Participant Information and Consent Form Version -5 dated -19/05/2011 BakerIDI Heart and Diabetes Institute Full Project

Title: Assessment of the effect of moxonidine and diet on cardiac, renal and endothelial function in young subjects with central obesity Principal Researcher: Dr Elisabeth Lambert Associate Researchers: Dr Gavin Lambert, Dr Nora Straznicky, Dr Chiew Wong, A/Prof Markus Schlaich, Miss Carolina Ika Sari, Mrs Mariee Grima, Miss Reena Chopra, Miss Petra Marusic, Mr Donovan Martin 1. Introduction You are invited to take part in this research project. This Participant Information and Consent Form tells you about the research project. It explains the tests and treatments involved. Knowing what is involved will help you decide if you want to take part in the research. Please read this information carefully. Ask questions about anything that you dont understand or want to know more about. Before deciding whether or not 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 dont wish to take part, you dont have to. You will receive the best possible care whether you take part or not. If you decide you want 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 take part in the research project; consent 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 to keep. 2. What is the purpose of this research? The prevalence of obesity is increasing rapidly among adults and has more than doubled in the past 10 years. Metabolic abnormalities are is often associated with obesity. These are characterized by accumulation of fat in the abdominal region, high blood pressure, unfavourable blood cholesterol profile, elevated blood sugar and alteration in the function of your hormone insulin (which is responsible in the maintenance of your blood glucose level).
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Persons with metabolic abnormalities have an increased risk of developing type 2 diabetes as well as heart and kidney disease and have a tendency to experience greater anxiety and depression. The prevalence of obesity and metabolic disorders is also very high in children and young adults. While there are increasing numbers of studies interested in assessing risk factors for cardiovascular and kidney disease in middle age to older obese subjects, few studies have addressed these issues in young adults. Our laboratory has a particular interest on the sympathetic nervous system activity, which is the part of the nervous systems that regulate many physiological functions of your body such as blood pressure and heart rate. We have previously observed that an elevated sympathetic activity plays a role in the complications of obesity. The aim of the present study is to evaluate whether treatment with a drug called moxonidine, whichworks by decreasing the activity of part of your nervous system is beneficial in reducing the damage to organs. We will in parallel compare the effect of moxonidine to a diet induced calorie restriction. At present, Moxonidine is a medication that is approved in Australia by the Therapeutic Goods Administration (TGA) to treat high blood pressure. It has never been given to treat obesity related organ damage but we believe that it has the potential to reverse these damages.Therefore the use of the drug in this study is experimental. A total of 77 males will participate in the study and will be allocated to 4 different groups: Control group (n=11). These participants will be asked not to take any medication and not to lose any weight during the course of the study Moxonidine group (n=22). These participants will be asked to take the medication and not to try to lose any weight Diet group (n=22). These participants will be asked not to take any medication but follow a diet in order to lose weight Moxonidine + diet group (n=22). These participants will be asked to take the medication as well as follow a diet in order to lose weight This study also involves the use of a device, EndoPAT 2000. This device is approved by TGA and is used to measure the health of your blood vessels. This research has been initiated by the investigator: Dr Elisabeth Lambert. 3. What does participation in this research involve? You will be required to come on 2 study dates before starting any treatment and 24 weeks after starting your treatment and 6 follow up visits (or more if deemed necessary) within 24 weeks. Study Day Procedures Study day 1 (Week 0) Before starting any treatment You will be asked to visit the The Alfred Hospital in the morning. You will be required to have fasted at least 10 hours before your study appointment and have abstained from caffeine for 18 hours, alcohol for 24 hours and exercise for 36 hours. You will receive a medical check-up and we will collect some data regarding your weight, height, blood pressure, current medication etc. to determine your eligibility to participate in this study.
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If you fulfil the inclusion criteria, the following procedures will be performed: 1. Psychometric tests: These tests will be conducted in order to test your level of stress, anxiety and quality of life. Half of the test will be done in a form of simple written questionnaires; the other half will be performed as oral questions. These tests will take around hour. 2. Blood vessel function testing: You will be required to rest on a bed for this procedure. A device will be placed around one finger of each hand and a cuff placed around your arm. The cuff will be inflated for 5 minutes, and then quickly released so we can measure the blood volume changes in your fingertip. To measure the elasticity of your arteries (i.e. the ability of the arteries to relax and contract), a hand-held meter will be placed on the surface of your skin at the base of the neck. Using this device we will measure the blood flow through your aorta, the large artery leading away from your heart. A small pen like device will also be placed on the side of the neck over your pulse. The procedure is not painful but requires you to remain still and relaxed. 3. Food Diary record: You will be given a form in order to record your food intake for 4 consecutive days. A member of the team will explain to you before your study day - on how to keep this record. This will enable us to assess your normal calorie intake before treatment. This record must be filled in before you come in for your study. 4. Echocardiogram: This is a test for studying the hearts anatomy. It is non-invasive and entirely safe. You will lie on an examination table, and the echo technician will place a transducer (a device that resembles a computer mouse) over the chest wall. The transducer is moved back and forth across the chest wall, collecting several views of the heart. A Vaseline-like gel is applied to the chest wall to aid in sliding the transducer back and forth. The test takes 30 60 minutes to complete. Microneurography, venepuncture and oral glucose tolerance test (OGTT): When you come in for your study, we will take a small amount of blood (53mL or 3.7 tablespoons). We will use this to measure your fasting blood parameters including your blood sugar level and cholesterol. We then will measure the activity of your nerves by inserting a very fine electrode (like an acupuncture needle) into a nerve in your leg, just below the knee. The procedure should not be painful but is sometimes associated with feelings of pins and needles or involuntary twitches of the foot during the placement of the needle. It is important you inform us of any discomfort. We will monitor the electrical activity of this nerve as the same time as your blood pressure (using a small cuff placed around your finger) and the activity of your heart (ECG) by placing 3 ECG dots or stickers on your chest. We will do these measurements for about 20 minutes while you rest quietly. Then, you will be asked to consume a sweet drink containing 75-g of sugar. We will continue our recordings for 2 hours while you will be allowed to watch a movie or read. We will take another blood sample at the end. We will afterwards provide you with lunch. 6. Renal function and ambulatory blood pressure monitoring: Before you leave the hospital you will be given a bottle in order to collect your urine in the next 24 hours. We will use the urine to analyse the level of compounds (albumin and creatinine) to assess your renal function. We will also give you an ambulatory blood pressure monitoring equipment and explain to you how this works. Your blood pressure level will be automatically recorded every hour during the day and every hour during the night for the next 24 hours. To record your blood pressure more accurately, you will be required to wear the blood pressure cuff which is connected to a portable blood pressure machine for 24 hours. You can take the cuff
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off if you need to go to the shower, but you will have to wear the cuff during the night and throughout the day. 7. Venepuncture: One of the investigators (Miss Carolina Sari, Miss Petra Marusic, Mrs Mariee Grima, Miss Reena Chopra or Mr Donovan Martin) or a research nurse at the Alfred Hospital will take a sample of your blood. The amount of blood we take is 60 mL, which is equivalent to 4 tablespoons. This enables us to measure your cholesterol level, fasting blood glucose level and other biochemical in your blood. 8. DEXA Scan: We will take you to the radiology Department to have a DEXA scan, which quantifies body composition. We will be measuring the fat mass of your abdomen/trunk, arms and legs.

