Thyroid DysfunctionPhase 4TRUST BONENCT02491008
Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction
A Phase 4 study testing Levothyroxine in people with Thyroid Dysfunction and Bone Mineral Density, run by Insel Gruppe AG, University Hospital Bern at 2 sites in Switzerland.
Trial 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. Read more about this study
- Who is it for?
- Ages 65 years and older
- Conditions the study is for
- Thyroid Dysfunction, Bone Mineral Density, Osteoporosis
- What is being tested?
- Levothyroxine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 145 participants
- Where
- 2 sitesSwitzerland
- Study dates
- Jan 2014to Dec 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 years and older
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Community-dwelling patients aged >= 65 years with subclinical hypothyroidism
- Written informed consent
Who cannot join
- 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
Show all 9Show fewer
- 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 locations and contacts
2 sites in 1 country.
Switzerland2 sites
Clinic for General Internal Medicine, Bern University Hospital Bern
Bern, 3010
Department of General Internal Medicine
Lausanne, Canton of Vaud, 1011
About this study
Official title: Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction: a Prospective Evaluation and Impact of Treatment
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.
Read the 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.
- Being tested
- Levothyroxine, Placebo
- Keywords
- Thyroid Dysfunction, Bone mineral density, Osteoporosis, Fractures, Bone, Randomized Controlled Trial
- Medical subject headings
- Osteoporosis, Fractures, Bone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LevothyroxineDrug
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).
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Drug: Levothyroxine | Experimental | 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). Receives: Drug: Levothyroxine |
| Drug: Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in bone mineral density (BMD)
Measured: baseline and one year follow up
Secondary outcomes (2)
Change in bone biomarkers
Measured: baseline and one year follow up
Bone mineral density (BMD)
Measured: 1 year follow up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2015 (estimated)
- Study startJan 2014
- Primary completionDec 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Thyroid DysfunctionStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 145 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Collaborators
- University of Lausanne Hospitals
- Responsible party
- Sponsor
- Investigators
- Nicolas Rodondi, MD MAS, Principal investigator, Clinic for General Internal Medicine, Bern University Hospital Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02491008
- Sponsor's protocol ID
- 162/11_3
- Other IDs
- SNF 320030_150025
- Acronym
- TRUST BONE
- Status last verified
- Jan 2017
- First submitted
- 2 Jul 2015
- Last updated
- 1 Feb 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010 Sep 22;304(12):1365-74. doi: 10.1001/jama.2010.1361.
PubMed 20858880Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005 Nov 28;165(21):2460-6. doi: 10.1001/archinte.165.21.2460.
PubMed 16314541Buchi 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.
PubMed 35381390Gonzalez 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.
PubMed 31702015
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Novel Biomarkers and Skeletal Outcomes Associated With Subclinical Thyroid Dysfunction: a Prospective Evaluation and Impact of Treatment
- ClinicalTrials.gov ID
- NCT02491008
- Acronym / sponsor ID
- TRUST BONE / 162/11_3
- Keywords
- Thyroid Dysfunction, Bone mineral density, Osteoporosis, Fractures, Bone, Randomized Controlled Trial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 145 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Collaborators
- University of Lausanne Hospitals
- Study start
- Jan 2014
- Primary completion
- Dec 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 7 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Drug: Levothyroxine | Experimental | Drug: LevothyroxineThe 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: Placebo | Placebo comparator | Drug: PlaceboControl 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. |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (2 listed)
- Community-dwelling patients aged >= 65 years with subclinical hypothyroidism
- Written informed consent
Key exclusion criteria (9 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LevothyroxineThe 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 | Drug: Levothyroxine |
| PlaceboControl 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 | Drug: Placebo |
Primary outcome
Change in bone mineral density (BMD)
Time frame: baseline and one year follow up
2 secondary outcomes
Change in bone biomarkers
Time frame: baseline and one year follow up
Bone mineral density (BMD)
Time frame: 1 year follow up
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2017.
- Background: PubMed 20858880Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010 Sep 22;304(12):1365-74. doi: 10.1001/jama.2010.1361.
- Background: PubMed 16314541Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005 Nov 28;165(21):2460-6. doi: 10.1001/archinte.165.21.2460.
- Derived from this study: PubMed 35381390Buchi 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.
- Derived from this study: PubMed 31702015Gonzalez 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nicolas Rodondi, MD MAS principal investigator
Clinic for General Internal Medicine, Bern University Hospital Bern
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Levothyroxine in people with Thyroid Dysfunction and Bone Mineral Density, run by Insel Gruppe AG, University Hospital Bern at 2 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in bone mineral density (BMD) (time frame: baseline and one year follow up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02491008, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2017.