UNIVERSITY OF PENNSYLVANIA HEALTH SYSTEM

Transcription

1 Bristol Myers-Squibb, AI467003, Version 2, 4-JUN-2012: A Phase IIb Randomized, Controlled, Partially Blinded Clinical Trial to Investigate Safety, Efficacy and Dose-response of BMS in Treatment-naive HIV-1-infected Subjects, Followed by an Open-label Period on the Recommended Dose CONSENT TO PARTICIPATE IN A RESEARCH STUDY AND RESEARCH SUBJECT HIPAA AUTHORIZATION Your contacts for this study at the Hospital of the University of Pennsylvania [HUP] are: Principal Investigator: Pablo Tebas, MD (215) Coordinator: Joseph Quinn, RN, BSN (215) Study Nurse: Jenna Lewis, RN, BSN (215) Site address: 502 Johnson Pavilion Philadelphia PA Hour Emergency Number (215) Ask for the Immunodeficiency Program Doctor on call 1. Participation You are being considered for participation in a research study because you have been diagnosed with human immunodeficiency virus (HIV-1 positive) infection and have not been previously treated with antiretroviral (ARV) drugs (drugs used to treat the HIV in your body). Your eligibility to participate in this study will be decided based on the screening procedures described below and other eligibility criteria. Your participation is voluntary which means you can choose whether or not you want to participate. If you choose not to participate, there will be no loss of benefits to which you are otherwise entitled. Before you can make your decision, you will need to know what the study is about, the possible risks and benefits of being in this study, and what you will have to do in this study. The research team is going to talk to you about the research study, and they will give you this consent form to read. You may also decide to discuss it with your family, friends, or family doctor. You may find some of the medical language difficult to understand. Please ask the study doctor and/or the research team about this form. If you decide to participate, you will be asked to sign this form. An independent Ethics Committee or Institutional Review Board has reviewed the objectives and the proposed conduct of this study and has approved the study to be conducted by the research center. Your primary doctor will be informed about your participation in this research study. 2. Purpose of the Study The purpose of this study is to assess the safety, efficacy (how well it works), tolerability and blood levels of three doses of the study drug, HIV nucleoside reverse transcriptase inhibitor (NRTI) BMS , in combination with efavirenz and lamivudine when compared to tenofovir in combination with efavirenz and lamivudine in treatment of human immunodeficiency virus-1 infection (HIV-1). Even though there are different types of antiretroviral medications providing various treatment options for previously untreated (naïve) patients, new treatment options continue to be studied to provide new options for treatment naïve patients. 3. Approximate Number of Participants and the Expected Duration of Your Participation in the Study About 300 treatment-naive HIV-1 infected subjects are expected to participate in this study at approximately 100 research centers around the world. About 10 patients are expected to participate Page 1 of 22 Global SIS/ICF Master US Version 6, 12 JUN2012

2 at the University of Pennsylvania. Although you may meet all the criteria for participation, you may not be enrolled to participate in this study. If you are enrolled, the duration of your participation is expected to be 96 weeks for the first part of the study (Stage 1). The purpose of the second part of the study (Stage 2) is to collect long term safety and efficacy data. Stage 2 will last for at least 96 weeks and may be extended by the Sponsor, Bristol-Myers Squibb (BMS), until BMS becomes commercially available. Overall, the study duration is expected to be over 3.5 (three and half) years. 4. Study Treatments If you are eligible for the study, you will be chosen by chance (like a flip of a coin) to be in one of the four study treatment groups and will receive medication to take orally as follows: Group 1: BMS mg once a day + Efavirenz 600 mg once a day + Lamivudine 300 mg once a day Group 2: BMS mg once a day + Efavirenz 600 mg once a day + Lamivudine 300 mg once a day Group 3: BMS mg once a day + Efavirenz 600 mg once a day + Lamivudine 300 mg every day Group 4: Tenofovir 300 mg once a day + Efavirenz 600 mg once a day + Lamivudine 300 mg once a day There is a 66.7% chance that you will be enrolled into a treatment group that provides BMS (at either a 100, 200 or 400mg dose), and a 33.3% chance that you will be enrolled into the treatment group that provides tenofovir at a 300mg dose. Your study drug treatment regimen will always include efavirenz 600mg and lamivudine 300mg. If you are enrolled into Groups 1, 2, or 3, neither you nor your study doctor will know which dosage of the study treatment you are receiving, except in an emergency, through at least 48 weeks of your participation in the study. Once the optimal dose of BMS has been selected, the study will be unblinded (you will be made aware of your treatment regimen) and you may transition to the optimal dose if this is required through the remainder of the study. If you are enrolled into Group 4 (Tenofovir plus Efavirenz plus Lamivudine), you and your doctor will be aware of the treatment from the beginning of the study. You should take all tablets/capsules in the treatment regimen at the same time of the day. All doses should be taken without food, on an empty stomach, at bedtime. Dosing times and study appointment times must be carefully considered through Week 24 due to the requirements of the PK collection (collection of blood samples to study the amount of drug in your blood). If you are in Treatment Groups 1-3, you will be taking a total of 6 capsules/tablets each day, one capsule from each of 4 bottles of blinded BMS (some bottles may contain an active dose of BMS and others may contain a placebo capsules (no active drug) and 1 tablet of efavirenz* and 1 tablet of lamivudine If you are selected for Treatment Group 4 (the reference treatment group), you will be taking a total of 3 tablets each day: 1 tablet of tenofovir and 1 tablet of efavirenz* and 1 tablet of lamivudine * If you develop tuberculosis and your doctor treats you with a drug called rifampin, your dose of efavirenz will need to be increased slightly to 800mg. This adjustment will only need to be made if you weigh over 50 Kg (110 pounds) and it will require you to take an additional tablet or capsule of 200mg efavirenz each day while you are being treated with rifampin. Page 2 of 22

