Aged 45-70 - the entry criteria are based on a relative risk of at least two-fold and are similar to IBIS-I. At least one of the following must be satisfied:

1) First degree relative who developed breast cancer at age 50 or less

2) First degree relative who developed bilateral breast cancer

3) Two or more first or second degree relatives who developed breast or ovarian cancer

4) Nulliparous (or first birth at age 30 or above) and a first degree relative who developed breast cancer

5) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer

6) Mammographic opacity covering at least 50% of the breast in absence of HRT use within the last 3 months

Also aged 60-70 - because of their higher baseline risk, women aged 60-70 can enter the study with a smaller relative risk:

7) First degree relative with breast cancer at any age

8) Age at menopause >= 55 years

9) Nulliparous or age at first birth 30 years or above

Aged 40-44 - who are postmenopausal (usually because of a bilateral oophorectomy) are eligible if they satisfy one or more of the following criteria (approximately 4-fold risk or greater):

10) Two or more first or second degree relatives who developed breast or ovarian cancer at age 50 or less

11) First degree relative with bilateral breast cancer who developed the first breast cancer at age 50 or less

12) Nulliparous (or first birth at age 30 or above) and a first degree relative who developed breast cancer at age 40 or less

13) Benign biopsy with proliferative disease and a first degree relative who developed breast cancer at age 40 or less

All Age Groups (40—70) - women who have had certain breast conditions will also be eligible. These are:

14). Lobular carcinoma in situ (LCIS)

15) Atypical ductal or lobular hyperplasia in a benign lesion

16) DOIS, diagnosed within the last 6 months, and treated by mastectomy

1. IBIS-II (Prevention)

2. Introduction

You are being invited to take part in a research study. Before you decide 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 others if you wish. Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

Consumer for Ethics in Research (CERES) publish a leaflet entitled ‘Medical Research and You’. This leaflet gives more information about medical research and looks at more questions you may want to ask. A copy may be obtained either in the unit where you are being treated or from CERES, PO Box 1365, London N16 0BW. Thank you for reading this.

Randomised Trial: Sometimes, because we do not know the best way of treating patients, we need to compare different treatments. People are randomly put into groups by a computer. The groups are given different treatments, and these are compared to see if one treatment is better.

Blind trial: In a double blind trial neither you nor your doctor will know which treatment group you have been allocated to (Although, if your doctor needs to find out he/she can do so).

Placebo: A placebo is a non-active treatment such as a pill which looks like the real thing but is not. It contains no active ingredient (i.e. therapeutic agent) but it can contain lactose.

Codebreak: Is when information regarding which trial treatment you have been taking is given to yourself and maybe your doctor.

Adjuvant: Treatment given for cancer after the first main treatment, e.g. tamoxifen would be adjuvant treatment for a woman who has had a lumpectomy or mastectomy for breast cancer.

Enzyme: A protein that acts as a catalyst for the body’s metabolic processes, i.e. causes a change to happen.

Oestrodial: Is one of the natural oestrogen hormones.

3. What is the purpose of the study?

This study has been set up to investigate whether the new drug, anastrozole, can be used effectively to prevent breast cancer. We will be investigating how well tolerated this drug is and how effective it is compared to a placebo. This is a randomised, double blind study, which means that you will have an equal chance of receiving anastrozole or placebo. The reason for this is because we do not know whether anastrozole is more effective than no treatment. The study is double blind in order to reduce any bias when it comes to reporting or recording side effects. Neither you nor your local co-ordinator will know which treatment group you are randomised to.

4. Why have I been chosen?

You have been chosen to take part in the research study because you are postmenopausal and aged between 40-70 years with either, a family history of breast cancer, or a personal history of non-invasive breast cancer or an atypical benign breast lesion.

We are inviting 6,000 women whom, like you, are at increased risk of developing breast cancer to join this study. At least a quarter of these women will be recruited in various centres around the UK.

5. Do I have to take part?

It is up to you to decide whether or not to take part. If you do decide to take part you will be given this information sheet to keep and be asked to sign a consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. A decision to withdraw at any time, or a decision not to take part, will not affect the standard of care you receive.

6. What will happen to me if I take part?

Before you are able to join the study you will be asked to comply with certain conditions.

You may not be able to join if:

• You have osteoporosis. An x-ray of your spine and a bone scan will be required to check that you do not have any early signs of osteoporosis. However, you may still be able to join the study if you are willing to take bisphosphonates (bone medication).
• You are using oestrogen-based hormone replacement therapy (HRT). You would have to change to an alternative non-hormonal treatment.

You should discuss these with your doctor before making your decision.

If you decide to join the study, you will be randomly assigned to one of two groups (i.e. you have a 50/50 chance of being assigned to either group):

1. anastrozole – 1mg
2. placebo

You will be asked to take one tablet every day for five years. The placebo tablets contain inactive substances. No one (apart from the Co-ordinating Centre) will know who is taking the tablets with the active ingredients.

