Appendix 1: Patient Information leaflet for screening
Thyroid hormone replacement for older persons with mild thyroid dysfunction.
In the past 3 years blood was drawn at your general practice office or in the hospital. The results showed that you may be eligible for participating in the IEMO 80+ Thyroid Trial. For this reason your general practitioner or hospital specialist sends you this letter and the information leaflet regarding this research study.
1. What is the purpose of the research study?
Thyroid hormone has many important functions in the human body, for example supporting the correct function of the muscles, circulation, the brain and metabolism. When a shortage of thyroid hormone is present, bodily functions may not work optimally.
The results of one of your blood tests from the past suggest that you may have mild thyroid dysfunction (subclinical hypothyroidism). This is when thyroid hormone levels are within the normal laboratory limits, but signs are present that the body is urging the thyroid gland to work harder. This is usually a chance finding. This particular blood test result is common in older persons: of all persons aged 65 years and over 1 in 6 may have subclinical hypothyroidism. It is currently unknown whether it is beneficial to treat subclinical hypothyroidism with artificial thyroid hormone. The IEMO 80+ Thyroid Trial was set out to investigate this problem. The purpose of the IEMO 80+ Thyroid Trial is to find out what effects (good and bad) thyroxine replacement has in older people with subclinical hypothyroidism. In total 150 Dutch participants will participate in the IEMO 80+ Thyroid Trial.
2. What drug will be investigated?
We investigate the effect of synthetic thyroid hormone (Levothyroxine) in older persons with subclinical hypothyroidism. This thyroid hormone is given by tablet orally (by mouth). We will compare the effects of the thyroid hormone tablets with effects of a placebo tablet. The placebo tablets contain no active drug, but are identical in look, taste and smell.
3. How will the research study be conducted?
You have been asked to take part in this study because your recent screening blood test has suggested that you may have subclinical hypothyroidism. In some persons subclinical hypothyroidism corrects over time, whilst in other persons a clear shortage of thyroid hormone is identified. For this reason the first phase (the selection phase) will determine whether you have a persistent subclinical hypothyroidism. Only when this is the case, are you eligible for the second phase of the study (the treatment phase).
If you agree to participate in the selection phase of the study we ask you to complete and sign the consent form and send this in the enclosed envelope to the study center in the Leiden University Medical Centre. The study center will return a laboratory form and will ask you to visit your general practice laboratory or hospital research facility for a screening visit within 2 weeks. In this screening visit a blood test will be performed to assess the levels of thyroid hormone. The results of this test will be send to the research center in the Leiden University Medical Centre. If you are unable to visit the laboratory, please contact the study center. They will arrange for a laboratory nurse to visit you at home.
If the results from the screening test indicate that you are not eligible for the treatment phase, the study center will inform you in writing with the screening results and an explanation. The screening result will be shared with your general practitioner or hospital specialist.
If the results from the screening tests are satisfactory you will be invited to take part in the treatment phase of the study. A research nurse will contact you with the screening results and to plan an appointment for a home visit. During this home visit the research nurse will explain the treatment phase of the research study and you may decide to participate in the treatment phase.
If you decide to take part, you will be asked to complete and sign a second consent form. After signing the form some medical questions will be asked (including general questions regarding health, medication use and quality of life) as well as some additional measurements taken (including blood pressure, heart rhythm and grip strength).
After the home visit a computer will randomly allocate you to either the levothyroxine or placebo treatment group. The chance of allocation to either group is equal (50%). The study drug will be taken daily, at least 30 min before breakfast, during a maximum of 2 years.
A research nurse will perform home visits at the start of the research study, after 6–8 weeks, after 12 months and after 24 months. We will ask you to visit the general practice laboratory before every home visit to assess thyroid hormone levels.
4. What are the possible risks and benefits in participating?
It is not certain whether you will gain personal benefit from participating in the research study. After all, the purpose of this research study is to assess whether treatment with levothyroxine provides important benefits. A potential benefit is that your thyroid function will be assesses regularly, both in the screening and treatment phase. For future older persons with subclinical hypothyroidism the research study may yield important information. The blood measurements taken will most likely not result in harmful effects.
5. What happens if you decide not to participate in the research study?
Your participation is entirely voluntary and you are not in any way obliged to take part. You decide whether you want to participate. If you decide not to participate, no further action is required, and you are not required to provide a reason for not participating. If you do decide to participate, you reserve the right to withdraw from the research study at any given time without providing a reason to do so. Whether you decide to participate or not will in no way affect the standard of care you receive or the relationship you have with your general practitioner or hospital specialist.
6. Will the research study result in additional expenses/provide compensation?
No. You will not be charged for expenses related to the study medication or blood tests. Participating in this research study will not affect your policy excess for medical insurance. No compensation is provided for participating in the research study.
7. Further information?
Should you have any additional questions regarding the research study you are welcome to contact the IEMO secretary, telephone 071–526 84 93, or the central study coordinator: The Institute for Evidence-Based Medicine in Old Age | IEMO.
