Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction (TRUST BONE)

Insel Gruppe AG, University Hospital Bern

Status and phase: Completed; Phase 4

Conditions: Osteoporosis; Bone Mineral Density; Thyroid Dysfunction; Fractures, Bone

Treatments: Drug: Levothyroxine; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02491008

162/11_3

SNF 320030_150025 (Other Grant/Funding Number)

Details and patient eligibility

About

Thyroid hormone is a key regulatory hormone for a range of physiological systems, including the skeleton. Previous studies have suggested that subclinical thyroid dysfunction (SCTD) may be associated with deleterious skeletal effects. However, controversy persists on the clinical relevance of SCTD as well as on optimal thresholds for treatment. Available data have substantial limitations: 1) limited prospective data are available to assess the associations between SCTD and non-cardiovascular outcomes, such as fractures 2) lack of data from large RCTs to investigate the pathophysiological mechanisms of associations between thyroid hormone and bone loss. The aim of the study is to examine the relationship between subclinical hypothyroidism and thyroid hormone replacement in regard to skeletal fragility, bone mineral density (BMD), bone loss and metabolism, and the risk of fractures in elderly participants. The listed parameters will be assessed by dual energy X ray absorptiometry (DXA) and novel bone imaging techniques at baseline, at 1 year of follow-up. The study will be nested in the TRUST trial (clinicaltrials.gov ID: NCT01660126), and will make use of its study infrastructure to determine bone biomarkers from biospecimens at baseline, and at 1 year of follow-up from 145 Swiss participants with persistent subclinical hypothyroidism randomized to either thyroxine or placebo in Bern and Lausanne.

Full description

Background

Thyroid hormone is a key regulatory hormone for other physiological systems, including the skeleton. Previous studies have suggested that SCTD may be associated with deleterious skeletal effects. However, controversy persists on the clinical relevance of SCTD as well as on optimal thresholds for treatment. Available data have substantial limitations: 1) limited prospective data are available to assess the associations between SCTD and non-cardiovascular outcomes, such as fractures 2) lack of data from large RCTs to investigate the pathophysiological mechanisms of associations.

Objective

To examine, within a large RCT of elderly participants with subclinical hypothyroidism (the TRUST trial), the impact of thyroxine therapy on the association between SCTD and skeletal fragility, bone mineral density (BMD), bone loss and metabolism, and the risk of fractures.

Methods

The existing trial infrastructure (TRUST thyroid trial-Euresearch FP7,clinicaltrials.gov ID: NCT01660126) will be utilized to collect biospecimens from the 145 Swiss participants with persistent subclinical hypothyroidism randomized to either thyroxine or placebo in Bern and in Lausanne. The assessment is performed by means of dual energy X ray absorptiometry (DXA) and peripheral quantitative computed tomography (pqCT) as a novel bone imaging technique at baseline, and at 1 year of follow-up. In parallel, bone turnover markers in the blood plasma will be measured at baseline and at 1 year of follow-up.

Enrollment: 145 patients

Sex: All

Ages: 65+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Community-dwelling patients aged >= 65 years with subclinical hypothyroidism
• Written informed consent

Exclusion Criteria

• Subjects currently under levothyroxine or antithyroid drugs (amiodarone, lithium)
• Recent thyroid surgery or radio-iodine (within 12 months)
• Grade IV NYHA heart failure
• Prior clinical diagnosis of dementia
• Recent hospitalization for major illness or elective surgery (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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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145 participants in 2 patient groups, including a placebo group

Drug: Levothyroxine

Experimental group

Description:

The intervention will start with Levothyroxine 50 mcg daily (reduced to 25 mcg in subjects \<50 kg of body weight or if known coronary heart disease - previous myocardial infarction or symptoms of angina pectoris) vs. matching placebo; at 3 months, if the serum TSH level is \<0.4 mU/L, dose will be reduced by 25 mcg; TSH \>=0.4 and \<4.6 mU/L, no change to dose; TSH \>=4.6 mU/L, additional 25 mcg. 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 which will be prescribed is 150 mcg (after 4 increments of 25 mcg at 3 months, 1, 2, 3 years; from the starting dose of 50 mcg).

Treatment:

Drug: Levothyroxine

Drug: Placebo

Placebo Comparator group

Description:

Control patients will obtain a placebo pill of the same characteristics as the intervention drug, and mock titration will be carried out identically to the intervention drug. Pharmaceutical composition of placebo (100 mg): Lactose monohydrate 66 mg, Maize starch 25 mg, Gelatin 5 mg, Croscarmellose sodium 3.5 mg, Magnesium stearate (vegetable source) 0.5 mg.

Treatment:

Drug: Placebo