THE UNIVERSITY OF BRITISH COLUMBIA UBC Division of Endocrinology Gordon and Leslie Diamond Centre 2775 Laurel Street, 4th Floor Vancouver, B.C. Canada V5Z 1M9 Telephone Fax E-mail
(604) 875-5929 (604) 873-5925
[email protected]
UNIVERSITY OF BRITISH COLUMBIA SUBJECT INFORMATION AND CONSENT FORM ADULT PARTICIPANTS Version 5.2a 26th August 2014 Title: Pilot clinical trial of Ustekinumab in patients with new-onset T1D. Protocol number:
00001-U
Product:
Ustekinumab (humanized, anti-p40 monoclonal antibody)
Principal investigator: Dr Tom Elliott, MBBS FRCPC BC Diabetes (clinical site) 4102 - 2775 Laurel Street Vancouver, BC V5Z 1M9 604-875-5900 Sponsor: Dr Jan Dutz, MD FRCPC Department of Dermatology and Skin Science University of British Columbia. Tel: 605 875 4747 Funded by:
Juvenile Diabetes Research Foundation: Canadian Clinical Trials Network (JDRF-CCTN)
Collaborator:
Immune Tolerance Network (ITN)
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For Emergencies only: In case of an emergency, please contact Dr. Thomas Elliott at tel. 604-875-4111 during office hours. After hours please call the VGH Switchboard 604-875-5000 and ask for the endocrinologist on call, or go to the nearest hospital emergency department. For non-emergency contacts: Call Marla Inducil (clinical trial coordinator) at 604-875- 4634
Introduction You have been invited to join a clinical research study of a new investigational agent (drug) at the University of British Columbia by the study doctor/principal investigator, Dr Thomas Elliott, and colleagues. The study is being sponsored by Dr Jan Dutz, who has received funding from the Juvenile Diabetes Research Foundation; Canadian Clinical Trials Network. This research study will examine the effects of an investigational (experimental) agent called ustekinumab in adults aged 18-35 years old with newly diagnosed Type 1 diabetes mellitus. You are being invited to consider joining this study because you have been recently diagnosed with Type 1 diabetes. The study is funded by the Juvenile Diabetes Research Foundation, (JDRF). The purpose of this informed consent is to:
(1) Explain why this research is being done, (2) Explain what will be done at each visit, and (3) Inform you of all the potential risks and benefits.
It is important that you read this consent form carefully to help you decide, (Make an informed decision) whether or not you want to take part in this research study.
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If there are any words or information in this consent form that you do not understand, ask the study doctor to explain them to you. If you understand the study and the procedures required and you decide to take part in this study you will be asked to sign this consent form. No ‘study’ procedure will be done until you have: 1) Read this consent form. 2) Have had a chance to ask any question that you may have. 3) Signify a complete understanding of this consent form by signing below. It is important that you understand this consent form before you sign it. You will be given a copy of the consent form for your records. Your decision to take part in this study is completely voluntary. You are free to decide if you do or do not want to take part in the study. Your decision will have no effect on whether you continue to receive health care or on the type of care or quality of care you receive from your doctor, the study doctor, or the hospital/clinic. In this study, ustekinumab will be given to you as an injection into the layer just beneath the skin (subcutaneous). This is the same type of injection that is required to administer insulin. In this study ustekinumab is considered an ‘investigational agent’: while ustekinumab is already approved by Health Canada for treatment of another condition called Psoriasis, it is not currently approved as safe and effective for use in patients with Type 1 diabetes, though Health Canada has approved the use of ustekinumab in this trial. All participants in this study will be given ustekinumab. This is a Phase 1 study, which means that it is designed to test the drug in a small group of people to evaluate its safety, establish a safe dosing range and to identify any side effects.
Background Ustekinumab, manufactured by Janssen Pharmaceuticals, is an antibody. Antibodies are special proteins produced in the body by the immune system, which attach to foreign substances such as viruses and bacteria to destroy or inactivate them. Ustekinumab is an artificially produced antibody called a monoclonal antibody. It attaches to and reduces the effect of specific substances produced by the immune system that damage insulin-producing cells in the pancreas. Because it affects the
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activity of the immune system, it may also reduce its beneficial ability to fight infection. Ustekinumab, administered by subcutaneous injection, has been given to many adult patients with psoriasis and is routinely prescribed now for psoriasis. Most of the subjects treated with ustekinumab receive the same, or similar dosage that will be used in this study. In past treatment of adult patients with psoriasis using ustekinumab, it was administered in the same fashion that will be used in this study: injection to the layer under the skin. Ustekinumab has been extensively studied in lab tests using mice, monkeys and both human and animal blood cells. Your study doctor has access to and can provide, if necessary, detailed documentation that describes ustekinumab studies in humans, in animals and in the laboratory. Your study doctor will be referring to this document to answer any specific questions you may have. The majority of the procedures, tests and evaluation in the study involve standard medical care. Some of the blood tests in this study are considered experimental, because they are newly developed tests that are still being designed and standardized. These experimental tests will measure the effects of ustekinumab on your immune system. They involve taking immune cells from your blood and detecting if their function or number is altered when we give the drug. The exact nature of these immune tests are available in more detail from the study staff. Since it is not known whether the results of these newly designed blood tests will be sufficient to predict or indicate generalized health specifics (tell us anything about your health) until they are perfected, the results of these tests will not be given to you. Who is conducting this study? This study is being conducted by Dr Thomas Elliott at the BC Diabetes site. The sponsor is a clinical scientist investigator based at the University of British Columbia, Dr Jan Dutz. The funding is being provided to Dr Jan Dutz by the Juvenile Diabetes Research Foundation (JDRF) Canadian Clinical Trials Network (CCTN).The Immune Tolerance Network (ITN) is a clinical trial consortium based in the United States, who have agreed to collaborate in the design of this study with their expertise in clinical trial in type 1 diabetes. ITN will also provide some of the more specialist blood tests that are used to monitor subjects in clinical trials with type 1 diabetes as these are not easily available locally.
