Patient Information and Consent Form (Consent to Continue) Full Project Title: A randomised, placebo-controlled trial of erythropoietin in ICU patients with traumatic brain injury ErythroPOietin in Traumatic Brain Injury: “EPO – TBI” Principal Investigator: Dr Ng Wai Hoe (NNI) Dr Tan Hui Ling (TTSH) Sites: National Neuroscience Institute Tan Tock Seng Hospital 11 Jalan Tan Tock Seng 11 Jalan Tan Tock Seng Singapore 308433 Singapore 308433 Version number: 1.6 Date: 18 March 2013 Introduction You have been enrolled in this research project in accordance with Singapore law which allows the patient’s spouse, parent, guardian or legal representative to consent to the patient taking part in medical research where the patient is unable to provide consent for himself/herself. Your legally acceptable representative consented to your taking part in this research at a time when you were unable to consent for yourself. You are now invited to consider whether you wish to continue taking part in this research project. You are invited to continue to take part in this research project because you have a moderate or severe traumatic brain injury (TBI). The research project is testing a new treatment for TBI. The new treatment is a medication called erythropoietin. Please read this information carefully. Ask questions about anything that you don't understand or want to know more about. Before deciding whether or not you should continue to take part, you might want to talk about it with a relative, friend or your local doctor. Participation in this research is voluntary. If you don't wish to continue to take part, you don't have to. You will receive the best possible care whether you continue to take part or not. If you decide that you want to continue to take part in the research project, you will be asked to sign the consent section. By signing it you are telling us that you: understand what you have read; consent to continuing in the research project; consent to continuing to have the tests and treatments that are described; consent to the use of your personal and health information as described. You will be given a copy of this Participant Information and Consent Form (Consent to Continue) to keep. What is the purpose of this research? Traumatic brain injury (TBI) is usually caused by a blow to the head such as in a car accident or in a fall. Many people who have a TBI do not survive or, if they do, suffer from long-term disability. Previous studies have shown that about 1,000 people in Australia and New Zealand suffer a moderate or severe TBI every year. With current best available treatment and therapies many of these patients have loss of brain function. This can result in varying degrees of long term disability. When a patient sustains a traumatic brain injury there are two stages to the injury. The initial impact to the head causes immediate damage to the brain. The second stage is the secondary injury phase, and it can evolve over hours or weeks. This stage can cause more damage to the brain. The treatment of brain injury focuses on trying to minimize the secondary injury and there is much research being done to try to find treatments that will prevent it. Erythropoietin (EPO) has recently been recognised as a drug that may offer some protection to the brain injured by trauma and help reduce the effects of secondary injury. The aim of this study is to determine if EPO reduces secondary brain injury and helps patients make a better recovery after traumatic brain injury. We also plan to monitor the effect of EPO on the rate of deep vein thrombosis (DVT - blood clots in the large veins, usually in the legs) in patients with moderate or severe TBI in the intensive care unit (ICU). EPO has been approved for use for other purposes in Australia for some years. It is used for the treatment of anaemia (low blood count) in patients who are on kidney dialysis for a long time, patients who have had a major operation and patients on treatment for cancer. However, it is not approved for use in TBI patients. Therefore, EPO is an experimental treatment for TBI which means that it must be tested to see if it is an effective treatment for moderate or severe TBI. A large study of ICU patients found that EPO helped trauma patients to survive their injuries. It was noted that patients who got high dose EPO had a greater chance of developing a blood clot. However, other studies show that the risk of getting a blood clot can be reduced if EPO is given to patients with a blood count at the low end of normal and a dose of 40,000 units or lower. This information has been included in the design of EPO-TBI study. This study is a double-blind, randomised controlled trial. Patients participating in the trial will receive either EPO (40,000 units) or placebo (sodium chloride 0.9% [salty water] that looks like EPO) weekly for up to 3 doses. The study is double-blind because we need to work out whether or not the study drug is effective. To do this we need to be able to compare two groups of people by randomly assigning them to receive either the EPO or placebo. Double-blind means that neither you, nor your legally acceptable representative nor the study staff will know what treatment is given to you. A randomised controlled trial means that the study treatment is allocated randomly (by chance, like flipping a coin). A computer will be used to allocate the