INSTITUTION HEADED PAPER

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1 PATIENT INFORMATION SHEET INSTITUTION HEADED PAPER 1. Study title Treatment Intensities and Targets in Rheumatoid Arthritis Therapy (the TITRATE trial). 2. Key Facts TITRATE is a trial for patients with rheumatoid arthritis who have intermediate disease their arthritis falls between being very active and being in remission. With standard care, patients with intermediate disease see their rheumatology team at least every year. Their treatment is maintained but not increased. An alternative is intensive management, which involves monthly visits to the rheumatology unit to increase drug treatment and provide supportive care. Intensive management could make rheumatoid arthritis less active and reduce disability. But it may also not be very helpful and could cause more side effects. Half of the patients in the trial will receive standard care and half will receive intensive management over a period of a year. The TITRATE trial will find out which approach is best for patients. 3. Invitation paragraph We would like to invite you 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. One of our team will go through the information sheet with you and answer any questions you have. Talk to others about the study 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. 4. What is the purpose of the study? We want to improve how rheumatoid arthritis is treated. Our long-term aims are to minimise disability, reduce joint damage and enhance quality of life. We know the activity of rheumatoid arthritis varies when patients are receiving treatment. Sometimes it can be very active. At other times it is in remission. We also know that when patients have very active disease, they need intensive management and that when their disease is in remission, they need less intensive treatment. Patients with very active rheumatoid arthritis usually have high levels of disability and poor quality of life. When patients with active rheumatoid arthritis receive intensive management, their joint inflammation is reduced. Such management also reduces their disability levels and improves their quality of life. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

2 When patients are in remission, they have low levels of joint inflammation with low levels of disability and their quality of life is often high. The management of remission focuses on maintaining but not increasing treatment intensity. Most of the time, disease activity falls between these two extremes. These patients have intermediate disease activity. Their arthritis is neither very active nor completely inactive. We know that over time, such intermediate activity arthritis will result in long-term disability and reduced quality of life. There is genuine uncertainty about how best to manage rheumatoid arthritis with intermediate disease activity. The present trial is intended to help reduce this uncertainty. One approach is to maintain but not increase the intensity of management when patients have intermediate disease activity. Current treatment recommendations, from bodies such as the National Institute for Health and Clinical Excellence (NICE), suggest seeing such patients at least annually, unless there are flares in their disease activity. Such flares require urgent assessment and intensive management. The result of following these current treatment recommendations is that such patients treatment intensities usually remain unchanged. Another approach is to give patients with intermediate disease activity intensive management. This means treating patients with intermediate disease activity in the same way as patients with active disease. It will result in increasing the intensity of treatment until patients achieve remission. We consider such intensive management should take a holistic approach and would involve supporting patients in a range of ways in addition to adjusting their medication. This will include providing information about the disease and its treatment and helping patients manage their symptoms. Intensive management of intermediate disease activity involves both risks and benefits. There are three main risks. The first risk is that it may not work. Just because intensive management helps patients with active disease does not mean it will help patients with intermediate disease. The second risk is that it may lead to an excessive number of side effects. There is always a tradeoff between feeling better because treatments work and feeling worse because treatment causes side effects. The third risk is that it costs too much to make it worthwhile. Although this is not a risk to patients, high cost treatments are a risk for the NHS and for society as a whole if they don t work very well. There are also three main benefits. The first benefit is that patients may become less disabled because their joint inflammation is better controlled. The second benefit is that they may have less joint damage. Finally, intensive management could lead to an improvement in overall quality of life. When there is genuine uncertainty of this sort, it can be resolved by undertaking a clinical trial. The TITRATE trial has therefore been set up. It will compare the benefits and risks of intensive management compared with current conventional treatment in patients with intermediate levels of disease activity. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