You will have check-ups every year and regular mammograms. If you decide to take part, your GP will be told that you are involved in the study and will be notified about any important findings. You will also be asked to provide a blood sample. This will be considered as a gift to Cancer Research UK and will be stored securely by the charity indefinitely. We do not know exactly what tests may be carried out in the future, but it is likely that some of these may be of a genetic nature. Your sample will be identified by a study number only, and any test results will not be available individually but will only be reported anonymously on a group basis. In order to protect you, the blood samples will be made completely anonymous before any genetic tests are performed. We would also like your permission for us to have access to any relevant tissue specimen should you have further investigations or operations. If you do not wish to do this you may still participate in the trial, but you should tick the appropriate ‘No’ boxes on the Consent form.

You may receive additional questionnaires from time to time requesting further relevant information, some perhaps even after active participation has been concluded.

Please note that you are always able to contact your research centre between your yearly appointments.

Unfortunately funding for the study is not sufficient to cover individual travel expenses for clinic visits. However, your local clinic may be able to make special arrangements for you

7. What do I have to do?

It is important that you take the medication regularly. This will be one tablet a day for five years. If you are already taking other medication you may take these tablets at the same time, otherwise you may take them at any time of the day. If you forget to take a tablet one day do not take two the next day, but just continue on the one a day regime for the five years. There are no dietary restrictions associated with this study. You will still be able to drive, drink and take part in any sport you wish to.

Taking part in the study should not have any major affect on your daily activities. However, if you are a blood donor, the Blood Transfusion Centre has advised us that women participating in this study should not give blood.

If you have life assurance or private medical insurance, you may need to inform the company about your involvement with the study, though this should not affect your status from their point of view. You may wish to discuss this with your own company before you decide whether to take part in the study or not.

You should inform any doctor or person treating you for a medical condition that you are involved with the study and may be taking anastrozole. Remember, you will not know whether you are taking the placebo or the ‘real thing’.

8. What is the drug that is being tested?

Anastrozole is a drug that is being used to treat breast cancer. It works by blocking the production of oestrogen by interfering with an enzyme called aromatase. Therefore it is called an aromatase inhibitor. In postmenopausal women, oestrogens are produced primarily from the conversion of other hormones through the aromatase enzyme complex in peripheral tissues, e.g. fatty tissue. Anastrozole prevents this happening, thus reducing the amount of oestrogen in the body. This reduction has been shown to produce a beneficial effect in women with breast cancer. It cannot block oestrogen produced by the ovaries, so can only be used in postmenopausal women.

Until recently its use as an adjuvant in early breast cancer has been restricted to clinical trials, but it has now been licensed for use in the adjuvant setting in several countries.

9. What are the alternatives for preventing breast cancer?

Tamoxifen has been shown to reduce the risk of breast cancer by 30-40%, but it also has some side effects. These include gynaecological problems and an increased risk of blood clots which can lead to serious disease. Tamoxifen is not routinely indicated for women as a preventive treatment for breast cancer, but may be appropriate for selected women on an individual basis. You may wish to discuss this with your doctor.

Cancer Research UK recommends women at increased risk of developing breast cancer:

- to exercise regularly

- enjoy a healthy, balanced diet

- avoid being overweight

- attend routine breast screening

10. What are the side effects of any treatment received when taking part?

All medicines have some side effects and anastrozole is no exception.

There is a concern about bone loss with long-term use, because anastrozole works by lowering oestrogen levels. For this reason we need to do a baseline bone density scan on all women to identify those who may have osteoporosis. This is currently being studied in women with breast cancer and will also be investigated in our study. There are also concerns about the quality of life, in particular memory and concentration, associated with a long-term reduction in oestrogen levels and this will be monitored during the study.

If you suffer any of the side effects described above or any other symptoms you should report them. If you become in any way concerned, you should contact your local centre (Contact details can be found in section 20 of this document).

11. What are the possible disadvantages and risks of taking part?

In addition to potential side effects in the previous section, you should be aware of the following:

• There is lactose in the placebo formulation and if you suffer from lactose intolerance you will not want to participate in the study.
• Your future insurance status for life insurance or private medical insurance may be affected by taking part in this study. 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 participation will not affect your medical insurance.

12. What are the possible benefits of taking part?

• You will be offered annual follow up by one of many specialist breast care teams involved in the study. You will receive appropriate screening and checks, and any problems or concerns you may have will be discussed. You will be advised if any further investigations are necessary.
• You will receive up to date information from your Local IBIS Team on any new research findings.
• You will automatically become a member of a growing body of women who are playing a vital part in the future treatment and understanding of breast cancer.
• You will have a 50% chance of receiving anastrozole. This may reduce your risk of getting breast cancer.
• The information we get from this study may help us to treat future patients with breast cancer better.

