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IRB Project 070328

UNIVERSITY OF CALIFORNIA, SAN DIEGO CONSENT TO ACT AS A RESEARCH SUBJECT

BASALT STUDY: BEST ADJUSTMENT STRATEGY FOR ASTHMA IN THE LONG TERM (BASALT)

Stephen Wasserman, M.D. and Joe Ramsdell, M.D. and their associates are conducting a research study to find out more about asthma. The purpose of this study is to compare three approaches to adjusting asthma medications to see which is best over a period of time long enough to be clinically meaningful (36 weeks of intervention; 44 weeks total). This study is being sponsored by the Asthma Clinical Research Network (ACRN). It is funded by the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI). Drs. Wasserman and Ramsdell are being paid to conduct this study.

The study is designed to compare the effects of three strategies, or approaches, to adjusting inhaled corticosteroids which are commonly used medications for asthma. The three approaches to adjusting your inhaled corticosteroids asthma medications are 1) standard US consensus guidelines, 2) adjustment based on a measurement of inflammation of your airways, exhaled nitric oxide (eNO), or 3) adjustment based on your symptoms. The medications used in this study are all (Food and Drug Administration (FDA) approved for the treatment of asthma.

People with asthma who have symptoms more than twice a week are advised to use a corticosteroid in an inhaler (beclomethasone, budesonide, or fluticasone, for example) to help control their asthma. In many cases, this treatment results in good control of asthma. Experienced doctors suggest that after asthma is controlled, medications may be reduced, and if asthma then becomes symptomatic again, that medications be increased. However, it is not known what the best way to adjust therapy. Current guidelines base adjustments on many factors, including the frequency of symptoms, and objective measures of your lung function. However, these guidelines do not take into consideration the amount of irritation (inflammation) present in your lungs. Most asthma physicians believe that inflammation in the lungs should be controlled, and a new machine that measures eNO, a correlate of inflammation in the lungs, has been approved by the FDA for use in asthma patients. One study has shown some benefit of managing asthma by the use of eNO, but its use has not been compared with other strategies. Finally, a previous ACRN study has shown that patients with mild asthma are as well treated with symptomatic treatment as with regularly scheduled asthma treatment.

The ACRN estimates that it might have to screen as many as 640 people in order to randomize 320 people in this study. There are 10 centers participating. Depending on enrollment at the specific sites, up to 90 people may be screened at any one site and up to 60 people may be enrolled so that up to 40 people are randomized at the site.

BASALT Consent V4 Page 1 of 18 Protocol V24.1 IRB Project 070328

One study has shown some benefit of managing asthma by the use of eNO, but its use has not been compared with other strategies. Finally, a previous ACRN study has shown that patients with mild asthma are as well treated with symptomatic treatment as with regularly scheduled asthma treatment.

The adjustment strategy to which you are assigned will not be known by you, by the investigators, or by the study coordinators.

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

ACRN registration. Before you may be screened for participation in any ACRN study, you must first be entered into the ACRN Registry. This Registry has been set up to collect basic background information that, for the most part, should not change over time. Collected information is limited to: your initials, date of birth, gender, racial/ethnic identification, and the last four digits of your Social Security Number. Like all study data, your Registry information will be coded with a unique ACRN identification number. No information that directly identifies you will be entered into the ACRN database or sent to the Data Coordinating Center (at Penn State University, Hershey, PA). Registry data help us track your participation in multiple ACRN studies over time so that this can be accounted for in certain data analyses.

Your agreement to provide the information required for the ACRN Registry is completely voluntary. However, if you do not agree to provide all of the necessary information, you cannot be screened for, or enrolled in, any ACRN studies. Once you consent to be entered into the Registry, your data cannot be removed and will be maintained in the ACRN database into the future. You will only be asked to supply Registry information one time during your participation in ACRN studies.

(See chart on page 18 for the time of each study visit)

Visits 1a and 1b: Screening phase and run-in (pre-randomization) phase If you agree to join this study, you will have breathing tests performed to find out about your asthma. These breathing tests may include tests before and after inhaling an asthma medicine which relaxes your airways (albuterol) and/or after inhaling a chemical (methacholine) which can produce a mild asthma attack. You will also be asked to fill out an asthma questionnaire and will have blood drawn for levels to test your sensitivity to steroid medications. All tests will be performed on one day if possible, but might take two days to complete. The breathing tests will tell us if you qualify for the study. If the breathing tests show that you have the kind of asthma needed for this study, you will learn about study procedures and be given a corticosteroid inhaler (beclomethasone HFA [QVAR], 40 micrograms per puff) to be used at a dose of 2 puffs (80 micrograms) twice a day. You will also be given a peak flow meter to measure your peak flow every morning and evening.