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Jan Dutz, as sponsor of this study may reimburse Dr Thomas Elliott or BC Diabetes for all or part of the costs of conducting this study or they may provide the BC Diabetes some or all of the standard or experimental medications being used in this study. However, neither BC Diabetes nor any of the investigators or staff conducting this study will receive any personal payments for conducting this study. Subjects have the right to enquire further about funding if they wish to do so. Purpose and Aims of the Research Study The purpose of this research study is to compare the risks (safety) and benefit (effectiveness) of ustekinumab at two different doses and two different frequencies of injections. You will be given ustekinumab at a specific dose and frequency. You have 100% chance of being given the study drug. No matter which dose or frequency you receive, you will continue to take insulin injections and receive the high standard of care for someone with Type 1 diabetes. From this point on in the consent form, the term ‘study drug’, will indicate the drug ustekinumab. Type 1 diabetes is caused by a problem with the body’s immune system. In Type 1 diabetes, the immune system attacks and destroys beta cells, which are the cells in your pancreas that produce insulin. Insulin is needed for the body to use (metabolize) glucose (sugar). After the beta cells are destroyed, the body cannot produce enough of its own insulin. Instead, a person with Type 1 diabetes must inject himself or herself with insulin in order to control blood sugar levels. Ustekinumab is being studied to determine if it may delay, reduce, or completely halt the destruction of beta cells. If the beta cells can be protected, blood sugar control may be improved, at which time it may no longer be necessary to administer as heavy a dosage of insulin as is usually used in the treatment of Type 1 diabetes. Ustekinumab is not yet a substitute for insulin. This is a research study; it is suspected but not yet known how effective ustekinumab will be for future treatment of Type 1 diabetes. Inclusion and Exclusion criteria for the Study To be eligible for the study you must: • have been diagnosed with type 1 diabetes according to the standard criteria (your diagnosing clinician should have followed the Canadian Diabetes Association criteria).
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• have been diagnosed with type 1 diabetes no more than 100 days from the day of entry into the study. • have the full capacity to be able to understand and consent to taking part in the study. • be between the ages of 18 and 35 at the first dose of the study drug. • be willing to record insulin usage, blood glucose testing results and any side effects of taking the drug. We shall also perform blood testing to check that you have a minimum level of function in your pancreas and that the cause of your diabetes is likely to be an immune system problem. These blood tests must be confirmed before you are allowed to enter the study. You will NOT be able to enter the study if: • the study doctor does not think you are able to understand fully and consent to taking part. • you have had a history of cancer, any significant or active disease (that could increase the risk of taking this drug), • you have had any significant severe infection for the 6 weeks prior to taking the first dose of the study drug, • you have had any previous or have a current tuberculosis infection, • you have used another investigational study drug within the three months prior to taking ustekinumab, • you are taking medications that are known to effect sugar processing abilities. • you are on any other treatment that is known to cause a significant or ongoing change in your immune system or type 1 diabetes. • you have significant abnormal laboratory values (routine blood tests for kidney and liver function) during the screening period, other than those due to T1D. • you are pregnant, breastfeeding or planning to become pregnant during the 60 days after the last dose of the study drug.
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• you have received any live vaccines within 30 days prior to the first study drug dose and/or are expected to need to receive a vaccine during the study. • you have had a prior allergic reaction, including anaphylaxis, to any component of the study drug product. • you have had a prior allergic reaction, including anaphylaxis, to any antibody treatment. • you have undergone any major surgery within the 30 day period prior to the first drug dose and/or are anticipating requiring surgery during the study period. • you have Hepatitis B, Hepatitis C or HIV infection.
Study Plan and Length of the Study 20 subjects will be enrolled in the study. You will have an equal chance of being in any of four small groups of 5 people. The first group of 5 subjects will receive a smaller dose with more injections. The second group of 5 subjects will receive a larger dose with more injections. The third group of 5 subjects will receive a smaller dose with fewer injections. The fourth group of 5 subjects will receive a larger dose with fewer injections.
The year long study (one full year) will be conducted at the BC Diabetes Research Center. Should you agree to take part in this study, (you agree to join) and you meet all of the medical requirements necessary to participate in the study, (the doctors think you would be a good fit) you will go through a number of clinic or phone visits (the total maximum amount of extra time to be devoted will be 44 hours), which consist of: •
A screening period (up to 14 days before the first trial dose), during this screening visit, you will have a physical examination in addition to other tests. Based on the results of these tests and in conjunction with your medical history, the study doctor will determine if you are suitable to participate in the study.
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A dosing period, where you will receive subcutaneous (under skin) injections of ustekinumab at week 0 4 and 16 (with the potential of 2 more doses at week 28 and week 40, (depending on your patient group). You will be required to stay at the clinic for approximately 3-6 hours (at least 1 hour before dosing and 1 hour after dosing is administered and extra time may be required for blood tests). Based on the study doctor’s judgement of how you are doing and feeling, you may be asked to stay in the clinic longer, possibly even overnight, so that the study staff can take care of you.
•
You will be called for a phone visit at week 10 and one follow-up phone visit at week 52. In addition, you will have access to and may need to discuss insulin dose adjustments on a weekly basis with a member of the study personnel, as this is part of standard care for diabetes.
•
If the study doctor feels it is necessary you may need to come in for additional clinic visits.
A team consisting of medical doctors (called the data and safety monitoring board) will examine all the safety data for the trial. This team is independent from the doctors running the study.
