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D
Informed Consent Documents

R-89 (University of California, San Diego)

185

R-90 (University of Washington)

189

R-90 (University of California, San Diego)

198

R-90 (National Institutes of Health)

203

R-91 (National Institute of Diabetes and Digestive and Kidney Disorders)

210

PPPC

218

PPPA (University of Texas, Galveston)

225

PPPA (New England Medical Center, Boston)

231

PPPG

237

NOTE: All documents reproduced in this appendix are reprinted with the permission of the institution involved.



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Review of the Fialuridine (FIAU) Clinical Trials D Informed Consent Documents R-89 (University of California, San Diego) 185 R-90 (University of Washington) 189 R-90 (University of California, San Diego) 198 R-90 (National Institutes of Health) 203 R-91 (National Institute of Diabetes and Digestive and Kidney Disorders) 210 PPPC 218 PPPA (University of Texas, Galveston) 225 PPPA (New England Medical Center, Boston) 231 PPPG 237 NOTE: All documents reproduced in this appendix are reprinted with the permission of the institution involved.

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Review of the Fialuridine (FIAU) Clinical Trials R-89 (UNIVERSITY OF CALIFORNIA, SAN DIEGO) UNIVERSITY OF CALIFORNIA, SAN DIEGO MEDICAL CENTER CONSENT TO ACT AS A RESEARCH SUBJECT 89-619 ACTG 122 Drs. Douglas Richman, Stephen Spector, J. Allen McCutchan, Samuel A. Bozzette, Lisa DeJarnette, Samuel Yonren, Brett Cassens, Wayne Dankner, William Freeman and their associates are conducting a study to determine the safety, tolerance, pharmacokinetic profile and effect on viral cultures of an oral form of FIAC. FIAC is a medication that is active against herpes virus infections (herpes simplex, varicella zoster, and cytomegalovirus). FIAC has been used successfully in earlier studies to treat herpes infections in patients who have a compromised immune system. I have been asked to participate because I have a cytomegalovirus infection, but I do not have evidence of CMV retinitis. Ganciclovir is a drug which is presently used to treat CMV retinitis and other forms of CMV infection. However, ganciclovir must be administered intravenously and for prolonged periods, usually necessitating a central venous catheter. The purpose of my receiving oral FIAC is to test its safety, tolerance, and antiviral effects, so that it may be used to treat patients with serious CMV infections such as CMV retinitis. If I agree to be in this study the following will be done: I will have a complete history, physical exam, viral cultures, and blood drawn for laboratory tests at the time of enrollment, and at least every other week thereafter for up to 12 weeks. I will receive one of five possible dose regimens or oral FIAC. If my blood and/or urine continues to grow cytomegalovirus, and the dose I am taking is being tolerated by me and other people taking the same dose of FIAC, then I will be increased to the next higher dose level. Once my blood or urine becomes culture negative for CMV for at least four weeks I will remain at that dose level for the remainder of the study. I will not need to be hospitalized; however, I will need to spend at least two hours at the UCSD Treatment Center during the second week and the eighth week in order to have bloods drawn for FIAC levels. If I take part in the pharmacokinetic study, then I will need to spend one day in the Outpatient Clinical Research Unit in order to have blood drawn and urine collected for eight hours after my first daily dose of FIAC.

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Review of the Fialuridine (FIAU) Clinical Trials I will have ophthalmologic exams done at my enrollment onto the study and during weeks 2, 4, 8, and 12. If I develop CMV retinitis during the study, I will be allowed to continue FIAC if I desire, or withdraw from the study. I will have electrocardiograms performed at entry and day 7, day 14, and weeks 4, 8, and 12. If I am sexually active I will use effective contraceptive during FIAC treatment and for 30 days following treatment. If I have been taking AZT without difficulty over the past month, then I can continue to take AZT while on the study; however, I must take 600mg. or less per day. I have not taken and I will continue not to use acyclovir, ganciclovir, foscarnet, or interferon during the study. If I have not been taking AZT previously, I understand that I cannot start AZT until after the 12 week study period. After the 12 week study period has ended, I will not continue to receive FIAC. Participation in this study may involve some added risks or discomforts: It is possible that FIAC may cause my white blood cells, red blood cells, or platelets to decrease. This may predispose me to bleeding, anemia, and infection. Some other side effects that I may experience include nausea and perhaps vomiting. It is also possible that confusion, jerking, and even seizures may occur while I am taking this medication, although this is unlikely on the doses I will receive. In animal studies there was evidence of heart damage in those animals receiving very high doses of FIAC. It is not known whether FIAC may cause sterility or infertility in humans, however, this is a possibility. Since interactions between FIAC and other medications are incompletely understood at this time, I must not take other medications without first consulting with my study physician or nurse practitioner. I realize that I may receive no benefit from participating in this study. The knowledge gained may help others in the future. Dr. ______________ has explained this study to my child and me and answered my questions. If my child or I have other ?? or if we wish to report a research-related problem, I may call Dr. _______________ at 298-7021.