For questions or problems you may also contact the independent general practitioner, Dr. Niels H. Chavannes, telephone 071–526 84 44, n.h.chavannes@lumc.nl. He is up-to-date with all proceedings of the trial, but is not involved with the conduct.
8. Appendices
1. Informed consent form.
2. envelope.
Appendix 2: Patient Information leaflet for randomisation
Thyroid hormone replacement for older persons with mild thyroid dysfunction
Several weeks ago your general practitioner or hospital specialist has invited you for a blood screening test. According to the test results you still have mild thyroid dysfunction (subclinical hypothyroidism). You are being invited to take part in a research study:
The IEMO 80+ Thyroid Trial
In this leaflet you’ll find detailed information regarding the research study. Please take your time to review the contents carefully and discuss these with your partner, friends or family. Should you have additional questions you are welcome to discuss these with your general practitioner, a researcher or the research nurse. Additionally you may contact the independent general practitioner, who knows a lot about the study, but is not involved with the conduct. Contact information can be found on the final page.
1. What is the purpose of the research study?
Thyroid hormone has many important functions in the human body, for example supporting the correct function of the muscles, circulation, the brain and metabolism. When a shortage of thyroid hormone is present, bodily functions may not work optimally.
The results of one of your blood tests from the past suggest that you may have mild thyroid dysfunction (subclinical hypothyroidism). This is when thyroid hormone levels are within the normal laboratory limits, but signs are present that the body is urging the thyroid gland to work harder. This is usually a chance finding. This particular blood test result is common in older persons: of all persons aged 65 years and over 1 in 6 may have subclinical hypothyroidism. It is currently unknown whether it is beneficial to treat subclinical hypothyroidism with artificial thyroid hormone.
Having subclinical hypothyroidism is associated with slightly higher odds of developing cardiovascular diseases. Earlier small scale research demonstrated that treatment with synthetic thyroid hormone may provide beneficial effects on the circulation in older persons with subclinical hypothyroidism. Alternatively, synthetic thyroid hormone treatment may also result in unwanted side effects. Both the good and bad effects of thyroid hormone treatment have not been proven to this date.
The purpose of the IEMO 80+ Thyroid Trial is to find out what effects (good and bad) thyroxine replacement has in older people with subclinical hypothyroidism.
The research study has a specific aim to prevent cardiovascular diseases, and to improve the quality of life (for example by alleviating tiredness complaints), muscle strength and brain function. In total 150 persons in the Netherlands will take part in the IEMO 80+ Thyroid Trial. ‘IEMO 80+’ means that the research study is performed in persons aged 80 years and older. IEMO is an abbreviation for the Institute for Evidence-Based Medicine in Old Age, the institute responsible for coordinating the research study.
2. What drug will be investigated?
We investigate the effect of synthetic thyroid hormone (Levothyroxine) in older persons with subclinical hypothyroidism. This synthetic thyroid hormone is identical to the thyroid hormone produced by the human body and is the standard treatment when a definite shortage of thyroid hormone is identified in the blood. This thyroid hormone is given by tablet orally (by mouth). We will compare the effects of the thyroid hormone tablets with effects of a placebo tablet. The placebo tablets contain no active drug, but are identical in look, taste and smell. You will not be informed which of the two treatments you will receive. The study nurses are also unaware of your allocation.
You will start with 1 tablet, that will contain either 50 micrograms of levothyroxine (or 25 micrograms if your weight is below 50 kg or have a history of coronary strictures) or placebo. After 6–8 weeks all participants will have their blood hormone levels analysed. Based on these results a decision is made to change the treatment dose. If the laboratory results indicate a change in treatment dose is warranted a research nurse will explain this to you. From this point annual blood tests will monitor the response to the treatment (after 12 and 24 months).
3. How will the research study be conducted?
You have been asked to take part in this study because your recent screening blood test has suggested that you may have subclinical hypothyroidism.
If you agree to participate in the selection phase of the study we ask you to complete and sign the consent form and send this in the enclosed envelope to the study center in the Leiden University Medical Centre. We ask your permission to store additional blood samples for future research on blood and hereditary materials (DNA) that may influence the effects of thyroid hormone on bodily functions (such as the circulation, muscle strength, memory problems or frailty). The DNA will be isolated from the blood and stored for future research. This blood sample (equivalent to 8 teaspoons) will be taken during the first home visit. Other research not related to this research study will not have access to the stored blood and DNA samples and any information in the samples cannot be retraced to individual persons. If you object to the storage of blood and DNA you may choose not to participate in this particular portion of the trial.
After signing the consent form some medical questions will be asked (including general questions regarding health, medication use and quality of life) as well as some additional measurements taken (including blood pressure, heart rhythm and grip strength). This home visit will take approximately1 to 1.5 h.
After the home visit a computer will randomly allocate you to either the levothyroxine or placebo treatment group. The chance of allocation to either group is equal (50%). The study drug will be taken daily, at least 30 min before breakfast, during a maximum of 2 years.