Visit 2 You will then return to the clinic in 2 weeks to make sure that you are doing the study procedures properly and taking your study drug every day. You will also have additional tests performed including giving a sample of blood for genetic and other testing such as skin testing for allergy,

BASALT Consent V4 Page 2 of 18 Protocol V24.1 IRB Project 070328 completing asthma questionnaires, and performing breathing tests before and after inhaling albuterol that relaxes your airways. You will continue to take your inhaled corticosteroid inhaler until the next visit.

Visit 3 You will return to the clinic in another 2 weeks to fill out asthma questionnaires and to complete breathing tests to see if you qualify for the rest of this study or for a companion asthma study (TALC). If you qualify for this study, additional breathing tests will be performed and asthma questionnaires filled out, and a sample of your sputum will be collected after you inhale a strong salt solution. After all of the tests are done, you will be given 3 inhalers with the instructions on how to use each inhaler until the next visit.

Visit 4 The BASALT trial will require that you use 3 different inhalers properly for the duration of the trial. Two weeks after visit 3, you will return to the clinic, complete asthma questionnaires, and let us inspect that you used inhalers according to instructions. If you are doing well with using the inhalers, we will perform additional breathing tests and you will enter the main study and be randomized (assigned by chance, like a lottery) to a specific treatment as described above. If something is unclear to you about the use of the inhalers, we will give you additional instruction, and ask you to take the inhalers for another two weeks. You will return in two more weeks to repeat Visit 4 and undergo procedures as described above.

Study (post-randomization) phase The rest of the study includes an additional 8 study visits over the next 36 weeks. During this time, you will be treated with three inhalers (“A”, “B”, and “C”). Each inhaler will be dosed and adjusted separately.  Inhaler “A” will be adjusted in clinic each time you come in, based on your lung function and symptoms.  Inhaler “B” will be adjusted in clinic on the basis of your eNO measurement – our way to measure inflammation in your lungs.  Inhaler “C” is different. It will be taped together with your rescue inhaler, albuterol. Every time you need to use your rescue bronchodilator inhaler, you will also take a dose from Inhaler “C”. In addition, during the first two weeks after the randomization, you will take Inhaler “C” at a dose of 2 puffs once a day.

At every visit, you will receive verbal and written instructions on how to use your inhalers. Only one of the three inhalers will contain active inhaled corticosteroid (beclomethasone HFA, or QVAR), but neither you, the investigator, nor the study coordinator will know which inhaler is active.

For the first 3 visits after randomization you will return to the clinic every 2 weeks and then until the end of the study every 6 weeks to complete asthma questionnaires. At those times, we will measure your lung function by performing breathing tests, measure eNO (lung inflammation), and assess your symptoms. We will give you verbal and written instructions on how to take each of the inhalers (“A”,

“B”, and “C”) until the next visit. Between clinic visits that are 6 weeks apart, we will call you every two weeks to be sure you have no questions about how to use your study drugs, and to assess how well your asthma is controlled. However, we will not adjust inhalers “A” and “B” on the phone calls unless the error was made during the adjustment at the scheduled clinic visit. Study procedures and their frequency during the study are listed below and in the summary table at the end of this document.

The main risk of participating in this study is that your asthma might worsen during the study. You will have a home rescue plan and rescue medications in place and will be closely monitored.

Additional details of the study follow:

Study visit procedures: Descriptions of each procedure are listed below. See the table at the end of this document to find out which of the following procedures will be done at each visit.

Informed consent (1 time). The study and all study procedures will be explained to you. You will be able to ask any questions you have about the study. If you agree to participate in the study, you will be asked to sign the consent document.

Medical history (1 time). You will be asked questions about your current and past general health status, including a history of any heart disease. You will be asked about all of the prescription and over-the-counter medications and supplements you use.

Physical examination (11 times). We will listen to your lungs and heart, examine your ears, nose and throat and measure your blood pressure and heart rate. The extent of the evaluation done each time will depend on the study visit, with a comprehensive evaluation being performed at the beginning of the study to ensure that it is safe for you to participate.

Blood tests (each test 1 time). At Visit 1, blood will be drawn to look at your resistance to steroid medications. At Visit 2 blood will be taken for measurement of blood eosinophils and for measurement of serum IgE level. Measuring your blood eosinophils and IgE level tells us about your allergy response system. These blood tests will require a total of about 4 tablespoons of blood.