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Review of the Fialuridine (FIAU) Clinical Trials If I am injured as a result of participation in this research, the University of California will provide any medical care that I may need to treat those injuries—except when they are a consequence or research designed to benefit me directly. The University will not provide any other form of compensation to me if I am injured. I may call (619) 534-4520 for more information about this. Participation in research is entirely voluntary. I may refuse to take part or withdraw at any time without jeopardy to my medical care at this institution. Research records will be kept confidential to the extent provided by law. Study forms will contain only a code number, and perhaps my initials (but not my name) for identification. Study records may be reviewed by the AIDS Clinical Trials Coordinating Center, the NIAID, Oclassen Pharmaceuticals, or the U.S. Food and Drug Administration to ensure that they are accurate and fulfill federal regulations. I have received a copy of this consent document to keep and a copy of ''The Experimental Subject's Bill of Rights.'' I agree to take part in this study. Subject's Signature Date Witness Parent or Legal Guardian Date

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Review of the Fialuridine (FIAU) Clinical Trials UNIVERSITY OF CALIFORNIA, SAN DIEGO EXPERIMENTAL SUBJECT'S BILL OF RIGHTS The faculty and staff of the University of California, San Diego wish you to know: Any person who is requested to consent to participate as a subject in a research study involving a medical experiment, or who is requested to consent on behalf of another, has the right to: Be informed of the nature and purpose of the experiment. Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be used. Be given a description of any attendant discomforts and risks reasonably to be expected from the experiment. Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable. Be given a disclosure of any appropriate alternative procedures, drugs, or devices that might be advantageous to the subject, and their relative risks and benefits. Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise. Be given an opportunity to ask any questions concerning the experiment or the procedures involved. Be instructed that consent to participate in the medical experiment may be withdrawn at any time, and the subject may discontinue participation in the medical experiment without prejudice. Be given a copy of a signed and dated written consent form when one is required. Be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on the subject's decision. If you have questions regarding a research study, the researcher or his/her assistant will be glad to answer them. You may seek information from the Human Subjects Committee - established for the protection of volunteers in research projects - by calling (619) 534-4520 from 8 am to 5 pm, Monday through Friday, or by writing to the above address.

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Review of the Fialuridine (FIAU) Clinical Trials R-90 (UNIVERSITY OF WASHINGTON)

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Review of the Fialuridine (FIAU) Clinical Trials UNIVERSITY OF WASHINGTON HARBORVIEW MEDICAL CENTER CONSENT FORM UW ORIGINAL CONSENT FORM The Tolerance of HIV-Infected Patients to Oral Doses of FIAU Teresa Tartaglione, Pharm.D. Asst. Professor, Pharmacy 223-3193 Thomas M. Hooton, M.D. Asst. Professor, Medicine 223-3240 Ann Collier, M.D. Asst. Professor, Medicine 223-3295 Julie McElrath, M. D., Ph.D Asst. Professor, Medicine 222-3056 Frudy Jones, A.R.N.P. Clinician, Medicine 223-3134 Phyllis Holzworth, A.R.N.P Clinician, Medicine 223-3184 Becky Royer, P.A.C. Clinician, Medicine 223-3325 Lawrence Corey, M.D. Professor, Medicine and Laboratory Medicine 526-2117 Emergency 24 hr. number Page infectious Disease Fellow 223-3000 INVESTIGATOR'S STATEMENT Purpose and Benefits Cytomegalovirus (CMV), Varicella Zoster virus (VZV), and Herpes Simplex Virus (HSV) infection are significant opportunistic diseases seen in patients who are immunocompromised. Many HIV-infected patients are also coinfected with hepatitis B virus. CMV is known to cause many serious infections including inflammation of the retina in one or both eves ("retinitis"). This is one of the infections associated with AIDS and may lead to blindness. Although herpes and hepatitis B infections do not cause AIDS, severe herpes and hepatitis B disease may occur following advanced immunocompromised states. FIAU is an investigational new drug which has not been tested previously in humans The United States Food and Drug Administration (FDA) allows the use of FIAU only in research with a limited number of subjects. FIAU is similar to another investigational new drug, FIAC, which has been tested previously in approximately 100 patients, including AIDS patients with CMV infection. The purpose of this research study is to determine the safety and tolerance over a two week period of four different doses of FIAU in HIV-infected patients including some with CMV, VZV, HSV, or hepatitis B infection. You may benefit if your CMV, HSV, VZV or hepatitis B infection improves or stabilizes while receiving FIAU therapy, although no benefits can be guaranteed. The information gained will provide some initial information on the dosing and side effects of FIAU which may be of future benefit to HIV-infected patients. Procedures This study will last for 14 days exclusive of the screening and any followup visits. If you agree to participate in this study, you will have a complete history and physical examination performed. At the screening and baseline visits you will have blood drawn for

