UNIVERSITY OF CALIFORNIA, SAN DIEGO



UNIVERSITY OF CALIFORNIA, SAN DIEGO

CONSENT TO ACT AS A RESEARCH SUBJECT

BEA 2180 Study: A multinational, randomized, double-blind, placebo- and active-controlled, parallel group efficacy and safety comparison over 24 weeks of three doses (50 µg, 100 µg, 200 µg) of BEA 2180 to tiotropium 5 µg and placebo delivered by the Respimat® inhaler in patients with chronic obstructive pulmonary disease (COPD)

(BIPI Protocol 1205.14)

Joe W. Ramsdell, M.D. is conducting a research study to find out more about chronic obstructive pulmonary disease (COPD). You are being asked to participate in this study because you have COPD. There will be approximately 20 participants at this site. The purpose of this study is to determine the optimum (best) dose for BEA 2180 BR for treating the symptoms of COPD. The sponsor of this study is Boehringer Ingelheim Pharmaceuticals, Inc. and Dr. Ramsdell is being paid by the sponsor to conduct this study.

BEA 2180 BR is an investigational (experimental) drug which means that it has not been approved by the Food and Drug Administration (FDA) and it is not available to people who are not in research studies like this one. The Respimat® device will be used to inhale the study drug. It uses a liquid solution of BEA 2180 BR that is inhaled by the mouth using an earth-friendly delivery device. Studies with the Respimat® device have also shown that more of the drug reaches the lung as compared to other metered devices and dry powder inhalers.

This study will also compare BEA 2180 BR to tiotropium, which is also supplied in the Respimat device. Tiotropium Respimat® is considered to be an investigational drug as well, which means that is has not been approved by the Food and Drug Administration (FDA); however, tiotropium (HandiHaler®) delivered in a dry powder formula has been approved in a number of countries. Tiotropium is also a long-acting anticholinergic (an inhaled medication commonly used in COPD treatment). You will also receive a rescue medication called albuterol which is FDA approved for quick relief of your symptoms. You most likely already use this drug, or one like it, as part of your usual care.

BEA 2180 BR belongs to this group of drugs known as long-acting anticholinergics. Inhaled long-acting anticholinergics help you to breathe easier.

If you agree to be in this study, the following will happen:

About 2000 patients from the U.S., Canada, Mexico, Spain, Germany, Russia, Poland, Hungary, Taiwan and Korea will take part in this study. This study will use competitive enrollment. This means that when a target number of subjects have entered the treatment phase of the study, all further enrollment will be closed. There will be approximately 10 participants at this site. If you are in the screening phase and the target number is reached, you will be allowed to continue and enter the study if you continue to qualify.

If you qualify and agree to participate in this study, at Visit 2 you will be randomly assigned by chance (assigned by chance to a specific order of treatments, like a lottery) to receive one of the following five study treatments:

● BEA 2180 BR 50 micrograms

● BEA 2180 BR 100 micrograms

● BEA 2180 BR 200 micrograms

● Tiotropium 5 micrograms

● Placebo (an inactive substance)

You will have an 80% chance (4 in 5) of receiving an active drug. You will have a 60% chance (3 in 5) of receiving BEA 2180 BR (at one of 3 possible doses) and a 20% chance of receiving tiotropium (1 in 5). You will have a 20% chance (1 in 5) of receiving placebo. The study is designed to test three possible doses of BEA 2180 BR to see which one is most effective.

This study is double-blind, which means that you, the study doctor and the study staff will not know which of the study drugs you will be receiving. In case of emergencies the study doctor can find out which dose you are taking.

This study is broken up into three parts: the Screening Period, the Study Phase Period, and the Follow-Up Period). Your participation in this study is expected to last approximately 29 weeks and will involve 10 visits to the study site. However, if you have an exacerbation (an increase in severity of symptoms) of your COPD, the time that you are in the study could be extended.

STUDY VISITS

Informed Consent Visit (This visit will last approximately one hour)

Before any study-related procedures are performed, and if you wish to participate in this study, you must read and sign this consent form. The following will be reviewed and explained by the study staff.

• Review the study requirements including the procedure for follow up of subjects who leave the study early.

• You will be asked not to do any strenuous activity or exercise for at least 12 hours before each visit.