Genetics testing (1 time optional). Blood will be taken for isolation of DNA and genetic testing (described below). This blood sample will require a total of about 2 tablespoons of blood and is optional. Your blood sample will be labeled with a unique study identification number, your initials, gender, racial/ethnic group information and your birth year and sent to a lab affiliated with the Brigham and Women’s Hospital (Boston, MA). The lab will replace your study number with a different barcode number to code the sample so that it cannot be linked to you, except with your permission. Labs at Brigham and Women’s Hospital and Wake Forest University (Winston-Salem, NC)) will analyze the sample and tell the Data Coordinating Center (DCC) (Hershey, PA) what types of asthma-related genes are present. The DCC will bring together the barcode and study identification number. The DCC will link the genetic results with other information gathered in the study, like the

BASALT Consent V4 Page 4 of 18 Protocol V24.1 IRB Project 070328 breathing test results. Please see the Genetics Testing section of this consent for further information about genetics testing, the handling of your specimens, and the use of genetic testing in this and other studies.

The Boston and Wake Forest labs and the DCC will not know your name or other personal identifying information. The study physicians and study coordinators will not know your gene types.

Allergy skin testing (1 time). 12-16 drops of common allergens like dust mite, cat, and molds will be placed on the soft part of your forearm. Your skin will be scratched or pricked at each drop. Fifteen minutes later a study coordinator will look for redness or swelling (like a mosquito bite) where the tests were done. Redness and swelling means that you are allergic to the allergen in that drop.

Electrocardiogram (ECG) (1 time). An ECG measures the electricity produced by the heart. You will be asked to remove your shirt so that the ECG leads may be placed in the appropriate areas for good measurements. The rate at which your heart beats at rest will be determined with this test.

Pregnancy test (5 times). Females must not be pregnant or plan to become pregnant during the study. If you are a female and can become pregnant you will give a urine sample for a pregnancy test. You will know the pregnancy test results within minutes of starting the test. You cannot continue in the study if the pregnancy test is positive. If you are able to get pregnant (not surgically sterile or post- menopausal), you must use birth control during the entire study. Acceptable birth control methods include abstinence, birth control pills, diaphragm, intra-uterine device (IUD), Norplant, Depo-Provera, NuvaRing, birth control patches (e.g., Ortho Evra), single or double (condom plus foam/jelly or condom plus diaphragm) barrier methods, or surgical sterility.

Exhaled nitric oxide collection (10 times). You will be asked to slowly blow air into a mouthpiece attached to a machine that measures nitric oxide. The amount of nitric oxide in the air coming from the lungs is thought to increase when the lungs are irritated or inflamed. This test will measure the amount of nitric oxide in your lungs.

Exhaled breath condensate collection (4 times). You will breathe in and out of a tube for 10 minutes. The tube will collect the moisture from your breath. This test is being done to try to measure inflammatory substances in your lungs that we believe may be related to asthma.

Spirometry (every visit). You will wear a nose clip and breathe out forcefully into a machine. The machine measures how much air you blow out and how fast it comes out. This test tells us how well your lungs are working. Your asthma must be within a certain range in order to join the study. This test will be performed with bronchodilator reversibility testing, with methacholine challenge, or by itself on certain study days.

Bronchodilator reversibility testing (2 or 3 times with albuterol and 1 time with ipratropium). You will perform spirometry and then take 4 puffs of either albuterol or ipratropium. At the visits where you are given albuterol, you will repeat spirometry 15 minutes later. At visits where you are given

BASALT Consent V4 Page 5 of 18 Protocol V24.1 IRB Project 070328 ipratropium, you will repeat spirometry 30 minutes later. This test measures the improvement in your breathing after taking the different medications.

Methacholine challenge (2 or 3 times). Methacholine is the drug that causes narrowing of the airways, like a mild asthma attack. The sensitivity of your airways will be determined by seeing how much your airways narrow as you breathe in gradually increasing doses of methacholine. Spirometry will be performed after each dose of methacholine to measure your airway change. The test will be stopped either when your breathing tests decrease by at least 20% or there is no response to the highest dose of methacholine. At that point, you will be given albuterol to open your airways up again.

Sputum induction (2 times). Sputum induction will be performed to measure the number of inflammatory cells and certain chemicals involved in the inflammatory process that make asthma worse. You will be asked to breathe in a strong salt solution (3% salt, hypertonic saline) for up to 12 minutes to make you cough in order to bring up a sample of sputum (mucus) from your lungs. You will be given albuterol prior to this test to prevent excessive narrowing of your airways during the test, and your breathing capacity will be monitored during the test for safety.