TREATMENT At the end of study day 1, you will be randomised to one of the four study groups. There will be 17 participants in each study group. The Alfred pharmacy will dispense the moxonidine if you have been allocated this treatment. You will take your medication at a low dose of 0.2mg per day for the next 2 weeks and then we will check your blood pressure and you will continue on 0.4mg per day for the next 22 weeks. If you have been allocated to follow a diet, a nutritionist (Mariee Grima) will spend some time with you to explain how to follow the DASH diet. This diet is low in fat and animal fat with an emphasis on fruits, vegetables, wholegrains and low fat dairy products. You will be provided with nutrition counseling, diet instructions, recipes and comprehensive meal plans and will be required to complete food diaries. To help you maintain an adequate diet, you will be provided with a number of food items such as fruit, vegetables, dairy products and convenient meals for the duration of the study. Not all food will be provided, so you will still have to purchase some food. Follow up visits (every 2 weeks after study day 1) You will be asked to come in 2 weeks after your study day 1. The aim of this visit is to verify your compliance, measure your blood pressure, weight and provide you with nutrition counselling as well as to record any occurrence of adverse events. You will receive a medical check-up. At the first follow-up visit your dose of moxonidine will be readjusted if you experience any signs of low blood pressure. Otherwise, your dose will be increased to 0.4mg per day. You will be required to come for 6 follow-up visits or more if deemed necessary.