3 If intensive management is beneficial, it needs to pass three tests. First and foremost, it must result in more patients achieving remission of their arthritis than current treatment. Secondly, it must not cause too many side effects or add to the burden of the disease for patients. Finally, it needs to be affordable with the benefits being sufficiently large to justify the costs involved. 5. Why have I been invited? We are approaching you because you are currently attending a specialist rheumatology clinic and were diagnosed with rheumatoid arthritis at least six months ago. In the opinion of your Consultant Rheumatologist, you have what is known as an intermediate level of disease activity. 6. Do I have to take part? No. It is up to you to decide whether or not to take part. We will describe the study and go through this information sheet, which we will then give to you. After reading this information sheet and asking any questions you have, if you decide to take part, we will ask you to sign a consent form to show you have agreed to participate. You are free to withdraw at any time, without giving a reason. This would not affect the standard of care or the treatment that you receive. 7. What will happen to me if I take part? Sometimes we don t know how best to treat patients. To find out, we compare different approaches to treatment. In TITRATE, we will divide patients into two groups. One group will have standard care. The other will have intensive management. At the end of the trial we will compare the groups and see if one group does better than the other. If you take part in the TITRATE trial, you will have one of these approaches to treatment. We need to make sure the groups are the same to start with. So we put each patient into one of the groups by chance. This is called randomisation. It makes certain that the chance of being in one group or the other is equal. If you take part in TITRATE, you will be randomly placed in one treatment group or the other. Before the trial starts, you need to sign a consent form. This shows you are happy to take part in the trial. Next, your rheumatologist, nurse or another member of the research team will make certain you are suitable to take part. They need to check you have intermediate disease activity. They also need to make certain that you do not have any health problem that might interfere with intensive management. After making certain you can take part in the trial, a member of the research team will assess your arthritis in detail. Your joints will be assessed to see how swollen and tender they are. They will arrange blood tests and will X-ray your hands and feet to find out how severe your arthritis is and whether it has damaged your joints. They will also ask you to complete some questionnaires about how your arthritis affects your life, your views about your symptoms and your treatment, TITRATE PATIENT INFORMATION SHEET_Version 3.0_

4 your mood, and the services you have recently received. This initial assessment will take about 90 minutes. You will then be randomly assigned to one of two treatment groups. One group will have standard care and the other intensive management for one year. We will repeat the assessments of both groups after six and 12 months. We will ask you to return to the clinic on both occasions to see a member of the research team. The researcher will repeat the assessments and some of the questionnaires you completed at the beginning of the study, although X-rays of your hands and feet will only be repeated during your final visit at 12 months. The treatment approaches in the standard care and intensive management groups are different. These are explained next. Standard care If you are chosen at random to enter this group, you will receive standard treatment for one year. Standard care for patients with intermediate disease activity involves keeping drug treatment stable. It is not usual to provide additional supportive treatment as part of standard care. National guidance from NICE currently recommends that patients with intermediate disease activity should be seen at least once a year. During these annual assessments, patients often have hand and feet X-rays taken to assess whether their arthritis is getting worse. Most patients having stable treatment with disease-modifying drugs like methotrexate need to have regular blood monitoring for safety. These blood tests are carried out every one or two months. Much of this blood monitoring is organised by patients general practitioners (GPs). Some patients with intermediate disease will have flares in their arthritis. When flares occur, patients need to be seen urgently. Usually treatment is increased. Sometimes flares persist. Persisting flares are often treated using one of the new biological treatments. These biological treatments are given in line with national guidance from NICE. Patients who need to start a biological treatment have a range of screening tests, including a chest X-ray, to make sure it is safe for them to start this treatment. We know the ways in which rheumatology units provide standard care for patients with intermediate disease activity varies across England. Local care pathways may supplement national guidance from NICE. Those patients receiving standard care will continue to follow any local care pathways together with national guidance throughout the trial. Intensive management If you are chosen at random to enter this group, your arthritis will be managed intensively over a period of a year. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

5 Intensive management will involve 12 monthly visits to the rheumatology clinic to see a trained rheumatology specialist practitioner. This might be one of the nurses at your clinic or another healthcare professional. The goal of intensive management is to achieve remission. Your first visit will usually take place within one month of being screened. You will be given a handbook that will provide information about strategies for managing your rheumatoid arthritis. Your practitioner will spend time with you developing a shared treatment plan. This will involve discussing with you different treatment options and working out which options you want and those you do not want to have. At each monthly visit, your practitioner will assess your rheumatoid arthritis. This will include assessing your joints and taking a blood test. They will also suggest changes to your drugs. These suggestions will take account of your wishes, the drugs you have taken previously, your current disease activity and any side effects of treatment. You will be given drugs approved for rheumatoid arthritis. They will all be given at their approved dosages. They will all be monitored using national recommendations. Although intensive management may lead to patients having more drugs, this does not necessarily mean there will be an increase in side effects. This is because giving several drugs together at low dosages can give fewer side effects than giving one drug at a higher dosage. You will need regular blood tests for safety monitoring whilst taking disease-modifying drugs like methotrexate. These blood tests will be needed every month. They will be done as part of your intensive management. Patients who have flares while following intensive management will be able to receive biological treatments in the same way as patients following standard care. In addition, if patients continue to have several swollen and tender joints after six months of intensive management, they may also be able to receive biological treatments. These treatments will be in line with guidance from the British Society for Rheumatology and the approved use of these treatments. Standard care does not currently involve using biologics in this way. Your practitioner will also discuss with you additional ways of managing your symptoms and coping effectively with rheumatoid arthritis. They will ask you some questions and may ask you to complete some questionnaires to understand how your arthritis affects you. Together, you will identify what you feel are your main problems. These problems may include pain, fatigue and difficulties taking your drugs. Sometimes, you might be asked to complete diaries at home, and try out ways to overcome problems like pain and fatigue using supportive, non-drug treatment approaches. Each monthly visit will last between 30 and 60 minutes. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