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Review of the Fialuridine (FIAU) Clinical Trials AIDS virus and immune function tests as well as for routine blood tests (four tablespoons). You will also have other routine baseline studies, including chest X-rays, EKG, urinalysis, stool guaiac (for detection of blood), and an eye examination (only if you are infected with CMV). You will receive FIAU as an outpatient as soon as it has been determined that you meet the criteria for entry. The dose of FIAU will be assigned sequentially (in order of patient enrollment) per kilogram of body weight. Your FIAU dose will range from 1.0 to 5.0 mg/kg/day. FIAU will be given orally every 8 hours with about 2 tablespoons of water and will be Taken either one hour prior to or three hours after meals. You may receive FIAU for up to 14 days or until your CMV, HSV or VZV infection worsens or until you experience significant toxicity. You will have regular check-ups to monitor your infection and your tolerance of FIAU. These will be performed on days 2, 3, 5, 7 10 and 14. Treatment may be discontinued or modified depending on your response. Standard blood tests, urinalysis, stool guaiac, CMV, HSV, VZV and/or HBV (hepatitis B virus) tests, eye exams, EKG, and tests measuring the concentration of FIAU in your blood will be done at some of these visits. Approximately 17 tablespoons of blood will be drawn during the two week study. You are requested to avoid heavy exercise for 1 day prior to each day that blood is to be drawn (e.g., days 2, 3, 5, 7, 10, and 14). if you have chronic HBV infection, you will be required to have a one week and four week followup visit. At this visit you will have a brief history and physical exam; blood (2 teaspoonfuls) will also be drawn at each of these visits. While you are taking FIAU you may not take acyclovir (ZoviraxR), ganciclovir (DHPG), foscarnet or interferon. You may be allowed to take zidovudine (also known as azidothymidine AZT, RetrovirR) for the duration of the this study if you've been taking the drug for at least 6 weeks, if you are receiving less than or equal to 600 mg per day, and if your red cell, white cell and platelet counts have not dropped significantly. If you start taking AZT after you've begun this FIAU study, you will be dropped from the study. You are allowed to take aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia. Risk and Discomforts Although FIAU has not been administered to humans, there are a number of known side effects of FIAC that patients have experienced in other studies. You may experience nausea and vomiting. FIAU may also cause toxicity to your blood-forming cells; specifically your white cells, red cells and platelets may be reduced in number. Reduction of your white cells may cause you to experience more frequent infections. A decrease in red blood cells can cause fatigue and too few platelets may cause bleeding. With FIAC, these effects reversed with lowering of the dose or drug discontinuation. Some of your blood chemistry values may change while on FIAU therapy. Reversible neurologic toxicity following FIAC administration has been infrequently reported but FIAU may also cause confusion, muscle jerking and seizures. Polymyositis

