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CONSENT FORM FOR RESEARCH

|RIGHTS AS A HUMAN RESEARCH PARTICIPANT |

|You have the right to make a voluntary decision to participate in this research study. |

|IF YOU HAVE QUESTIONS, DISCUSS THEM WITH THE INVESTIGATOR BEFORE YOU AGREE TO PARTICIPATE. YOU HAVE THE RIGHT TO ASK QUESTIONS AT ANY TIME |

|AND HAVE THEM ANSWERED AS SOON AS POSSIBLE. |

|You have the right to take time to review this research consent form carefully. You should discuss it with others, and if appropriate seek a |

|second opinion, and make an informed decision. |

|You have the right to be informed of significant new findings related to this research study which may affect your willingness to continue |

|participating in this study. |

|You have the right not to participate or to withdraw from this research study at any time without any penalty or loss of benefits to which you|

|would be entitled outside of the study. Choosing so will not change the quality of care you receive at Cedars-Sinai Medical Center (CSMC). |

A 12 month, multi-center, randomized, open-label non-inferiority study comparing the safety and efficacy of concentration-controlled Everolimus with low dose tacrolimus to CellCept® (mycophenolate mofetil) with standard dose tacrolimus in de novo renal transplant recipients

WHO IS CONDUCTING THIS RESEARCH STUDY?

Principal Investigator: Rafael Villicana, MD (310) 423-2641

Co-Investigator(s): Alice Peng, MD (310-423-2641)

Stanley Jordan, MD (310-423-2641)

Joseph Kahwaji, MD (310-423-4975)

Ashley Vo, PharmD (310-423-2641)

Marina Lukovsky, PharmD (310-423-2641)

After hours contact: Rafael Villicana, MD (310) 423-2641

This research study is sponsored by Novartis. They provide funding to cover the costs of conducting this study.

WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?

The purpose of this study is to compare the safety and efficacy of everolimus with low dose tacrolimus to CellCept® with standard dose tacrolimus in kidney transplant patients.

Everolimus in combination with cyclosporine (Neoral®), an immunosuppressive therapy, has been approved and registered in over 70 countries worldwide and has been approved by the FDA for the prevention of rejection in renal transplant recipients. However, Neoral®-based treatment options are not the most commonly used in the United States. Instead, many kidney transplant patients are treated with tacrolimus-based therapies. The use of everolimus in combination with tacrolimus has not been approved by the FDA. The regimen consisting of Cellcept with tacrolimus with steroids is considered to be standard of care at Cedars Sinai. The investigational regimen replaces Cellcept with everolimus and attempts to decrease the dose of tacrolimus.

1. WHY AM I ASKED TO PARTICIPATE?

You are being asked to take part in this research study because you have been scheduled to undergo kidney transplant surgery. Patients who undergo this kind of surgery are given medication to prevent rejection of the transplant. There are a number of such medicines available, e.g., everolimus, CellCept®, Neoral®, tacrolimus and others. Usually, several of these medicines are combined to help prevent transplant rejections.

In the study a combination of the following medications will be used:

• Everolimus

• CellCept®

• Tacrolimus

HOW MANY PEOPLE WILL PARTICIPATE?

About 10 people will take part in this study at CSMC. About 590 people all together will take part in this study at 60 centers throughout the USA and Canada.

HOW LONG WILL I BE IN THE STUDY?

We think you will be in the study for about 12 months. Please see the section “What Study Procedures Are Involved?” for additional information.

WHAT STUDY PROCEDURES ARE INVOLVED?

This section provides a summary of procedures if you take part in this study. A flowchart of procedures is attached to the end of this consent form. The flowchart shows a timeline for research-related or standard of care procedures. Research-related procedures are those that are performed solely to collect data for research. In other words, they would not be performed if you did not take part in the study. Standard of care procedures would occur even if you did not take part in the study.