Review diary cards and study drug use (every visit). A study coordinator will review your diary cards and study drug use after your enrollment in the study to check on your asthma symptoms, asthma control and general health, and to ensure that you are compliant with the at-home study procedures.

Asthma questionnaires.  Asthma Evaluation Questionnaire (11 times)  Asthma Control Questionnaire and Asthma Symptom Utility Index (11 times)  Asthma Quality of Life Questionnaire (2 times)  Coordinator and patient asthma medication questionnaire (1 time)  Symptom Free Day Questionnaire (10 times)  Healthcare Utilization Review (10 times).

Answering questionnaires will help us see how you feel about your asthma, your asthma medications, and how asthma affects your life.

ACRN Satisfaction Questionnaire (1 time). When you leave the study you will be asked to complete an anonymous questionnaire that measures your level of satisfaction with study facilities, personnel, and other aspects of your study participation. This questionnaire is optional and is completed at or after final study visit.

Sleep and Day Alertness Questionnaire (2 times). Answering this questionnaire will help us determine the effect of asthma treatment on symptoms related to sleep disorders.

Telephone contacts (10 times). Between clinic visits that are 6 weeks apart, your study coordinator will call you every two weeks to check if you have any questions about how to use your inhalers and to assess your asthma symptoms, asthma control and general health.

Study Drugs: You will get three inhalers (“A”, “B”, and “C”); one of them will contain an inhaled corticosteroid. The other two will not have active drug, and contain placebo. Neither you, the investigator nor the study coordinator will know which inhaler is active. You must take the prescribed number of inhalations from each inhaler every morning and every evening of the study. Inhaler “C” will be attached to your rescue inhaler. Every time you have symptoms that require you to use the rescue (albuterol, bronchodilator) inhaler, you should also take 2 puffs of Inhaler “C.” Inhalers “A” and “B” will be adjusted at your clinic visits, and the proper dosing will be explained to you verbally and in writing. The study coordinator will talk with you about how long you should avoid medications before each study visit.

The inhaled corticosteroid will be beclomethasone HFA (QVAR), 40 or 80 micrograms/puff. This medication reduces airway inflammation. It is FDA approved for the treatment of asthma.

The placebo inhalers will look like the active inhaled corticosteroid drugs described above but will not contain active medication. They will have similar ingredients but no steroid in the respective placebo inhalers.

Rescue drug. You will use albuterol to relieve asthma symptoms. Albuterol is FDA approved to relax the muscle in the airways, and is approved by the FDA for use in patients with asthma.

Prednisone ‘Rescue’ pills (for emergency use only). You will be given the oral steroid prednisone to keep at home with you. This drug will only be used if you experience a significant asthma exacerbation and are instructed on its use by study personnel.

Budesonide ‘Rescue’ Inhaler is inhaled steroid. If you experience treatment failure, you will be asked to come to the study clinic for evaluation at which time this drug may be given to you.

Home procedures: Completing all of the home procedures should take about 10 minutes a day. Try to do the home procedures about the same time each day. Please bring your peak flow meter, diary cards and study inhalers with you to all study visits.

It is VERY important that you understand how to measure your peak flow rate, how to complete the diary cards and how to take the study inhalers. Please ask questions until these procedures are CLEAR to you. If you don’t do the home procedures, you might be asked to leave the study.

Peak flow monitoring. You must check your peak flow rate twice every day during the study. You will use a hand-held, electronic peak flow meter provided by the study. The peak flow meter must be returned at the end of the study.

Diary cards. You will record your peak flow rate, asthma symptoms, the number of puffs from your study inhalers, the number of puffs of rescue inhaler you have taken, any changes in your health, and any other prescription or over the counter medications you are using on your diary cards.

Study inhalers. You will take the recommended dose of Inhaler “A”, and Inhaler “B” twice every day, in the morning and in the evening. You will take two puffs of Inhaler “C” every time you have the need to use your rescue albuterol inhaler. To help remind you to take Inhaler “C”, your rescue inhaler will be attached to Inhaler “C”. All study drugs and placebos will be supplied to you, and you, your study coordinator, and the study physician will not know which medications you are taking.

Are there any side effects or risks involved?

Risks of study procedures: Descriptions of potential risks with each procedure are listed below.

Physical Examination. There are no risks associated with this study procedure.

Blood drawing. 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.

