Participant information sheet for randomisation
Patient information sheet for the trust study
Thyroid hormone replacement for subclinical hypothyroidism – the TRUST study.
Invitation paragraph:
You are being invited to take part in a research study. Before you decide whether or not to take part it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with friends, relatives and your GP if you wish. Ask us if there is anything that is not clear or if you would like more information. Thank you for reading this information sheet.
Background
You have been asked to take part in this study because your recent screening blood test has told us that you have subclinical hypothyroidism. Subclinical hypothyroidism means that the thyroid gland, which is found in your neck, is not producing the right amount of thyroid hormones that your body needs to do its job well. Thyroid hormones are important as they help regulate different parts of the body, including the circulation, heart, muscle and brain. Subclinical means that there are no noticeable symptoms. Without a blood test, it is impossible to know that you have subclinical hypothyroidism. Subclinical hypothyroidism is a common condition among older men and women affecting up to 1 in 6 of over-65s.
How many people like me (participants) will be taking part in this study?
There would be up to 750 people enrolled in this study from Scotland, Ireland, The Netherlands and Switzerland.
What is the purpose of the study?
We aim to determine whether treating subclinical hypothyroidism with Levothyroxine gives health benefits to older people. Small studies have reported less fatty lining in blood vessels (atherosclerosis) and improved heart function with medication (Levothyroxine), but no large clinical trials have been performed. However, there may be unwanted side effects of Levothyroxine supplements too, these include an irregular heart beat (arrhythmia) and bone thinning (osteoporosis) which can lead to an increased risk of bone fracture.
The purpose of this study is to find out what effects (good and bad) of Levothyroxine replacement have on older people with subclinical hypothyroidism. We are interested in how well Levothyroxine works to:
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prevent heart and circulatory system problems (such as stroke)
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improve muscle function (such as strength)
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improve health related quality of life (by reducing symptoms such as tiredness)
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improve speed of thinking
You would be monitored carefully to ensure that you are not over-medicated with Levothyroxine; we believe this is important to reduce the risk of any side effects.
Why have I been chosen?
You have been chosen to be invited to take part in this study as your blood tests have shown that you have a mildly underactive thyroid gland with no symptoms or with symptoms at a level that treatment is not certain to be beneficial, and you are 65 years of age or older. You have had a screening assessment that has shown that your thyroid blood tests remain mildly underactive and you are suitable to enter the study.
Do I have to take part?
You are not in any way obliged to take part - it is up to you to decide. If you do decide to take part you will be asked to sign a consent form. Even if you decide to take part you are still free to withdraw at any time and without giving a reason. This will not affect the standard of care you receive.
If I agree to take part, will I get the Levothyroxine drug?
Once you have completed all the baseline information you will be assigned either to receive daily Levothyroxine, or to receive a placebo. A placebo is a pill which looks, tastes and smells like the real thing but is not; it contains no active ingredient. You will be assigned to one group or the other using a process of randomization. Randomization means that you have the same chance of being assigned to the Levothyroxine group or the placebo group. It is like tossing a dice or flipping a coin. This helps to make sure that the patients in each group (Levothyroxine or placebo) of the study are roughly the same, so that we can be sure that we get the correct answer to the question that the study is asking. If you chose to enter the study you would have a 50:50 chance of getting Levothyroxine or placebo. A computer will choose which group you are put in. Neither you, the doctors, study nurses or any of the people involved in the study will choose or know what group you will be in (although, if your doctor needs to find out he / she can do so).
What else will happen to me if I take part?
The first (baseline) study visit will be at your GP surgery or at your local hospital Clinical Research Facilities (if it suits you better, this can be done at your own home). We anticipate this visit will last for 60–90 min.
This assessment will include:
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Check of any new medical problems, changes to your medicines or home circumstances.
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A heart rhythm check, using an electronic recorder. To do this the research nurse will instruct you to hold a recording box in one hand, and press it gently over the front-left side of your chest for 30 s.
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Assessment of your quality of life, using 2 thyroid symptom questionnaires and a general quality of life questionnaire.
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Measurement of your grip strength; you will be asked to squeeze a portable grip measure machine as hard as you can, 3 times in succession.
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A 30-point memory questionnaire.
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Measurement of your speed of thinking, using a paper exercise taking 1 min.
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Assessment of how you are managing in everyday activities, using an Activities of Daily Living questionnaire, and how you are managing socially using a short questionnaire.