This is a randomized research study. “Randomized” means that you will be assigned to a study group by chance, like flipping a coin. You will be randomized into one of 2 study groups, and will have an equal chance of being placed in one of the groups.

The following procedures will be conducted during this research study:

Screening/Baseline period:

The study doctor or study staff will check that you are able to participate in this study. This period takes place before and up to 24 hours pre-transplantation prior to the first dose of study medication. The study doctor will ask you about your health and your medical history. The doctor will perform a physical examination to measure your height, weight, blood pressure and heart rate.

You will be asked about all medications you have been taking, including over-the-counter medicines, prescription drugs, vitamins, and supplements. Blood and urine will be taken for laboratory testing. Virologic testing will also be done. If you are female you will be tested to see if you are pregnant. The pregnancy test must be negative in order for you to stay in the study. If you are male your blood will be tested for hormone levels.

Day 1:

You will be randomized to one of two treatment groups and begin study medication:

Group A: Concentration controlled everolimus with low dose tacrolimus with/without corticosteroid

Group B: CellCept® with standard dose tacrolimus with/without corticosteroids

Both you and your study doctor will know which drugs you are taking during this study. Again, your vital signs will be assessed. You will again have blood taken and urine will be collected.

Visits:

Study visits will take place on Days 3, 4, 5, 7, 14, 28, and Months 2, 3, 4, 6, 7, 9, and 12. At all visits your pulse and blood pressure will be measured. Blood samples will be drawn for standard laboratory evaluations and to measure levels of the immunosuppressant drugs in your system at all visits except Day 4. Urine samples will be collected at all visits except Day 4. CMV and BK tests will be performed at Day 28 and Months 2, 3, 4 and 6. For males hormone tests will occur at Months 6 and 12. At the end of the study a final physical exam will be performed.

You will be asked to complete the SF-36 quality of life questionnaires at Day 28 and Months 3, 6, and 12.

In this study, biopsies of your kidney will be collected at baseline and Month 6. A very small sample of kidney tissue (called a biopsy) will be taken with a fine needle. This material will be checked by a pathologist for any early or late signs of damage to the transplant.

A biopsy of your kidney will also be done in case you should be showing any clinical signs of transplant rejection. This is a routine procedure done as part of your normal care.

Blood will be drawn to monitor safety and efficacy of your immunosuppressive regimen. Approximately 4-20 ml (1 – 4 teaspoons) of blood will be drawn approximately 14 times during the study.

You will be asked to complete a questionnaire. This questionnaire asks 36 questions about your general health profile. It will take about 5-10 minutes to complete. Questionnaires will ask you to respond to questions about energy level, exercise endurance, mood, etc. If you feel uncomfortable or embarrassed answering any question, you may skip it. The questionnaire will be labeled with a unique study number that will link your identity so that only the research team can recognize you.

WHAT ARE THE POSSIBLE RISKS OR DISCOMFORTS?

While participating in the research study, you may experience certain side effects as described below. There also may be other side effects or risks that we cannot predict. Many side effects may go away shortly after the study medication or procedure is stopped. However, in some cases they can be serious, long-lasting, and/or permanent.

As mentioned in the section “What Study Procedures Are Involved?” some of the procedures used in this study are standard of care. These procedures would occur even if you did not take part in the study. There may be risks associated with these standard of care procedures.

Risks of Everolimus

Everolimus: The following adverse reactions are very common in heart and kidney transplant patients (>1/10 patients):

• Leukopenia (lowered white blood cell counts). This can lead to bigger risk of infection.

• Increased cholesterol

• Increased hyperlipidemia (high blood fat) levels.

These increases can change back to the way they were before. If any of them happen, your doctor may be able to treat them.