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Review of the Fialuridine (FIAU) Clinical Trials (inflammation of many muscles) has been reported in one patient receiving FIAC and was reversible with drug discontinuation. Non-reversible cardiac toxicity (damage or death to heart muscle and tissue) at very high FIAC doses has been observed in animal studies. These neurologic and cardiac effects may occur with FIAU. FIAU may also affect the production of healthy sperm and/or fetal development. Since FIAU is an investigational drug, there may be other previously unknown side effects. The risks of drawing blood include mild pain, bruising, or rarely infection at the needle site. If you take this drug during pregnancy you may expose your unborn child to significant hazards of deformity. if you are a woman, you must avoid pregnancy while taking this drug, and, if you are sexually active, you must agree to use some form of barrier contraception while you participate and for at least 3 months following study completion. If you are a woman of child-bearing potential, you will be required to have a serum (blood) pregnancy test prior to entry in the study. If you do become pregnant while on this study, you must notify the investigator immediately. If you are a man with a female partner of child-bearing age, should your partner become pregnant, there is the possible risk of deformity in the child. Therefore, it is important that you or your partner use barrier contraception. The amount of radiation exposure from the chest x-rays will be about 110 mrem; this is about the same as normal exposure from background radiation in Seattle during one year. Alternatives If you choose not to participate in the study, it will have no effect on your continued care. Other alternatives at this point include careful observation by your doctor and either treatment by Foscarnet, interferon or Ganciclovir depending on your individual infection. Other treatment includes treatment against human immunodeficiency virus (HIV) which causes AIDS (such as Zidovudine), in order to contain the underlying HIV infection which made you vulnerable to infections. Other Information All information and test results will be strictly confidential. You and your laboratory samples will be identified by code. All records with identifying information will be kept in locked files, and will be available only to the investigators with the following exception. Representatives of the U.S. Food and Drug Administration (FDA), National Institutes of Health (NIH), Oclassen Pharmaceuticals (makers of the drug) will have the right to review study data and will have access to identifying information. The FDA,. the NIH, and Oclassen Pharmaceuticals reserves the right to review subjects' personal medical records as relevant to this study. You should also understand that the investigators of this study are requesting your permission to review your medical records for purposes of this research study. The medical records utilized

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Review of the Fialuridine (FIAU) Clinical Trials in this study will be entered into a centralized computer data base but only code numbers will be used. No publication or public discussion of the results of this research will contain information that could identify you. The research records will be kept indefinitely. Part of the blood samples will be saved, and may be used in the future for other HIV-related tests. These samples will be identified only by code number and will be accessible only to studies involving current University of Washington investigators. The study drug, FIAU, laboratory tests, and clinic visits will be provided free of charge. However, costs of hospitalization and/or medications required for treatment of side effects will be the financial responsibility of you and your insurance company. Some insurance companies may not reimburse you for expenses arising from investigational studies. If significant findings are noted during the study that might affect your willingness to continue hue to participate, these findings will be provided to you. Investigator's Signature Date SUBJECT'S STATEMENT I am 18 years of age or older. The study described above has been explained to me. I understand that I may refuse to participate and may withdraw from the study at any time without penalty and without loss of benefits to which I am otherwise entitled. I understand that if I withdraw, the investigators will retain access to my study data and any stored specimens. I was given an opportunity to ask questions and understand that future questions I may have about the research or my rights as a research subject will be answered by the investigators listed on page 1. Subject's Signature Date Copies to: Subject Investigators' file tart/cf-fiau.doc 9/14/90

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Review of the Fialuridine (FIAU) Clinical Trials UNIVERSITY OF WASHINGTON HARBORVIEW MEDICAL CENTER CONSENT FORM 19 REVISED CONSENT FORM The Tolerance of HIV-Infected Patients to Oral Doses of FIAU Teresa Tartaglione, Pharm.D. Asst. Professor, Pharmacy 223-3198 Thomas M. Hooton, M.D. Asst. Professor, Medicine 720-4200 Ann Collier, M.D. Asst. Professor, Medicine 223-3293 Julie McElrath, M.D., Ph.D Asst. Professor, Medicine 326-4179 Trudy Jones, A.R.N.P. Clinician, Medicine 223-3184 Lawrence Corey, M.D. Professor, Medicine and Laboratory Medicine 526-2117 Emergency 24 hr. number Page Infectious Disease Fellow 223-3000 INVESTIGATOR'S STATEMENT Purpose and Benefits Many HIV-infected patients are coinfected with hepatitis B virus. Although hepatitis B infections do not cause AIDS, severe hepatitis B disease may occur following advanced immunocompromised states. FIAU is an investigational new drug which has recently been tested in a small number of humans. The United States Food and Drug Administration (FDA) allows the use of FIAU only in research with a limited number of subjects. FIAU is similar to another investigational new drug, FIAC, which has been tested previously in approximately 100 patients, including AIDS patients with CMV infection. The purpose of this research study is to determine the safety and tolerance over a two to six-week period of two different doses of FIAU in HIV-infected patients with hepatitis B infection. You may benefit if your hepatitis B infection improves or stabilizes while receiving FIAU therapy, although no benefits can be guaranteed. The information gained will provide some initial information on the dosing and side effects of FIAU which may be of future benefit to HIV-infected patients. Procedures If you agree to participate in this study, you will have a complete history and physical examination performed. At the screening and baseline visits you will have blood drawn for AIDS virus and immune function tests as well as for routine blood tests (four tablespoons). You will also have other routine baseline studies, including chest X-rays, EKG, urinalysis, and stool guaiac (for detection of blood). You will receive FIAU as an outpatient as soon as it has been determined that you meet the criteria for entry. Your FIAU dose will range from 0.1 to 1.0 mg/kg/day. FIAU will be given orally every 8 hours with about 2 tablespoons of water and will be taken either one hour prior to or three hours after meals. You may receive FIAU for up to 14 days.