• Smoking is discouraged for 12 hours prior to and during all visits and not permitted 30 minutes prior to pulmonary function tests (PFT or breathing tests)

• You will be instructed on other restrictions for the screening visit PFT.

• The study doctor or staff will review the current medications you are using for your COPD. Depending on what medications you are using, you will be asked to either stop taking some of these medications for the duration of your study participation or to not take some of your medications for a certain number of hours before Visit 1 and future visits. The study doctor or staff will discuss this with you.

• You will be scheduled for Visit 1 between 2 and 30 days of this visit, depending on what medications you will be asked to stop taking.

Screening Period (Visit 1) (This visit will last approximately three hours)

You will be asked to read and sign this informed consent at or before this visit and before any study procedures are performed. You may be asked to fast (not eat) before a visit. The following tests and procedures will be performed to determine if you qualify for this study.

• Your personal data will be taken (height, weight, date of birth, gender, how long you have had COPD, and smoking history)

• Your complete medical history including medications that you are taking or have taken within the last 3 months will be reviewed

• A complete physical examination will be performed which includes taking blood pressure, checking heart rate, taking your temperature, vital signs, and looking at your general appearance.

• Review of your health

• Vital signs (blood pressure and pulse)

• An electrocardiogram (ECG-which measures the electrical activity of the heart)

• Blood (approximately two teaspoons) and urine samples will be taken for laboratory testing and pregnancy test (women of child bearing potential only). You must have fasted (not eaten anything) for at least 8 hours before these samples are taken.

• A PFT will be performed before and 30 minutes after taking albuterol, a medicine that has been approved by the FDA

• Receive training from the staff on the use of albuterol HFA MDI (salbutamol/albuterol) that you will use for your rescue medication. You will also receive training on how to use the Respimat( device.

• If you qualify, you will be given an electronic peak flow meter. You will be trained on this handheld electronic device. You will be shown how to perform your peak flow procedure (PEFR).

• You will be given albuterol HFA MDI (salbutamol/albuterol) to be taken as rescue medication as needed during the screening period and throughout the study.

• You will be given a paper diary to record the time that you take your study drug and to record the number of times that you take your rescue medication.

You will be scheduled to return for Visit 2 after 14 days. During this time you need to follow instructions from the study staff on using the electronic peak flow meter and recording items in your paper diary. In addition, study staff will instruct you as to what medications you can or cannot take during this time.

Study Phase Period (Visits 2-9) (The visit length ranges from one hour to four hours)

If you qualify to continue participation in this trial and you agree to continue, you will be scheduled to return for 8 additional visits. At Visit 2 you will enter the Study Phase Period for this study and receive your first dose of study drug. Each of the Study Phase Visits 2, 5, 7 and 9 will last approximately 4 hours and Visits 3, 4, 6 and 8 will last approximately 1 hour. Visits 2, 3 and 4 will be separated by one week and Visit 5 will occur 2 weeks after Visit 4. Visits 5, 6 and 7 will be separated by 4 weeks. Visit 8 will be 6 weeks after Visit 7 and Visit 9 will be 6 weeks after Visit 8.

You will need to stay in the clinic during your visits, and should not leave without instruction from your study doctor. One follow-up visit (Visit 10) will occur 3 weeks after Visit 9. The following tests and procedures will be performed:

• You will be asked if you have followed the medication restrictions and other restrictions explained to you at the last visit.

• Your smoking status will be reviewed.

• Review of your health since the last study visit.

• Review of medicines you have taken.

• Review of your diary and your electronic peak flow meter.

• Measurement of your vital signs (blood pressure and pulse rate).

• Collection of blood (approximately two teaspoons) and urine samples for laboratory tests (Visit 9, only). Study personnel will remind you that must not eat anything for at least 8 hours prior to collecting these samples.

• Receive the study drug.

• You will receive rescue medication albuterol HFA MDI (salbutamol/albuterol). At each visit, study personnel will review how much you have used the rescue medication and determine whether you need a new supply.

• Your study doctor will make an evaluation as to your general health status.

• PFTs will be done at approximately 40 minutes and 15 minutes before study drug is given and again at 15, 30 minutes, 1, 2, and 3 hours after the study drug is given at Visits 2, 5, 7 and 9. PFTs will be done at approximately 40 minutes and 15 minutes before study drug is given on Visits 3, 4, 6 and 8.