Additional common side effects (>1/100) in transplant patients are:

• Hypertension

• Gastrointestinal disorders

• Edema (swelling)

• Thrombocytopenia (decreased blood platelets)

• Anemia (decreased red blood cells)

• Thrombotic thrombocytopenic purpura (blood clot with skin color changes) /hemolytic uremic syndrome (kidney failure)

• New onset diabetes (increase in blood sugar)

• Graft thrombosis (blood clot in new kidney)

• Lymphocele (collection of fluids)

• Surgical wound complications/impaired wound healing (problem with healing at the site of the operation)

• Stomatitis/mouth ulceration (mouth sores)

• Acne

• Increased urine protein

• Erectile dysfunction (lack of ability to have sex)

A few patients had low testosterone (male sex hormone), sexual dysfunction, and male infertility. The clinical meaning of these findings remains to be determined; however, male infertility was reversible in most cases following interruption of therapy.

Your testosterone levels will be measured before the study, at Months 6 and 12 (male patients). If your testosterone level is low, your doctor will follow up.

Risks of CellCept

|Very Likely (occurs in greater than |Likely (occurs in 10-25% of patients) |Less Likely (occurs in 1-9% of |Rare (occurs in less than 1% of |

|25% of patients) | |patients) |patients) |

|Diarrhea |Reduced red blood cells (lead to |Viral, bacterial and fungal |All immuno-suppression treatments |

|Abdominal pain |fatigue) |infections |increase risk of developing |

|Nausea/vomiting |Reduced platelets (increased risk of |Muscle pain (myalgia) |lymphomas and other malignancies |

|Hypertension |bleeding) |Rash |particularly skin cancer |

|Edema |Reduced white blood cells (increased |Liver tests abnormalities | |

|Electrolyte abnormalities (may |susceptibility to infections) | | |

|require electrolyte supplements) |Fever | | |

|Elevated cholesterol | | | |

A small number of cases of PML (Progressive Multifocal Leukoencephalopathy), a rare progressive illness of the nervous system that can cause severe disability or death, have been reported.

Possible Side Effects of Tacrolimus

Tacrolimus has been approved by the FDA for preventing acute rejection in liver and kidney transplant patients. The most common side effects, according to the product package insert, that have been seen with tacrolimus include injury to the kidney, shaking, hair loss and increased blood pressure. Other side effects that have been seen with tacrolimus include weakening of the immune system, acne, headache, diarrhea, nausea, vomiting, and decreased magnesium, potassium and calcium in blood. It may also cause abdominal discomfort, fever and increased serum cholesterol. Similar to other immune-suppressing drugs, tacrolimus may increase the risk of developing cancers, including cancer of the skin or the lymph node.

Tacrolimus may not be effective in preventing rejection in your case, and your kidney transplant may develop acute rejection. If that happens, your transplant doctor will treat the rejection according to standard practice of the hospital.

Risks of Tacrolimus

|Very Likely (occurs in greater than 25% |Likely (occurs in 10-25% of |Less Likely (occurs in 1-9% of |Rare (occurs in less than 1% of |

|of patients) |patients) |patients) |patients) |

|Diarrhea |Vomiting |Viral, bacterial and fungal |All immunosuppression treatments |

|Constipation |Reduced red blood cells (lead to |infections |increase risk of developing |

|Nausea |fatigue) |Sun sensitivity |lymphomas and other malignancies |

|Abdominal pain |Reduced platelets (increased risk |Viral kidney infection |particularly skin cancer |

|Hair loss |of bleeding) |Injury to kidneys | |

|Headache |Reduced white blood cells | | |

|Insomnia |(increased susceptibility to | | |

|Tremor |infections) | | |

|fever |Rash | | |

|Hypertension |Itching | | |

|Edema | | | |

|Electrolyte abnormalities (may require | | | |

|electrolyte supplements) | | | |

|Elevated cholesterol | | | |

|Elevated blood sugar | | | |

Blood Draw

Blood drawing may cause some pain and has a small risk of bleeding, bruising, or infection at the puncture site. There is also a small risk of fainting.

Biopsy

Biopsies will be performed as part of this study. The biopsies will be performed by highly trained physicians who are experienced in performing this procedure. The risks associated with obtaining kidney biopsies are bleeding, infection, and blood clot formation. Precautionary measures will be taken to ensure that renal biopsies expose you to the least amount of risks possible.