patient to one of the two treatments so study staff cannot influence or predict this process. This study is funded by the Australian and Victorian Governments and has been designed by investigators from the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). The study is managed by the Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) at Monash University. The study will be conducted at hospitals in Australia, New Zealand, Singapore, France and Finland and will enrol 606 patients over 3.5 years. In Singapore, we plan to enrol approximately 30 patients at National Neuroscience Institute / Tan Tock Seng Hospital over a period of 3 years. What does participation in this research involve? You were eligible for the study because you received a moderate or severe traumatic head injury. If you are a woman of child bearing potential a blood sample (10 mls or 2 teaspoons) was collected to see if you are pregnant if test had not already been performed. You were randomly allocated by a computer to receive a subcutaneous (SC) injection (a small injection under the skin) of either: EPO 40,000 units (1 ml in volume) or placebo (sodium chloride 0.9% (salty water)1 ml in volume) within 24 hrs after the brain injury has occurred. Randomization means assigning you to one of the two groups by chance, like tossing a coin or rolling dice. The injection was given in the upper arm, thigh or abdomen (tummy). You had a 1 in 2 or 50% chance of receiving EPO. The injection was given again on days 8 and 15 if you stayed in the ICU over this time. If you were discharged to the general ward no further doses were given. No additional blood samples were collected specifically for the study. Results from blood samples collected as part of routine daily care while you were in the ICU were recorded. You were closely monitored for blood clots in the legs. Treatments to prevent blood clots from occurring were started as soon as possible after ICU admission. Support stockings or compression pads wrapped around the legs were ordered by the doctor. When bleeding after the injury had settled, blood thinning medication was commenced. These treatments described are part of standard care for TBI patients. An ultrasound scan of the upper legs was done before or at least within 48 hours after the first dose of study drug was given. The ultrasound was done twice a week whilst you were in the ICU so that if any blood clots developed they were detected early and treated immediately. The ultrasound is a test that is done at the bedside where a small flat scanner (like a computer mouse) is placed on the thigh. A sticky gel is used to assist the scanner to see the leg veins on a computer screen. You would only receive study drug once a week, for up to 3 doses and the scheduled leg ultrasounds (up to 7 scans) while you were in the ICU. To complete the entire schedule takes 21 days. If you were well enough to be discharged to the ward before 21 days, you did not receive the total schedule of study drug or ultrasounds. The ICU doctor monitored you for any signs of blood clots, which is part of standard care of the TBI patient. Information about your injury and management during your hospital stay will be collected from your medical record. Follow up A follow up phone interview will be conducted 6 months after the injury by a research member from the hospital to find out how well you have recovered from the brain injury. A discussion may also be held with your relative and the rehabilitation staff involved with your care to help us assess recovery. The phone interview will take 30 minutes to complete. Once you are entered into the study, your contact details will be released to the research member conducting the interview. You will receive a phone call shortly before 6 months from research staff looking after you who will arrange a convenient time for the phone interview. You will not be paid for your participation in this research. Kidney function monitoring ICU patients with TBI can be at risk of developing kidney damage. Kidney damage increases the risk of brain swelling which may slow recovery of the brain and increase hospital stay. EPO has been shown in many experimental studies to protect the kidneys from damage. In addition to the protective effects on the brain, EPO has also been shown to protect the kidneys damaged after an injury. Kidney function is monitored by collecting information about urine output and blood test results. This is part of standard care in the ICU. What are the possible benefits? You may not receive any benefits from this research but possible benefits may include a better recovery and quality of life for future patients with moderate or severe TBI. . What are the possible risks? Medical treatments sometimes cause side effects. You may have none, some or all of the effects listed below, and they may be mild, moderate or severe. The ICU doctors closely monitored you for any side effects. If you develop any of these side effects, the doctor will let you know. Many side effects go away shortly after treatment ends. However, sometimes side effects can be serious, long lasting or permanent. If a severe side effect or reaction occurred, the ICU doctor may have stopped the study drug. The ICU doctor would have discussed the best way of managing any side effects with your next of kin. The side effects of EPO related to the dose given include: a temporary increase in blood pressure that returns to normal when EPO is discontinued, diarrhoea, nausea, vomiting, headache and flu-like symptoms. In patients with other conditions these events occurred in less than 5% of patients. This is similar to patients who received placebo. All patients in ICU have an increased risk (approx. 