T3 Safety Study

Cardiff University requires access to NHS England data for the purpose of the following research project: T3 Safety Study

The following is a summary of the aims of the research project provided by Cardiff University:

Hypothyroidism or underactive thyroid gland is a condition in which the thyroid gland does not produce sufficient amounts of thyroid hormones to meet the energy needs of the body. The condition is common and affects about 2-3% of the population. Hypothyroidism is a common cause of morbidity in the general population and carries an increased risk of cardiovascular disease and cognitive dysfunction. Levothyroxine (T4) is the conventional treatment for hypothyroidism and is prescribed to approximately 3% of the population in England. The majority of patients who receive T4 report an increased sense of well-being within weeks of commencing treatment and are able to continue lifelong treatment without further problems. A proportion of patients however do not feel better with T4 even with normalisation of thyroid hormone levels. Some patients who do not derive benefit from T4 claim improved well-being with Liothyronine (T3) which is the metabolically active thyroid hormone. However, the long-term safety of T3 has not been established and current NICE guidelines do not advocate its routine use in practice.

The objective of the T3 Safety Study is to determine the long-term safety of T3. The project will evaluate long-term survival and adverse cardiovascular events (myocardial infarction, arrhythmias, heart failure, or strokes) in patients treated with T3 and compare these risks to control patients treated conventionally with T4.

The following NHS England data will be accessed:

• Hospital Episode Statistics Admitted Patient Care – necessary to record hospital admissions with cardiovascular events, namely heart rhythm disorders, heart failure, acute myocardial infarction, and strokes.

• Civil Registration Mortality – necessary to capture patients who have died during the follow up period.

The level of the data will be pseudonymised.

The data will be minimised as follows:

• Limited to data for a study cohort of ~3,000 patients treated with T3, Armour Thyroid, or Natural Desiccated Thyroid (NDT) for at least 3 months between 1998 and 2013, identified from historical clinic records from an independent medical practice. This data is currently held by the Vaccine Research Trust, a registered charity.

• Limited to data between 1998 to 2022.

• For each individual patient, Cardiff University will filter the data up to 20 years after, and up to 5 years before they joined the trial (from the date when they started receiving T3 treatment), and limit to conditions relevant to the study identified by specific ICD or OPCS codes.

Armour Thyroid and NDT are medicinal mixtures of T3 and T4 produced from extracts of animal thyroid glands.

Because T3 is rarely prescribed in the NHS, many patients procure T3 through independent practitioners that operate outside of the NHS.

Mortality from all causes is the primary outcome of interest in the study. As the number of cases are relatively low, the complete number of years (April 1998 to March 2022) of follow up requested is necessary because T3 treated patients are relatively young and background mortality rates at this age are relatively low, making it necessary for a long follow up period to observe sufficient outcomes for an adequately powered analysis.

Cardiff University is the research sponsor and the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The research is in the public interest given the pressing public health need to understand the long-term safety profile of T3 and to establish whether T3 increases the risk of death and adverse cardiovascular events. The safety of the drug T3 has not been established and it is of importance to public health safety to understand whether T3 adversely affects cardiovascular health.

The funding is provided by the British Thyroid Foundation (BTF), a leading UK charity dedicated to supporting thyroid disease patients and their families. The funding is specifically for the study described. Funding is in place until 30/12/2023.

Swansea University is a data processor acting under the instructions of Cardiff University. All data linkage will be undertaken by the Secure Anonymised Information Linkage (SAIL) databank at Swansea University. SAIL's role is limited to

• Linking clinical data provided by the Vaccine Research Trust to HES/Civil Registration (deaths) data, using a pseudonymised Study ID

• Providing control datasets of individuals without thyroid disease and patients treated conventionally with T4 using routinely held data on the SAIL databank and then

• Making available a final pseudonymised file of linked data available to substantive employees of Cardiff University or researchers who hold honorary contracts with Cardiff University.

The Vaccine Research Trust have no decision-making responsibility for the purposes and means of the processing of NHS England data, nor can they access the NHS England data once disseminated. This is a one-off standalone project confined to England and Wales and only substantive employees of Cardiff University or researchers who hold honorary contracts with Cardiff University will have access to pseudonymised participant data.

SAIL is a databank of routinely collected health data run by the Population Data Science Group at Swansea University in Wales.

The SAIL Databank is a central repository that contains only pseudonymised data. The SAIL pseudonymisation process uses a split file encryption procedure that ensures that individual patient identifiable data remains unknown to SAIL analysts or researchers. The final SAIL study file will include a study number generated by SAIL which will be unique to the study and different from other study identifiers created by the Vaccine Research Trust and NHS England.

Data will be accessed by individuals with an honorary contract with Cardiff University. The individuals will act as an agent of Cardiff University at all times under supervision from employees of Cardiff University.

PATIENT AND PUBLIC INVOLVEMENT

Formal consultations were held with the members and executives of the British Thyroid Foundation (BTF) and Thyroid UK who reviewed the study protocol in detail. The response from the BTF and from the Thyroid UK executives was overwhelmingly positive and both patient groups were supportive of the study and were acceptable to the proposed plan of using confidential information without consent for the study.

At the initial protocol development stage, the study was discussed in detail with T3 and T4 users within and outside the NHS in informal group discussions held during the annual meetings of the British Thyroid Association. Feedback from the patients at these meetings was positive and supportive of the study. In addition, the Vaccine Research trust approached a mix of former patients of an independent medical practice and sent them information on the proposed study along with a questionnaire survey which was e-mailed out in September 2020. The survey included questions on participants’ opinions of the study relevance, the study data approach, the transfer of confidential patient information from the Vaccine Research Trust, and whether they would be happy for their data to be used as part of the research study. Out of 10 patients surveyed, 6 responded with a positive response. Four individuals did not respond, comprising two individuals who were uncontactable and two individuals who did not respond.