A blood sample (equivalent to 8 teaspoons) will then be taken to measure your blood count and to store blood for future laboratory analysis of factors that predict future illnesses; this will include storage of your genes (DNA) to allow us to examine any inherited factors that lead to illness in later life. A further small sample (equivalent to 3 teaspoons) will be repeated one year later, and stored for future research on the effects of thyroid hormone. You have the option of opting out of this part of the study if you wish.
Some of the above measures (general quality of life, speed of thinking and grip strength) and taking extra blood for future laboratory analysis will only be done in some of the research sites – so you may not be offered these tests.
You will be reviewed face-to-face by the study nurses at 6 to 8 weeks and 12 months then annually up to a maximum of 3½ years. In addition the study nurses will contact you by telephone at interim periods; 6, 18 and 30 months. It is anticipated that the review visits will take around 30 min, and telephone calls 15 min.
At all of these contacts the study nurses will enquire about any new illnesses or changes to your usual medicines.
At 6 to 8 weeks, 12 months, and annually thereafter, a blood test (volume 2 teaspoons) will be taken to check your thyroid levels. This is to ensure that if you are treated with levothyroxine we give you the right dose; if you receive placebo we will know that your thyroid is not slowing down further – if this occurs you will require review by your GP. If your thyroid tests need adjustments to be made to your dose of tablets you will be asked to return for a further blood test in 6 to 8 weeks. A member of the research team may contact you via telephone to confirm that you have received the study medicines.
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The heart rhythm check will be repeated annually and at your final visit.
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The quality of life measurements will be repeated at 6 to 8 weeks and at 12 months and at your final visit.
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The hand-grip measure and blood pressure (blood pressure was checked at screening visit) will be repeated at 12 months and at your final visit.
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Your weight and waist circumference which was checked at the screening visit will be repeated at 12 months and at your final visit
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The speed of thinking paper exercise, and questionnaires on activities of daily living, social function, and home circumstances and support will be repeated at your final visit.
Travel expenses will be provided to cover the costs of attending all your visits.
The total duration of the study is 5 years (finishing in 2017). If you take part in the study your personal participation will be for at least 1 year, and could be as long as 3 ½ years (42 months).
What do I have to do?
During the study you will be asked to take between 1 and 3 tablets, once every day, and attend the study visits as listed above, including reporting any illnesses or side effects. There are no lifestyle restrictions or dietary restrictions from taking part in this study. You will still be able to drive, take part in sport, or give blood, should you wish to do so. During the study you should continue to take your regular medication.
What is the drug that is being tested?
The drug that is being tested is Levothyroxine, given as a tablet orally (by mouth). This is a hormone that occurs naturally in the body. It is the standard treatment when there is no doubt that the thyroid gland is underactive. Levothyroxine is used by between 3 and 5% of the population. We are testing whether it gives benefits to older people with a mildly underactive thyroid.
We will start the treatment with a low dose either 25ug or 50ug. The dose will be reviewed at 6 to 8 weeks and 12 months then annually. Adjustments will be made depending on a thyroid blood test; some people will require an increase, and some a decrease. Over the course of the study the dose will be increased to a maximum of 3 tablets per day (150ug). Similar adjustments will be also be made for some people in the placebo group, to ensure that people do not guess which group they have been allocated to.
What are the alternatives for treatment?
The main options for people with a mildly underactive thyroid gland are either to start Levothyroxine tablets, or to be followed up with no treatment. In either case a regular (e.g. annual) blood test is usually required.
What are the possible side effects of Levothyroxine?
Side effects from levothyroxine treatment are only rarely seen, particularly if blood tests are done regularly and adjustments to Levothyroxine dose are made to keep thyroid hormone levels in the normal range. If Levothyroxine is prescribed in too high a dose there is a risk of side effects. These could include development of an irregular heart rhythm called atrial fibrillation. This can cause tiredness, shortness of breath and an increased risk of stroke. Increased strain on the heart with excessive thyroxine doses could worsen angina (chest pain coming from the heart) or cause breathlessness and leg swelling. If you are overmedicated with thyroxine there may be an increased risk of thinning of bones (osteoporosis) and fractures.
If you are on an anticoagulant it is possible that the dose may need to be adjusted to prevent your blood becoming too thin. If you have diabetes there is a possibility that starting on levothyroxine might require an increase in dosage requirements of insulin or other anti-diabetic therapy. If you are taking anti-depressant tablets there is a possibility of abnormal heart ryhthms.
However these problems are unlikely so long as we do regular blood tests to ensure that we do not overmedicate you.
For those allocated to the inactive tablets (placebo) there is a risk that their thyroid gland may slow down further, and they may develop symptoms of an underactive thyroid, including tiredness and lethargy.