Study Drug (ustekinumab) and Dosing This study is designed to determine the optimal dose and frequency of ustekinumab in order to cause a suitable effect on the immune system. (How much of the drug is needed to affect the immune system in a way that we predict will cause a benefit) Thus there are four groups you may be a part of. The first group will receive 45mg of ustekinumab on weeks 0, 4, 16, 28 and 40. The second group will receive 90mg of ustekinumab on weeks 0, 4, 16, 28 and 40. The third group will receive 45 mg of ustekinumab on weeks 0, 4 and 16. The fourth group will receive 90mg of ustekinumab on week 0, 4 and 16.
The study drug will be given to you through a small needle into the skin of the abdomen. This is the same procedure as when insulin is injected as a treatment for Type 1 diabetes. The study staff will prepare the study drug and administer it to you.
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Study Procedures
Study visits: The table below describes the 7 visits you will be expected to attend in the study and the one telephone call, during this one year study. Details of what to expect at each visit are explained in the sections below
When Duration
Screening Visit 1 2 weeks before study 4 hours
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Week 4
Telephone Call Week 10
Week 16
Week 28
Week 40
Follow up Visit 7 Week 52
Week 0 3-6 hours
3-6 hours
1 hour
3-6 hours
3-6 hours
3-6 hours
4 hours
Screening visit (lasting approximately 4 hours): Before you have any screening test done, the study staff will give you a verbal and thorough explanation of the study. You will be given ample time to read and review the consent form, ask questions and make a decision if you are willing to participate in the study. A total of up to 70ml (about 5 tablespoons) of blood will be collected at the screening visit. If you agree to take part in the study, you will voluntarily need to sign this form and provide a review of your medical history as well as other tests including: •
Questions about your medical history, all medication and vitamins, any over the counter medicines etc., which you are taking or have taken in the past. The study staff will contact the doctor who is currently treating your diabetes to get documentation of the circumstances of your diagnosis with Type 1 diabetes (circumstances meaning, if you were diagnosed elsewhere).
•
A physical exam, including your weight and height.
•
Measurements of your vital signs: your heart rate (pulse), breath rate, body temperature, and blood pressure.
•
A heart tracing called an electrocardiogram (ECG) will be recorded to ensure you have no heart problems before entering the study. This will involve 12 sticky pads being attached to the chest, arms and legs to measure the heart’s electrical signal.
•
Routine blood tests, to check your overall health. Examples of these routine safety tests include tests to measure your white and red blood cells, your liver
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and kidney function and the electrolytes (salts and other chemicals in your blood). •
You will have a Mixed Meal Tolerance Test (MMTT) to measure how much insulin your body is making. Your blood sugar level must be between 3.9mmol/L and 11.1mml/L or the test will be postponed and rescheduled for another day. At this visit, the MMTT will require the collection of blood samples. The MMTT is described briefly below:
Mixed Meal Tolerance Test To be eligible for this study, you must have some beta cells that are still making a certain amount of insulin. This will be measured using a test called the Mixed Meal Tolerance Test (MMTT). The MMTT measures the amount of C-peptide, a byproduct of the production of insulin, present in your blood. The more C-peptide that is detected in your blood the more insulin your body is producing. The study staff will provide an information sheet with a detailed description of the MMTT and will be able to answer any question you may have about the test. One MMTT test will be done at the screening visit. Other MMTT tests will be done at weeks 4, 28 and week 52 of the study. You will be asked to eat your typical dinner the evening before the MMTT and to begin fasting at 9 pm that evening. ‘Fasting’ refers to an 8 hour fast prior the first blood draw. You can have you regular dinner meals and nothing after bedtime. Water can be taken at any time during the fast. On the morning of the MMTT test you will not be able to take insulin according to your regular schedule. Your study doctor will explain exactly what dosage of insulin can or cannot be taken before the test begins. You will have your blood sugar level checked by finger-stick in the clinic before the test. Your blood sugar level must be between 3.9mmol/L to 11.1mml/L or the test will be postponed and rescheduled for another day. A small tube (catheter) will be placed in your vein (like an IV) so that blood can be collected without the need for separate needle pokes. A total of seven separate blood samples will be taken from the tube (catheter) (4ml each) for a total of 28ml (2 tablespoons). After the first two blood samples are taken, you will be given a glass of Boost ™, which is a liquid meal replacement. You must drink the full amount given to you within 5 minutes. During the next two hours, you will have five blood samples
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taken. At the end of the test you will be given a snack. You will resume your usual insulin regimen after the test is completed. Other tests that will be completed at the screen visit include: •
A blood test for the ‘auto-antibodies’ (antibodies that attack your own tissue) that are commonly found in people with Type 1 diabetes.
•
Blood tests for HbA1c (a measure of your average blood sugar over the past 610 week).
•
Blood tests to analyze your immune system before treatment has begun.
•
Blood samples may also be taken for genetic testing in order to conduct some of the immunological tests that are required.
•
Blood samples may be frozen for future analysis of immunological markers. These samples will only be used for immunological tests that are directly related to this study and would not be used for other purposes.
•
Some blood samples may be sent to other laboratories for analysis but there will be no way to identify you as the source of these samples
•
Blood tests for Hepatitis B and C viruses (which cause diseases of the liver) and HIV. If a positive result for hepatitis or HIV is found, your study doctor will inform your family physician and the local public health authorities, as required by law.