6 Your rheumatology practitioner will have received training in delivering intensive management. We would like your practitioner to audio-record each monthly session. This will allow us to check whether the training has been effective. These recordings will be stored anonymously and will be uploaded onto a secure password-protected website. In order to preserve your anonymity, we will ask you and your practitioner not to mention any identifying information (such as your name) during your sessions. A small proportion of the recordings (randomly selected) will then be reviewed by trained members of the research team. This is to find out how the intensive management approach was delivered in general; they will not be used to change the care of individual patients. The researchers can only listen to the recordings. They will not be able to download them. At the end of the trial, the recordings will be destroyed. If you have any concerns about audio-recording, you can opt out of having some or all of your sessions recorded. The key points about intensive management are as follows: 1. You will be seen every month, your arthritis will be closely monitored, and your treatment will be tailored to your needs. The goal is to achieve remission. 2. The intensity of your drug treatment will be gradually increased until you achieve remission. It will involve a wide range of different treatment options used in a way that you find acceptable. 3. We will also provide additional ways of helping you to manage your symptoms. 8. Expenses and payments All patients who are suitable for this trial need to attend routine follow-up appointments in a rheumatology clinic for specialist advice. Most patients make their own way to these clinic appointments. Some patients may need hospital transport to attend, and the way this is provided varies depending on your local NHS trust practices. These arrangements will not change in the trial. Patients receiving standard care will continue to follow their current management approach and we will not be able to pay the transport costs for these routine visits, though hospital transport will be provided as usual if needed. Patients receiving intensive management will need to attend the hospital more often. We will also not be able to pay the transport costs for these visits, though hospital transport will be provided as usual if needed. The reason for this is that intensive management has to be possible in real life. If patients find the additional visits to hospital are too difficult or are unaffordable in the trial, the same will be true in real life and the approach will be impractical. However, as we will be able to undertake safety monitoring within the trial, patients may not necessarily have to attend for more medical visits because they will not also need regular blood tests at their GPs. We can provide help for attending the research visits. There will be four of these visits during the trial. Whichever group you are in, it is possible to claim up to 15 for each assessment visit (up to four) for the study. This is a total of 60 over the course of the study, and is to cover additional expenses incurred (for example, extra parking fees). TITRATE PATIENT INFORMATION SHEET_Version 3.0_

7 We will try to make certain that the intensive management visits coincide with the research visits whenever possible to minimise any inconvenience. 9. What will I have to do? All patients will be asked to attend four assessments over 12 months. These will consist of a brief screening assessment to check you are eligible for the study, a full baseline assessment at the beginning of the study, a mid-point assessment at six months and a final assessment at 12 months. All patients will be offered drug treatment to control their arthritis. Most treatment will be given as tablets. Some treatments will be given by injections. Occasional patients might need treatments given by infusion in hospital. All patients taking drugs for their arthritis will need to have blood tests for routine safety monitoring as required. The X-rays of your hands and feet taken initially and at 12 months to see if there is more joint damage are also usually taken as part of routine care. As a result there will be no increase in X-ray exposure. Patients receiving standard care will be asked to attend their rheumatology clinic at least once a year. Some patients may be seen more often if there is a clinical need or if this is routine practice in your local rheumatology unit. Your rheumatologist or specialist nurse will tell you about local practice. Where possible your mid-point and final assessments will be arranged to coincide with any standard clinic visits for your convenience. Patients receiving Intensive Management will be asked to attend for 12 monthly Intensive Management sessions. These will be in addition to the four research visits. The maximum number of visits will be 16 over the 12 months. However, we will try and arrange for the research visits and the assessment visits to occur at the same time to minimise the number of hospital visits. During the course of the trial, we will ask you not to take part in other research studies. This is because it is best only to take part in one research study at a time. You will be able to take any existing drug treatment for your arthritis or for any other conditions you have as directed by your doctor. You can continue to consult your GP during the study about your arthritis or any other condition during the trial. We will let your GP know you are taking part in the trial. The tables below show the number of visits required for the study, what will happen at each visit, and approximately how long each visit is expected to last. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