3 If you are assigned to be in the Treatment Group 4, you and your study doctor will know that you will be taking the medications as outlined above. If you are assigned to be in one of the 3 treatment groups that contains BMS , you and your study doctor will again know which drugs you are taking as outlined above, but you will be blinded to the actual strength of the dose of the BMS drug until that information is revealed to you a year or more after you start the study when the study will be unblinded. BMS is an investigational drug being developed to treat human immunodeficiency virus-1 infection (HIV-1) which means that it s not currently approved by the United States Food and Drug Administration (FDA). BMS is a nucleoside reverse transcriptase inhibitor (NRTI). This type of drug helps prevent the virus from making necessary proteins to finish the steps in making more viruses in your body. There are several drugs in the NRTI class that have been approved by the FDA. Some examples of common medications you may have heard of before are as follows: Stavudine: Also called d4t, Zerit, Zerit XR. Zidovudine: Also called AZT, ZDV, Retrovir. Zidovudine was the first antiretroviral drug approved by the FDA for the treatment of HIV. Didanosine: Also called ddi, Videx, Videx EC. Lamivudine: Also called 3TC, Epivir. This NRTI is approved for the treatment of both HIV and hepatitis B. Abacavir: Also called ABC, Ziagen. Emtricitabine: Also called FTC, Emtriva. Tenofovir: Also called TDF, Viread. Prior to agreeing to participate in this study, it will be important for you to discuss all of your other treatment options with your doctor to ensure you consider all the drugs that you can take to treat your HIV. 5. Study Procedures This study has been developed to include the following 3 phases: Screening A 30 day period in which your eligibility for the study will be assessed Stage 1 Day 1 through Week 96. You will have a study visit on Day 1, Week 1 and then every 4 weeks from Week 4 through Week 24 and every 8 weeks from Week 24 through Week 96. Stage 2 Week 108 through the end of the study. You will have study visits every 12 weeks and fewer procedures completed at your study visits during this stage. In addition, there is an optional intensive Pharmacokinetic (PK) visit at Week 2. Pharmacokinetic is the way drugs are taken into, move around, and are eliminated from the body. This optional visit will be completed by a subset of approximately 12 subjects in each of the 4 treatment groups. This visit will require a series of 12 blood draws over a 24-hour time period. The blood draws begin with pre-dose (0-hour) blood sample which is taken at approximately 24 hours after the dose you took the day before. The total amount of blood that will be collected is approximately 212 ml (about 14.1 tablespoons). Because dosing with the study drugs is done at bedtime, this start of the intensive PK blood sampling must begin in the evening, prior to your evening dose, and end the next evening prior to your next dose of medication. Due to the timing of the blood samples, an overnight stay in the hospital or research center will be required. Page 3 of 22