10%) of developing clots in the blood vessels (called thrombosis or embolism). EPO may pose an additional risk for developing clots. A recent study revealed 8.7% of patients receiving EPO developed a clot in the legs compared to 5.8% of patients who received the placebo injection. Although it is extremely rare, EPO may also cause fits (less than 1%), chronic anaemia (very rare), arterial thrombosis and heart attack. It is for these reasons that frequent ultrasounds of the upper legs have been scheduled so the formation of blood clot can be detected early. As part of routine care of the ICU patient, continuous monitoring of the heart rhythm and blood pressure is performed. This allows clinical staff to monitor these heart functions continuously for any changes. Allergic reactions to EPO are rare. They include rash, itching, anaphylactic reaction (allergic shock) and accumulation of fluid around the eyes. Having an injection may cause some discomfort or bruising (0.2% of patients) and should resolve quickly with minimal treatment. Alternative treatment If you choose not to take part in this study, the alternative is to have what is considered standard care for your condition. The doctor-in-charge will decide on what other drugs and therapies may be available to treat your traumatic brain injury. What is not standard care or experimental in this study? The administration of the study drug EPO and the ultrasound scans are the only procedures that are non-standard. Every other procedure is current standard of care. All the procedures performed in this study are the procedures of routine care in National Neuroscience Institute and Tan Tock Seng Hospital. They are not performed solely for the purposes of this study but to ensure that patients receive excellent treatment. What if I am taking placebo instead of EPO? Receiving placebo is the same as not having any additional treatment except for the standard medical care which you will continue to receive during the study. Costs of participation The patient does not need to pay for the placebo or the EPO study drug or any study related procedures. However, any standard medical care will be charged to you during the research study. What if new information arises during this research project? During the research project, new information about the risks and benefits of the project may become known to the researchers. If this occurs, you will be told about this new information and the doctor will discuss whether this new information affects you. Can you have other treatments during this research project? It is important to tell the doctor and the research staff about any treatments or medications you may be taking, including over-the-counter medications, vitamins or herbal remedies, acupuncture or other alternative treatments. You should also tell the doctor about any changes to these during your participation in the research. Do I have to take part in this research project? Participation in any research project is voluntary. If you decide that you would not wish to take part in this study, you may request to be withdrawn from the study. If you consent to continue and then later change your mind, you can withdraw from the study at any time. Any decision you make will not affect either your relationship with National Neuroscience Institute / Tan Tock Seng Hospital. Withdrawing from the study will not affect your care in anyway and you will continue to receive the best current treatment and care. If you do decide to withdraw the researchers would like to keep the information that has been collected so far. This is to help them make sure that the results of the research can be measured properly. Please tell the researcher if you do not want them to do this. Could this research project be stopped unexpectedly? This research project may be stopped for a variety of reasons including: Unacceptable side effects; The drug/treatment being shown not to be effective; and The drug/treatment being shown to work and not need further testing. How will I be informed of the results of this research project? Once the project has been completed, a summary of the results will be available from the investigator on request. What will happen to information about me? The information gathered about you by the researchers or obtained during the trial from any procedures, will be held by the researchers in strict confidence. Your trial records without your name attached will be made available to the Coordinating Centre at the ANZIC–RC, at Monash University in Australia. All the people who handle your information will adhere to traditional standards of confidentiality and will also comply with all relevant privacy legislation in your country. In Australia this is the Privacy Act 1988. The Ethics Committee has obtained assurances from ANZIC-RC that the ‘Information Privacy Principles’ laid down in the Act will be met, and will oblige the investigator and other hospital staff to meet strict privacy standards. If the results of the trial are published in a medical journal, as is intended, no