•
A tuberculosis (TB) skin test (called a ‘PPD skin test’) to confirm that you do not have tuberculosis. This test involves a small needle to inject a small amount of inactive tuberculosis (TB) material into the upper layers of your skin. About three days later, you will need to come back to the clinic so that the study doctor or nurse can examine the area for the size of any redness or swelling (you can also have this done by another doctor or healthcare provider who is qualified to evaluate PPD skin tests, and the documented results can be sent to your study doctor). The study doctor may recommend that you have an additional blood test for TB or a chest x-ray. If you do have TB, you will not be able to join this study and your study doctor will inform your family physician and the local public health authorities, as required by law.
•
You will also be given a blood glucose meter (a device that measures your blood sugar via finger-stick) and will need to measure your blood sugar at least
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4 times a day throughout the study. This is standard practice for a patient with new-onset Type 1 diabetes. You may be asked to measure your blood sugar more frequently by the study doctor. You will bring the record of the blood sugar values that you record to every study clinic visit, so that the study doctor can upload and review your blood sugar values and help you manage your diabetes. You may also be asked, via a telephone conversation, to communicate these values so that your study doctor can adjust your insulin dose with your help. •
You will be asked to keep a record of the insulin dose you give yourself. This may be requested at any period during the duration of the study and is good practice when you are first diagnosed with Type 1 diabetes. It is very important you record zero units for any day on which you do not take any insulin. You will be asked to bring these records to study visits and again, may be asked to communicate them over the phone to study personnel, in order to assist in adjusting your insulin dose.
•
Throughout the study you will report low blood sugar episodes by phone to the study doctor or his personnel. Your study doctor will explain to you how and when to report these episodes. This won’t take longer than just a few minutes over the phone.
•
As a participant in the study it is important that you try to keep your blood sugar level as tightly controlled as possible by checking your blood sugar level at least 4 times a day; follow the diet recommended to you by the diabetes educator, dietician or nurse, and take your insulin as directed by your doctor.
Pregnancy Because we do not know if or how an unborn baby/fetus could be harmed, you should avoid becoming pregnant. Talk to your study doctor about the risks to your unborn baby/fetus if you did get pregnant. Work with your study doctor to find the best solution to make sure you do not get pregnant, if you wish to be in the study If you are a woman and are able to become pregnant (you have not been in menopause for at least one year and have not had your uterus removed or your tubes tied), you will have a pregnancy test to confirm you are not pregnant (this test will be performed on the blood drawn at all visits). Women must also be willing to use an effective method of birth control such as birth control pills, or a condom with
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spermicidal jelly (these methods will be explained by the study staff), from the beginning of the screening period through at least 60 days after receiving the last dose of the study drug. If you become pregnant during the study, your blood-testing schedule will be reduced. If you are a woman and able to become pregnant, there might be risks to the embryo or fetus, which are currently unforeseeable. There are no precautions a male subject will need to take with regards to their female partners of childbearing potential.
First Dosing Visit and Baseline Tests (lasting approximately 3-6 hours) This visit will take place on the morning of the first dose of the study drug. You will bring all records of your blood sugar readings and insulin usage done since the screening visit to this appointment. The study staff will ask you if there have been any changes in your health status or in any of your medications since they last saw you. You will have a physical exam and your vital signs will be measured. Blood will be drawn at this visit. This will include blood tests for HbA1c (a measure of your average blood sugar over the past 6-10 weeks). Routine blood tests, to check your overall health, may be repeated. Examples of these routine safety tests include tests to measure your white and red blood cells, your liver and kidney function and the electrolytes (salts and other chemicals in your blood). A blood sample will be collected from which cells and DNA will be stored to perform testing in direct relation to this study, (these samples will only be stored for up to 25 years following enrolment into the study). This blood sample will be used for testing immunological and genetic parameters to assess if the treatment had an effect. Approximately 200ml of blood (14 table spoons) will be taken at this visit. Other Dosing Visits (approximate time 3-6 hours) These clinic visits will last 3-6 hours and occur on weeks 4, 16, 28 and 40. Not all participants will receive a dose at weeks 28 and 40 but you will still have to attend the visit for blood tests. You will need to bring your blood sugar readings to each clinic visit so that the study doctor can review them. On each dosing visit, you will be asked about any change in your health status or medications since your last study visit. You will be weighed each morning, and your vital signs will be measured. Blood will be drawn at each visit. This will include blood tests for HbA1c (a measure of your average blood sugar over the past 6-10 week). Routine blood tests, to check
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your overall health, may be repeated. Examples of these routine safety tests include tests to measure your white and red blood cells, your liver and kidney function and the electrolytes (salts and other chemicals in your blood). A blood sample will be collected from which cells and DNA will be stored to perform testing in direct relation to this study, (these samples will only be stored for up to 25 years following enrolment into the study). This blood sample will be used for testing immunological and genetic parameters to assess if the treatment had an effect. The clinic at weeks 4 and 28 will also include another MMTT as described above. You will need to fast overnight and change your insulin use for the MMTT. The study staff will remind you on how to do this. Approximately 150ml of blood (10 table spoons) will be taken at the week 4, 16 and 40 dosing visits. At the week 28 dosing visit approximately 200ml of blood (14 table spoons) will be taken. On each dosing visit, you will remain in the clinic for at least 1 hour after the dose is given before you will be able to go home. If medically needed, based on the study doctor’s judgment, you may be asked to stay in the clinic longer, possibly even overnight, for the clinic staff to monitor you. Prior to each visit you should have been regularly recording your insulin use for a minimum of 7 days in a row. It is very important you record zero units on day on which you do not take any insulin. Prior to the first dosing visit and at week 28, you will also be asked to check your blood glucose levels more frequently (7 times a day) for a minimum of 7 days in a row.
