BMC Endocr Disord. 2017; 17: 6.
Published online 2017 Feb 3. 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)
David J. Stott,corresponding author1,21
Jacobijn Gussekloo,2 Patricia M. Kearney,3 Nicolas Rodondi,4,5 Rudi G. J. Westendorp,6,7 Simon Mooijaart,8 Sharon Kean,9 Terence J. Quinn,1 Naveed Sattar,10 Kirsty Hendry,1 Robert Du Puy,2 Wendy P. J. Den Elzen,11
Rosalinde K. E. Poortvliet,2
Jan W. A. Smit,12 J. Wouter Jukema,13 Olaf M. Dekkers,8 Manuel Blum,14 Tinh-Hai Collet,15 Vera McCarthy,16 Caroline Hurley,17 Stephen Byrne,18 John Browne,3 Torquil Watt,19 Douglas Bauer,20 and Ian Ford9
1 Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
2 Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands
3 Department of Epidemiology and Public Health, University College Cork, Cork, Ireland
4 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
5 Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland
6 Leyden Academy on Vitality and Ageing, Leiden, Netherlands
7 Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
8 Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
9 Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
10 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
11 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands
12 Radboud University Medical Center, Nijmegen, The Netherlands
13 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
14 Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
15 Service of Endocrinology Diabetes and Metabolism, University Hospital of Laussanne, Lausanne, Switzerland
16 School of Nursing and Midwifery, University College Cork, Cork, Ireland
17 Department of Epidemiology and Public Health and Clinical Research Facility, University College Cork, Cork, Ireland
18 School of Pharmacy, University College Cork, Cork, Ireland
19 Department of Internal Medicine, Copenhagen University Hospital Herlev, Gentofte, Denmark
20 Department of Medicine, University of California, San Francisco, USA
21 Glasgow Royal Infirmary, Room 2.42, 2nd Floor New Lister Building, G31 2ER Glasgow, UK
David J. Stott, Phone: 01412018510, Email:
ku.ca.wogsalg@ttotS.J.divaD.
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.
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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.
Study population
The trial is running in four countries (UK, Ireland, the Netherlands and Switzerland). Potential subjects are identified from clinical laboratory databases and recruited from the community, aged ≥65 years with SCH, diagnosed on the basis of persistently elevated TSH levels (4.6–19.9 mU/L) with fT4 within the reference range. Baseline and follow-up TSH was measured by clinical laboratories affiliated with each clinical centre. TSH is measured on a minimum of two occasions at least three months apart, over a maximum period of 3 years. All subjects gave individual informed consent to participate (See Appendix 1 and 2; Additional files 1 and 2 for model patient information sheet and consent forms).
Exclusion criteria for the study:
i) Subjects currently prescribed Levothyroxine, anti-thyroid drugs, amiodarone or lithium.
ii) Recent thyroid surgery or radio-iodine (within 12 months).
iii) Grade IV NYHA heart failure.
iv) Clinical diagnosis of dementia.
v) Recent hospitalisation for major illness or elective surgery (within 4 weeks).
vi) Recent acute coronary syndrome, including myocardial infarction or unstable angina (within 4 weeks).
vii) Acute myocarditis or pancarditis.
viii) Untreated adrenal insufficiency or adrenal disorder.
ix) Terminal illness.
x) Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
xi) Subjects participating in ongoing RCTs of therapeutic interventions (including Clinical Trials of Investigational Medicinal Products; CTIMPs).
xii) Plan to move out of the region in which the trial is being conducted within the next 2 years.
The dose is changed according to the serum TSH level as follows; 6–8 weeks after randomisation a blood sample is taken for serum TSH, with three possible actions:
1.TSH <0.4 mU/L: treatment dose reduced to 25 micrograms levothyroxine in those starting on 50 micrograms; reduced to 0 in those starting on 25 micrograms – blinding maintained by giving placebo matching the 25 micrograms dose; these patients will have a further check TSH after 6–8 weeks; if TSH remains <0.4 mU/L patient will be withdrawn from randomised treatment.
2.TSH ≥0.4 and <4.6 mU/L: no change to the treatment dose; patient to be reviewed at 12 months.
3.TSH remains elevated (≥4.6 mU/L): additional 25 micrograms levothyroxine, giving a total daily dose of 75 micrograms levothyroxine for those starting on 50 micrograms, or a total daily dose of 50 micrograms levothyroxine for those starting on 25 micrograms
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https://www.ncbi.nlm.nih.gov/pmc/articl ... le_156.pdf
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291970/