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

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ClinicalTrials.gov Identifier: NCT02491008
Recruitment Status : Completed
First Posted : July 7, 2015
Last Update Posted : February 1, 2017
Sponsor:
Collaborator:
University of Lausanne Hospitals
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Thyroid Dysfunction Bone Mineral Density Osteoporosis Fractures, Bone Drug: Levothyroxine Drug: Placebo Phase 4

Detailed 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 145 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction: a Prospective Evaluation and Impact of Treatment
Study Start Date : January 2014
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Drug: Levothyroxine
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).
Drug: Levothyroxine
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).

Placebo Comparator: Drug: Placebo

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.

Drug: Placebo

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.





Primary Outcome Measures :
  1. Change in bone mineral density (BMD) [ Time Frame: baseline and one year follow up ]

Secondary Outcome Measures :
  1. Change in bone biomarkers [ Time Frame: baseline and one year follow up ]
  2. Bone mineral density (BMD) [ Time Frame: 1 year follow up ]


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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02491008


Locations
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Switzerland
Department of General Internal Medicine
Lausanne, Vaud, Switzerland, 1011
Clinic for General Internal Medicine, Bern University Hospital Bern
Bern, Switzerland, 3010
Sponsors and Collaborators
University Hospital Inselspital, Berne
University of Lausanne Hospitals
Investigators
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Principal Investigator: Nicolas Rodondi, MD MAS Clinic for General Internal Medicine, Bern University Hospital Bern

Publications:
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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT02491008     History of Changes
Other Study ID Numbers: 162/11_3
SNF 320030_150025 ( Other Grant/Funding Number: SNF )
First Posted: July 7, 2015    Key Record Dates
Last Update Posted: February 1, 2017
Last Verified: January 2017

Keywords provided by University Hospital Inselspital, Berne:
Thyroid Dysfunction
Bone mineral density
Osteoporosis
Fractures, Bone
Randomized Controlled Trial

Additional relevant MeSH terms:
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Thyroid Diseases
Osteoporosis
Fractures, Bone
Endocrine System Diseases
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Wounds and Injuries
Carboxymethylcellulose Sodium
Laxatives
Gastrointestinal Agents