13. What if new information becomes available?

Sometimes during the course of a research project, new information becomes available about the treatment/drug 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 your care to continue. 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 interests to withdraw you from the study. He/she will explain the reasons and arrange for your care to continue.

An Independent Data Monitoring Committee will be over-seeing the study on a frequent basis and will ensure that any concerning issues are investigated and women are informed of any relevant new information as it becomes available. This patient information sheet and all other study literature will also be updated as and when new data becomes available.

14. What happens when the research study stops?

Recruitment to the study will continue for 4 years or until 6000 women are recruited. All women will be actively participating for five years and then will be followed up for a further five years by annual questionnaire. During all this time trial data will be regularly checked by the Independent Data Monitoring Committee and should important new information be discovered, women will be informed and advised appropriately. Currently anastrozole is not licensed for use for breast cancer chemoprevention, so it is not available outside a clinical trial.

At this stage, we are asking women to maintain the double blind protection of the trial and not to request a codebreak unless this is essential for their future health.

We will unblind in the following circumstances:

i) Where the woman develops breast cancer

ii) Where it is considered necessary by any clinician involved in her care

15. What if something goes wrong?

Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that ‘the sponsor’, without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury, not previously warned about, results from giving either drug or any other procedure carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected.

16. Will my taking part in this study be kept confidential?

If you consent to take part in the research any of your medical records may be inspected by the organisation sponsoring the research for purposes of analysing the results. These records may also be looked at by an independent auditing body and regulatory authorities to check that the study is being carried out correctly. Representatives from the ethics committee may also wish to review some of the data. Your name, however, will not be disclosed outside the hospital, GP surgery, Cancer Research UK or relevant NHS Registers.

17. What will happen to the results of the research study?

The study hopes to recruit the total number of volunteers over 4 years and each woman will take the study medication for 5 years. This means that it will be quite a long time before any results are available. However, an Independent Data Monitoring Committee will scrutinise data every 6 months and should important information come to light they will recommend that we inform all women included in the study.

18. Who is organising and funding the research?

The largest cancer charity in the UK - Cancer Research UK - are sponsoring this study.

The sponsors of this study will reimburse each of the Local Recruiting Centres for including women in this study.

19. Who has reviewed the study?

If you have any question about the study either contact your local centre:

Or alternatively, contact the Central Co-ordinating Office by writing to or calling:

1. IBIS-II (DCIS)

2. Introduction

You are being invited to take part in a research study. Before you decide 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 others if you wish. Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

Consumer for Ethics in Research (CERES) publish a leaflet entitled ‘Medical Research and You’. This leaflet gives more information about medical research and looks at more questions you may want to ask. A copy may be obtained either in the unit where you are being treated or from CERES, PO Box 1365, London N16 0BW. Thank you for reading this.

Randomised Trial: Sometimes, because we do not know the best way of treating patients, we need to compare different treatments. People are randomly put into groups by a computer. The groups are given different treatments, and these are compared to see if one treatment is better.

Blind trial: In a double blind trial neither you nor your doctor will know which treatment group you have been allocated to (Although, if your doctor needs to find out he/she can do so).

Placebo: A placebo is a non-active treatment such as a pill which looks like the real thing but is not. It contains no active ingredient (i.e. therapeutic agent) but it can contain lactose.

Double dummy: This is used in a trial with two active groups (i.e. both tablets contain a therapeutic agent) where the two substances in the trial look very different from each other. Each substance has a placebo match and each volunteer must take one active substance and one placebo without knowing which is which. In this study the tablets look very different from each other and therefore to establish a truly ‘blind’ design each woman has to take one active tablet and one placebo.

Codebreak: Is when information regarding which trial treatment you have been taking is given to yourself and maybe your doctor.

Adjuvant: Treatment given for cancer after the first main treatment, e.g. tamoxifen would be adjuvant treatment for a woman who has had a lumpectomy or mastectomy for breast cancer.

Enzyme: A protein that acts as a catalyst for the body’s metabolic processes, i.e. causes a change to happen.

Oestrodial: Is one of the natural oestrogen hormones.

3. What is the purpose of the study?

This study has been set up to investigate which of the two drugs, tamoxifen or anastrozole, is most effective at preventing local recurrence or a second breast cancer after completion of your surgery for ductal carcinoma in-situ. We will be investigating how well these drugs are tolerated. This is a randomised, double blind, double dummy study, which means that you will have an equal chance of receiving either drug. The reason for this is because we do not know whether anastrozole is more or less effective than tamoxifen. The study is double blind in order to reduce any bias when it comes to reporting or recording side effects. Neither you nor your local co-ordinator will know which treatment group you are randomised to.

