Clinical trial NCT01660126: Thyroid Hormone Replacement for Subclinical Hypothyroidism
Official title: Multi-modal Effects of Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism; a Randomised Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Subclinical Hypothyroidism
Keywords: Aged
Cardiovascular disease
Levothyroxine
Randomised controlled trial
Quality of life
Subclinical hypothyroidism
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: University College Cork
name: University of Bern
name: Leiden University Medical Center
First posted: 2012-08-08
Enrollment: 737
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Thyroid-specific quality of life - Hypothyroid symptoms and Fatigue symptoms (co-primary outcomes)
timeFrame: Measured at baseline and 12 months
Secondary outcomes:
measure: Health-related quality of life
timeFrame: measured at baseline; 3 month; 12 month and final follow up (expected mean follow-up of 18 months).
measure: Handgrip strength
timeFrame: Measured at baseline; 12 months and final follow up (expected mean follow-up of 18 months).
measure: Executive cognitive function
timeFrame: Measured at baseline and final follow-up (expected mean follow-up of 18 months).
measure: Total mortality
timeFrame: Up to final follow up (expected mean follow-up of 18 months).
measure: Basic Activities of Daily Living
timeFrame: Measured at baseline and final follow-up (expected mean follow-up of 18 months).
measure: Extended activities of daily living
timeFrame: Measured at baseline and final follow-up (expected mean follow-up of 18 months).
measure: Haemoglobin
timeFrame: Measured at baseline and 1 year
measure: Fatal and non-fatal cardiovascular events
timeFrame: Expected mean follow-up of 18 months.
measure: Generic thyroid specific quality of life
timeFrame: Final follow-up
measure: Thyroid-specific quality of life - Hypothyroid symptoms
timeFrame: Measured at 6-8 weeks and at final review
measure: Thyroid specific quality of life - Fatigue symptoms
timeFrame: Measured at 6-8 weeks and at final review
Other outcomes:
Locations:
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde
Study officials:
affiliation: University of Glasgow
name: David J Stott, MBChB MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Jacobijn Gussekloo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bern
name: Nicolas Rodondi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University College Cork
name: Patricia Kearney, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Copenhagen
name: Rudi JG Westendorp, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buchi AE, Feller M, Netzer S, Blum MR, Gonzalez Rodriguez E, Collet TH, Del Giovane C, van Heemst D, Quinn T, Kearney PM, Westendorp RGJ, Gussekloo J, Mooijaart SP, Hans D, Bauer DC, Rodondi N, Aeberli D. Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: A nested study within a randomized placebo controlled trial. Bone. 2022 Aug;161:116404. doi: 10.1016/j.bone.2022.116404. Epub 2022 Apr 2.
citation: Du Puy RS, Poortvliet RKE, Mooijaart SP, Stott DJ, Quinn T, Sattar N, Westendorp RGJ, Kearney PM, McCarthy VJC, Byrne S, Rodondi N, Baretella O, Collet TH, van Heemst D, Dekkers OM, Jukema JW, Smit JWA, Gussekloo J, den Elzen WPJ. No Effect of Levothyroxine on Hemoglobin in Older Adults With Subclinical Hypothyroidism: Pooled Results From 2 Randomized Controlled Trials. J Clin Endocrinol Metab. 2022 May 17;107(6):e2339-e2347. doi: 10.1210/clinem/dgac106.
citation: Zijlstra LE, Jukema JW, Westendorp RGJ, Du Puy RS, Poortvliet RKE, Kearney PM, O'Keeffe L, Dekkers OM, Blum MR, Rodondi N, Collet TH, Quinn TJ, Sattar N, Stott DJ, Trompet S, den Elzen WPJ, Gussekloo J, Mooijaart SP. Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials. Front Endocrinol (Lausanne). 2021 May 20;12:674841. doi: 10.3389/fendo.2021.674841. eCollection 2021.
citation: de Montmollin M, Feller M, Beglinger S, McConnachie A, Aujesky D, Collet TH, Ford I, Gussekloo J, Kearney PM, McCarthy VJC, Mooijaart S, Poortvliet RKE, Quinn T, Stott DJ, Watt T, Westendorp R, Rodondi N, Bauer DC. L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial. Ann Intern Med. 2020 Jun 2;172(11):709-716. doi: 10.7326/M19-3193. Epub 2020 May 5.
citation: Gonzalez Rodriguez E, Stuber M, Del Giovane C, Feller M, Collet TH, Lowe AL, Blum MR, van Vliet NA, van Heemst D, Kearney PM, Gussekloo J, Mooijaart S, Westendorp RGJ, Stott DJ, Aeberli D, Bauer DC, Hans D, Rodondi N. Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz058. doi: 10.1210/clinem/dgz058.
citation: Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RGJ, den Elzen WPJ, Postmus I, Poortvliet RKE, van Heemst D, van Munster BC, Peeters RP, Ford I, Kean S, Messow CM, Blum MR, Collet TH, Watt T, Dekkers OM, Jukema JW, Smit JWA, Langhorne P, Gussekloo J. Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. JAMA. 2019 Nov 26;322(20):1977-1986. doi: 10.1001/jama.2019.17274.
citation: Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, Kean S, Kelly M, Krebs D, Langhorne P, McCarthy G, McCarthy V, McConnachie A, McDade M, Messow M, O'Flynn A, O'Riordan D, Poortvliet RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland HA, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J; TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3.
citation: Stott DJ, Gussekloo J, Kearney PM, Rodondi N, Westendorp RG, Mooijaart S, Kean S, Quinn TJ, Sattar N, Hendry K, Du Puy R, Den Elzen WP, Poortvliet RK, Smit JW, Jukema JW, Dekkers OM, Blum M, Collet TH, McCarthy V, Hurley C, Byrne S, Browne J, Watt T, Bauer D, Ford I. 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.