• ECGs will be performed approximately 20 minutes prior to receiving the study drug and again 2 hours after the study drug is given at Visits 2, 5 and 9.

• A physical examination (Visit 9 only) will be performed.

• Questionnaires to ask you about your health status and well-being will be given to you to complete.

Sub-study Visits 2a and 2 b: (These visits will last approximately two hours)

There will be approximately 300 subjects participating in the sub study portion of this trial. The sub-study will involve two additional visits 2 days after Visit 2 (Visit 2a) and 4 days after Visit 2 (Visit 2b). Participation in the sub-study is optional. If you agree to participate in the sub study, the following tests and procedures will be performed:

• You will be asked if you have followed the medication restrictions and other restrictions explained to you at the last visit

• Your smoking status will be reviewed

• Review of medicines you have taken

• PFTs will be done at approximately 40 minutes and 15 minutes before study drug is given

Additionally, if participating in the sub-study, you will be asked to do two additional PFTs immediately after you take your study drug and 10 minutes after your take your study drug at Visits 2, 5, 7 and 9.

Sub-study Participation

Please initial below whether you agree to participate in the sub study portion of this trial.

________ Yes, I want to participate in the sub study.

________ No, I do not want to participate in the sub study.

Follow-Up Visit (Visit 10) (This visit will last approximately two hours)

The following procedures will be performed:

• You will be asked if you have followed the medication restrictions and other restrictions explained to you at the last visit

• Your smoking status will be reviewed

• Review of your health since the last study visit

• Review of medicines you have taken

• Review of your diary and your electronic peak flow meter

• One PFT will be performed

• Your study doctor will make an evaluation as to your general health status

• Questionnaires to ask you about your health status and well-being.

• Your participation in the trial is over.

If you drop out prior to Visit 10 (This phone call visit will last less than 15 minutes)

The purpose for collecting follow-up information is to determine your health status. This information is necessary to interpret the clinical trial data correctly. For this reason, you will be asked whether you give your permission for the study staff to contact you (or someone you designate, like your family doctor) to ask about your status at the time that you should have completed Visit 10 by telephone.

If you are pregnant, planning to become pregnant, or are nursing an infant you will not be able to take part in this study. If you are a woman who is able to have a child, you cannot take part in this study unless you have been using a reliable form of birth control for the previous 3 months before the study, throughout the study and follow-up period.

Some effective methods of birth control are implants, injectables, combined oral contraceptives, some IUDs, or a vasectomized partner. You must discuss with your study doctor if the method of birth control you are using is reliable, safe and effective for you. You must have a negative pregnancy test prior to treatment and must not become pregnant while in the study. If you become pregnant during the study you must tell the study doctor or staff right away

Subject Responsibilities

The following is a list of requirements for you:

• You should keep your study drug at room temperature.

• You should not enter this study if you have any serious health problems. Discuss any health problems with the study doctor.

• You will use your electronic peak meter to record your flow measurements and complete your diary each day at home. Study personnel will instruct you as to how to do this.

• If you are currently participating in another investigational drug study or have done so within the past month, you may not enter this study.

• The morning dose of study drug should be taken at about the same time each morning between 7:00 a.m. and 10:00 a.m. However, you should not take your study drug on the morning of any test day. The study drug will be given to you in the clinic.

• Certain medications shouldn’t be taken during this study. These will be explained to you by the study doctor. If you need to take these medications during the study, you shouldn’t enter the study.

• You must schedule your clinic visits at about the same time for each visit between 7:00 a.m. and 10:00 a.m.

• It is important to come to scheduled study visits. It is also important to tell the study doctor or staff of any problems that you are having. The study doctor and staff also need to know about any medicines you are taking even if they are obtained without a prescription.

• You must remain in the building where the PFTs are performed.

• You should not smoke or take part in any strenuous activities for 12 hours before any of your PFTs. You should not smoke on PFT days.

• In general, on testing days you should not drink anything with caffeine (coffee, tea, colas) or anything that is very cold. If you have any questions about what to drink, ask the study coordinator for help.

• You should avoid cold temperatures, environmental smoke, dust or areas with strong odors (e.g. perfumes) on PFT days

• You will be instructed on the proper way to use the Respimat( device to take your study drug. It is important that you follow these instructions.

• You must bring all of your study related materials (study drug, rescue medication, electronic peak flow meter, and diary) with you at each visit.