Currently we do not know exactly how successful tamoxifen is in preventing local recurrence or a second breast cancer. The American DCIS study claims a significant reduction in breast cancer incidence but the UK DCIS (study) shows only a moderate benefit and it is too early to establish whether there will also be an effect on deaths. We need to look closely at the type of woman who may benefit most from taking tamoxifen. We do know, however, that tamoxifen is not the sole candidate for use in preventing local recurrence or a second breast cancer. A new group of drugs, known as aromatase inhibitors, have recently been shown to be effective in treating breast cancer and have few side effects. They are promising candidates for use in DCIS and we hope to provide important information about their value in this study as anastrozole is one of the drugs in this group.

You have been chosen to take part in the research study because you are postmenopausal and aged between 40-70 years with locally excised DCIS diagnosed in the last six months, in which there are tumour free margins of at least 1mm.

We are recruiting 4,000 women whom, like you, have already been diagnosed with DCIS. At least a quarter of these women will be recruited in various centres around the UK

5. Do I have to take part?

It is up to you to decide whether or not to take part. If you do decide to take part you will be given this information sheet to keep and be asked to sign a consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. A decision to withdraw at any time, or a decision not to take part, will not affect the standard of care you receive.

Before you are able to join the study you will be asked to comply with certain conditions.

You will not be able to join if:

• You have a history of blood clots
• You have had a previous stroke or transient ischaemic attack

You may not be able to join if:

• You have osteoporosis. An x-ray of your spine and a bone scan will be required to check that you do not have any early signs of osteoporosis. However, you may still be able to join the study if you are willing to take bisphosphonates (bone medication).
• You are using oestrogen-based hormone replacement therapy (HRT). You would have to change to an alternative non-hormonal treatment.

You should discuss these with your doctor before making your decision.

If you decide to join the study, you will be randomly assigned to one of two groups (i.e. you have a 50/50 chance of being assigned to either group):

1. tamoxifen 20mg and anastrozole placebo
2. tamoxifen placebo and anastrozole 1mg

You will be asked to take two tablets every day for five years. The placebo tablets contain inactive substances. No one (apart from the sponsor) will know who is taking the tablets with the active ingredients. Tamoxifen and anastrozole look quite different from each other, which is why we need to have a placebo tablet for each of the active tablets and why the study is called ‘double dummy’.

You will have check-ups every year and regular mammograms. If you decide to take part, your GP will be told that you are involved in the study and will be notified about any important findings. You will also be asked to provide a blood sample. This will be considered as a gift to Cancer Research UK and will be stored securely by the charity indefinitely. We do not know exactly what tests may be carried out in the future, but it is likely that some of these may be of a genetic nature. Your sample will be identified by a study number only, and any test results will not be available individually but will only be reported anonymously on a group basis. In order to protect you, the blood samples will be made completely anonymous before any genetic tests are performed. We would also like your permission for us to have access to any relevant tissue specimen should you have further investigations or operations. If you do not wish to do this you may still participate in the trial, but you should tick the appropriate ‘No’ boxes on the Consent form.

You may receive additional questionnaires from time to time requesting further relevant information, some perhaps even after active participation has been concluded.

Please note that you are always able to contact your research centre between your yearly appointments.

Unfortunately funding for the study is not sufficient to cover individual travel expenses for clinic visits. However, your local clinic may be able to make special arrangements for you.

It is important that you take the medication regularly. This will be two tablets a day for five years. If you are already taking other medication you may take these tablets at the same time, otherwise you may take them at any time of the day. If you forget to take your tablets one day do not take two lots the next day, but just continue on the two a day regime for the five years. There are no dietary restrictions associated with this study. You will still be able to drive, drink and take part in any sport you wish to.

Taking part in the study should not have any major affect on your daily activities. However, if you are a blood donor, the Blood Transfusion Centre has advised us that women participating in this study should not give blood.

If you have life assurance or private medical insurance, you may need to inform the company about your involvement with the study, though this should not affect your status from their point of view. You may wish to discuss this with your own company before you decide whether to take part in the study or not.

You should inform any doctor or person treating you for a medical condition that you are involved with the study and you are taking tamoxifen or anastrozole. Remember, you will not know which one you are taking.

8. What are the drugs that are being tested?

We know that tamoxifen has major benefits for women who have had surgery for breast cancer. Previous research has shown that if taken for up to five years, tamoxifen can:

• Reduce the risk of breast cancer returning by more than one-third
• Reduce breast cancer deaths by nearly one-quarter
• Reduce the risk of developing cancer in the other breast by nearly half

In 1999 an American study reported on the use of tamoxifen as an adjuvant agent in DCIS and showed a 37% reduction of recurrence. However, so far a UK DCIS study has only found a 17% reduction.

Tamoxifen may also help with other health problems. The drug reduces the level of fats (cholesterol) that can ‘fur up’ blood vessels. One study showed that tamoxifen halved the rate of fatal heart attacks in postmenopausal women, but other studies have not found an effect.