4 If your doctor is participating in this portion of the trial, you may be considered for participation. Again, this is the visit applicable for only a subset of 12 subjects in each treatment group. Important points during Primary Study Stage 1 After 150 subjects complete 8 weeks of treatment, an independent group of scientific experts will evaluate the data collected from all subjects. Based on their recommendations, the study may continue, or, the study or one or more of the treatment groups may be discontinued. In the event that a treatment group is discontinued, those subjects in that treatment group will be unblinded and offered another better option of dosing with BMS , or will discontinue and get other appropriate therapy based on your doctor s recommendation. This same process will be followed once all 300 subjects complete Week 8. When the last subject (300) enrolled completes their Week 24 study visit, BMS, the Sponsor, will conduct an analysis of the data and determine which dose or doses of BMS is determined to be best to continue in the study. In the event that the decision cannot be made based on the Week 24 data, an analysis will be completed based on the Week 48 data. After the best dose or doses has been chosen, the study will then be fully open-label and you will be unblinded, which means you will be made aware of your treatment regimen. At every study visit, the test which measures how much HIV is in your body will be done and your study doctor will be continually looking at those results to determine how well this virus in your body is responding to the study treatments overall, especially after you ve been taking the study medications for at least 24 weeks. If the HIV in your body responds very well to the study treatments, the best outcome would be that the test which measures how much HIV is in your body will show a result of < 50 copies/ml. If the result is 200 c opies/ml at or after Week 24, a confirmatory test will be done within 4 weeks after the draw date of the original sample, unless your study doctor thinks there is the reason for high result, and in this case your study doctor and BMS medical team will decide when this additional test will be done. If after 24 weeks, those test results are 50 copies/ml or higher, your doctor will look at these and other lab test results and will be able to tell you, on an ongoing basis through your participation in the study, if you can remain in the study. If the HIV in your body fails to respond well enough to the study treatments ( virologic failure ), your study doctor will determine if you should stop the study treatments and be treated with other anti-hiv medications to which your body may respond better (see General Risks Related to Drug Resistance in Section 7 for some information about your other treatment options should virologic failure occur). At any time prior to selection of the best dose or doses at Week 24 (or at Week 48, if needed), in the event that a BMS treatment group is discontinued, the subjects in that particular treatment group will be unblinded and will begin dosing with the highest available remaining dose of BMS If this happens and the test which measures how much HIV is in your body shows: A result of less than 50 copies/ml at your most recent visit, you will be reassigned to a treatment group that has the highest available remaining dose of BMS A result of 50 copies/ml or higher at your most recent visit, your study doctor will determine how your treatment will be managed. Tests and Procedures Page 4 of 22

5 The following tests and procedures that will be completed during each part of the study are described as follows: Screening Visit- about 30 days prior to Study Stage 1 At this visit, the study doctor/staff will ask you some questions and you will undergo the following test procedures to check if you can take part in this study: You will be asked to review and sign the informed consent form in case you decide to take part in this study A full physical examination will be done Vital signs (seated blood pressure, heart rate, breathing rate, temperature), height and weight will be measured Your past significant medical history will be collected You will be asked about your demographics (age, race, ethnicity, gender, geographic region) You will be evaluated for adverse events starting after informed consent signature. An adverse event can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease whether or not considered related to the study drug. An ECG (electrocardiogram) will be performed Urine or blood will be collected for pregnancy test for women of child bearing potential Blood drawn for various tests related to HIV (viral quantity, resistance and variety), for Hepatitis testing (Hepatitis B and C), tests to verify the ability of your body to fight infection (immune system, which is responsible for defending your body against diseases), hematology, fasting chemistry and lipids (to verify red and white cells, glucose, liver proteins, cholesterol and other substances in your blood when you haven t eaten for a specific period of time) and to verify if you re likely to respond to study treatment Urine sample collection for urinalysis. You will have approximately 53.5 ml of blood (approximately 3.6 tablespoons) collected at the screening visit. Laboratory results from the Screening visit will be assessed by your study doctor, and if certain test results are abnormal in any way (e.g., if you are anemic), your study doctor may suggest that it is not in your best interest to participate in this optional Week 2 visit. Even if you previously agreed to participate, you can decline participation at any time. After the screening visit, if you are identified as able to participate, you will be randomly selected for one of the four treatment groups. Stage 1 Day 1 through Week 96 This part of the study will take 96 weeks for a total of 19 visits. At the week 10 visit, you may or may not be required to come to you study doctor s office (see below). The following procedures will be done: On Day 1, the study staff will check if you still meet the requirements to be in the study. If you are still eligible and you would still like to participate, you will be assigned to one of the four treatment groups. A full physical examination, height and weight will be done at the following visits: o Weeks 12, 24, 48, 96 or early termination (ET) visit Page 5 of 22

6 A targeted/as needed physical examination (examination of the heart, lungs, skin, abdomen, any as needed organ system and general appearance) will be completed at the following visits: o Day 1 and Weeks 4, 8, 16, 20, 32, 40, 56, 64, 72, 80, 88 Vital signs (seated blood pressure, heart rate, breathing rate, temperature), will be measured at the following visits: o Day 1 and Weeks 4, 8, 12 16, 20, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96 or ET Collection of adverse events at all study visits Review of all medications that you are currently taking at the following visits: o All study visits with the exception of Week 1 Electrocardiogram (ECG) at the following visits: o Day 1, Weeks 4, 12, 24, 48, 96, or ET Urine or blood will be collected for pregnancy test if you are a women of child bearing potential at the following visits: o All visits with the exception of Week 1 Blood drawn for tests related to hematology, fasting chemistry and lipids (to verify red and white cells, glucose, liver proteins, cholesterol and other substances in your blood) at the following visits: o All visits with the exception of Week 1 and Week 2 o At week 10, an in-office study visit may not be necessary. At this visit, a single tube of blood (approximately 3 ml or about one half of a teaspoon) will need to be collected for a routine blood test. No other study assessments will be completed and you may or may not have to see your study doctor in order to have this done. Your study doctor will provide instructions to you at the Week 8 visit. Urine sample collection for urinalysis at the following visits: o All visits with the exception of Week 1 and Week 2 Blood drawn for tests related to HIV and immune system (HIV RNA, CD4, CD8 and T-cell) at the following visits: o All visits Blood drawn for hepatitis testing (Hepatitis B and C) at the following visits: o Weeks 24, 48, 96 or ET Blood drawn for tests related to drug resistance at the following visits: o All study visits with the exception of Week 1 Blood drawn for tests related to biomarkers (other potential tests that may be considered important to treating your disease or for the determination of safety of the drug) at the following visits: o Day 1, Weeks 12, 24, 48, 96 or ET Urine collected for tests related to biomarkers (other potential tests that may be considered important for treating your disease or determination of the safety of the drug) at the following visits: o Day 1, Weeks 12, 24, 48, 96 or ET Blood drawn to check how the BMS is distributed in your body at the following visits: o Weeks 4, 8, 12,16, 20, 24 for treatment groups 1, 2, and 3 only o And at any additional visit if and when you are receiving treatment with a drug called rifampin, for treatment groups 1, 2 and 3 only Skin biopsy (collection of a tiny piece of skin from the abdomen or buttocks) to assess the effects of the drugs on your DNA at the following visits: o Day 1, Weeks 24, 48 or ET Page 6 of 22