Study day 2 (Week 24) 6 Months after treatment initiation At the end of your 6 months treatment period, you will be asked to come to the hospital. You will once again be required to have fasted at least 10 hours before your study appointment and have abstained from caffeine for 18 hours, alcohol for 24 hours and exercise for 36 hours. You will receive a medical check-up and we will collect some data regarding your weight, height, blood pressure, current medication etc.) The same procedures as study day 1 (procedures 1 to 8) will be performed.

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Study Diagram

2 weeks 4 weeks

4 weeks 4 weeks

4 weeks

4 weeks

4 weeks

Study day 1 Randomisation

Study day 2 Study conclusion

= First initial follow up Treatment initiation = Follow up visits = 4-day food diary record

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4. What will happen to my test samples? By consenting to take part in this study, you also consent to the collection, storage and use of tissue samples as specified below. Venous blood samples (approximately a cup or 120 ml over the course of the study) for the measurement of glucose, cholesterol and stress biomarkers With your consent, in the future we may perform genetic analyses on your samples related to the sympathetic nervous system. This is optional, and should you agree to do this, you will be asked to sign a separate consent form. These future research projects will be reviewed and approved by an ethics committee. The information generated from the genetic analyses does not have the capacity to provide information about an identifiable participants risk of having children with a genetic disorder, nor does it have the potential to detect information of social significance (e.g. non-paternity or non-maternity information) that may influence access to insurance or employment. You may ask to be notified when the project results are published in a scientific journal. This will be reidentifiable grouped data and will not directly relate to your individual participation. Counselling will not be provided. Specimens will either be analysed immediately by the Alfred Hospital Pathology department or they will be stored frozen. The storage of samples is mandatory. If you do not wish to have your sample stored, please notify the researchers immediately. This may affect your eligibility in participating in the study. Labelling on frozen specimens will include your initials, study and date of specimen collection and hence will be re-identifiable. Samples will be stored in locked cupboards and freezers at the Baker IDI Heart and Diabetes Institute and will only be accessible to researchers and laboratory staff involved in this particular research project or other research in the future that is closely related to this research project. There will be no commercial interest with future use of the samples. The data generated by these samples will be kept on the database of the Human Neurotransmitters Laboratory at the BakerIDI Heart & Diabetes Institute. Only researchers involved in the study will have access to that data. The genetic analysis being undertaken does not have the potential to produce information relevant to your future health or that of your family. The samples will be stored indefinitely. 5. What are the possible benefits?

No direct therapeutic benefits can be expected from participating in this study. However, participation in this study will help in the continuing search for better medication to treat obesity 6. What are the possible risks? Moxonidine is generally well-tolerated. Reported side effects include dry mouth, headache, fatigue, dizziness, nausea, sleep disturbances (rarely sedation), weakness, dilation of blood vessels and rarely, skin reaction Insertion of the leg electrode carries a very low risk of long term complications. The technique has been used in over 5000 experiments world wide. To date there have only been 3 cases reported of slight muscle weakness lasting from 2 to 6 months. There is a moderate risk of experiencing tingling and/or a mild ache in the leg muscles for a day or two afterwards. There have been no permanent consequences reported. This research study involves exposure to a very small amount of radiation. As part of everyday living, everyone is exposed to naturally occurring background radiation and receives
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a dose of about 2 millisieverts (mSv) each year. The effective dose from this study is less than 0.01 mSv. At this dose level, no harmful effects of radiation have been demonstrated as any effect is too small to measure. The risk is believed to be minimal.
Have you been involved in any other research studies that involve radiation? If so, please tell us. Please keep information contained within the Patient Information and Consent Form about your exposure to radiation in this study, including the radiation dose, for at least five years. You will be required to provide this information to researchers of any future research projects involving exposure to radiation