Telephone Call/ Phone visits (approximate time 1 hour) At week 10, you will be called by a member of the clinical study team, in order to be asked questions about any adverse effects (side effects); to review your blood glucose reading and adjust insulin as necessary. This will be an opportunity for you to seek advice between dose titrations of your insulin. Support will always be available over the phone if you have any questions or concerns especially about titrating your insulin dose to correct your blood glucose readings. Prior to this call you should have been regularly recording your insulin use for a minimum of 7 days in a row. It is very important you record zero units on day on which you do not take any insulin.
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Follow Up Visit (approximate time 4 hours) You will be required to attend one follow up visit at 1 year after the first dose was given. The study staff will ask you if there have been any changes in your health, whether you have been admitted to the hospital or an emergency room, visited another doctor, or had any changes in your medications since they last saw you. Your vital signs will be measured again. The visit will take 4 hours. If you are having difficulty managing your diabetes and another doctor is helping you with your regimen, the study staff will call your regular doctor to discuss ways in which you might improve your control. Your other doctors can be given the results of the tests performed as part of the study, such as the results of your HbA1c (this is a measure of the sugar on your red blood cells that gives a hint of your control of diabetes) An MMTT (as described above) will be done at the follow up visit. You will need to fast overnight and change your insulin use for the MMTT. The study staff will remind you what to do. You will bring a record of your blood glucose readings and insulin use to the follow up visit so that the study doctor can review the readings. Prior to the visit you should have been regularly recording your insulin use for a minimum of 7 days in a row. It is very important you record zero units on day on which you do not take any insulin. You will also be asked to check your blood glucose levels more frequently (7 times a day) for a minimum of 7 days in a row prior to this follow up visit. Blood will be drawn at this visit. This will include blood tests for HbA1c (a measure of your average blood sugar over the past 6-10 week). Routine blood tests, to check your overall health, may be repeated. Examples of these routine safety tests include tests to measure your white and red blood cells, your liver and kidney function and the electrolytes (salts and other chemicals in your blood). A blood sample will be collected from which cells and DNA will be stored to perform testing in direct relation to this study, (these samples will only be stored for up to 25 years following enrolment into the study). This blood sample will be used for testing immunological and genetic parameters to assess if the treatment had an effect. Approximately 200ml of blood (14 table spoons) will be taken at this visit.
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At this time, ustekinumab is not licensed for use outside of research studies for patients with Type 1 diabetes. The study doctor will discuss treatment options with you at the end of the study.
Sample Storage All samples will be de-identified and stored at the Child and Family Research Institute, located on 950 West 28th street, Vancouver, BC. The samples will be kept for up to 25 years for future use in relation to the current study. For example, the samples will be used to conduct further immunological or genetic testing in relation to this study that might not be immediately available after the study is complete. After the samples are no longer needed they will be destroyed.
Withdrawal Visit: If you are unwilling or unable to attend visits over the long-term, you may be asked to attend as many study visits as you can possible do, even if some visits are skipped. If you are unwilling or unable to have all scheduled assessments (for example if you can’t have blood samples taken), you may be asked to undergo other safety assessments. If you leave the study for any reason before the 12 months are complete, or if you are withdrawn from the study for medical or other reasons, you will be asked if you will return to the clinic for a withdrawal visit. The withdrawal visit is important, but not mandatory. The withdrawal visit should take place as soon as possible after your decision to leave the study. The study staff will ask you if there have been any changes in your health or if you have taken any medications since they last saw you. A physical exam will be performed, vital signs will be measured, and you will be weighed. Study staff will ask for permission to perform blood tests that will include routine tests of your health and experimental tests to investigate the effects of ustekinumab. You will be asked if you agree to undergo a voluntary MMTT and to report your insulin intake for 7 days prior to the visit. This withdrawal visit is not a requirement, as subjects will be permitted to stop participation whenever they wish to do so.
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Restrictions During the Study: Several restrictions (things you are not allowed to do) apply during the study, and you will have to follow these carefully, both for your safety and in order not to influence the study results. Before taking any drugs, herbal or natural, remedy, that you think you may need or that another doctor prescribes or recommends to you, you should contact the study doctor to make sure it is allowed. You cannot have any vaccines, including the flu vaccine, within the 30 days before the first dose of the study drug and for at least 14 days after the last dose of the study drug. You cannot take immunosuppressive agents (drugs that suppress your immune system), such as Methotrexate Cyclosporine, anti-TNF agents, or systemic high-dose corticosteroids within the month before the first dose of the study drug or for 3 months after the last dose of the study drug. If you have taken any investigational (experimental) drug within the 3 months before the first dose of study drug or are planning to take any investigational drug during the 2 years after the last dose of study drug, you may not be enrolled. If you wish to enroll in another study during the 2 years after the last dose of study drug, the investigator must be contacted.
Risks/Side Effects: There may be risks associated with some aspects of this study. Please read this section for information about the possible risks. If you have further questions about the possible risks and side effects, please ask your study doctor.
Risks associated with blood sampling:
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During the study you will have frequent blood sampling. As a result of needle sticks, there is a risk of bruising or tenderness where the needle is inserted (12%) , but this normally clears up without treatment. On rare occasions (less than 1%), fainting may occur or infections can develop from having blood drawn or other injections. These infections are routinely treated with antibiotics and typically resolve without any lasting problems.
Risks associated with the Mixed Meal Tolerance Test: During the MMTT, in addition to the risks associated with needle sticks noted above, you may experience fluctuations in blood sugar because you will have withheld insulin and will be taking in calories (from the liquid meal replacement). Please review all possible symptoms of high and low blood sugar with the study coordinator before beginning the MMTT to assist the study staff in being fully aware of what aspects your symptoms may include.