Reproductive Risks

Taking part in this research study can affect an unborn baby. Therefore, you should not become pregnant. Women should not breastfeed a baby while on this study. You must check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. Examples of accepted methods include condoms, Norplant, Depo-Provera, IUDs, and birth-control pills. You should also not nurse your baby while on this study. Ask your doctor about counseling and more information about preventing pregnancy.

Pregnancy

CellCept® can cause fetal harm when administered to a pregnant woman. These risks include and increase in pregnancy loss during the first 3 months and an increased risk of birth defects and have been shown in women exposed to systemic CellCept® during pregnancy. CellCept® therapy should not be started until a negative pregnancy test report is obtained. CellCept® has been associated with increased risk of pregnancy loss (miscarriage) during the first 3 months, as well as an increased risk of birth defects.

Immunosuppressive medications may have an effect on pregnancy or on an unborn baby. Therefore, if you are women capable of becoming pregnant, a negative pregnancy test within 1 week prior to beginning drug therapy is required.

The risks to an unborn human fetus or a nursing child from everolimus are not known. Women who are pregnant or nursing a child may not participate in this trial. You must confirm that, to the best of your knowledge, you are not now pregnant, and that you do not intend to become pregnant during the trial. If there is any possibility that you may become pregnant during the study, the study doctor will discuss appropriate birth control measures with you.

If you suspect that you have become pregnant during the trial, you must notify the study doctor immediately and come in for a pregnancy test. You will not be able to participate in the trial if you become pregnant.

If you do become pregnant during the study, we will collect pregnancy outcomes on you including details of the birth, and the presence or absence of any birth defects, abnormalities, or complications. Thus by signing this consent, you are agreeing to have this information about you and your child collected from your medical records in the rare case that you become pregnant during your participation in this research study.

Unforeseeable Risks to the Developing Embryo or Fetus (an unborn baby)

If you are pregnant, or become pregnant during participation in this research, the study drug might involve risks to the embryo or fetus, which are currently unforeseeable. It is important that you contact the study doctor immediately if you think you may be pregnant.

Incidental Findings

It is possible that the study procedures could detect a possible medical problem that is unrelated to the purpose of this study that was previously unknown. If the research procedures uncover findings that may be important for you to know about, such as the possibility of a previously unknown medical condition, you will be informed by a member of the research team. Or, you may authorize the release and communication of the findings to your primary physician. These findings may require additional testing or treatment. The cost of any additional tests or related treatment will be your responsibility.

ARE THERE DIRECT BENEFITS IN TAKING PART IN THE STUDY?

If you agree to take part in this research study, there may or may not be direct medical benefit to you. The potential benefit to you is that the treatment you get may work better and may have fewer side effects than the medicine your doctor can prescribe. However, no benefit is guaranteed.

2. HOW CAN MY PARTICIPATION BENEFIT OTHERS?

While no benefit is ever guaranteed, we hope the information learned from this research study will benefit other patients with kidney transplant in the future by helping us to find an optimal immunosuppressant regimen.

WHY WOULD MY PARTICIPATION BE STOPPED?

The investigator may decide to take you off this research study for any reason, even if you would like to continue. Some examples of why the investigator might take you off the study include the following: the investigator determines that it is in your best medical interest; your condition worsens; you become pregnant; you need treatment not allowed in this study; the whole study is stopped at CSMC or at all sites for any reason; or you are unable to comply with the protocol.

You may also decide to withdraw from the research study at any time. However, the researchers may continue to analyze data previously collected from you before you withdrew from the research study. If you decide to leave the study, you should tell the Study Doctor or study staff. They will make sure that proper procedures are followed and a final visit is completed for your safety.

While you are free to discontinue your participation at any time, we encourage you to complete a Final Study Visit. During this visit, we will conduct tests to confirm it is safe to remove you from the study treatment, and discuss any information that may be important to share with your treating physician.