Genetic testing. Please see the separate section on genetics testing.

Allergy skin testing. There may be mild pain from the needle scratch and your arm might itch or burn where the test was done. A “mosquito bite” reaction is expected if you are allergic. This usually goes away within 30 to 60 minutes after the skin test, although it sometimes lasts 24-48 hours. Hives and wheezing rarely occur. Symptoms such as itching all over your body, and swelling of your skin, tongue or eyelids occur in about 1 out of 10,000 people. Emergency care is available to treat these rare reactions.

Electrocardiogram (ECG). A localized rash or irritation may occur where the patches are placed.

Pregnancy test. There may be unknown risks to the fetus/unborn child if you become pregnant while in this study. Although birth control is required, you should notify your study doctor or study personnel immediately if you become pregnant during the study. You must stop the study if you become pregnant. There are no risks associated with the act of taking a urine pregnancy test.

Exhaled nitric oxide collection. There are no known risks involved with this procedure.

Exhaled breath condensate collection. There are no known risks involved with breathing into the collection system.

Spirometry. Spirometry might make you cough, feel short of breath or dizzy, or your chest feel tight. Treatment with albuterol will be available if you need it.

Bronchodilator reversibility testing. Taking the 4 puffs of albuterol or ipratropium that are required for this study can make your heart race or make you feel jittery. Less often it can increase your blood pressure, or cause nausea or headache. These feelings are temporary.

Methacholine challenge. The methacholine challenge is expected to make your airways "tighter.” You will likely experience coughing, chest tightness, shortness of breath, and/or wheezing during this procedure. Most people would describe this as feeling like they are having a mild asthma attack. Methacholine challenges are carried out in such a way that the danger of severe symptoms is minimized. However, if your symptoms are severe enough, treatment with albuterol will be given immediately and the challenge will not continue. Following all challenges, asthma symptoms will be reversed with albuterol at the end of the test.

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

Sputum induction. Breathing in the strong 3% salt, hypertonic saline (higher concentration) solution will be irritating to your throat and chest and will encourage you to cough. The main risk associated with this procedure is that it may cause an asthma attack. This possibility is reduced by treating you with albuterol before beginning the hypertonic saline, and by monitoring your lung function during the test. The test will be stopped after you produce an acceptable sputum sample, or sooner if your lung function worsens to an unacceptable level or if you choose to stop the test.

Telephone Contacts. There are no risks associated with this study procedure.

Risks with study drug: Changing your asthma medications. When you participate in this study your asthma treatment might change. At first, you will be put on a standard dose of an inhaled corticosteroid. After randomization visit, the doses of Inhalers “A” and “B” may be adjusted and you may receive either more or less medication than before you entered the study. If you were taking other asthma medications, they will be discontinued during the study. It is possible that changing your asthma medications might worsen your asthma. You will be evaluated prior to the study to make sure it will be safe for you to enter the study. We will monitor you closely during the study to make sure your asthma is not getting worse. It is important that you perform your peak flows and complete your diary as instructed. You must contact the study center if you hit any pre-instructed trigger values or if you feel that your asthma is getting worse.

Beclomethasone HFA (QVAR) is an FDA approved asthma medication that is an inhaled corticosteroid. Inhaled corticosteroids are the most common medications used for the long-term control of asthma. They can produce hoarseness, sore throat, and yeast infections of the mouth or throat in up to 5% of people taking the medication. Less often, usually only when taken at high doses

BASALT Consent V4 Page 9 of 18 Protocol V24.1 IRB Project 070328 for long periods, inhaled corticosteroids can cause adrenal gland suppression (a change in some of the hormones your body makes), weight gain, bruising and elevated blood sugar.

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.

Ipratropium bromide. Ipratropium bromide is an FDA-approved medication for COPD (emphysema, chronic bronchitis). While ipratropium causes bronchodilation (opens your airways), it acts more slowly than albuterol. This drug is only used once in this study for reversibility testing at Visit 2. Occasional side effects are dry mouth, cough, nervousness, nausea, dizziness, and headache. Less common side effects are difficulty urinating, palpitations (abnormal heart beat), or blurred vision.

Placebo. Placebo is an inactive drug that is unlikely to be associated with any side effects. You may take an inhaled corticosteroid twice every day and will have albuterol to use as needed to treat asthma symptoms.

It is important for you to do two things: 1) take all the study drugs according to our directions and 2) call us if your asthma or general health worsens at any time.