A research nurse will perform home visits at the start of the research study, after 6–8 weeks, after 12 months and after 24 months. We will ask you to visit the general practice laboratory before every home visit to assess thyroid hormone levels.
4. What is expected of you?
If you decide to participate in the research study, you will be asked:
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To take between 1 and 3 tablets, once every day, in the morning
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To attend home visits with a research nurse for measurements
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To visit the general practice laboratory for thyroid hormone tests (after 6–8 weeks, after 12 months and after 24 months).
There are no lifestyle or dietary restrictions in this research study. Data from your medical records at the general practice office or hospital specialist will be collected. Your general practitioner or hospital specialist will be informed of your participation in the study.
5. Are there other treatment options?
There are no other treatment options for mild thyroid dysfunction (subclinical hypothyroidism).
6. What are the possible side effects?
Side effects from levothyroxine treatment are only rarely seen, particularly if blood tests are done regularly and adjustments to levothyroxine dosages are made to keep thyroid hormone levels in the normal range. If levothyroxine is prescribed in too high dosages there is a risk of side effects such as heart palpitations, tremors, sweating, feeling agitated, tiredness and shortness of breath and chest pains. Overmedication may cause leg swelling and there may be an increased risk of thinning of the bones (osteoporosis) and fractures.
If you suffer from epilepsy overmedication with thyroid hormone may result in an increased risk of seizures.
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 are allocated to the inactive tablets (placebo) there is a risk that the thyroid gland may slow down further, and they may develop symptoms of an underactive thyroid, including tiredness and lethargy. Should this develop during the research study the blood tests will identify an underactive thyroid and your general practitioner or hospital specialist will be consulted for starting treatment.
7. What are the possible risks and benefits in participating?
It is not certain whether you will gain personal benefit from participating in the research study. After all, the purpose of this research study is to assess whether treatment with levothyroxine provides important benefits. A potential benefit is that your thyroid function will be assesses regularly, both in the screening and treatment phase. For future older persons with subclinical hypothyroidism the research study may yield important information. The blood measurements taken will most likely not result in harmful effects.
8. What happens if you decide not to participate in the research study?
Your participation is entirely voluntary and you are not in any way obliged to take part. You decide whether you want to participate. If you decide not to participate, no further action is required, and you are not required to provide a reason for not participating. If you do decide to participate, you reserve the right to withdraw from the research study at any given time without providing a reason to do so. Whether you decide to participate or not will in no way affect the standard of care you receive or the relationship you have with your general practitioner or hospital specialist.
9. What happens after the research study is finished?
When the treatment phase of the study completes, the results will be analysed by the coordinating researchers. This process will last several months after the last participant has finished the duration of the study. You and your general practitioner will be informed in writing of your results during the study, and whether you were allocated to the levothyroxine or placebo group. Based on this information you and your general practitioner may discuss whether further treatment with levothyroxine is in your best interest.
10. Are you insured during the research study?
All participants of the research study are covered by insurance for potential damages resulting from the study, both during the study period and within 4 years of ending the study. At the end of this letter you will find the insured amounts, exceptions and contact information of the insurance agency.
11. What if new information becomes available?
The data from all study participants are reviewed at fixed time points by a specially installed independent commission. If the safety or quality of life of the participants is in jeopardy, this commission is entitled to stop the research study. The study team will contact you directly should this occur.
12. What happens to the data collected?
In this research study data from interviews, questionnaires and measurements will be collected. As well as blood sample analysis. All data and materials collected will be handled and stored confidentially. Only the lead investigator will have access to personal information. Unauthorized personnel will have no access to your data. The results from this research study will be published in scientific journals; the data will not be traceable to individual persons. Anonymised research data will be made available to the IEMO 80+ Thyroid Trial investigators.
13. Will your general practitioner/hospital specialist be informed of study participation?
We think it is important that your general practitioner or hospital specialist is informed when study medication is given. For this reason we will inform your general practitioner or hospital specialist in writing of your participation. A specific section of the consent form explains this in more detail. It is not possible to participate in the research study without this consent.
14. Will the research study result in additional expenses/provide compensation?
No. You will not be charged for expenses related to the study medication or blood tests. Participating in this research study will not affect your policy excess for medical insurance. No compensation is provided for participating in the research study.
15. Who has reviewed the study?
The Medical Ethics Committee from the Leiden University Medical Centre has reviewed and approved the research study.
16. Further information?
Should you have any additional questions regarding the research study you are welcome to contact the IEMO secretary, telephone 071–526 84 93, or the central study coordinator: The Institute for Evidence-Based Medicine in Old Age | IEMO.
For questions or problems you may also contact the independent general practitioner, Dr. Niels H. Chavannes, telephone 071–526 84 44, n.h.chavannes@lumc.nl. He is up-to-date with all proceedings of the trial, but is not involved with the conduct.