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Review of the Fialuridine (FIAU) Clinical Trials AUG 09 '94 10:11 P.3/3 FIAU/HEPATITIS B Marshall H. Kaplan, MD Procedures to be Followed You have previously been evaluated, and the results of your examination and laboratory values indicate that you have chronic hepatitis B, and you do meet all the entry requirements required to enroll in this study. Approximately one week before beginning treatment, you will have a liven biopsy if you have not had a liver biopsy, that we can use, within the past year. A liver biopsy means that the skin on your right side will be numbed and a needle will be inserted to remove a small piece of liven tissue. You will be instructed in breathing techniques to make the procedure easier and safer. After the biopsy you will lie on your right side for several hours You will have to remain at the hospital for approximately one day for this procedure. Also your blood will be drawn for analysis. One of the blood tests will verify that you are not infected with the human immunodeficiency virus (HIV), which can cause AIDS. A separate consent form will be signed permitting us to test you for HIV. Your doctor has explained the risks and benefits of the test for AIDS. other blood tests will verify that you are not infected with hepatitis C or D virus. Based on the results of your liver biopsy, you will be enrolled in the study at a visit approximately seven days later. You will not eat after dinner on the day before your admission visit and will not have breakfast until after you are seen the next morning. At the admission visit, chest x-rays, a EKG, your medical history, and current assessment of your symptoms will be obtained. In addition, if you are a female capable of having children, you must have a negative pregnancy test (urine test) before you may be enrolled in the study. Prior to receiving your first dose of study drug, your blood will be drawn for analysis and you will provide a urine specimen. You will receive the first dose of study drug at the hospital and blood will be drawn immediately before the dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours after the dose. In addition, you may have additional blood drawn at 12 and 24 hours after the dose depending on the treatment group to which you are assigned. Follow-up evaluations (laboratory and/or clinical) will occur on Day 7, 14 and 21 of your treatment period. On Day 7 and Day 14, your blood will be drawn right before your morning dose. The night before these visits, you will not eat after dinner until your visit the next morning. At your Day 21 visit, you will take your morning dose of study drug at the hospital and your blood will be drawn immediately before the dose and after the dose at the same intervals as your first visit. After you have taken one month of study drug therapy, you will begin monthly visits to the hospital. You will continue the monthly visits, which will involve a physical examination, current assessment of your symptoms, blood tests and a urine test, until you finish taking your study medication. You will then have a visit to the hospital every a months. One year after you have completed study drug therapy, you will have a liver biopsy, if your lab tests show that you have benefitted from the drug and you will continue to see the physician every six months for one more year. If your lab tests show that you have not benefitted from the study drug, your physician will instruct you on when your next visit, will be. Blood draws for each visit will require approximately 2-4 tablespoonsful (30-60 ml) of blood. All evaluations and laboratory tests for this study will be free of charge. Approved 2/26/93