Risks associated with ustekinumab: Further detail of the side effects described below can be obtained for the study doctor who also has access to a detailed document, which is given to doctors and patients when they are prescribed ustekinumab. The most common side effect, by far, of ustekinumab is the common cold, which is also called nasopharygitis or a upper respiratory tract infection. Nasopharyngitis occurred in 7.2% of subjects given the drug and a upper respiratory tract infection occurred in 4.8%. This data is from subjects given ustekinumab in three major studies (PHOENIX1, PHOENIX2 and ACCEPT), which included 2502 patients with psoriasis and/or psoriatic arthritis. In these studies half the subjects were given 45mg at weeks 0, 4 and then every 12 weeks and half the subjects were given 90mg at weeks 0, 4 and then every 12 weeks after. These are mild episodes that may or may not be attributed to taking the drug and so do not require the drug to be discontinued. Since ustekinumab stops certain parts of the immune system, you have a potential risk to have infections or reactivate infections that are hidden in the body (latent). In clinical studies serious infections are very infrequent in patients given ustekinumab and no greater than you would expect in the general population. However, if you have a serious active infection you should not be enrolled in the study or given the
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drug. We will test you to see if you have a previous tuberculosis infection that might still be in your body. If there is any evidence of this then you will not be able to participate in the study. Study staff will also be available to answer any concerns yo might have that you are developing an infection whilst on ustekinumab. In 5418 ustekinumab treated subjects that were given ustekinumab in the clinical development program (combining many different clinical trials), one developed a very rare brain swelling disorder (reversible posterior leukoencephalopathy syndrome). It is unclear as to what the exact cause of this condition is but it can cause headaches, seizures, confusion and problems with eyesight. The one patient who developed this had been given much higher doses of ustekinumab than is given in this study and as soon as the drug was stopped he made a full recovery. We will provide access to a study doctor at all times for you to report any of these symptoms if you are taking the study drug. This risk level though, is very low (0.03%). The safety and efficacy of ustekinumab in combination with phototherapy or immunosuppressive agents have not been evaluated. You should not be included in the study if you have used any strong immunosuppressive agent (e.g. systemic highdose corticosteroids on a chronic basis, methotrexate, cyclosporine or anti-TNF agents) within the 30 days prior to the first study drug dose, and are expected to require treatment for the duration of the study. (intranasal, inhaled and topical corticosteroid medications are permitted at recommended dosages). You should also try to avoid tanning beds and extended exposure to sunlight without sunscreen. As no current data is available on whether or not live vaccines pose a risk when used in conjunction with ustekinumab, it is recommended that live vaccines are not given with ustekinumab. It is important that you are not in the study if you have received any live vaccines (e.g. varicella, measles, mumps, rubella, cold attenuated intranasal influenza vaccine, BCG and smallpox) within 30 days prior to the first study drug dose and are not expected to need to receive a live vaccine during the study. You should inform the study doctor if you think this is possible. Cancer is always a theoretical risk when you give a drug that affects the immune system. Some patients that were given this drug have developed skin cancer (42 out of 3117 patients or 1.3%) but not at a rate that is more than the general population, suggesting that standard environmental and genetic factors cause cancer more so than the study drug. However, the use of ustekinumab has not ever been tested in patients with a history of cancer and so the drug will not be given to you if you have had a past history of cancer.
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The safety data described below reflect exposure to ustekinumab in three major studies (PHOENIX1, PHOENIX2 and ACCEPT), which included 2502 patients with psoriasis and/or psoriatic arthritis. In these studies half the subjects were given 45mg at weeks 0, 4 and then every 12 weeks and half the subjects were given 90mg at weeks 0, 4 and then every 12 weeks after. Some other minor side effects that were reported in more than 1% of patients include headaches (6%), fatigue (3%), joint pain (3%), diarrhoea (2%), back pain (2%), stomach cramps/nausea (2%), itchiness (2%), dizziness (1%), redness around the injection site (1%) and muscle pains (1%). These are rare and mild episodes that may or may not be attributed to taking the drug and so do not require the drug to be discontinued. Even more rarely (less than 1%) there have been infections of the skin with bacteria or shingles. There were cases of depression. Again, these are extremely rare and mild side effects that may or may not be attributed to taking the drug and so do not require the drug to be discontinued. There was also a slight increase in blood glucose in patients given ustekinumab but this was not thought to have any effect on the patients. We will be monitoring your blood glucose very carefully during the trial.
Risk of an Allergic Reaction: As with any study drug, there may be a risk of an allergic reaction (2%). Symptoms that may occur during any such allergic reaction, including food allergies and bee stings, could consist of rash, hives, itching skin, difficulty breathing, lowered blood pressure, swelling, and even death. (severe anaphylactic shock). If any of these symptoms occur, contact your study doctor immediately or seek emergency care. You will be immediately treated with standard medicines used to treat such reactions. Also the needle cover on the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals allergic to latex. There is a risk that you will develop intolerance to monoclonal antibodies, such that you will not be able to use them in the future.
Risks Associated with Pregnancy and Breastfeeding: The effects of ustekinumab on the human foetus are unknown. If you are pregnant or trying to become pregnant, you may not enrol in the study. Every precaution must be
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taken to prevent pregnancy while you are participating in the study, from the beginning of the screening period through 2 months after the last dose of study drug. It is also not known whether ustekinumab is secreted in human breast milk or if there is a risk to the breastfed infant. If you are breastfeeding, you may not enrol in the study. If you become pregnant during the study, you should notify the study doctor immediately. If the pregnancy occurs during the dosing period, dosing will be stopped. With your permission, the study staff will follow up with you at least until the baby is born to review your and the baby's health and another consent form would need to be signed for this. If you become pregnant at any time during the study you will have a modified followup schedule and no MMTT will be performed during your pregnancy or for three months after the birth.