7 DEXA Scans to assess the effects of the drugs on your whole body (by looking at bone and fat density) at the following visits: o Day 1, Weeks 24, 48, 96 or ET (See Section 7 for a description of this test) CT Scans to assess the effects of the drugs on the distribution of fat in your abdomen at the following visits: o Day 1, Weeks 48, 96 or ET (See Section 7 for a description of this test) These limited CT scans will only be used to evaluate changes in body fat by the investigator; the images will not be read by a radiologist and a radiology report will not be generated because there are not enough images to provide any clinically relevant information. You will be given study medications and instructions on how to take it at the following visits: o All study visits with the exception of Week 1 and Week 2 The amount of blood collected at each of the study visits will vary. At most, you will have approximately ml (about 7 tablespoons) collected and at the minimum, you will have 38 ml (about 2.5 tablespoons) collected. Your nurse or doctor will try and minimize the number of needle sticks for your comfort. Stage 2 Week 108 and Every 12 Weeks until End of Treatment Starting at Week 108, you will have fewer study visits, once every 12 weeks, and fewer tests at each visit. During these visits, the following procedures will be completed: A full physical examination will be done Vital signs (seated blood pressure, heart rate, breathing rate, temperature), height and weight will be measured Collection of adverse events Review of all medications that you are currently taking Urine or blood will be collected for pregnancy tests for women of child bearing potential Blood drawn for tests related to hematology, fasting chemistry and lipids (to verify red and white cells, glucose, liver proteins, cholesterol and other substances in your blood) Urine sample collection for urinalysis Blood drawn for tests related to HIV and immune system (CD4, CD8 and T-cell) Blood drawn for tests related to drug resistance You will be given study medication and instructions on how to take it A total of approximately 46 ml of blood (about 3 tablespoons) of blood will be collected at each of the Stage 2 visits. Routine testing blood samples and Pharmacokinetic (PK) blood samples: Multiple blood samples will be taken during the study. These will be sent to ICON Central Laboratories located at 123 Smith Street, Farmingdale, NY, 11735, for analysis. 6. Your Responsibilities At each visit: You will be asked how you feel and possible side effects will be discussed. It is important that you are completely truthful with the study staff regarding your health history and medication use since incomplete or false information could put your health at risk. For your safety, you must keep all your study visit appointments and undergo the procedures as scheduled. You should fast for 8 hours before you come to a visit during stage 1 You must inform your study doctor of any medication that you take while you are in the study. Certain drugs and herbal products may interfere with study drug levels in your blood. Page 7 of 22