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Review of the Fialuridine (FIAU) Clinical Trials AUG 09 '94 10:12 P.4/3 FIAU/HEPATITIS B Marshall M. Kaplan, MD During your dosing period, the first 3 months in the study, you will bring your study medication bottle)s) with any remaining syrup still in them to the hospital and give it to the person designated by the doctor for recording and collecting or reissuing drug. You rill be given a flow sheet of your specific appointments, dates and instructions. Risks and Possible Side Effects There may be risks for you if you agree to be in this study. FIAT is a new investigational drug taken for 14 to 28 days by 54 patients with chronic hepatitis B. An additional 100 patients have been treated for up to 8 weeks with a similar drug, FIAC that is turned into FIAU in humans. Both drugs appear to have similar side effects, These side effects are primarily nausea and fatigue but may include stomach pain, vomiting, headache, and muscle aches. Changes in laboratory tests that measure liver, kidney, and muscle function, and anemia have also occurred. These laboratory changes are expected to improve, once the study drug is stopped. In laboratory test animals given extremely high doses (much higher than in this-study), changes in heart muscle with nonreversible toxicity, skeletal muscle, the formation and production of sperm, fetal development and kidney toxicity have been found. Additionally, chromosomal changes have been detected in mice given high, doses of FIAU. The effect of this in humans is unknown. Because this drug may penetrate the skin and become incorporated into your genetics material, you should use caution in handling the medication and wash thoroughly with soap and water should it come in contact with your skin. The major effects of liver biopsy are pain, fainting, bacteria in the blood, puncture of an internal organ (other than the liver), and bleeding. Local pain and discomfort at the liver biopsy site occurs in 1 out of 5 patients, is usually mild, and lasts 1 to 12 hours. Fainting and bacteria in the blood occur in 2% or less of the patients biopsied, Puncture and bleeding are very rare. In the event that your blood tests suggest damage to muscle, you may be asked to have a thigh muscle biopsy. This will be done under local anesthesia at no expense to you. This procedure may cause temporary discomfort at the biopsy site. Some minor discomfort is caused when blood is drawn from my vein. Bleeding, bruising or infection may also occur at the site where blood samples are obtained. In addition to these effects, other unpredictable bad effects due to the study drug or test procedures may occur. If you should have an adverse effect any time during the study, you should tell your doctor immediately. Any new significant information developed during the course of this research which may change your wish to continue in this study will be provided to you and to the doctor. Approved 2/26/93 Valid through 1/19/94

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Review of the Fialuridine (FIAU) Clinical Trials AUG 09 '94 10:12 P.5/3 FIAU/HEPATITIS B Marshall M. Kaplan, MD For Men and Women of Childbearing Potential: The medication used in this research study may involve risks to you or to an embryo or fetus if you are pregnant at any time during the study. If you are pregnant or should you intend to become pregnant, you should not be enrolled in this study. Males should also not father a child while in this study. If you choose to participate, you must use adequate birth control to prevent pregnancy during this study, while you are on study medication and for 3 months after the study medication has stopped (up to a total of S months). Adequate methods of contraception include birth control pills, diaphragms, or cervical caps, used with contraceptive jelly, condoms with contraceptive foam, IUD's (intrauterine devices), NorplantR, or abstinence. Should you become pregnant at any time during this time frame, you must immediately notify your physician, and your participation in the study will be terminated. A pregnancy test will be performed prior to your enrollment in the study. Benefits It is not known whether you will benefit from this study or not. Because you have chronic hepatitis B, an infection for which the new drug. is being considered as therapy, you may medically benefit by the partial or complete healing of your infection. The study may also be of benefit to other patients with this type of infection in the future. Other Treatment As an alternative to participation in this study, you may be treats with interferon. You understand that you could choose this drug rather than participate in this research study. Therapy for chronic hepatitis B is limited. Only interferon-alpha-2b (Intron-A) is approved in the United States for the treatment of hepatitis B. You understand that you could choose this therapy rather than participate in this research study. Costs While you are enrolled in the study, during the medication phase (90 days) and the follow up period (up to 2 years after medication) and during the one week pretreatment phase, all laboratory tests, hospital, outpatient clinic and physician charges will be provided to you at no cost. In addition all study medication will be provided to you at no cost to you or your insurance carrier. Phone Numbers If you have any questions or problems during this study, you may call Dr. Marshall Kaplan at (617)-956-5877. Either he or an associate will be available to answer your questions. You may contact the GI Office of Clinical Trials at (617)-956-4532, either study nurse may also he of assistance. In the event of an emergency, call (617)—956—5114 and ask for the "GI Physician on Call" and explain to the physician that you are a part of this study. Approved 2/26/93 Valid through 1/19/94