Unknown risks: As with any investigational agent, there may be side effects or risks that are not yet known. Although there is extensive experience with ustekinumab in human treatment, it cannot be known in advance whether any medical problem may occur in patients with Type 1 diabetes. If you suffer a serious or lasting injury as a result of participation in this study, it may affect your ability to obtain private health insurance, your employability, and/or quality of life.
Genetic risks: In addition to the risks of physical harms outlined in this consent form, there are also possible non-physical risks associated with taking part in this study. For example, disclosure of genetic or tissue marker research data could result in discrimination by employers or insurance providers toward you or your biological (blood) relatives. The chance that research data would be released is estimated to be small.
Possible Benefits It is not known whether or not you will directly benefit from your participation in this study. Ustekinumab may not have any benefit for you. The information from this
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study will help the study team move forward with future larger scale trials of this product in diabetes and other similar diseases. Participating in a clinical trial for Type 1 diabetes is a way in which you, as an individual can help to find a cure for this disease and its complications.
Alternative Therapy You do not have to be in this study to get treatment for your Type 1 diabetes. There are a number of therapy options for the treatment of diabetes. Your study doctor can discuss your treatment options with you. You will continue standard treatment for your diabetes throughout the study.
Confidentiality of Your Records Your confidentiality will be respected. However, research records and health or other source records identifying you may be inspected in the presence of the Investigator or his or her designate by representatives of BC Diabetes, Health Canada, and The University of British Columbia Clinical Research Ethics Board (a committee that reviews research studies to help ensure that the rights, safety and welfare of the participants are protected and that the study is carried out in an ethical manner) for the purpose of monitoring the research. No information or records that disclose your identity will be published without your consent, nor will any information or records that disclose your identity be removed or released without your consent unless required by law. You will be assigned a unique study number as a participant in this study. This number will not include any personal information that could identify you (e.g., it will not include your Personal Health Number, SIN, or your initials, etc.). Only this number will be used on any research-related information collected about you during the course of this study, so that your identity will be kept confidential. Information that contains your identity will remain only with the Principal Investigator and/or designate. The list that matches your name to the unique study number that is used on your research-related information will not be removed or released without your consent unless required by law. Your rights to privacy are legally protected by federal and provincial laws that require safeguards to insure that your privacy is respected. You also have the legal
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right of access to the information about you that has been provided to the sponsor and, if need be, an opportunity to correct any errors in this information. Further details about these laws are available on request to your study doctor Your date of birth will also be provided if requested by the sponsor or responsible regulatory agency. This is to confirm you meet the eligibility criteria stated for the study of being between 18 and 35 years of age. Also your PHN number may be provided to a doctor if you are admitted for a medical emergency, whilst participating in the study. A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time. Your personal information or information that could identify you will not be revealed without your express consent unless required by law. If facts become known to the researchers which must be reported by law to public health authorities or legal authorities, then your personal information will be provided to the appropriate agency or authority. For example, results of your HIV, Hepatitis B or C and Tuberculosis screening tests will need to be reported to provincial public health authorities (BC Center for Disease Control) if they are positive. By signing this consent form, you authorize the study doctor to release your study related records to the study sponsor (Dr Jan Dutz), the University of British Columbia Clinical Research Ethics Board, Juvenile Diabetes Research Foundation Canadian Clinical Trials Network and Health Canada. Results of this study may be published in scientific journals or presented at medical meetings but none of these publications or presentations will identify you by name. National and international data protection regulations give you the right to control the use of your medical information. By signing this consent form you specifically authorize your medical information to be checked, transferred, and processed as follows: The monitors, auditors, and inspectors mentioned above may review your medical information by direct access to your medical records at the study site in accordance with the first paragraph of this section. This inspection is to check the accuracy of study records, and to verify the clinical trial procedures and/or data.
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Study results including your anonymous medical information (for example, your medical history and results of all tests performed in the study will be submitted only with your initials, study number and date of birth), may be processed, which means it will be collected, entered into computer databases, verified, analyzed, printed, and reported as necessary for legitimate scientific purposes. Your identity will not be known to the person or persons analyzing the data or preparing materials for publication. Any samples sent outside of Canadian borders may increase the risk of disclosure of information because the laws in those countries, (for e.g. the Patriot Act in the United States) dealing with protection of information may not be as strict as in Canada. However, all study samples that might be transferred outside of Canada will be coded (this means it will not contain your name or personal identifying information) before leaving the study site. By signing this consent form, you are consenting to the transfer of samples, to organizations located outside of Canada. In particular, the Immune Tolerance Network (ITN) a clinical trial consortium in the United States, ITN is a clinical trials consortium that often perform trial of new agents in type 1 diabetes in the United States. They are conducting some clinical testing (C-peptide level analysis and auto-antibody analysis). All other tests are being done in Canada. You have the right to withdraw your permission to use and disclose your health information, at any time by sending a written note to the study doctor at the address listed on page 1 of this consent form or verbally informing the study doctor Dr Thomas Elliott. Your permission does not have an expiration date. However, if you choose to withdraw your permission, you will be discontinued from the study and any study data collected prior to your withdrawal may still be processed along with other data collected as part of the clinical study. You may access your medical information as allowed by national law and request changes if the information is not correct. If you give permission, your regular family physcian and specialist (diabetes doctor) will be notified of your participation in the study so that your study doctor, specialist doctor and your family doctor can provide proper medical care. Your study records including confidential information about you collected during the study will be kept at a secure location for 25 years after study completion as required by Canadian clinical trial regulations.