ARE THERE ANY OTHER OPTIONS?

You do not have to take part in this research study. There are other treatments available for preventing acute rejection of kidney transplants, including Neoral®, tacrolimus, sirolimus and cellcept. The study doctor can discuss with you the risks and benefits of these and other available treatments.

HOW WILL MY PRIVATE INFORMATION BE KEPT CONFIDENTIAL?

CSMC values and respects your private information. Federal and state laws protect your privacy. Every reasonable effort will be made to keep your records confidential, such as storing your private information in a secure location where only authorized individuals will have access to it. When possible, investigators will assign a unique code to your research information so that people who see the coded data will not be able to identify you.

If information from this study is published, presented at scientific meetings, or used for teaching, your name and other personal information will not be used.

People inside and outside of CSMC may need to see your information for this study. Information collected about you during the course of this research may be subject to inspection by accrediting agencies, government and regulatory groups in the United States and other countries (e.g. Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), etc.), safety monitors, and companies that sponsor the study and their authorized agents. These agencies are responsible for the oversight of this research. You will be asked to sign a separate “Authorization Form” that outlines who your information may be shared with for the purposes of this research and under what circumstances.

WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?

You or your insurance company will not be charged for the research-related procedures, the drug, CellCept® or for the study drug, Everolimus. The cost of the medication Tacrolimus, as well as the standard of care procedures will be charged to your insurance company. If your insurance company does not pay, you may have to pay for those charges. Please see section “What Study Procedures Are Involved?” and the attached flowchart regarding the differences between research-related vs. standard of care procedures.

WILL I BE PAID?

You will be paid $50 for each research study visit. The total amount you will receive if you complete the whole study is $800. If you do not complete the entire research study, you will only be paid for those visits and procedures you do complete. You may be required to complete a W-9 Form in order to receive payment. The W-9 Form will be maintained by our accounting department at CSMC. If payment exceeds $600 in a calendar year, a 1099 Form will be filed with the IRS in accordance with federal tax law.

WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN THIS STUDY?

Contact your study doctor at once, if you feel that you are ill or have been injured because of taking part in this study. If it is a medical emergency, call 911 or go to an emergency room. Promptly notify your study doctor of your situation.

Who pays for my research related illness or injury?

A research injury or illness is a direct result of the Study Drug or a procedure performed only as a part of the study and is not part of your standard clinical medical treatment. You will not pay for the costs of care provided at CSMC or in any emergency room provided that you are being treated for a research injury or illness. The Medical Center may, however, ask for reimbursement where allowed from parties such as your health plan. Losses such as lost wages will not be paid. If you choose to obtain non-emergency care elsewhere, you or your health plan may be responsible for the costs of that care.

WHAT IF I HAVE QUESTIONS OR PROBLEMS?

If you have questions or concerns about this research, please contact the Principal Investigator or one of the co-investigators listed under “Who is conducting this research study?” on the first page of this consent form.

If you have questions regarding your rights, concerns, or complaints about taking part in this study, please contact:

CSMC Institutional Review Board (IRB)

Phone: (310) 423-3783

Email: ResearchConcerns@

The CSMC IRB has been established to review, approve, and monitor all human research at CSMC with the purpose of minimizing risks and protecting the rights and welfare of research participants.

CONSENT PROVISIONS

If you sign this form below, it means that:

(1) You have carefully read and understood the information presented in this informed consent form;

(2) The information concerning the research study and its involved procedures has been fully explained to you and your questions have been answered to your satisfaction;

(3) You have received all of the information you desire regarding your participation in the research study;

(4) You have considered the potential risks, anticipated benefits and alternatives (and their relative risks and benefits) of participation;

(5) You are voluntarily agreeing to participate in this research study;

(6) You understand that by consenting to participate in the research, you are not giving up any of your legal rights [other than the postponement of your access to your research study records as described in the attached form, entitled “Authorization For Use and Disclosure of Identifiable Health Information (Research)]”; and

(7) You have been provided with a copy of the “Experimental Subject’s Bill of Rights”, if applicable to this research study, and have been provided with an opportunity to ask questions regarding the Bill of Rights.