Participation in this study may involve some added risks or discomforts. These include:

The study drug BEA 2180 BR. The following risks have been identified as risks: rhinitis (runny nose), headache, COPD exacerbation, cough, shortness of breath, throat pain, and nasopharyngitis (inflammation of the nose and throat).

Tiotropium. Tiotropium may cause side effects: dry mouth, constipation, increased heart rate, blurred vision, glaucoma (increased eye pressure), urinary difficulty and urinary retention (inability to pass urine).

Albuterol. You most likely already use this drug, or one like it, as part of your usual care. Albuterol might cause tremors, nervousness, dizziness, difficulty sleeping, headache, rapid or irregular heart beats, drying and irritation of your mouth, sore throat, upset stomach, and coughing. If such symptoms occur, they usually go away within a short time and do not require treatment.

Blood Draw. Blood drawing may cause a small amount of pain. In addition, a temporary bruise or "black and blue mark" may develop. Rarely, people faint after blood drawing. Very rarely, the vein in which the needle has been inserted may become inflamed or infected, but that can be treated.

ECG. Skin irritation from the ECG electrode pads or pain when removing the pads is a possible risk.

Pulmonary Function Tests (PFT). Discomfort is unusual during lung function testing; however, some people experience a sense of dizziness and/or headache when performing the tests. These feelings are usually temporary. Treatment will be available, if needed.

Questionnaires. The questionnaires are not tests. There is no right or wrong answers to these questions. You may skip any question that you feel uncomfortable answering.

Placebo. Placebo is an inactive medication that is unlikely to be associated with any side effects. You will have albuterol to use as needed to treat COPD symptoms.

Birth Control/Pregnancy Risks. No studies have been done on BEA 2180 BR in pregnant women or women who are nursing their infant. It is not known if BEA 2180 BR is safe for pregnant women, unborn babies and infants who are nursing. It is also not known if BEA 2180 BR has an affect on sperm or eggs.

General Risks

Your condition may worsen, remain the same or not improve as a result of taking part in this research study.

It is important that you tell the study doctor or staff if you do not feel well or experience any side effects, whether or not you think they have happened as a result of taking part in this study and even if they have disappeared with or without the treatment you may have taken.

If you experience any unusual symptoms, contact your study doctor as soon as possible at the telephone number listed below in this consent form.

Unforeseen Risks

There may be other risks from participating in this study that are unknown. All drugs have a potential risk of an allergic reaction (redness or swelling), which if not treated promptly, could become life-threatening.

New Findings

If any new findings or new information is learned about this study or the study drug, that may affect your willingness to continue to take part in this study, you will be told as soon as possible.

You will be compensated for your time and travel expenses up to a maximum of $1,175.00 including the sub-study and follow-up visits. This amount will be distributed as follows:

Visit 1 $50.00 Visit 6 $50.00

Visit 2 $200.00 Visit 7 $200.00

Visit 3 $50.00 Visit 8 $50.00

Visit 4 $50.00 Visit 9 $200.00

Visit 5 $200.00

Sub-Study Compensation

Visit 2a $50.00 Visit 2b $50.00

Follow-up visit compensation $25.00

The total amount will be distributed at the end of the study. Should you discontinue the study early, or are removed early from the study by your study doctor or Boehringer Ingelheim, you will be reimbursed for your time and travel expenses up to the point of discontinuation. Failure to follow the study guidelines may result in your dismissal from the study. Regardless of whether you choose to withdraw from the study or are removed by an investigator, your physician, or Boehringer-Ingelheim, you will be asked to come in for a final evaluation visit.

If you are injured as a direct result of participation in this research, the University of California will provide any medical care needed to treat those injuries.  Boehringer Ingelheim Pharmaceuticals, Inc., the sponsor of this study, will pay for all reasonable medical and hospital costs required for the diagnosis and treatment of any adverse effect directly related by the study drug, the study procedures, or laboratory work required by the protocol.  Neither the University nor Boehringer Ingelheim Pharmaceuticals, Inc. will provide any other form of compensation if you are injured.  You may call the UCSD Human Research Protections Program office at (858) 455-5050 for more information about this, to inquire about your rights as a research subject, or to report research-related problems.

Dr. Ramsdell and/or ________________ has explained this study to you and answered your questions. If you have other questions or research-related problems, you may reach the study coordinator or Dr. Ramsdell at (619) 471-0819 during regular business hours or (619) 543-6222 and have the study doctor on-call paged.