8 Research Assessments Visit Time Taken What will happen Screening 30 minutes Review by rheumatologist, nurse or member of research team to check you are eligible to take part. First Assessment 90 minutes These will include: Six Month Assessment 45 minutes Detailed assessment of arthritis, blood test and X- rays Questionnaires (e.g. about impact of arthritis on Final Assessment 65 minutes your life) Collection of information about your medication and the services you have received. The numbers of questionnaires administered at each assessment will vary, with more at baseline, and the six-month assessment will not include X-rays. Standard Care Visit Time Taken What will happen Clinic Visit (one or more) minutes A standard outpatient review. Up to 12 visits to GP for safety monitoring 5-10 minutes Blood taken and results checked. Intensive Management Visit Time Taken What will happen Review by trained rheumatology specialist practitioner (a nurse or other healthcare professional) at local rheumatology clinic. Sessions will involve: Discussing additional ways of managing symptoms and coping with rheumatoid arthritis. 12 visits (including Provision of information. safety monitoring) minutes Developing a shared treatment plan with your practitioner (first visit). Identifying problems/issues you would like to work on. Adjusting your medication if you are experiencing symptoms of arthritis. 10. What are the alternatives for diagnosis or treatment? The study compares intensive management with standard care for patients with rheumatoid arthritis. If you do not wish to take part in the study you will continue to receive standard care. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

9 11. What are the possible disadvantages and risks of taking part? The main disadvantage of taking part is that more time will be spent having detailed assessments of your arthritis. All patients will have detailed assessments every six months which will last up to 90 minutes. Patients who are receiving intensive management will also have monthly visits which will last up to one hour. If you have intensive management you are likely to receive more drug therapy. It is possible that this will result in more side effects, though there is little evidence that this is likely to occur. This is because close monitoring and adjustment of treatment is more likely to limit the risk of side effects. 12. What are the side effects of any treatment received when taking part? All the treatments used in the TITRATE trial will be standard drugs given at standard doses for rheumatoid arthritis. Whilst all treatments used have side effects, these will be the same as those experienced in standard care. If you have intensive management it is possible you will have more side effects because you are taking more treatment. But it is also possible that close monitoring will reduce the risk of side effects. You will be given full information (including details of possible side effects) about any treatment prescribed in the trial. 13. What are the possible benefits of taking part? We cannot promise the study will help you but your arthritis will be monitored very closely by the rheumatology research team. You will have a dedicated member of the research team who you will be able to contact directly with any questions or concerns relating to your participation in the study. Although not a direct benefit to you, it is hoped that the information we get from this trial will help improve the treatment and management of rheumatoid arthritis in the future. 14. What happens when the research study stops? Your rheumatologist will continue to monitor your arthritis according to national guidelines and local practices. 15. What if relevant new information becomes available? Sometimes we get new information about the treatment being studied. Although it is unlikely that this would happen for the whole treatment package in this trial, it is always a potential development. If it occurs your supervising rheumatologist will tell you and discuss whether you should continue in the study. If you decide not to carry on, your research doctor will make arrangements for your care to continue. If you decide to continue in the study he may ask you to sign an agreement outlining the discussion. It is also possible that the study might be stopped for another reason. Once again, your supervising rheumatologist will tell you and arrange your continuing care. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

10 16. What will happen if I don t want to carry on with the study? You can withdraw from the study at any time. If you decide to withdraw from the study, your standard of care will not be affected. You will still need to attend for your routine follow-up assessments as part of your standard NHS care. If you would be happy to do so, we would like to continue to collect information from you at these less frequent follow up appointments. Whether you agree to this is completely up to you and will again not affect your standard of care should you decide that you wish to have no further participation in the study. If you withdraw from the study all clinical information that we have obtained up to the point of you coming out of the study will continue to be used for the purpose of the study. It is possible, though unlikely, that during the course of the study your health will change and you may not be in a position to continue to take part. Sometimes illness can mean patients are no longer able to make decisions about the management of their arthritis or their participation in research studies. If this is the case we would not continue to treat you within the study. However, the research team would retain any personal data already collected and continue to use it confidentially in connection with the study. 17. What if there is a problem? If you have a concern about any aspect of this study, you should ask to speak to the researchers who will do their best to answer your questions (Professor Scott, the Chief Investigator, can be contacted on or on ). If you remain unhappy and wish to complain formally, you can do this through the NHS Complaints Procedure. Details can be obtained from your hospital. In the event that something does go wrong and you are harmed during the research and this is due to someone s negligence then you may have grounds for legal action for compensation. If the harm arises from the work of the clinicians involved in the trial, you may be able to make a claim against the NHS Trust administering your care but you may have to pay your legal costs. In the case of any harm arising from the design or management of the research, you will be fully insured by King s College London s indemnity policy. The normal National Health Service complaints mechanisms will still be available to you. If the researchers find any evidence of poor clinical practice by looking through the trial documents or listening to the audio-recordings of the intensive management sessions, they will follow guidance from the General Medical Council in how they raise concerns. 18. Will my taking part in this study be kept confidential? Yes. We will follow legal procedures and all the information about your participation in this study will be kept confidential. If you join the study, some parts of your medical records and the data TITRATE PATIENT INFORMATION SHEET_Version 3.0_

