Thyroid DysfunctionPhase 4NCT02832960
The TRUST Trial - CardioVascular Imaging ECHO
A Phase 4 study testing Levothyroxine in people with Thyroid Dysfunction and Atherosclerosis, run by Insel Gruppe AG, University Hospital Bern at 3 sites in Switzerland.
Trial summary
Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events… Read more about this study
- Who is it for?
- Ages 65 years and older
- Conditions the study is for
- Thyroid Dysfunction, Atherosclerosis, Heart Failure
- 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
- 185 participants
- Where
- 3 sitesSwitzerland
- Study dates
- Jun 2016to 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
3 sites in 1 country.
Switzerland3 sites
Clinic for General Internal Medicine, Bern University Hospital Bern
Bern, 3010
Cardiology Division, Geneva University Hospitals
Geneva, Canton of Geneva, 1211
Department of General Internal Medicine
Lausanne, Canton of Vaud, 1011
About this study
Official title: Impact of Thyroid Hormone Replacement on Cardiac Function: a Randomized Placebo-Controlled Trial in Older Adults With Subclinical Hypothyroidism
Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes. The goals of this proposal are to address the impact of thyroid replacement on cardiac function. The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline. The main outcome will be CV imaging modalities measured by echocardiography at the close-out visit. Assessment of the impact of thyroid replacement on cardiac function and subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo.
Read the detailed description
Background: Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Subclinical hypothyroidism (SHypo), defined as elevated serum TSH levels with normal thyroxine values, is common in older adults (5-10%). Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes (largest trial to date: 45 participants). Imaging endpoints are especially well-suited for early trials with investigational therapies for HF treatment and prevention, as well as validated and strong surrogate markers of clinical outcomes.
Specific Aims: The goals of this proposal are to address the impact of thyroid replacement on 1) cardiac function as measured by echocardiography.
Methods: The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline (4 death and 17 withdrawal). The main outcome will be CV imaging modalities measured by echocardiography at the close-out visit. Transthoracic echocardiography will be performed for the assessment of diastolic function (abnormalities of the pulsed wave mitral valve inflow pattern and mitral annulus tissue velocities, left atrial volume index, left ventricular [LV] mass index) and cardiac systolic function (LV ejection fraction and regional function). Ultrasound of carotid intima media thickness (CIMT) will be used to assess subclinical atherosclerosis and plaque burden. All images will be centralized at the core lab for a blinded and standardized interpretation.
Expected value of the proposed project: Controversies persist regarding the indications for screening and treatment of SHypo due to the lack of an appropriately powered RCT addressing the impact of thyroid replacement on CV outcomes. Assessment of the impact of thyroid replacement on cardiac function and subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo. The strengths of this study include the combination of: 1) High feasibility of the project in collaboration with the largest RCT on SHypo making it possible to investigate the mechanisms of associations with CV disease; 2) Innovative project with combined CV imaging to assess cardiac function with thyroid replacement therapy vs. placebo; 3) Excellent power given the large sample size and participants' older age. The sample size for this proposal will be 5-fold higher than previous small trials of thyroid replacement on CV outcomes. The collaboration of CV imaging modalities expertise with the ongoing largest trial on SHypo, is a unique opportunity to address the clinical and scientific issue of the impact of SHypo on the CV system.
- Conditions
- Thyroid Dysfunction, Atherosclerosis, Heart Failure
- Being tested
- Levothyroxine, Placebo
- Keywords
- Thyroid Dysfunction, Atherosclerosis, Heart Failure, Cardiovascular imaging, Randomized Controlled Trial
- Medical subject headings
- Atherosclerosis, Heart Failure
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 |
|---|---|---|
| 1 | 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 |
| 2 | 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.
Diastolic cardiac Function as measured by echocardiography
Measured: one year follow up
Systolic cardiac Function as measured by echocardiography
Measured: one 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 posted14 Jul 2016 (estimated)
- Study startJun 2016
- 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 (2)Papers the sponsor has linked to this study.
- Other trials for Thyroid DysfunctionStudies of the same condition, open and under way.
- 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
- 185 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Collaborators
- University of Lausanne Hospitals, University Hospital, Geneva
- Responsible party
- Sponsor
- Investigators
- Nicolas Rodondi, MD MAS, Principal investigator, University Clinic of General Internal Medicine, Bern University Hospital, Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02832960
- Sponsor's protocol ID
- 162/11_4
- Other IDs
- 974a
- Status last verified
- Feb 2017
- First submitted
- 12 Jul 2016
- Last updated
- 28 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 20858880Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, Nanchen D, den Elzen WP, Balmer P, Luben RN, Iacoviello M, Triggiani V, Cornuz J, Newman AB, Khaw KT, Jukema JW, Westendorp RG, Vittinghoff E, Aujesky D, Rodondi N; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012 Aug 28;126(9):1040-9. doi: 10.1161/CIRCULATIONAHA.112.096024. Epub 2012 Jul 19.
PubMed 22821943
Study at a glance
From the registry record, last updated by the sponsor on 28 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Thyroid Hormone Replacement on Cardiac Function: a Randomized Placebo-Controlled Trial in Older Adults With Subclinical Hypothyroidism
- ClinicalTrials.gov ID
- NCT02832960
- Acronym / sponsor ID
- 162/11_4
- Conditions
- Thyroid Dysfunction, Atherosclerosis, Heart Failure
- Keywords
- Thyroid Dysfunction, Atherosclerosis, Heart Failure, Cardiovascular imaging, Randomized Controlled Trial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 185 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Collaborators
- University of Lausanne Hospitals, University Hospital, Geneva
- Study start
- Jun 2016
- Primary completion
- Dec 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 14 Jul 2016 (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.
Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes. The goals of this proposal are to address the impact of thyroid replacement on cardiac function. The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline. The main outcome will be CV imaging modalities measured by echocardiography at the close-out visit. Assessment of the impact of thyroid replacement on cardiac function and subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo.
Detailed description
Background: Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and morbidity, particularly with the current context of an aging population. Subclinical hypothyroidism (SHypo), defined as elevated serum TSH levels with normal thyroxine values, is common in older adults (5-10%). Prospective cohort studies, as well as analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of CHD or HF events among adults with severe SHypo. However, no large randomized controlled trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging outcomes (largest trial to date: 45 participants). Imaging endpoints are especially well-suited for early trials with investigational therapies for HF treatment and prevention, as well as validated and strong surrogate markers of clinical outcomes.
Specific Aims: The goals of this proposal are to address the impact of thyroid replacement on 1) cardiac function as measured by echocardiography.
Methods: The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months from baseline (4 death and 17 withdrawal). The main outcome will be CV imaging modalities measured by echocardiography at the close-out visit. Transthoracic echocardiography will be performed for the assessment of diastolic function (abnormalities of the pulsed wave mitral valve inflow pattern and mitral annulus tissue velocities, left atrial volume index, left ventricular [LV] mass index) and cardiac systolic function (LV ejection fraction and regional function). Ultrasound of carotid intima media thickness (CIMT) will be used to assess subclinical atherosclerosis and plaque burden. All images will be centralized at the core lab for a blinded and standardized interpretation.
Expected value of the proposed project: Controversies persist regarding the indications for screening and treatment of SHypo due to the lack of an appropriately powered RCT addressing the impact of thyroid replacement on CV outcomes. Assessment of the impact of thyroid replacement on cardiac function and subclinical atherosclerosis within a trial will aid decisions and evidence-based guidelines development to treat a potential modifiable risk factor, such as SHypo. The strengths of this study include the combination of: 1) High feasibility of the project in collaboration with the largest RCT on SHypo making it possible to investigate the mechanisms of associations with CV disease; 2) Innovative project with combined CV imaging to assess cardiac function with thyroid replacement therapy vs. placebo; 3) Excellent power given the large sample size and participants' older age. The sample size for this proposal will be 5-fold higher than previous small trials of thyroid replacement on CV outcomes. The collaboration of CV imaging modalities expertise with the ongoing largest trial on SHypo, is a unique opportunity to address the clinical and scientific issue of the impact of SHypo on the CV system.
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 |
|---|---|---|
| 1 | 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). |
| 2 | 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 | 1 |
| 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 | 2 |
Primary outcome
Diastolic cardiac Function as measured by echocardiography
Time frame: one year follow up
Systolic cardiac Function as measured by echocardiography
Time frame: one 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 28 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 22821943Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, Nanchen D, den Elzen WP, Balmer P, Luben RN, Iacoviello M, Triggiani V, Cornuz J, Newman AB, Khaw KT, Jukema JW, Westendorp RG, Vittinghoff E, Aujesky D, Rodondi N; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012 Aug 28;126(9):1040-9. doi: 10.1161/CIRCULATIONAHA.112.096024. Epub 2012 Jul 19.
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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
University Clinic of General Internal Medicine, Bern University Hospital, Bern
3 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 Atherosclerosis, run by Insel Gruppe AG, University Hospital Bern at 3 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 28 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 3 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?
Diastolic cardiac Function as measured by echocardiography (time frame: one year follow up). The study lists 2 primary outcomes in all. 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 NCT02832960, which also lists 2 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 28 Feb 2017; AzTrials last refreshed its copy on 27 Oct 2026.