University of California, San Diego

IRB Project 071163

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 Respimatâ 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