Genetics Testing:

What is the purpose of genetics testing? You are being asked to give blood for genetic testing (DNA analysis). Deoxyribonucleic acid (abbreviated DNA) is the genetic material contained in all cells of your body, including blood cells. It is the material that determines, among other things, your physical characteristics such as height, and the color of your hair and eyes. Genetic testing can also be used to determine if you are more likely to develop a particular disease, and how you respond to different medications. If you agree to genetic testing, about 2 tablespoons of blood will be collected to look for genetic markers that might predict how you react to certain asthma medications. If you do not agree to the genetic testing you can still participate in this particular study.

Another purpose of this study is to identify genes and/or variations in genes related to asthma, allergies, and related diseases. Identifying genes related to asthma may help develop a potential new treatment for people with asthma who have certain genes.

How will my blood be handled? Your blood sample taken for genetics testing will be assigned a code number and will be saved. Only the code number, your initials, gender, racial/ethnic group information and year of birth (not complete date of birth), will be used in identifying your sample to the centers performing the genetic testing. Currently, the genetics blood sample will be sent to the Channing Laboratory at Brigham and Women’s Hospital in Boston, MA. In the future, with the permission of the ACRN Steering Committee, the samples may be transferred to other laboratories for analysis, including laboratories at Wake Forest University (Winston-Salem, NC). In each case, only the code number, initials, gender, racial/ethnic group information and birth year will be transferred with your sample.

How will the genetic information be handled? The coded results (that do not identify you) of the genetics testing will be sent to our central DCC in Hershey, PA. The coded results will only be released to other scientists working on this study. The scientists will only use the code number and the bar code to correlate genetics with important clinical information like the results of your breathing tests done during study visits. The Hershey center has information about your results in the study but does not receive information about your name, address, or complete social security number. Thus, it is almost impossible for the genetics results to be associated to you unless your center provides additional identifying information to the DCC (which it will not do) or unless the DCC provides additional information to your center (which it may do under specific circumstances which require approval outlined below).

We may want to perform studies where it would be necessary to get in touch with you based on your genetic information. Only your specific study center will have enough information to do this. Your specific study center will only be provided with enough information to contact you based on your genetic information if both the Steering Committee of the ACRN approves and the local study center Human Research Protections Program (HRPP) agrees that doing such testing and contacting you are appropriate.

 You agree to be contacted  You do not agree to be contacted

What tests will be performed on blood samples? Initially we will perform tests on the DNA for the molecules that allow you to respond to inhalers such as albuterol and steroids. We are trying to determine whether your variants in different genes are associated with your response (or lack of response) to different asthma medications, and whether they are associated with asthma, allergic diseases, or any other information we collect about you in the study. These coded data will be shared among the investigators.

In addition, another purpose of this study is to identify genes and/or variations in genes related to asthma, allergies, and related diseases. Identifying genes related to asthma may help develop a potential new treatment for people with asthma who have certain genes. We will only perform these tests on your coded samples with the permission of the Steering Committee of the ACRN. Samples will be stored as long as the ACRN is active.

Who will see the results of the genetic testing? Coded (not identifiable to you) genetic information will be seen by the study investigators at your site and in the ACRN and by investigators that the ACRN agrees to share such information with.

Currently, individual results will not be known and you cannot be notified of your results; therefore, your results cannot become part of your medical record. However, the investigators at your center, with the HRPP approval, as mentioned above, might undertake a study in which they do genetic analysis specific to you in order to contact you about a study based on your genes related to asthma or allergies or the response to drugs used to treat those conditions. At that point, if approved by the Steering Committee of the ACRN and the HRPP, only the investigators at the UCSD Clinical Trials Center (CTC) would be aware of any results linked to you and would contact you to ascertain your interest in providing more information or participating in a study.

Will the genetics samples have commercial value? What are my rights to my DNA sample? Who will have control of it and who will own it? During and after the study, you are the owner of the sample. This gives you the right to have the sample material destroyed by ACRN/NIH at any time. If you choose to have your samples destroyed, please contact your study doctor.

If you decide to have your sample destroyed, any information which was generated prior to your request will not be withdrawn, but no further studies will be done.

The sponsor is responsible for the destruction of the sample at the end of the storage period. Any commercial product developed at ACRN as a result of this genetics study would be from the analysis of all samples collected in this study, not from an individual subject’s sample.

You may decide not to sign this authorization (by choosing not to sign this consent form), or you may revoke (cancel) this authorization in writing at any time. However, you can only participate in the study if you authorize the use and disclosure of the information as described above. If you decide not to sign this consent form, you will not be enrolled in the pharmacogenetics part of the study.