8 You must tell your study doctor before stopping or starting any herbal products or medications, including ones you can buy without a prescription (over-the counter medicines), such as vitamins, supplements and other special products. It is also recommended for you to avoid grapefruit and other citrus fruits in large quantities during the study. You should take your study medication as instructed by the study doctor/staff You should bring all study medication, used and unused, including all packaging (even empty), with you to all study visits. You must not have any vaccines within 4 weeks of having blood drawn for tests related to HIV. 7. Risks / Possible Adverse Drug Reactions Risks and possible drug reactions related to BMS BMS has not been studied extensively in subjects with HIV-1 so there is limited information on side effects of this drug and the ability of this drug to help stop the virus from making proteins to make more viruses. In subjects that have been treated with BMS , there have been no ECG changes, laboratory changes, or changes in vital signs. The most common side effects are nausea (feeling like throwing up), headache, abdominal pain, and fatigue (being tired). There has been 1 severe episode of anxiety (nervousness) and paranoia in a subject treated with BMS but this subject had a history of anxiety. In addition, two subjects treated with 600 mg of BMS experienced serious side effects of infections that led to hospitalization. BMS is in a similar class of drugs as tenofovir and while we cannot predict what type of side effects may occur in subjects taking BMS in this study, it may be likely that side effects will be similar to those of other NRTIs like tenofovir. In addition, side effects may be affected by the combination of efavirenz with BMS See the following sections for risks associated with efavirenz and tenofovir. BMS may have the effect of causing resistance mutations in your HIV that can make your virus resistant to certain medications in the future. This could result in more limited treatment options for you after this study is over (see also General Risks Related to Drug Resistance in Section 7 for more information on this effect of HIV medications in general). BMS Toxicity in Animal Studies In a recent 6 month rat study, a single case of hemangiosarcoma (a cancer of the blood vessels that is known to occur spontaneously in healthy rats) was observed in one out of 50 rats receiving a very high dose of BMS While the clinical significance of this hemangiosarcoma is currently unknown, it is not considered that this finding poses a significant safety risk to you in this study. In two recent studies performed on a total of 52 monkeys, 3 monkeys developed thrombocytopenia (a low number of platelets, which help your blood to clot) after receiving BMS for approximately 10 weeks. The monkeys were exposed to a very high level of BMS , much more than the highest level of BMS that will be given to some of the subjects in this study. It is uncertain whether thrombocytopenia will occur in human subjects in AI who will be receiving much lower doses of BMS Some people with low platelet counts have no symptoms at all, but when the platelet count becomes very low, people may experience any one or more of the following: Bruising easily Nose bleeds Page 8 of 22

9 Bleeding of the gums after brushing or flossing Petechia (small red dots or areas of purple discoloration on your body) You should tell your study doctor immediately if you observe any of these symptoms. You should not take any medications unless the Investigator has advised you to do so It is also important to restrict your physical activity until you can be examined by your study doctor. Even though low platelet counts have not been seen in humans or with any of the doses of BMS being used in this study, your doctor will closely monitor you by drawing your blood at study visits. Risks related to efavirenz Side effects: Rash, nausea, vomiting, depression, dizziness, headache, insomnia, abnormal dreams, diarrhea, dyspepsia (upset stomach), abdominal pain, liver toxicity, impaired concentration, anorexia and pain Subjects who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. Risks to pregnancy and fetal damage are explained in section 8. Risks related to lamivudine Side effects: Changes in body fat, chills, coughing, decreased appetite, diarrhea, difficulty sleeping, dizziness, ear, nose, and throat infection, general body discomfort, headache, indigestion (upset stomach), joint pain, muscle pain, nausea, sinus drainage, sore throat, stomach discomfort, tiredness. The following side effects can be severe and you should seek medical attention right away if any of these SEVERE side effects occur: rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; dark urine; depression (mental or mood changes); enlarged stomach; increased heart rate; numbness or tingling in the arms or legs; persistent sore throat, chills, or fever; severe muscle or joint pain; stomach tenderness or pain; unusual bleeding or bruising; unusual weakness or exhaustion; vomiting; yellowing of the skin or eyes. Risks related to tenofovir Tenofovir: Common side effects are severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); anxiety (nervousness); bone pain; chest pain; fever, chills, or sore throat; mental or mood changes (e.g., depression); numbness, burning, pain, or tingling in the hands or feet; pneumonia; severe or persistent nausea or vomiting; shortness of breath; stomach pain; symptoms of kidney problems (e.g., increased or decreased urination, increased thirst); symptoms of lactic acidosis (e.g., unusual weakness or tiredness; unusual muscle pain; fast or difficult breathing; stomach pain with nausea and vomiting; feeling cold, especially in the arms and legs; dizziness or lightheadedness; fast or irregular heartbeat); symptoms of liver problems (e.g., yellowing of the skin or eyes; dark urine; pale stools; persistent loss of appetite). Page 9 of 22

