vitality and Ageing, Leiden, Netherlands.
⁸ Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
¹⁰ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
¹¹ Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹² Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹³ Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴ Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁵ Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
¹⁶ Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁷ Service of Endocrinology Diabetes and Metabolism, University Hospital of Laussanne, Lausanne, Switzerland.
¹⁸ School of Nursing and Midwifery, University College Cork, Cork, Ireland.
¹⁹ Department of Epidemiology and Public Health and Clinical Research Facility, University College Cork, Cork, Ireland.
²⁰ School of Pharmacy, University College Cork, Cork, Ireland.
²¹ Department of Internal Medicine, Copenhagen University Hospital Herlev, Gentofte, Denmark.
²² Department of Medicine, University of California, San Francisco, USA.

Abstract

Background: Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH.

Methods: Participants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture.

Discussion: This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition.

Trial registration: Clinicaltrials.gov NCT01660126 ; registered 8th June 2012.

Keywords: Elderly; Levothyroxine; Quality of life; Randomised controlled trial; Subclinical hypothyroidism; Thyroid disease.

Publication types

Randomized Controlled Trial

MeSH terms

Aged
Blood Banks
Clinical Protocols
Double-Blind Method
Hormone Replacement Therapy*
Humans
Hypothyroidism / drug therapy*
Patient Safety
Thyroxine / administration & dosage*

Substances

Thyroxine

Associated data

ClinicalTrials.gov/NCT01660126