The drug also reduces the rate of bone loss (osteoporosis) in the spine after the menopause. Recent evidence from the American prevention study showed a one-third reduction in fractures of the wrist, hip and spine.

Anastrozole is a drug that is being used to treat breast cancer. It works by blocking the production of oestrogen by interfering with an enzyme called aromatase. Therefore it is called an aromatase inhibitor. In postmenopausal women, oestrogens are produced primarily from the conversion of other hormones through the aromatase enzyme complex in peripheral tissues, e.g. fatty tissue. Anastrozole prevents this happening, thus reducing the amount of oestrogen in the body. This reduction has been shown to produce a beneficial effect in women with breast cancer. It cannot block oestrogen produced by the ovaries, so can only be used in postmenopausal women.

Until recently its use as an adjuvant in early breast cancer has been restricted to clinical trials, but it has now been licensed for use in the adjuvant setting in several countries.

9. What are the alternatives for diagnosis or treatment?

10. What are the side effects of any treatment received when taking part?

There is a great deal of information about the possible side-effects of taking tamoxifen for up to five years, but less is known about anastrozole, as it is a much newer drug. However, there are now over 550,000 total women years of use and our knowledge of side effects is developing all the time.

The most common side effects for both drugs are menopausal type symptoms and these can reappear in women who have already been through the change. With tamoxifen these usually present as hot flushes and changes in vaginal bleeding and secretions. This occurs in about 10% of postmenopausal women. Similar effects are found with anastrozole but they are less fully documented. Most of these side effects may also be related to normal hormonal changes.

There are also some very rare but potentially serious side effects: Several research studies have suggested an increased risk of cancer of the lining of the womb (endometrial cancer) in post-menopausal women taking tamoxifen. This is a rare form of cancer and available evidence suggests that the normal risk of 4 women in every 10,000 each year developing the disease is increased to 8-12 per 10,000 per year as a result of taking tamoxifen. Most cases of endometrial cancer are detected early and can be treated by removal of the womb (hysterectomy) and fortunately this is usually completely successful. However, late-stage or high-grade tumours have been seen very rarely.

Any unusual vaginal bleeding should be reported to your GP without delay. This could be due to a number of causes, but your doctor will check whether it could be endometrial cancer so that any necessary treatment can be carried out as early as possible.

Tamoxifen has also been reported to increase the risk of blood clots. This is rare but can occasionally have serious consequences. Women at high risk of blood clots should not participate in this study.

Eye problems have occasionally been reported in women taking tamoxifen. Recent research has shown that tamoxifen can cause a slight increase in the development of cataracts. A very rare eye complication - tamoxifen retinopathy - can cause impaired eyesight, but this usually disappears when treatment is stopped. If you do take part in the study, tell your GP about any changes in your eyesight as soon as they occur. Studies to date have not found that any other cancers are associated with the use of tamoxifen.

Anastrozole does not appear to have some of the other side effects of tamoxifen, such as blood clots or endometrial cancer, but there is a concern about bone loss with long-term use, because anastrozole works by lowering oestrogen levels. For this reason we need to do a baseline bone density scan and x-ray of the spine on all women to identify those who may have osteoporosis. This is currently being studied in women with breast cancer and will also be investigated in our study. There are also concerns about the quality of life, in particular memory and concentration, associated with a long-term reduction in oestrogen levels and this will be monitored during the study.

If you suffer any of the side effects described above or any other symptoms you should report them. If you become in any way concerned, you should contact your local centre (Contact details can be found in section 20 of this document).

11. What are the possible disadvantages and risks of taking part?

In addition to potential side effects in the previous section, you should be aware of the following:

12. What are the possible benefits of taking part?

• You will be offered annual follow up by one of many specialist breast care teams involved in the study. You will receive appropriate screening and checks, and any problems or concerns you may have will be discussed. You will be advised if any further investigations are necessary.
• You will receive up to date information from your Local IBIS Team on any new research findings.
• You will automatically become a member of a growing body of women who are playing a vital part in the future treatment and understanding of breast cancer.
• You will have a 50% chance of receiving either tamoxifen or anastrozole. Both of these treatments may reduce your risk of getting a recurrence of breast cancer.
• The information we get from this study may help us to treat future patients with breast cancer better.

13. What if new information becomes available?

Sometimes during the course of a research project, new information becomes available about the treatment/drug 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 your care to continue. 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 interests to withdraw you from the study. He/she will explain the reasons and arrange for your care to continue.

An Independent Data Monitoring Committee will be over-seeing the study on a frequent basis and will ensure that any concerning issues are investigated and women are informed of any relevant new information as it becomes available. This patient information sheet and all other study literature will also be updated as and when new data becomes available.