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Review of the Fialuridine (FIAU) Clinical Trials AUG 09 '94 10:13 P.6/3 FIAU/HEPATITIS B Marshall M. Kaplan, MD PARTICIPANT'S STATEMENT I have read this consent form and have discussed with Dr. Marshall Kaplan or his representative the procedures described above. I have beer give the opportunity to ask questions, which have been answered to my satisfaction. I understand that any questions that I might have will be answered verbally or, if I prefer, with a written statement. I understand that I will be informed of any new findings developed during the course of this research study. I understand that my participation is voluntary. I understand that I may refuse to participate in this study. I also understand that if, for as reason, I wish to discontinue my participation in this study at any time. I will be free to do so, and this will have no effect on my future care or treatment by my physicians or this hospital. I understand that in the event I become ill or am injured as a result of my participation in this study, medical care will be provided to me. If follow the directions of the doctors in charge of this study and I become ill or am injured because of the study drug or because of a properly performed study procedure, Eli Lilly and Company, the sponsor, will pay the medical expenses for the treatment of the injury or illness which are not covered by my medical insurance. I understand that no other compensation for such injury or illness ocher than for medical treatment will be provided. If I have any questions concerning my rights as a research subject in this study, I may contact the Human Investigation Review Committee at (617)-956-7512. I have been fully informed of the above-described study with its risks and benefits, and I hereby consent to the procedures set forth above. A copy of my signed consent will be reviewed by a representative of Eli Lilly and Company and I will receive a copy. I understand that as a participant in this study my identity and my medical records and data relating to this research study will be kept confidential, except as required by law, and except for inspections by the U.S. food and Drug Administration which regulates investigational drug studies, and the study sponsor. Approved 2/26/93 Valid through 1/19/94

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Review of the Fialuridine (FIAU) Clinical Trials PPPG

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Review of the Fialuridine (FIAU) Clinical Trials Protocol H3X-LC-PPPG(a) Page 1 of 6 CONFIDENTIAL Fialuridine (LY303256): Bioequivalence of Syrup and Tablet Formulations, and Influence of Timing of Meals on Pharmacokinetic Variables Informed Consent Document INTRODUCTION You are invited to take part in a research study of an investigational drug for the treatment of hepatitis B (viral liver infection) known as fialuridine (FIAU, LY303256). We plan to study up to 22 volunteers. Your participation in this study is expected to last up to 4 weeks. PURPOSE The purposes of this study are to determine how your body handles a syrup form and two tablet forms of FIAU, and to determine the influence of food on how your body handles FIAU. PROCEDURES Before entering the study you were interviewed by a physician who asked about your medical history and completed a general physical examination. In addition, you have had blood and urine tests done, a heart tracing performed, and may have had a chest x-ray performed if you had not had one within the last six months. Based upon these tests you are being invited to participate in this study. Your participation in this study will require that you be admitted to the Lilly Clinic. You will receive five single doses of FIAU on five separate dosing days, with each dose being given at approximately 8 AM. Each dose of FIAU will be separated by 3 to 7 days without dosing. Each dose will be 5 mg of FIAU, either as a single 5 mg tablet, as five 1 mg tablets, or as I teaspoonful of syrup. On three of the dosing days you will receive one of these dose forms following an overnight fast and will continue to fast for 4 hours after receiving the dose. The total fasting time is up to fifteen hours. On one dosing day you will receive the 5 mg tablet following an overnight fast and immediately before a Fialuridine (FIAU, LY303256)   IRC Approval Date: March 9, 1993 Subject initials_________________

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Review of the Fialuridine (FIAU) Clinical Trials standard breakfast, and on one dosing day you will receive the 5 mg tablet following an overnight fast and at some time between 1 hour before and 2 hours after a standard breakfast. You will not smoke, or drink caffeine-containing beverages during the study. You will not take any medications (except for an occasional pain medicine) during the study period. Prior to the start of dosing a blood sample will be obtained. On each dosing day approximately 12 blood specimens will be drawn. A blood specimen for safety analysis will be obtained the day after each dose of FIAU. The total volume of blood collected from you during the study will be about 517 ml, which is about one pint. RISKS You understand that there may be risks for your being in this study. FIAU is a new investigational drug taken for 14 to 28 days by 54 patients with chronic hepatitis B. An additional 100 patients have been treated for up to 8 weeks with a similar drug, FIAC, that is turned into FIAU in humans. Both drugs appear to have similar side effects. These side effects include stomach pain, diarrhea, nausea, vomiting, headache, and muscle aches or fatigue. Changes in laboratory test values that measure liver, kidney, and muscle function, and anemia (low blood count) have also occurred. These laboratory changes are expected to improve, once the study drug is stopped. In addition, laboratory test animals given extremely high doses of FIAU by mouth (3,500 times more than the dose planned for this study, adjusted for different animal weights) have shown decreased sperm production, and animals given extremely high doses directly into their veins (7,000 to 14,000 times more than the dose planned for this study, adjusted for different animal weights) have shown heart muscle damage. Needle punctures for blood draws are usually well-tolerated by most people. However, they may cause bleeding, bruising, discomfort, infections and/or pain at the needle site and dizziness.