11 collected for the study will be looked at by the Chief Investigator (Professor Scott) or staff working under his supervision to check that the study is being carried out correctly. Everyone will have a duty of confidentiality to you as a research participant and we will do our best to meet this duty. The company (Pfizer) that produces one of the drugs you may be offered during the course of the trial has asked us to provide them with information about any adverse clinical events experienced by patients taking this drug. They would like to know about the event itself, other treatment you may be taking and some general details, like your age and gender. This is so that Pfizer can monitor the drug and find out about any potential side effects which might not have been known about before. This is standard practice for Pfizer. All information that is collected about you during the course of the research will be kept strictly confidential, and any information about you that leaves the hospital/surgery will have your name and address removed so that you cannot be recognised. Any recordings that are made of your monthly consultations (for those assigned to Group 1 Intensive Management) will be kept securely until the end of the study and then they will be safely disposed of to preserve your anonymity. 19. Involvement of the General Practitioner/Family doctor (GP) We will notify your GP about your involvement in the study. Your rheumatologist will also keep them informed about the treatment you are taking and any changes made during the study in line with current medical practice. 20. What will happen to any samples I give? Patients with rheumatoid arthritis taking disease-modifying drugs usually need monthly blood tests for safety monitoring. This is part of routine care. These blood tests will continue throughout the trial. The results will be sent to your rheumatologist and GP. None of the blood samples will be kept for research purposes. If you are in the intensive management group, these blood tests will be taken when you are seen in the hospital. 21. What will happen to the results of the research study? The overall results of the study will be collected together by the Chief Investigator and his staff who intend to present and publish the findings to inform others about which treatment to use. This will take at least five years from the beginning of the study. When the results are published we will be happy to make them available to all the patients who took part. We will only make available the overall results of the study. No individual patient will be identified in any report or publication from this study. 22. Who is organising and funding the research? This research is funded by the National Institute of Health Research (NIHR) and is administered by King s College London, where the Chief Investigator, Professor David Scott, works. TITRATE PATIENT INFORMATION SHEET_Version 3.0_

12 23. Who has reviewed the study? All research in the NHS is looked at by an independent group of people, called a Research Ethics Committee, to protect your safety, rights, wellbeing and dignity. This study has been reviewed and given a favourable opinion by NRES (National Research Ethics Service) Committee West London. 24. Patient Representatives We have asked patients with rheumatoid arthritis to help advise us on this study. They are known as Patient Representatives and their role is to advise the trial s Steering and Data Monitoring Committee (a committee that makes decisions about the design and conduct of the study) from the patient perspective. If you would like to speak to a Patient Representative you can telephone the Trial Office on or titrate@kcl.ac.uk and we will pass on your details. 25. Further information and contact details For further information please contact: Dr. (Local Researcher) Telephone: OR Trial Coordinator Clinical Trials Group Academic Department of Rheumatology School of Medicine, King s College London Weston Education Centre, Denmark Hill, London, SE5 9RJ Telephone: (daytime) OR Professor DL Scott Professor of Clinical Rheumatology Academic Department of Rheumatology Room 3.48, School of Medicine, King s College London Weston Education Centre, Denmark Hill, London SE5 9RJ Tel during the normal working day. Outside the normal working day this number has an answer phone and your query will be dealt with as soon as possible. In emergencies only, please contact the 24-hour study contact line, which is: You will be given a copy of this Patient Information Sheet and a signed consent form to keep. We would like to thank you for reading this form and for considering taking part in the study. TITRATE PATIENT INFORMATION SHEET_Version 3.0_