If you have any additional questions during the course of your involvement in the research, please contact the investigator(s) and/or the IRB Office at any time.

We will give you a copy of this signed and dated consent form and a signed copy of the Experimental Subject’s Bill of Rights.

SIGNATURE BY THE SUBJECT:

Name of Subject (Print) Signature of Subject Date of Signature

SIGNATURE BY THE INVESTIGATOR:

I attest that all the elements of informed consent described in this form have been discussed fully in non-technical terms with the subject. I further attest that all questions asked by the subject were answered to the best of my knowledge. The subject has been provided with the Experimental Subject’s Bill of Rights.

Signature of the Investigator Who Obtained Consent Date of Signature

SIGNATURE BY THE WITNESS/TRANSLATOR

(Signature of a witness is only required when a non-English speaking subject is consented with the assistance of a translator and an IRB-approved ‘short form.’ The signature of the witness below attests that the translator has presented the elements of consent to the subject, orally and in his/her preferred language, and that a summary of the oral presentation, in a language the subject can understand, has been given to the participant.)

Signature of Witness Date of Signature

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EXPERIMENTAL SUBJECT’S BILL OF RIGHTS

In accordance with California Health and Safety Code 24172, any person who is required 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:

1. Be informed of the nature and purpose of the experiment.

2. Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be utilized.

3. Be given a description of any attendant discomforts and risks to the subject reasonably to be expected from the experiment.

4. Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable.

5. 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.

6. Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise.

7. Be given an opportunity to ask any questions concerning the experiment or the procedure involved.

8. 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.

9. Be given a copy of any signed and dated written consent form used in relation to the experiment.

10. 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.

___________________________________________ ___________________________

Signature of Experimental Subject Date

Distribution instruction for investigators:

The signed (i) Consent form, (ii) Authorization for Use and Disclosure of Identifiable Health Information and (iii) "Experimental Subject’s Bill of Rights" (the latter required if the research study involves medical interventions)* should be distributed to:

1) Medical Chart

2) Patient/Subject

3) Pharmacy (if a drug study)

4) Principal Investigator’s research records (original)

* PLEASE NOTE THAT IF THE RESEARCH STUDY DOES NOT INVOLVE MEDICAL INTERVENTIONS, YOU ARE NOT REQUIRED TO PROVIDE SUBJECTS WITH THE “EXPERIMENTAL SUBJECT’S BILL OF RIGHTS.” WHETHER OR NOT IT IS APPLICABLE TO THE STUDY, PLEASE BE SURE TO CUSTOMIZE THE TEMPLATE LANGUAGE ACCORDINGLY IN THE PARAGRAPHS IMMEDIATELY PRIOR TO THE SUBJECT AND INVESTIGATOR SIGNATURE LINES.

FLOWCHART OF PROCEDURES

| |Pre-op |Base-line |Day |Month |

|Visit Timepoint |

|Med History/ |X |X | | |

|Demography | | | | |

|Visit Timepoint |

Informed Consent |X | | | | | | | | | | | | | | | | |Randomization | | |X | | | | | | | | | | | | | | |Inclusion/exclusion |X |X | | | | | | | | | | | | | | | |Endocrine tests | |X | | | | | | | | | | |X | | |X | |Study med. record | | |X |X |X |X |X |X |X |X |X |X |X |X |X |X | |RAD trough level | | | |X | |X |X |X |X |X |X |X |X |X |X |X | |SF-36 questionnaire | | | | | | | | |X | |X | |X | | |X | |Kidney biopsy | |X | | | | | | | | | | |X | | | | |Adverse events | | |X |X |X |X |X |X |X |X |X |X |X |X |X |X | |

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