You may withdraw (cancel) your consent at any time in writing. If you sign this consent and decide later to withdraw your consent, your participation in the study will be stopped. Information collected up to the time you withdraw your consent will continue to be used as study information.

This genetic testing or other follow-up studies may lead to the development of a test that might tell in advance if a person will respond to certain asthma treatments, but you will not be able to share in the profits made by the company that sells it.

How long do you plan to keep my sample? Dr. Wasserman, his associates, or his successors in this study will keep your specimen and/or the information derived from it indefinitely.

What if I change my mind? Your agreement to provide a blood sample for DNA analysis is entirely voluntary. You may refuse to provide a blood sample without any loss of rights or privileges to which you are otherwise entitled. If you do not wish to provide a sample for DNA analysis, you can still participate in this study. It will be difficult to link your blood sample to you. It will be very difficult, but not impossible to withdraw your sample after it has been sent for genetic analysis. Therefore, please think very carefully about your decision to provide a blood sample for DNA analysis. If you do change your mind, you may contact Dr. Stephen Wasserman at UCSD Clinical Trials Center, 210 Dickinson St., CTF-A, Room 102, San Diego, CA 92103-8415 to notify him or the study coordinator of your decision to withdrawn your blood sample for DNA analysis.

Risks and Discomforts Related to Genetics Testing: Blood Draw. These risks have been described above in the risks section. The genetic blood sample will be taken when other blood samples are needed so that you will not have to undergo an extra needle stick.

Confidentiality. Information about your participation in a genetic study may influence insurance and/or employers regarding your health status. To help prevent disclosure, information about your participation and the result of the research will not be placed in your medical records. In addition, your sample will be coded and the key to the code kept in a separate locked physical or electronic file. Not sharing information about your participation in this study with others will lower these risks. Although every effort will be made to keep your participation confidential, the investigators cannot guarantee absolute confidentiality. Even though we will remove identifying information and do not intend to tell you or anyone else the results of the genetic testing on your sample, there is a very small chance that this information could accidentally become known to you, your doctor, or others. There might be other risks that we do not know about yet.

As we learn more about asthma-related genetic testing, we may contact you to provide or request more information.

Do you agree to genetics testing and the sharing of your coded genetic samples with NIH/NHLBI research centers/investigators for the purposes of identifying genes and/or variations in genes related to asthma, allergies, and related diseases (to be performed only with the agreement of the ACRN Steering Committee)? (Please initial) YES______NO______

In addition, do you agree to allow your center to identify and get in touch with you based on the results of genetics testing (to be performed only with the agreement of the ACRN Steering Committee and the Human Subjects’ Protection Board)? (Please initial) YES______NO______

Since this is an experimental treatment there may be some unknown risks that are currently unforeseeable. You will be informed of any significant new findings.

No direct benefit is promised to you if you join this study. Information from this study might help doctors decide which medications to give to people with asthma in the future.

You will receive up to $1690 for completing all phases of this study. If you don’t complete the study, you will be reimbursed for the visits you have completed.

Payment is as follows and as indicated on the following table for each study visit or set of visits.

Visit # Time (hours) Amount Visit # Time (hours) Amount 1a and 1b 150 minutes $230 9 1.0 $90 2 1.0 90 10 1.0 90 3 2.0 180 11 1.5 135 4 2.0 180 12 1.5 135 5 1.0 90 6 1.0 90 Completed PC 10 min each $20 each (10 total) 7 1.0 90 8 1.0 90 TOTAL $1,690

If you are injured as a result of participation in this research, the University of California will provide any medical care needed to treat those injuries. The University will not provide any other form of compensation if you are injured. You may call the UCSD HRPP 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.

______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. Wasserman at (619) 471-0819 during regular business hours or (619) 543-6222 and have the study doctor on-call paged.

Alternatives There may be other treatments for asthma which a doctor might prescribe but which will not be provided in this study. You should talk about other treatments with your doctor. You may also choose to get no treatment. Please make sure that you understand all of your choices before you decide to take part in the study. Before entering this study, or at any time during the research, you may ask for an opinion about your care from another doctor who is not associated in any way with this study

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.

Confidentiality Study personnel will treat your identity with professional standards of confidentiality. Study personnel, to confirm information related to deciding if you are eligible to join the study, may look at your medical records. Some aspects of the medical information gathered from this study may become part of your permanent medical record. Your identity, medical records, and data related to this study will be kept confidential, except as required by the law. Your records regarding this study may be subject to review by appropriate officials of the UCSD, HRPP the CTC, the National Institutes of Health (NIH) and their agents should the need arise. The results of this study may be published or presented at medical meetings. However, you will not be identified by name.