There may be side effects that the researchers do not expect or do not know about which may be serious. Tell your doctor immediately about any new or unusual symptoms that you get. 7. What if new information arises during this research project? During the study, new information regarding the risks and benefits of the study may become available. If this occurs, this new information will be provided to you. 8. Can I have other treatments during this research project? It is important to tell your 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 your doctor about any changes to these during your participation in the research. 9. Are there alternatives to participation? There are no alternatives to participation. Participation is of course voluntary. 10. Do I have to take part in this research project? Participation in any research project is voluntary. If you do not wish to take part you dont have to. If you decide to take part and later change your mind, you are free to withdraw from the project at any stage. Your decision whether to take part or not to take part, or to take part and then withdraw, will not affect your routine treatment, your relationship with those treating you or your relationship with The Alfred Hospital and BakerIDI Heart and Diabetes Institute 11. What if I withdraw from this research project? If you decide to withdraw from the project, please notify a member of the research team before you withdraw. This notice will allow that person or the research supervisor to inform you if there are any health risks or special requirements linked to withdrawing. If you decide to leave the project, the researchers would like to keep the tissue samples that have been collected. This is to help them make sure that the results of the research can be measured properly. If you do not want them to do this, you must tell them before you join the research project. 12. Could this research project be stopped unexpectedly? If for any reason the project is stopped, we will inform you. 13. What will happen when my participation in this research project ends? At the end of the project, the medication will be withdrawn from you.
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14. How will I be informed of the results of this research project? You will be provided with a summary of your results a few weeks following your participation. 15. What else do I need to know?

What will happen to information about me? Any information obtained in connection with this research project that can identify you will remain confidential. In any publication and/or presentation, information will be provided in such a way that you cannot be identified, except with your permission. Your information will be recorded in a locked cupboard and freezer in the Human Neurotransmitters Laboratory accessible only to the investigators of this study. Information about your participation in this research project may be recorded in your health records. Your health records and any information obtained during the study are subject to inspection (for the purpose of verifying the procedures and the data) by the relevant authorities, such as the Australian Governments Therapeutic Goods Administration, representatives of the Ethics Committee, the Baker IDI Heart & Diabetes Institute, or as required by law. By signing the consent section, you authorise release of, or access to, this confidential information to the relevant study personnel and regulatory authorities as noted above. How can I access my information? In accordance with relevant Australian and/or Victorian privacy and other relevant laws, 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 one of the researchers named at the end of 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? If you suffer an injury as a result of your participation in this research project, please contact the research staff. Hospital care and treatment will be provided by the public health care system (Medicare) at no cost to you if you are eligible for Medicare benefits and elect to be treated as a public patient. Is this research project approved? The ethical aspects of this research project have been approved by the Human Research Ethics Committee of The Alfred Hospital. This project will be carried out according to the National Statement on Ethical Conduct in Human Research (2007) produced by the National Health and Medical Research Council of Australia. This statement has been developed to protect the interests of people who agree to participate in human research studies.

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16. Consent I have read, or have had read to me in a language that I understand, this document and I understand the purposes, procedures and risks of this research project as described within it. I give permission for my doctors, other health professionals, hospitals or laboratories outside this hospital to release information to BakerIDI Heart and Diabetes Institute concerning my disease 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 freely agree to participate in this research project as described. I understand that I will be given a signed copy of this document to keep. Participants name (printed) Signature Date

Name of witness to participants signature (printed) Signature Date

Declaration by researcher*: I have given a verbal explanation of the research project, its procedures and risks and I believe that the participant has understood that explanation. Researchers name (printed) Signature Date

* A senior member of the research team must provide the explanation and provision of information concerning the research project. Note: All parties signing the consent section must date their own signature.

17.

Who can I contact?

If you require further information or if you have any problems concerning this project (for example, any side effects), you can contact the principal researcher or the other researchers responsible for this project:

Dr Markus Schlaich

Phone: (03) 8532 1502 After Hours (03) 95713523

Dr Elisabeth Lambert

Phone: (03) 8532 1345 Mobile: 0408507412

For complaints: If you have any complaints about any aspect of the project, the way it is being conducted or any questions about being a research participant in general, then you may contact:

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Name: Ms Rowan Frew Telephone: 9076 3848

Position: Ethics Manager, Alfred Hospital

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