10 General risks related to Antiretroviral Therapy Changes in fat distribution have been reported in association with combination antiretroviral therapy. These may include: Loss of body fat from areas such as legs, arms and face Increased fat appearing in areas such as abdomen (belly) and other internal organs, breasts and the back of the neck or back Within the first few weeks of treatment with anti-hiv medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions such as pain, redness, swelling and high temperature which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV. If you become concerned about any new symptoms or any changes in your health after starting HIV treatment, please tell your study doctor immediately. General Risks Related to Drug Resistance People being treated with drugs to treat HIV can sometimes develop resistance to one or more drug. This means that the drugs no longer work the way they are supposed to. Drug-resistant virus can also be transmitted to other people who are not being treated with HIV drugs. Mutations or changes in the HIV can cause resistance to one HIV drug or several HIV drugs, usually in the same class. However, it s important to understand that a mutation causing resistance to one ARV drug does not reduce the effectiveness of every drug in that class of drugs or of other types of drugs used to treat HIV infection. Your doctor will be monitoring the mutation of your virus on an ongoing basis and will keep you informed of the status of the results. In the event it is determined that you have developed resistance to one or more of the drugs you are assigned too, you may be discontinued from the study and may start another treatment regimen. If you experience virologic failure (see Section 5) in this study, you may likely lose the one-pill once-per-day option because of likely drug resistance to one or more of the drugs used in the once-a-day pill. For example, Atripla is an anti-hiv pill that combines three drugs TDF+FTC+EFV in a single pill taken just once per day, and if a subject fails in this study, it is likely that the subject will have developed resistance to 3TC/FTC and EFV - many of the same drugs used in the Atripla pill. It is important to be clear that if you are assigned to the new treatment (groups 1-3), it is possible that your virus may develop resistance to the drug and others in its class (NRTIs) and even resistance to the NNRTI, efavirenz, and other similar NNRTI drugs. This is unknown since there is no evidence to be sure that the new drug will or will not work well against your virus. Procedural Risks or Discomforts Blood Draws: Pain at the site of the blood draw, bruising, swelling, irritation or infection at the site of the blood draw, dizziness or faintness. ECG: The electrocardiogram (ECG) will measure the electrical impulses of your heart in order to allow the physician to observe the function of heart. This procedure may cause minimal discomfort during the attachment and removal of the ECG leads from your skin. Page 10 of 22

11 DEXA Scan: A bone density test also called densitometry or DEXA scan determines whether you have osteoporosis or are at risk of osteoporosis. Osteoporosis is a disease that causes bones to become more fragile and more likely to break and it is thought that some medications used to treat HIV can lead to decreases in bone density. In the past, osteoporosis could only be detected after you broke a bone. By that time, however, your bones could be quite weak. A bone density test makes it possible to know your risk of breaking bones before the fact. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. A bone density test is a fairly accurate predictor of your risk of fracture. During the test, you lie on a padded platform for a few minutes while a machine a mechanical armlike device passes over your body. It won't touch you. The test usually takes five to 10 minutes to complete. CT Scan: A computed tomography (CT) scan is an imaging method that uses x-rays to create cross-sectional pictures of the body. You will be asked to lie on a narrow table that slides into the center of the CT scanner. Depending on the study being done, you may need to lie on your stomach, back, or side. Once you are inside the scanner, the machine's x-ray beam rotates around you. It is important to remain still during the exam, because movement causes blurred images. You may be told to hold your breath for short periods of time. The scans take about 15 minutes or less to complete. For the purposes of this study, the results of the CT scan will be used to assess whether there have been changes to the fat distribution or lipodystrophy in your body. Exposure to Radiation: This research study involves exposure to radiation from the DEXA and CT scans. Therefore, you will receive a radiation dose. Some or all of these procedures may not be necessary for your medical care and may occur only as a result of your participation in the study. At doses much higher than you will receive, radiation is known to increase the risk of developing cancer after many years. At the doses you will receive, it is very likely that you will see no effects at all. Skin Biopsy: A skin biopsy removes cells or skin samples from the surface of your body. The sample taken from a skin biopsy is examined to provide information about your medical condition. For the purpose of this study, the tissue sample from the skin biopsy will be used to assess the toxicity of HIV drugs on your body at the level of your cells (individual body building blocks) by looking at the effects of BMS on your body s cells. A skin biopsy is a generally safe procedure, but complications can occur, including: Bleeding Bruising Scarring Infection Allergic reaction to a topical antibiotic 8. Risks to Reproduction, Unborn Babies and Nursing Infants 8A. General Statement You must not be pregnant or breastfeeding, and you should not become pregnant or breastfeed while you are taking the study treatments. If you are a Woman of childbearing potential, you must use at least two adequate methods to avoid pregnancy (including at least one barrier contraceptive, like a condom) for the duration of this study and for up to 12 weeks after the last Page 11 of 22

12 dose of BMS If you are male, you should avoid impregnating your partners during and until at least 12 weeks after drug exposure. You should immediately contact your study doctor if there is a change in your method to avoid pregnancy, if you start any prescription drug or other medication (including over-the-counter drugs and herbal supplements) not prescribed by the study doctor, or if you or your partner become pregnant during treatment in study. 8B. Unforeseeable Risks There may be unknown risks to you, your unborn baby or nursing infant if you are or become pregnant during this study or are breastfeeding during this study or if your partner becomes pregnant while you are treated in this study. 8C. Laboratory & Animal Reproductive Toxicology Findings NOTE: While laboratory and animal studies have been conducted to determine possible risks, the results do not necessarily show what will happen when the drug is used in humans. The following are summaries of animal study results for the drugs with which you may be treated: BMS : Safety data from embryo-fetal development and fertility studies in animals are not available at this time. Barrier (e.g., condoms) contraceptives should be used while taking BMS (see Section 8G). Female subjects should avoid pregnancy while taking BMS and for at least 3 months after exposure to the compound. Male subjects should avoid impregnating partners during and until at least 3 months after drug exposure. Efavirenz: Efavirenz did not affect fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected when given at approximately 0.15 times that in humans at the recommended clinical dose. Lamivudine: Animal reproduction studies have been performed in rats and rabbits at doses up to 35 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus (unborn baby). Tenofovir: Animal reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus (unborn baby) due to tenofovir. 8D. Human Pregnancy Outcomes BMS has not been studied in pregnant or lactating women; therefore, the use of this drug during pregnancy has not been determined to be safe. 8E. Findings with Similar Drugs in the Class Similar drugs in the same class as BMS include stavudine, zidovudine, didanosine, lamivudine, abacavir, emtricitabine, and tenofovir. There have been deaths reported in pregnant women who get lactic acidosis (build up of acid in the blood) after taking similar drugs in the class. Page 12 of 22