14. What happens when the research study stops?

Recruitment to the study will continue for 4 years or until 4000 women are recruited. All women will be actively participating for five years and then will be followed up for a further five years by annual questionnaire. During all this time trial data will be regularly checked by the Independent Data Monitoring Committee and should important new information be discovered, women will be informed and advised appropriately. At this stage, we are asking women to maintain the double blind protection of the trial and not to request a codebreak unless this is essential for their future health.

We will unblind in the following circumstances:

i) Where the woman develops breast cancer

ii) Where it is considered necessary by any clinician involved in her care

15. What if something goes wrong?

Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that ‘the sponsor’, without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury, not previously warned about, results from giving either drug or any other procedure carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected.

16. Will my taking part in this study be kept confidential?

If you consent to take part in the research any of your medical records may be inspected by the organisation sponsoring the research for purposes of analysing the results. These records may also be looked at by an independent auditing body and regulatory authorities to check that the study is being carried out correctly. Representatives from the ethics committee may also wish to review some of the data. Your name, however, will not be disclosed outside the hospital, GP surgery, Cancer Research UK or relevant NHS Registers.

17. What will happen to the results of the research study?

The study hopes to recruit the total number of volunteers over 4 years and each woman will take the study medication for 5 years. This means that it will be quite a long time before any results are available. However, an Independent Data Monitoring Committee will scrutinise data every 6 months and should important information come to light they will recommend that we inform all women included in the study.

18. Who is organising and funding the research?

The largest cancer charity in the UK - Cancer Research UK - are sponsoring this study.

The sponsors of this study will reimburse each of the Local Recruiting Centres for including women in this study.

19. Who has reviewed the study?

20. Contact for Further Information

If you have any question about the study either contact your local centre:

Or alternatively, contact the Central Co-ordinating Office by writing to or calling:

1. IBIS-II (Bone sub study)

2. Introduction

You have already agreed to take part in the main IBIS II Prevention Study and now you are being invited to take part in a second related study looking at how this treatment affects bone density. Please note, this information leaflet is specifically for the Bone sub study and you should have received a separate document explaining the main Prevention Study. Before you decide 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 others if you wish. Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

Consumer for Ethics in Research (CERES) publish a leaflet entitled ‘Medical Research and You’. This leaflet gives more information about medical research and looks at more questions you may want to ask. A copy may be obtained either in the unit where you are being treated or from CERES, PO Box 1365, London N16 0BW.

Randomised Trial: Sometimes, because we do not know the best way of treating patients, we need to compare different treatments. People are randomly put into groups by a computer. The groups are given different treatments, and these are compared to see if one treatment is better.

Blind trial: In a double blind trial neither you nor your doctor will know which treatment group you have been allocated to (Although, if your doctor needs to find out he/she can do so).

Placebo: A placebo is a non-active treatment such as a pill which looks like the real thing but is not. It contains no active ingredient (i.e. therapeutic agent) but it can contain lactose.

Codebreak: Is when information regarding which trial treatment you have been taking is given to yourself and maybe your doctor.

BMD (Bone Mineral Density):

This measures the mass of bone tissue. This mass is an indication of how strong your bone is and how likely you are to suffer a fracture. It is usually measured in a relative way as bone thinning occurs naturally with age (see T-score definition).

DXA (Dual X-ray Absorptiometry):

This is a scan to measure BMD. This test is the most accurate currently available. It takes about 10 to 15 minutes and is a simple, safe and painless procedure that uses very low doses of radiation.

T-score:

This is a standardised measure of bone mineral density where the reference is a healthy premenopausal woman. Thus a value of zero corresponds to the average bone mineral density for premenopausal women and negative values indicate varying degrees of bone loss. Levels below –2.5 indicate osteoporosis and levels between –1.0 and –2.5 indicate lesser degrees of bone loss known as osteopenia.

3. What is the purpose of the study?

The Bone Sub study has been designed to examine the effects of anastrozole on Bone Mineral Density (BMD) and the risks of developing osteoporosis and/or fractures among women participating in the IBIS-II (prevention) study. It will look at the following three areas:

• Changes in bone spine and hip among women receiving anastrozole. These will be compared to the changes in the placebo group.
• The effectiveness and tolerability of a bisphosphonate (a drug which prevents bone loss) in women taking anastrozole.
• How changes in blood levels of biochemical markers involved in the body’s process of making bone predict longer-term changes in bone mineral density.

4. Why have I been chosen?

If you have decided to join the IBIS-II (Prevention) study then you are also invited to join this Bone sub study. You will have plenty of time to discuss the implication of this. However, if you already have a serious problem with your bones, then we would ask you to make sure your study doctor knows this and you would not be eligible to join the sub study. These problems include:

You have been chosen to take part in the research study because you are postmenopausal and aged between 40-70 years with either, a family history of breast cancer or a personal history of non-invasive breast cancer or an atypical benign breast lesion.