The Vaccine Research Trust will transfer data to NHS England for the T3 cohort. The data will consist of identifying details (specifically, date of birth, and NHS number and a unique Study ID) for the T3 cohort to be linked with NHS England data.

NHS England will provide the relevant records from the HES APC and Civil Registration Deaths datasets to the SAIL databank at Swansea University. The data will contain no direct identifying data items. The data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

All NHS England data will be stored at the SAIL databank at Swansea University

The data will be accessed by authorised personnel via remote access from an office onsite of the premises of Cardiff University. The data will remain on the servers at Swansea University at all times.

Personnel are not technically capable of downloading or copying data to local devices.

The data will not leave England/Wales at any time.

The core dataset will only be accessed by individuals within the SAIL databank at Swansea University.

The core dataset contains:

- pseudonymised clinical records of T3 treated patients held in the Vaccine Research Trust,

- pseudonymised data from healthy control persons and T4 treated controls obtained from SAIL (SAIL contains person-based records and is linked to other health and social care datasets including the Patient Episode Database for Wales (PEDW), the Office for National statistics (ONS), the Welsh Cancer Intelligence and Surveillance Unit (WCISU), and the Primary Care GP dataset

- pseudonymised HES inpatient, outpatient, and accident and emergency records from all National Health Services (NHS) hospitals in England providing outcome data on hospital admissions with cardiovascular disease and osteoporosis for T3 treated patients.

Individuals within the SAIL databank will produce subsets of the data that will be accessed by researchers at Cardiff University. SAIL will link clinical data provided by the Vaccine Research Trust to HES/Civil Registration (deaths) data using the unique study ID for linkage and SAIL will also provide control datasets of individuals without thyroid disease and patients treated conventionally with T4 using routinely held data on SAIL. A final file comprising pseudonymised linked data with a new encrypted ID for the data groups (T3, T4 and controls) will be made available.

Access to the data including subsets will be restricted to substantive employees of Swansea University and Cardiff University who have authorisation from the Chief Investigator or researchers who hold honorary contracts with Cardiff University

All personnel accessing the data have been appropriately trained in data protection and confidentiality.

The data will be linked at person record level with clinical data obtained from the Vaccine Research Trust, The Vaccine Research Trust will send a separate file containing clinical details with the unique study ID attached to each record to the SAIL Databank at Swansea University.

There will be no requirement and no attempt to reidentify individuals when using the data.

Analysts/researchers from the Cardiff University will access the relevant subset of data and process for the purpose described in section 5a.

The expected outputs of the processing will be:

Reports: A report of findings to British Thyroid Foundation (BTF). The next report is due in December 2023, and the final report is expected to be published in December 2024.

· Submissions to peer reviewed journals: A report is planned for June 2024 which will target core clinical journals with broad international readership such as the British Medical Journal or the Lancet

· Presentations: It is hoped that the findings will be presented at the major thyroid and endocrine society meetings between 2023 and 2024: namely, Welsh Endocrine and Diabetes Society (WEDS), British Thyroid Association (BTA), British Endocrine Society (BES), European Thyroid Association (ETA) and American Thyroid Association (ATA).

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the datasets from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

· Public promotion of the research: the BTF will post a summary of the findings on their website (https://www.btf-thyroid.org) and in their bi-annual newsletter. The study findings will also be publicised on the websites of additional support groups, namely the Thyroid Patient Advocacy (https://www.tpauk.com), the Thyroid Trust (https://www.thyroidtrust.org), as well as websites of the main thyroid related professional bodies in the UK, namely the BTA https://www.british-thyroid-association.org) and the Society for Endocrinology (https://www.endocrinology.org).

It is hoped that this study will establish the safety of T3 therapy in this population of T3 users. The safety of T3 is still uncertain and has not been proven. Accordingly, many individuals who may potentially benefit from T3 are not prescribed T3 by their practitioners. Therefore, if T3 is proven to be safe this will have implications for how the drug is used and will have benefits for patients and health services as well as provide support for future randomised controlled trials of T3/T4 versus T4 alone.

If the safety of T3 is established, it will provide the option for T3 treatment for patients with hypothyroidism who do not feel better with T4. Such patients can be treated with T3 with the assurance that T3 therapy is not associated with an increased risk of death and cardiovascular risk. Patients will benefit directly by an improvement in their quality of life and improved productivity.

Safe use of T3 in the proportion of patients who do not respond to T4 will improve their quality of life. Ultimately, this will reduce the burden of such patients on healthcare services, including visits to general practice, laboratory tests, and secondary care referrals.

If the safety of T3 is established the findings of the study will support future randomised controlled trials of combination therapy with T3 and T4 versus T4 alone in the treatment of hypothyroidism. In the event that T3 users have increased mortality then additional sub-groups analysis will identify vulnerable sub-groups such as the elderly or individuals with pre-existing cardiovascular disease who will then be excluded from randomised controlled trials.

The findings of this study will inform future thyroid disease guidelines. T4 is the recommended therapy based on its established safety and efficacy. Combination therapy with T3 and T4 is known to be as effective as T4 alone but due to limited experience on T3 safety, T4 has remained the standard of care. If T3 is shown to be as safe as T4, then this could support a change to current treatment guidelines and provide an additional option of T3 in some patients.

Not stated in the register.