The study drug is investigational. Your insurance may not pay for this. The study drug will not cost you anything. Neither you nor your insurer will be responsible for this cost.

Potential Benefits

There is no guarantee that you will receive any benefit from taking part in this study. Possible benefits include your condition remaining the same or improving.

By taking part in this study, you may contribute information about BEA 2180 BR that may benefit other patients in the future and may lead to another medicine to treat COPD.

Alternative Treatments

Instead of being in this research study, you may have other treatment choices or you may choose no treatment at all. You should discuss all other treatment options with your doctor before you decide to take part in this study. You should ask your doctor about the benefits and risks of the other choices available to you.

Participation in research is entirely voluntary. You may refuse to participate or withdraw at any time without jeopardy to the medical care you will receive at this institution or loss of benefits to which you are entitled.

What about Confidentiality?

Your medical records will be treated as confidentially as possible under local, state and federal laws. Information from this study will be submitted to the sponsor. “Sponsor” includes any persons or companies, which are contracted by the sponsor to have access to the research information during and after the study.

Absolute confidentiality cannot be guaranteed. However, all information produced by your participation will not be identified by your name. If the study results are published in medical or scientific journals, you will not be identified by your name.

The information will also be given to the United States Food and Drug Administration (FDA). It may be given to governmental agencies in other countries where the study medicine may be considered for approval. Medical records which identify you and the consent form signed by you, will be looked at and/or copied for research or regulatory purposes by the sponsor and may be looked at and/or copied by:

• The FDA;

• Other Department of Health and Human Services (DHHS) agencies;

• Governmental agencies in other countries; and

• The Human Research Protections Program (HRPP) also known as the Institutional Review Board (IRB) is an independent committee established to help protect the rights of research subjects.

Do not sign this consent form unless you have had a chance to ask questions and have received acceptable answers to all of your questions.

Even with all of the study procedure precautions that will be taken to protect your confidentiality, there is a still a risk of loss of confidentiality. Research records will be kept confidential to the extent allowed by law.

Involuntary Withdrawal

You may be withdrawn from the study for the following reasons:

• The study doctor believes that it is in your best medical interest.

• You may also be withdrawn from the study if you do not follow the instructions given you by the study personnel.

• A serious reaction, which may require evaluation.

• Pregnancy.

• If you decide that you no longer wish to continue in this study, you will be required to come into the office for a Final Visit.

• Other administrative reasons.

The information in this form reflects what is known about the research study at the time it is signed. You will be told if any important new information is found during the course of this study that may affect your wanting to continue.

What happens if you change your mind?

You are still free to withdraw at any time during the study and without giving a reason. A decision to withdraw at any time will not affect the standard of care that you receive.

Should you decide to withdraw from the study at any time, information collected on you up until that point will still be provided to Boehringer Ingelheim Pharmaceuticals, Inc.

Primary Care Physician/Specialist Notification Option

Please initial below whether you want us to notify your primary care physician or your specialist of you taking part in this study.

________ Yes, I want the study doctor to inform my primary care physician/specialist of my taking part in this study.

________ No, I do not want the study doctor to inform my primary care physician/specialist of my taking part in this study.

________ I do not have a primary care physician/specialist.

________ The study doctor is my primary care physician/specialist.

Follow-Up Information after You Are Out of the Study

If your taking part in the study is stopped early either due to withdrawal of your consent or for other reasons, please initial below whether you agree to allow the collection of information on your health status. The collection of information on your health status will be done once by telephone at the time you would have originally completed the trial.

 _____ Yes, you agree to the collection of information concerning the status of your health after you are out of the study.

_____ No, you do not agree to the collection of information concerning the status of your health after you are out of the study.

Statement of Consent

You have read this form and its contents were explained. You agree to be in this research study for the purposes listed above. All of your questions were answered to your satisfaction.

You have received a signed and dated copy of this form and a copy of the Subject’s Rights and Responsibilities for your records.

You are not giving up any of your legal rights by signing this form. Nothing in this form is intended to change applicable federal, state, or local laws.

You agree to participate.

Participant’s Name (Printed) Participant’s Name (Signature) Date

Name of Person Obtaining Consent Name of Person Obtaining Consent Date

(Please print) (Please sign)

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