reader will be able to identify individual patients In any publication and/or presentation, information will be provided in such a way that cannot identify you, except with your permission. No identifying material will be used in any reports of this study. Records for the study will be kept in a secure filing cabinet in a secure office. A database with study information will be generated and this will be kept in a computer that is password protected. Records relating to the study will be kept for 15 years at this site. It is desirable that your local doctor is advised about your participation in this research project. By signing the consent section, you agree to your local doctor being notified about participation in this research project. Information about participation in this research project may be recorded in your health records. Regulatory Agencies (HSA, FDA, if relevant), Singhealth Centralised Institutional Review Board, NHG Domain-Specific Review Board and Ministry of Health will be granted direct access to your original medical records to check study procedures and data, without making any of your information public. By signing the Informed Consent Form attached, you (or your legally acceptable representative, if relevant) are authorizing such access to your study and medical records. How can I access my information? In accordance with relevant Australian and/or state privacy and other laws applicable in your country, you have the right to access the information collected and stored by the researchers about you. You also have the right to request that any information with which you disagree be corrected. Please contact a member of the study team listed in this document if you would like to access your information. What happens if I am injured as a result of participating in this research project? In the event that you suffer an adverse event or a medical accident during this study that arises from your participation in the study, you will be offered all full and necessary treatments by National Neuroscience Institute / Tan Tock Seng Hospital. The Ethics Committee has approved this study on the basis (amongst others) that the reported risk of such an event is either small or acceptable in terms of the risk you face as a result of your current illness or the benefit that is possible with the new treatment being tested. No provisions have been made in this trial to offer trial patients who suffer an adverse reaction monetary compensation, but the absence of such a provision does not remove your rights to seek compensation under common law. Is this research project approved? The ethical aspects of this research project have been approved by the Singhealth Centralised Institutional Review Board and NHG Domain Specific Review Board. This project will be carried out according to the Singapore Guideline for Good Clinical Practice produced by the Ministry of Health of Singapore. This guideline has been developed to protect the interests of people who agree to participate in human research studies. Who can I contact? If you want any further information concerning this project or if you have any medical problems which may be related to your involvement in the project (for example, any side effects), you may contact the Principal Investigator (National Neuroscience Institute), Dr Ng Wai Hoe at +65 6357 7191 or the Principal Investigator (Tan Tock Seng Hospital), Dr Tan Hui Ling at +65 6357 7771. If you have any concerns about any aspect of the project, the way it is being conducted or any questions about you being a research participant in general, then you may contact the Singhealth Centralised Institutional Review Board Secretariat at +65 6323 7515 or NHG Domain Specific Review Board Secretariat +65 6471 3266. Patient Information and Consent Form (Consent to Continue) Full Project Title: A randomised, placebo-controlled trial of erythropoietin in ICU patients with traumatic brain injury ErythroPOietin in Traumatic Brain Injury: “EPO – TBI” Principal Investigator: Dr Ng Wai Hoe (NNI) Dr Tan Hui Ling (TTSH) Sites: National Neuroscience Institute Tan Tock Seng Hospital 11 Jalan Tan Tock Seng 11 Jalan Tan Tock Seng Singapore 308433 Singapore 308433 Version number: 1.6 Date: 18 March 2013 I have read, or have had read to me in a language I understand, this document and I understand the purposes, procedures and risks of this research project as described within it. I consent to continue participation in the research project named above, according to the conditions outlined in this document. I give permission for doctors, other health professionals, hospitals or laboratories outside this hospital to release information to the ANZIC-RC concerning my injuries and treatment that is needed for this project. I understand that such information will remain confidential. I have had an opportunity to ask questions and I am satisfied with the answers I have received. I understand that I will be given a copy of this document to keep. Printed name of participant …………………………………….. Signature ................................................................................ Date: Time: Printed name of witness………………………………………...(if applicable) Signature …………………………………………………........... Date: Time: Printed name of investigator ………………………………….. Signature ............................................................................... Date: Time: