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  • Periodic Report Summary 3 - TRUST (Multi-modal effects of thyroid hormone replacement for untreated older adults with subclinical hypothyroidism; a randomised placebo-controlled trial)

TRUST Report Summary

Project ID: 278148
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 3 - TRUST (Multi-modal effects of thyroid hormone replacement for untreated older adults with subclinical hypothyroidism; a randomised placebo-controlled trial)

Project Context and Objectives:

Subclinical hypothyroidism (SCH) is a common condition (8-18%) among European older men and women. Although by definition SCH comprises biochemically mild thyroid hormone deficiency without overt symptoms, it is a likely contributor to multiple problems in older age. Thyroid hormone has multiple pleiotropic effects on numerous physiological systems, including the vascular tree, heart, skeletal muscle and brain. Therefore, levo-thyroxine substitution to overcome thyroid hormone deficiency has the potential to give multi-system benefits to older people with SCH. Small studies have reported reduced atherosclerosis and improved cardiac 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.

We are running a multicentre randomised placebo-controlled trial to assess the impact of thyroxine replacement in older adults with persisting SCH (excluding those in whom it is a temporary phenomenon who are less likely to benefit). We are including older men and women with a wide age range and of varying health status. Outcomes include health-related quality of life, cardiovascular events, muscle strength and executive cognitive function over 3-years of follow-up.

Principle research questions and objectives:
• Does thyroxine treatment for SCH give multimodal benefits for older people with SCH?
• Are benefits seen across a wide range of outcomes, including improving health-related quality of life, prevention of cardiovascular disease, and muscle function and cognition?
• Are benefits seen in specific subgroups of older people with SCH, including women, very elderly and those with mild degrees of SCH (e.g. TSH >4.6 but <10 mU/L)?
• Are any benefits offset by adverse effects, such as atrial fibrillation or heart failure?

Secondary research questions and objectives:
• To establish a strong European network of complementary research expertise on SCH in older people, including geriatric medicine, endocrinology and metabolic medicine, primary care, cardiovascular disease and biostatistics.
• To link this research expertise with strong focus on patient perspective and needs.
• To provide the necessary evidence to properly inform best practice for treatment of SCH in older people.
• To disseminate this evidence to healthcare practitioners and patients.
• To improve clinical practice in management of SCH in older people.
• To improve health and wellbeing of older people with SCH.
• To establish a blood biobank, to be used in future research into causes and mechanisms of health, disease and disability in later life.
• To determine the association of thyroid function with long-term risk of future illness and mortality in older people, using record linkage for the screenees.

Project Results:

Work package 1: Consortium Management
The study is coordinated from an administrative office (in Glasgow). The central steering committee has met regularly over the course of the grant funding period.
Membership is established, charters in place and systems of working established for both the Endpoint committee and the Independent Data and Safety Monitoring Committee (IDMC).
Systems are in place to ensure all ethics and drug regulatory authority and sponsor approvals are secured and up to date.

Work package 2: Screening and recruitment
Systems were been established in all four member / associated states to use laboratory databases to identify potential study patients (over 65s with biochemical test results consistent with persisting SCH). Over 3000 General Practices were invited to participate in the study, and over 1000 agreed to take part.
At the close of recruitment in December 2015 we had screened 2,659 patients and had enrolled 738 patients into the TRUST trial.

Work package 3: Patient randomisation, treatment and follow up
The randomisation schedule was prepared and maintained by the Robertson Centre for Biostatistics in Glasgow; it was communicated to and implemented by Mawdsley Brooks (who package and label levothyroxine and placebo). Patient allocation was conducted by the trial web portal by the study nurses at the time of the baseline study visit.
Electronic record systems (approved by the study sponsors) are established for pharmacovigilance reporting to appropriate regulatory authorities within each Member / Associated State.

Work package 4: Data management and biostatistics
A trial web portal has been established, including functionality for data handling (including electronic clinical record forms), data query resolution, drug supply management, endpoint adjudication facilitation and documentation and report dissemination.
The trial web portal is in English, however, for patient questionnaires these have also been prepared in local languages (Dutch, German and French). The electronic clinical record forms (eCRF) have been developed to allow direct data entry by the study research assistants / nurses onto networked laptops or PCs. Data are transferred to the data centre in Glasgow via the trial web portal. Systems are in place to allow data queries to be flagged to the sites for correction.

Work package 5: Thyroid function analysis
A general system and process of information transfer for thyroid function tests (TFTs) results from participating laboratories to the data centre has been established.
In total 2659 screening TFTs had been performed by the close of recruitment in December 2015.

Work package 6: Medicine manufacture, packaging and distribution
Medicines have been manufactured and provided by Merck Serono (donation free of charge). Packaging, labelling and distribution is performed by Mawdsley Brooks (approved subcontract). Technical Agreements with both of these companies are in place. Pharmacy support is arranged in all countries, supported by an electronic drug management system (developed by the Robertson Centre for Biostatistics). Resupply of blistered and packaged medicines, and appropriate regulatory approvals have all been put in place in time to ensure no gaps in supply throughout the study. Supplies of medicines are in place to enable treatment until date of last patient out of the study (31st October 2016).

Work package 7: Dissemination and transfer of knowledge
Language-specific website content has been developed and posters and newsletters produced in English, Dutch, French and German.
The TRUST study has been further publicised with two letters published in the Lancet and an editorial in the Journal of Clinical Endocrinology and metabolism.
As the ‘centre-piece’ of our dissemination efforts we have agreed with the New England Journal of Medicine that we will submit our primary paper to this journal for fast track review in early in 2017, aiming to publish at the same time as launching the results at the top scientific meeting in this field, the Endocrine Society ENDO meeting 2-4 April 2017 in Orlando USA.

Potential Impact:
This clinical trial will clarify whether levo-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 healthcare costs and promote healthy ageing of European older adults.

At the close of recruitment we have 738 patients enrolled into the TRUST trial. In our last periodic report we were confident that 540 was the minimum number of patients we would recruit; we also hoped that with the upscaling of geographical areas for recruitment in all countries we would see an increase in recruitment rate with the most optimistic predictions taking us up to a maximum of 750 patients. Our final recruitment numbers are therefore close to this maximum projected figure of 750 patients randomised.
While this is fewer patients than the 3000 initially proposed, the study will still contribute substantially to knowledge on treatment of subclinical hypothyroidism in older people, with good statistical power to detect a meaningful effect on symptoms and thyroid-specific quality of life, as well as good power for many of the secondary outcomes. We will however be underpowered to detect any effect on incident vascular disease.

It remains controversial what should trigger screening of thyroid function in older adults and at what TSH threshold to initiate levo-thyroxine therapy for SCH. Recommendations or guidelines are contradictory, reflecting current uncertainty. This is also reflected in wide variations in clinical practice, with some clinicians actively screening for thyroid dysfunction and treating SCH, while others do neither. Strong recommendation has been made in the Cochrane review of 2007, by international experts and by the US Preventive Services Task Force - recommending further randomised controlled trials in larger groups and with longer follow-up for clinical endpoints. Specific subgroups also recommended for inclusion were subjects with initial TSH level above and below 10mU/L and very elderly subjects. We have followed this guidance in our study.

The TRUST Clinical Trial has also provided the opportunity to establish a biobank of blood samples from elderly participants. Baseline samples have been stored for subjects randomised to the trial, and all the necessary approvals and systems are in place for an additional biobank blood sample to be stored at 1 year of follow-up. These samples will provide biological information that can be linked with the ongoing collection of clinical data relating to participants’ health, lifestyle and other circumstances.

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United Kingdom


Life Sciences
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