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


CONCLUSIONS
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.


BACKGROUND
Clinicaltrials.gov NCT01660126 ; registered 8th June 2012.
Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. David.J.Stott@glasgow.ac.uk.|Glasgow Royal Infirmary, Room 2.42, 2nd Floor New Lister Building, G31 2ER, Glasgow, UK. David.J.Stott@glasgow.ac.uk.
David J
DJ
Stott
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.
Jacobijn
J
Gussekloo
Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
Patricia M
PM
Kearney
Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.|Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
Nicolas
N
Rodondi
Leyden Academy on Vitality and Ageing, Leiden, Netherlands.|Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
Rudi G J
RG
Westendorp
Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
Simon
S
Mooijaart
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
Sharon
S
Kean
Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Terence J
TJ
Quinn
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Naveed
N
Sattar
Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Kirsty
K
Hendry
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.
Robert
R
Du Puy
Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Wendy P J
WP
Den Elzen
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.
Rosalinde K E
RK
Poortvliet
Radboud University Medical Center, Nijmegen, The Netherlands.
Jan W A
JW
Smit
Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
J Wouter
JW
Jukema
Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
Olaf M
OM
Dekkers
Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Manuel
M
Blum
Service of Endocrinology Diabetes and Metabolism, University Hospital of Laussanne, Lausanne, Switzerland.
Tinh-Hai
TH
Collet
School of Nursing and Midwifery, University College Cork, Cork, Ireland.
Vera
V
McCarthy
Department of Epidemiology and Public Health and Clinical Research Facility, University College Cork, Cork, Ireland.
Caroline
C
Hurley
School of Pharmacy, University College Cork, Cork, Ireland.
Stephen
S
Byrne
Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
John
J
Browne
Department of Internal Medicine, Copenhagen University Hospital Herlev, Gentofte, Denmark.
Torquil
T
Watt
Department of Medicine, University of California, San Francisco, USA.
Douglas
D
Bauer
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
Ian
I
Ford
D000368:Aged; D001771:Blood Banks; D002985:Clinical Protocols; D004311:Double-Blind Method; D020249:Hormone Replacement Therapy; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy*; D061214:Patient Safety; D013974:Thyroxine / Q000008:administration & dosage*
D013974:Thyroxine
Elderly; Levothyroxine; Quality of life; Randomised controlled trial; Subclinical hypothyroidism; Thyroid disease