13 8F. Significant Findings with Study Comparator Drugs Efavirenz is assigned by the US FDA as Pregnancy Category D (i.e., this means there is evidence of human risk to an unborn fetus based on adverse reaction data from investigational or marketing experience or studies in humans). Efavirenz may cause harm to a fetus when administered during the first trimester (first 3 months of pregnancy) to a pregnant woman. Pregnancy should be avoided in women receiving EFV. There are no adequate and well-controlled studies in pregnant women. Lamivudine is assigned by the US FDA as Pregnancy Category C (animal reproduction studies have shown an adverse effect on the fetus). There are no adequate and well-controlled studies of 3TC in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity (fetal harm). Tenofovir is assigned by the US FDA as Pregnancy Category B (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well controlled studies in pregnant women). If you have any questions about FDA pregnancy categories, please talk to the study doctor or study staff. 8G. Use of a Study-Prohibited Contraceptive Method There are no restrictions to any contraceptive method (method to avoid pregnancy) for this study as long as it is in agreement with your study doctor. You should make sure to use at least two contraceptive methods agreed to between you and your study doctor throughout the study, one of which should be a barrier contraceptive, like a condom. You should notify your study doctor if you do not use your contraceptive method as agreed or if you change it during the course of the study. 8H. Requirements for Pregnancy Testing During this study you will have pregnancy tests. The number of pregnancy tests you will have will vary based on the number of study drug treatments you receive. Pregnancy will be determined on basis of a blood or urine sample. 8I. Occurrence of Pregnancy or Suspected Pregnancy If you become pregnant, suspect pregnancy or if you missed your period or it is late, or if you have a change in your usual menstrual cycle (e.g., heavier bleeding during your period or bleeding between periods), you should immediately contact your study doctor. 8J. Discontinuation from the Study Should you become pregnant during this study, you will be permanently withdrawn from the trial in an appropriate manner and be referred for obstetric care. The sponsor has not set aside any funds to pay for any aspects of obstetric, child or related care and does not plan to pay for them. 8K. Pregnancy Reporting In case of a pregnancy, your pregnancy and its outcome is expected to be reported to the study sponsor. 8L. Information for Men with Partners of Childbearing Potential Page 13 of 22

14 Most study drugs do not pose a risk to a woman who becomes pregnant while her male partner is a study subject. However, you are asked to inform your study doctor if your partner becomes pregnant while you are enrolled in this clinical trial, and you and your partner will be asked to provide information about the pregnancy outcome. The sponsor has not set aside any funds to pay for any aspects of obstetric, child or related care and does not plan to pay for them. 9. Benefits Taking part in this study may or may not make your health/condition better. The knowledge gained from this study may be of help to future patients with HIV. 10. Alternative Treatment You may choose not to take part in the study. Many other treatments for HIV infection are available. If you decide not to participate in this study, your doctor can discuss the risks and benefits of other drugs and prescribe one or more that may be appropriate for you. 11. Study-related Injuries: Treatment and Costs If you are injured during your participation in this study, you should contact the study doctor as soon as possible in person or at the telephone number listed on page one of this consent form. Medical care may be obtained in the same way you would ordinarily obtain other medical treatment. If you suffer a study-related injury, the reasonable costs of necessary medical treatment of the injury will be reimbursed to the extent these costs are not covered by your insurance or other third party coverage. A study-related injury is a physical injury that is directly caused by the study drug or research procedures performed as described in the study protocol. A Study-related injury does not include injuries directly caused by any of the following: the natural course of your underlying disease or medical condition not following the instructions provided in this consent form or by study staff There are no plans to provide any other payments or other forms of compensation for a study-related injury (for example, for lost wages or discomfort). You do not give up any legal rights by signing this consent form. 12. Payment You will receive $25 for the screening visit for the study. For Stage 1 of the study, you will be seen for a baseline visit and then for 16 visits over a 2 year period will receive $50 per visit, or $875 total. Visits where a skin biopsy is taken (baseline, week 24, 48 and study discontinuation, an additional $25 will be compensated. Persons selected to participate in the Intensive PK study at week 2 will receive an additional $100. This compensation amount will need to be processed as a check and will take 4-6 weeks to reach you. If you go to Stage 2, you will be seen for week 108 and then will be seen every 12 weeks, until the study is cancelled or the drug is commercially available, the amount of compensation for this portion of the study will vary. For each visit you complete in Stage 2, you will receive $50 per visit. If you leave the study before completing all visits, you will be paid for each completed visit. Please note: In order to be compensated for your participation in this study, you must provide your Social Security Number. Additionally, please note that the University of Pennsylvania is required to report to the IRS any cumulative payments for participation in research studies that exceed a total of $600 in a calendar year. Page 14 of 22