Taking blood samples may cause slight discomfort and there may be a small chance of local bruising afterwards.
What are the possible disadvantages and risks of taking part?
If you have private medical insurance you should check with the company before agreeing to take part in the trial. You will need to do this to ensure that your medical insurance will not be affected.
What are the possible benefits of taking part?
Benefits to individual patients who take part in this study cannot be guaranteed. Even if it does not help you directly, the information we get from this study should help us make better decisions on treatment of future patients with subclinical hypothyroidism. If during the study, we find a medical condition of which you are unaware (e.g. high blood pressure), we will inform you and we will write to and inform your GP.
What if new information becomes available?
Sometimes during the course of a research project, new information becomes available about the treatment that is being studied. If this happens, your research doctor will tell you about it and discuss with you whether you want to continue in the study. If you decide to withdraw your research doctor will make arrangements for appropriate care to continue through your GP. If you decide to continue in the study you will be asked to sign an updated consent form.
Also, on receiving new information your research doctor might consider it to be in your best interest to withdraw you from the study. If this happens he / she will explain the reasons and arrange for your care to continue through your GP.
What happens when the research study stops?
When the research study stops your supply of study medicines will finish, and you will return any unused capsules to the research nurse. It is likely that the full results will not be available for several months. You and your GP will then be informed in writing of the key results of the study, and also which group you were in (Levothyroxine or placebo capsules).
After the study finishes there will then be a decision to make as to whether you then take Levothyroxine tablets as part of your routine care. This will be your decision, which you should make in consultation with your GP.
The study freephone will continue to be available for a minimum of 6 months after the study finishes; you will be able to use this to arrange to speak to one of the research doctors for further information or advice, should you wish.
After the study finishes the research team will continue to gather routine healthcare information about your hospital admissions and diagnoses, to enable further research to be done on long-term health outcomes in older people with subclinical hypothyroidism.
What if something goes wrong?
There are no special compensation arrangements if something goes wrong when you are taking part in this research project however you will receive the same legal protection as a standard National Health Service patient. If you are harmed due to someone’s negligence, then you may have grounds for legal action but you may have to pay for it. Regardless of this, if you wish to complain about any aspect of the way you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms will be available to you.
Will my taking part in this study be kept confidential?
All information which is collected about you will be kept strictly confidential. We will keep your personal details on a secure computer at Glasgow University and the Clinical Research Facility. This is required to allow us to communicate with you (e.g. by post or telephone), and for us to link to the routine health information that is held by the Scottish Government.
However your name and contact details will not be disclosed to any other people, other than to your GP or hospital doctor who is providing care to you. Your GP and any hospital doctors who are caring for you will be notified of your screening for participation in the trial. Agreement from you that your GP can be informed is a condition of entering the study.
Any information which leaves your GP surgery or hospital will have your contact details, including name and address, removed so that you cannot be recognised from it. Your anonymised details and results will be shared with our collaborating investigators in the Netherlands, Ireland, Switzerland and the USA.
What will happen to the results of the research study?
The results of the main part of the research should be available within 6 months of you completing the study, and it is expected the primary publication will be within 12 months. You and your GP will be informed in writing of the key results of the study (anticipated between 6 and 12 months after you finishing in the study), and also which group you were in (thyroxine or placebo tablets). The results and details of publications will also be placed on the study website, at the time of publication. You will not be identified in any report or publication.
Who is organising and funding the research?
The organisation funding the research is the European Union. The team conducting the research in Scotland is from the University of Glasgow (linking with Greater Glasgow Health Board); this research is in collaboration with Leiden University Medical Centre in the Netherlands, Cork in Ireland, and University of Berne in Switzerland. We are also collaborating with thyroid experts from the University of California in the USA.
Who has reviewed the study?
The research project has been reviewed by, and received approval from the following;
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The European Union grant reviewers (includes ethical review).
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The Scottish Multicentre Research Ethics Committee (MREC A).
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Thyroid Federation International, the umbrella organisation for patient support groups for those with thyroid disorders. It aims to work for the benefit of those affected by thyroid disorders throughout Europe and the world.
Contacts for Further Information
Further information can be obtained through the study freephone 0800 328 0772or on the study website (www.trusthyroidtrial.com). General information about thyroid problems can be found on the Thyroid Federation International website at www.thyroid-fed.org. The doctors who are running the clinical aspects of the study in Scotland are; Professor David J Stott and Dr Terence J Quinn, Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 4th floor Walton building Glasgow Royal Infirmary G4 0SF.