Costs and remuneration for taking part in this study
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The study drug that you receive will be provided to you free of charge. Study related tests; diabetes care and counselling by study doctors and health care personnel, and procedures are provided at no cost to you. You will be reimbursed for this study with an allowance that will vary depending on the distance you need to travel to the study centre. There are a total of 7 occasions when you are required to attend the clinic for an average of 4 hours in duration. The allowance will cover an accommodation allowance of $50-$300 total, a travel/parking allowance of $50-$200 for each of the seven visits, and an allowance to offset lost income of $420 ($15/hour) for four hours in each of the seven visits. This is intended to offset the costs of parking, travel and time off work that you might experience because of your participation in the study. If you withdraw from the study remuneration will be pro-rated according to how much time you spent in the study. Receipts will be required for accommodation and travel expenses.
Compensation for Study-Related Injury If you have any physical illness or injury as a direct result of the study drug being given to you, you will voluntarily receive appropriate medical care as would routinely be provided by the provincial medical services plan. You will not receive any other money for physical illness or injury as a result of your participation in this study. No compensation will routinely be made for lost wages, disability, etc. By signing this form, you do not give up any of your legal rights and you do not release the study doctor, participating institutions, or anyone else from their legal and professional duties. If you become ill or physically injured as a result of participation in this study, medical treatment will be provided at no additional cost to you. The costs of your medical treatment will be paid by your provincial medical plan. In the event of a research related injury, please speak to your study doctor Dr. Thomas Elliott at tel. 604-875-4111 during office hours. After hours please call the VGH Switchboard 604-875-5000 and ask for the endocrinologist on call, or go to the nearest hospital emergency department. You may also speak to the study sponosor Dr Jan Dutz at 604-875-4747.
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Voluntary Participation/Withdrawal Your participation in this study is entirely voluntary. You are free to decide whether or not to enter the study. If you do enter the study, you are free to withdraw at any time, for any reason, without penalty or loss of benefits to which you are entitled. Your decision to withdraw will not affect your future medical care. The study doctor may also withdraw you from the study if such action is in your best interest. The sponsor of the study (Dr Jan Dutz, Professor, University of British Columbia), and Health Canada have the right to stop the study at any time, for example, if subject safety is at risk or if not enough subjects in the study can be recruited to analyse the effects of the drug. If you want to stop your involvement in the study, you will be asked to return to the clinic for visits to assess your health and safety for at least 12 weeks after taking the study drug. If you withdraw from the study, if you are withdrawn, or if the study is stopped, you will be asked to return to the clinic as soon as possible for a withdrawal visit. You have the right to refuse these visits.
New Findings If new information about ustekinumab develops during the course of the study, that may affect your willingness to continue taking part in this study, your study doctor will provide this information to you in a timely manner. If you choose to enter this study and at a later date a more effective treatment becomes available, it will be discussed with you. You will also be advised of any new information that becomes available that may affect your willingness to remain in this study.
If You Have Any Questions If you have any questions about your decision to join this study, if you have experienced any unusual reaction or research related injury while in this study, or in case of an emergency, you should contact: Dr. Thomas Elliott at 604-875-4634 or the
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Study Coordinator, Marla Inducil at 604-875-4634. The study sponsor Dr Jan Dutz can be contacted at 604-875-4747.
In case of an emergency, please contact Dr. Thomas Elliott at tel. 604-875-4111 during office hours. After hours please call the VGH Switchboard 604-875-5000 and ask for the endocrinologist on call, or go to the nearest hospital emergency department.
If you have any concerns or complaints about your rights as a research participant and/or your experiences while participating in this study, contact the Research Participant Complaint Line in the University of British Columbia Office of Research Ethics by e-mail at
[email protected] or by phone at 604-822-8598 (Toll Free: 1-877822-8598).
Permission to inform doctor of study participation: I give permission, ☐ I do not give permission, ☐
for my primary care doctor and/or diabetes specialist to be informed about my participation in this study.
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Agreement to be in the Study •
I have read and understood the information on this consent form.
•
I have had the time to read this form and think about what is involved if I choose to join this study.
•
I understand that my participation in this study is voluntary.
•
I have read and been told about the information in this consent form and I have been able to ask questions and have had satisfactory responses to my questions.
• I understand that I am completely free at any time to refuse to participate or to withdraw from this study at any time, and that this will not change the quality of care that I receive. • I authorize access to my health records and samples as described in this consent form. • I understand that I am not waiving any of my legal rights as a result of signing this consent form •
I may ask the study personnel including the doctor for additional information at any time.
•
I have been told that my medical records can be reviewed at any time by the Sponsor, its agents, Health Canada, or other regulatory agencies and that my confidentiality will be protected but cannot be guaranteed.
•
I have been told that there are risks associated with my being part of this research study.
•
I will not donate blood while I am in the study and for at least 30 days after I finish dosing.
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I freely consent to participate in this study. I have been told that I will receive a dated and signed copy of this form for my own records. ----------------------------
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Participant’s signature
Printed Name
Date
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Signature of Person obtaining Consent
Printed Name
Date
If this consent has been done in a language other than that on this written form, with the assistance of an interpreter/translator, indicate:
Language: ---------------------
Was the participant assisted during the consent process in one of ways listed below? ☐ Yes ☐ No [Note: For typical situations where the person conducting the consent discussion simply reads the consent with the participant to ensure that informed consent is properly obtained, check “no”.] If yes, please check the relevant box and complete the signature space below: ☐ The consent form was read to the participant, and the person signing below attests that the study was accurately explained to, and apparently understood by, the participant (please check if participant is unable to read). ☐ The person signing below acted as an interpreter/translator for the participant, during the consent process (please check if an interpreter/translator assisted during the consent process).
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Signature of Person Assisting in the Consent Discussion
Printed Name
Date
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Investigator’s signature
Printed Name
Date
My signature above signifies that the study has been reviewed with the study participant by me and/or by my delegated staff. My signature may have been added at a later date, as I may not have been present at the time the participant’s signature was obtained.
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