5. Do I have to take part?

It is up to you to decide whether or not to take part. If you do decide to take part in this sub study you will be given this information sheet to keep and be asked to sign this second consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. You may also withdraw from this sub study and continue in the main study. A decision to withdraw at any time, or a decision not to take part, will not affect the standard of care you receive.

6. What will happen to me if I take part?

Once you decide to participate you will be asked to have a DXA scan. Depending on the results from this scan you will then be allocated to one of the following three groups as shown in the diagram (Figure 1).

• Group I. Women in this group will have good bone strength but will be recommended to take calcium and vitamin D to ensure this is maintained.
• Group II. Women in this group have some evidence of mild bone loss and it is unclear as to whether they may be at increased risk of further loss should they be taking anastrozole. The women will be randomised to take either bisphosphonate treatment or a placebo once a week. Therefore this group of women will have to take an extra tablet each week together with the daily tablet they are already taking in the main study.
• Group III. Women in this group have markedly reduced bone strength at the beginning and will only be able to participate in the main study as well as this sub study if they agree to take bisphosphonate treatment. Therefore this group of women will have to take an extra tablet each week together with the daily tablet they are already taking in the main study.

All women will be monitored and given advice on maintaining healthy bones. Supplementation with calcium and vitamin D is recommended for all women in this study. You will be attending follow up checks during your five-year participation in IBIS-II Prevention. In addition to these we will be asking you to have:

• Follow-up DXA scans of the spine and hip at 1 year, 3 years, 5 years and 7 years.
• Height and weight measurements at every DXA scan visit.
• An extra blood sample at 6 months as well as at entry into the study, 12 months and at the final visit.

7. What do I have to do?

It is important that you take all trial medication regularly and follow the advice given for the main study. In order to maximise the effect of the bisphosphonate treatment, tablets should be taken in the morning on an empty stomach with a full glass of water. You should then not eat or lie down for 30 minutes.

There are no dietary restrictions associated with this study. You will still be able to drive, drink and take part in any sport you wish to.

You will be asked to attend for DXA scans and blood tests at specific times so that any changes in your bones can be measured accurately.

8. What are the drugs that are being tested?

Anastrozole -you will already have received information about anastrozole in the Prevention Study Information leaflet. This study will also be investigating how anastrozole affects bone and the value of bisphosphonates in managing any bone loss. This drug will be taken by all women in Group III and half the women in Group II.

Bisphosphonates - are non-hormonal drugs that work by slowing down the cells which break down bone tissue (osteoclasts), thus allowing the bone building cells (osteoblasts) to work more effectively. This will result in halting the loss of bone mineral density and repairing the damage already done. There are several different types of bisphosphonates used to treat osteoporosis. The type used in this study requires only one tablet to be taken each week.

Vitamin D - stimulates the formation of new bone protein and calcium intake.

Calcium- is the mineral that gives the bones strength.

9. What are the alternatives for preventing Osteoporosis?

There are a number of approaches to dealing with osteoporosis in the general population. These include the use of hormone replacement therapy (HRT), drugs such as tamoxifen and raloxifene which affect oestrogen activity (SERMs), bisphosphonates and calcium and vitamin D supplementation. HRT and SERMs cannot be used here, because they interfere with the action of anastrozole, and HRT increases the risk of breast cancer. Currently we do not know the best way to prevent osteoporosis in women taking anastrozole. It is clear that some women are at greater risk of getting osteoporosis, especially if they have other conditions that affect their bones. We know that a healthy diet and weight bearing exercise helps to maintain good bone strength, but it is not clear how much benefit is obtained from taking calcium and vitamin D supplements. It is also unclear as to how effective bisphosphonate treatment is in the presence of anastrozole. We are also uncertain as to when bisphosphonates should be recommended.

10. What are the side effects of any treatment received when taking part?

Bisphosphonates are generally well tolerated and no serious side effects are reported. The most common problems experienced are usually associated with the digestive system. These can range from mild stomach pain and nausea to diarrhoea and some inflammation of the gut. These side effects are substantially reduced by taking treatment once a week, as will be the case in this study. In order to minimise the risk of any irritation in the lower end of the oesophagus (gullet), the tablet should be taken with a full glass of water first thing in the morning.

Apart from mild indigestion and constipation, calcium and Vitamin D have no untoward side effects unless taken in excessive doses.

11. What are the possible disadvantages and risks of taking part?

A DXA scan uses a small dose of X-rays. The total dose received from the five scans in this study is the same as that from a chest X-ray, a holiday flight to North America, or 1 weeks exposure to natural background radiation"

12. What are the possible benefits of taking part?

If serious bone loss is detected in a woman she will be offered bisphosphonate or other appropriate treatment under the direction of the local bone physician. We know that the sooner osteoporosis is diagnosed and treated then the better the outlook. This is because the bone thinning process can be stopped by medication.