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Review of the Fialuridine (FIAU) Clinical Trials In addition to these effects, fialuridine (FIAU, LY303256), or the procedures in this study, may have other unknown effects. In case you have any bad effects, make sure that you immediately tell the nurses or Dr. Hyslop at the Lilly Clinic at 276-4757. You should not participate in this study if you have: Concurrent viral infection(s) (AIDS/HIV, hepatitis C, hepatitis D). Low blood count tests. Received medical therapy for viral infections such as AIDS or hepatitis, including therapy with drugs under investigation as treatment for these infections, within the last six months. Such treatment could include drugs such as zidovudine, didanosine, zalcitabine, and interferon. Advanced cirrhosis on liver biopsy or significant liver disease. Abused alcohol or drugs within the preceding 6 months. VOLUNTARY PARTICIPATION Your taking part in this study is entirely voluntary. You may refuse to take part in the study or you may quit the study at any time without a penalty or loss of benefits to which you were entitled before taking part in the study. If you decide to stop being part of this study, Dr. Hyslop will talk to you about the process for stopping and the medical consequences of your making this choice. Dr. Hyslop or Eli Lilly and Company (the sponsor of this study) may stop this study, or your being a part of it at any time without your consent. TREATMENT AND COMPENSATION FOR INJURY If you follow the directions of the doctor in charge of this study and you are physically injured due to any substance or procedure given during your participation in this study, Eli Lilly and Company will decide either to provide treatment for the injury, or to pay for

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Review of the Fialuridine (FIAU) Clinical Trials those medical costs that are not covered by your medical insurance. Eli Lilly and Company does not agree to pay any additional money for injury. For further information about compensation or treatment available if injury occurs, contact Dr. Hyslop at 276-4757. BENEFITS You will be paid for taking part in this study. Since you do not have any of the conditions for which this drug is being developed, you will not medically benefit from being a part of this study. However, information obtained from the study will be of benefit to Eli Lilly and Company and may benefit patients in the future. QUESTIONS If you have any questions about this study or your rights, please contact Dr. Hyslop at 276-4757. If any important new information is found during this study that may affect your wanting to continue to be part of this study, you will be told about it. CONFIDENTIALITY If you agree to participate in this study, the information obtained will be shared with Eli Lilly and Company, the United States Food and Drug Administration, and similar agencies in other countries, all of whom may look at your medical records. Medical records that contain your identity will be treated as confidential by Eli Lilly and Company and will be shared only with these agencies or as required by law.

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Review of the Fialuridine (FIAU) Clinical Trials This informed consent has been read to me and all my questions have been answered to my satisfaction. I voluntarily agree to be part of this research study. I am between the ages of 21 and 55 years of age inclusive and as far as I know, am healthy. I understand that I may freely stop being a part of this study at any time. I have received a copy of this informed consent form to keep for myself. I understand that a copy of this form will also be retained by Eli Lilly and Company. Volunteer's Name: _______________________________________________________ Volunteer's Signature: ____________________________________________________ Witness (Investigator): ____________________________________________________ Witness (Other): _________________________________________________________ Date: __________________ Time: ________________________________________

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Review of the Fialuridine (FIAU) Clinical Trials You will be paid $25.00 for each day you participate in this study. In addition, if you satisfactorily complete your part in this study, you will receive an additional payment (Satisfactory Completion Payment) calculated at the rate of $15.00 for each day of your participation. Estimated Payment Schedule (calculated for 27 days total participation) Hospital stay - 27 days x $25.00/day = $ 675.00 Satisfactory Completion Payment = $ 405.00 TOTAL PAYMENT = $1080.00