15 13. Any Anticipated Expenses There will be no charge to you or your insurance company for any of the needed tests done while you are in this study. All clinic visits, physical examinations, study medication, laboratory tests, electrocardiograms, and any other tests connected with the conduct of this study are provided at no cost if you take part. 14. Voluntary Participation / Complete or Partial Discontinuation of Participation Your participation in this study is entirely voluntary. It is up to you to decide whether to take part or not. Even if you do decide to take part, you are free to leave the study at any time without giving a reason. This will not affect your future medical care in any way. Furthermore, your study doctor may withdraw you from the study if he/she feels this is in your best interest including, but not limited to: an adverse event (possible side effect), injury or medical condition which may place you at risk of further complications if you continue to participate, failure to take the study medication or follow study procedures as instructed, failure to keep your scheduled appointments, cancellation of the study, targeted number of participants needed for study have entered the treatment phase, administrative reasons, or the study may be stopped early. In addition, BMS, the Sponsor can terminate the study at any time. Your refusal to participate or your withdrawal from the study will involve no penalty or loss of entitled benefits, nor affect your ongoing medical care. If you decide to withdraw your consent to participate in the study, please notify the study doctor immediately. Your study doctor will ask your agreement to perform the final evaluation and to collect the data through a report form. If you do not agree, no new data on you will be added to the database. You will be informed if new findings are made which would affect your participation. You will be informed of any plans for new analyses on retained samples (for example, blood samples) that were not anticipated when you consented to participate and will be provided with a new consent form. You may at any time refuse further analyses and /or request that previously retained identifiable samples be destroyed to prevent further analysis (as per national legislation). 15. Sponsoring Company The pharmaceutical company sponsoring this study is Bristol-Myers Squibb Research and Development, located at Avenue de Finlande 8, Building F 1st Floor B-1420 Braine-l Alleud, Belgium and Research and Development, located at 5 Research Parkway, Wallingford CT in USA. 16. Confidentiality, Collection and Use of Study Data 16A. Collection of Study Data Your study doctor and study staff will collect information about you which is relevant to this study; specifically, information about your name, address, contact details, date of birth, medical records, health your race, ethnic origin and your life habits and sexual life. This collected information about you is called data or study data in this document. 16B. Confidentiality of Study Data and Key-coded Data For the purposes of your participation in this study and the protection of your identity, your study doctor will assign you a unique code, such as a series of numbers and/or letters. The study doctor will record the study data collected from you in a report form that uses your assigned code, not your name. This is to protect your study data by making it anonymous for most study purposes. The data that is recorded with your assigned code rather than your name is called key-coded data. The key-coded data will be entered into the study s computer database. Your study doctor will keep Page 15 of 22

16 a confidential list linking your name to your code and only authorized persons will have access to this list. The ways in which key-coded data may be used and shared is described below in Section 16C. Some study data will identify you (such as medical records), and the ways in which this data may be used and shared is described below in Section 16D. 16C. Use and Sharing of Key-Coded Data Your key-coded data may be shared with and used by the following: The study doctor and study staff The study sponsor, its current or future research partners, collaborators, assignees, licensees or designees and their affiliates, agents, and employees Other individuals and organizations that analyze or use your information in connection with these research activities, including laboratories and study sites (in the event you transfer to another study site); Domestic or foreign health authorities e.g., the Food and Drug Administration (FDA), and Institutional Review Boards (IRBs). Other persons required by law Your key-coded data will be used in connection with this study and may also be: used for other current or future research involving the same drug(s), the same or related health conditions, or for other relevant health research; transferred to individuals or companies located outside of the country or region in which you reside. However, all access to the key coded data will be controlled in accordance with applicable laws and regulations. This may include written agreements that require that the data be kept confidential and secure and be used only for the purposes permitted by this consent form or applicable laws and regulations; used in publications about this study but it will remain coded. Your identity will not be revealed in any compilation, study report or publication at any time. A description of this clinical trial will be available on as required by U.S. Law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search this website at any time. 16D. Use and Sharing of Study Data that Identifies You The authorization part of the consent gives more detailed information about how your personal health information may be used and disclosed by the University of Pennsylvania Health System (UPHS), the School of Medicine and the individual Principal Investigator, subject to University of Pennsylvania procedures. We will do our best to make sure that the personal information obtained during the course of this research study will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. If this study is being overseen by the Food and Drug Administration (FDA), they may review your research records. Page 16 of 22