13. What if new information becomes available?

Any relevant, new, scientifically proven information that becomes available during the running of the study will be made available to all participants. This will be accompanied by appropriate advice.

14. What happens when the research study stops?

Recruitment to the bone sub study will continue for 4 years or until 1000 women are recruited. All women will be actively participating for five years and a further DXA scan will be taken 2 years later to see if any long-term problems exist. During all this time trial data will be regularly checked by the Independent Data Monitoring Committee and should important new information be discovered, women will be informed and advised appropriately.

15. What if something goes wrong?

If you become ill you should consult your GP in the usual way, but always remind him / her of your participation in the study. Tell your IBIS local research coordinator of the illness at your next follow-up visit. Please telephone your local study centre at any time if you are worried about any symptoms. The monitoring provided in this sub study will allow treatment to be given early if substantial bone loss is detected.

If you are in Group II and need to know whether you have been taking bisphosphonates or placebo then the code may be broken to supply this information to you and your doctor if necessary.

Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that ‘the sponsor’, without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury, not previously warned about, results from giving either drug or any other procedure carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected.

16. Will my taking part in this study be kept confidential?

If you consent to take part in the research any of your medical records may be inspected by the organisation sponsoring the research for purposes of analysing the results. These records may also be looked at by an independent auditing body and regulatory authorities to check that the study is being carried out correctly. Representatives from the ethics committee may also wish to review some of the data. Your name, however, will not be disclosed outside the hospital, GP surgery, Cancer Research UK or relevant NHS Registers.

17. What will happen to the results of the research study?

The study hopes to recruit the total number of volunteers over four years and each woman will take the study medication for 5 years. This means that it will be quite a long time before any results are available. However, an Independent Data Monitoring Committee will scrutinise data every 6 months and should important information come to light they will recommend that we inform all women included in the study.

18. Who is organising and funding the research?

The largest cancer charity in the UK - Cancer Research UK - are sponsoring the IBIS-II study.

19. Who has reviewed the study?

20. Contact for Further Information

If you have any question about the study either contact your local centre:

Or alternatively, contact the Central Co-ordinating Office by writing to or calling:

A Longitudinal Study of the Effects of Anastrozole on Cognition in Post-menopausal Women at Risk of Developing Breast Cancer

We are inviting seven hundred women who are taking part in the main IBIS II trial to also take part in a study of memory and attention. You are being invited to take part in this research. Before you decide whether to join the study, please take time to read the information carefully. It is important that you understand why we are doing the research and what it will involve. Please ask us any questions you may have or if you would like more information.

During and after the menopause, women sometimes report that their memory, concentration and attention are not as good as they used to be. This may be related to changes in the amount of female hormones in the body especially oestrogen. We are conducting a study to investigate memory and attention in women who are having hormone treatment to prevent breast cancer. We need to know if anastrozole affects memory and attention. You are being asked to take part in this study.

We are asking all women joining the main IBIS II trial in certain hospitals to take part in the cognitive study as well. You have not been specifically selected for any other reason. We need to recruit 700 women for the cognitive study.

You do not have to take part in the cognitive study. If you decide not to do so it will not affect your right to join the main IBIS II trial. If you do wish to join the cognitive study we will ask you to sign a consent form. You are free to withdraw from the study at any time without giving a reason. This will not affect your participation in the main trial.

If you agree to take part, the researcher will arrange a convenient time and place to see you in the clinic or close to the hospital. The researcher will give you some memory tests. These will be similar to everyday situations such as trying to remember a telephone number or the details of a story so that you can retell it when you get home. The researcher will also ask you to complete a short form that measures your mood. This is because your mood may affect how you perform the memory tests. The total time needed will be about one hour.

What happens if I agree to join the study?

We will ask you to do the memory tests when you first join the main IBIS II clinical trial, before you begin taking your tablets. We will then ask you to do the tests again after 6 months, 2 years and 5 years. This is to measure any changes in your memory over time. If you agree to take part in the study, you are free to leave at any time. If you choose to leave the study, it will not affect your participation in the main IBIS II trial.

Taking part in the study of memory and attention will be of no direct benefit to you but the findings from the study may benefit people in the future. There are no disadvantages to taking part in the study other than the additional time you will be asked to spend in clinic while the cognitive tests are made.

Sometimes during the course of a research project new information becomes available about side effects of the drug that is being studied. If this happens the researcher will tell you about it and discuss with you whether you want to continue in the study. You are perfectly entitled to withdraw at any stage.

All the results we get from your test will be confidential. No one outside the research team will see your results, which will be stored without your name, just a number in the computer. Your name will not be disclosed to anyone outside the research team.

The Cancer Research UK funds this study of memory and attention.

If you would like any further information, please do ask the researcher who gives you this form.

Thank you very much for your help