To help protect your privacy, the ACRN has received a Certificate of Confidentiality from the NIH. With this Certificate, the researchers cannot be forced to disclose information that may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings. The researchers will use the Certificate to resist any demands for information that would identify you, except as explained below.

The Certificate cannot be used to resist a demand for information from personnel of the United States Government that is used for auditing or evaluation of federally funded projects or for information that must be disclosed in order to meet the requirements of the FDA.

You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or other person obtains your written consent to receive research information, then the researchers may not use the Certificate to withhold that information.

The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without your consent, information that would identify you as a participant in the research project in cases of suspected child abuse or intent to hurt self or others.

Discontinuation from the Study: You may voluntarily withdraw from the study at any time. Your decision to withdraw will involve no penalty or loss of benefits to which you would otherwise be entitled. You should notify the study doctor or study personnel if you choose to discontinue from the study.

Your participation in the study may be terminated with or without your consent for any of the following reasons:  Failure to follow the investigator’s instructions.  A serious reaction, which may require evaluation.  If the investigator feels it is in the best interest of your health and welfare.  The sponsor, ACRN, terminates the study.  Pregnancy.

You will be told if any important new information is found during the course of this study that may affect your wanting to continue.

Authorization Statement You have read and initialed each page of this paper about the study (or it was read to you). You have been informed about the possible risk and benefits of this study. You know that being in this study is voluntary. You choose to be in this study. You know you can stop being in this study and you will still get the usual medical care.

You have received a copy of this consent document and a copy of the Experimental Subject's Bill of Rights to keep.

You agree to participate.

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

Witness Name (Printed) Witness Name (Signature) Date

STUDY PROCEDURE TABLE: Screening and eligibility visits are 1a, 1b, 2, 3 and 4. Eligible subjects will be randomized after completing Visit 4 into the rest of the study. Visit 1 1a 2 3 4 5 6 7 8 9 10 11 12 b Visit length 2 1 1 2 2 1 1 1 1 1 1 1.5 1.5 (hours) Week 0 0 2 4 6-8 10 12 14 20 26 32 38 44 Window (reg/ext) ±3/ ±3/ ±3/ ±3/ ±3/ ±3/ ±5/ ±5/ ±5/ ±5/ ±5/ (Days) 5 5 5 5 5 5 7 7 7 7 7 Study Phase Allocation to BASALT X Informed Consent X Randomization X Medical History X Long Physical Exam X X Short Physical Exam X X X X X X X X X Blood for X IgE/Eosinophils Blood for sensitivity X of steroid medications Blood for genetic X analysis (optional) Pregnancy Test X X X X X Skin Testing X ECG X ENO X X X X X X X X X X EBC X X X X Spirometry X X X X X X X X X X X X X Albuterol Reversal (4 (X) X X X puffs) Ipratropium Reversal X (4 puffs) Methacholine (X) X X Challenge Sputum Induction X X AEQ X X X X X X X X X X X ACQ/ASUI X X X X X X X X X X X Questionnaires AQL Questionnaire X X SFD Questionnaire X X X X X X X X X Healthcare X X X X X X X X X Utilization Review (HUR) Sleep and Alertness X X Day Questionnaire

Coordinator/Patient X Questionnaire(CPQ) ACRN Satisfaction X Questionnaire Dispense Diary Card X X X X X X X X X X X X Diary Card Review X X X X X X X X X X X Dispense Medication X X X X X X X X X X X X Compliance review X X X X X X X X X X X (Doser, AM1, etc.)

Intervention Period Phone Contacts Structure Table

Visit 7 8 9 1 1 1 0 1 2 Phone Call 7a 7b 8a 8b 9 9 10 10 11 11 a b a b a b Length of call 10 10 10 10 10 10 10 10 10 10 (min) Week 14 16 18 20 22 24 2 28 30 3 34 36 3 40 42 4 6 2 8 4 Window(reg/ex +3/ +3/ +3/ +3/ + + +3 +3 +3 +3 t) (Days) +5 +5 +5 +5 3/ 3/ / / / / + + +5 +5 +5 +5 5 5 Adherence X X X X X X X X X X Encouragement SFD X X X X X X X X X X Questionnaire HUR X X X X X X X X X X Questionnaire

BASALT Consent V4 Page 18 of 18 Protocol V24.1