Novartis Clinical Trial Protocol CRAD001H2304: A 24 month, multi-center, open-label, randomized, controlled study to evaluate the efficacy and safety of concentration-controlled everolimus to eliminate or to reduce tacrolimus compared to tacrolimus in de novo liver transplant recipients

Why is this study being done? 
The purpose of this study is to test safety and success of the study drug everolimus combined with low doses of tacrolimus, or everolimus with a plan to stop tacrolimus at a certain time point in patients having had recent liver transplant. We will compare these regimens with a more often used plan of regular dose of tacrolimus. This is an open-label study which means that both doctor and patient will know which drugs are being given. Everolimus is an investigational drug, which means it is not approved by the US Food and Drug Administration (FDA).

Everolimus is a newer drug used after transplant which was approved to prevent acute rejection in kidney and heart transplant in more than 62 countries except United States, Canada, United Kingdom, Ireland and Taiwan. When combined with standard doses of Neoral, everolimus has been found to prevent early rejection of some organs (kidney and heart) in humans, and to help prevent chronic rejection of the new organ. Standard doses of Neoral combined with the use of everolimus that was not guided by checking everolimus levels in the blood did result in a decrease of kidney function which was thought due to the Neoral, rather than everolimus. In patients having had kidney transplant it could be shown that using everolimus guided by checking blood levels along with low doses of Neoral was helpful to prevent rejection and to maintain good kidney function. This was also confirmed in patients after heart transplant as well.

Who is Eligible to Participate?
This study will involve about 690 new liver transplant patients in about 70 study centers worldwide. We would like to enroll about 15 participants in this study at Vanderbilt University Medical Center.

Minimum Age: 18
Maximum Age: 70

What is Involved With this Study? 
For this study patients must give written informed consent, at a screening visit, before liver transplant and prior to any study-related events.

During the first 30 days ± 5 days after transplant, patients will receive the standard dose regimen of tacrolimus with steroids, with or without Cellcept as the doctor directs.

The baseline events will occur 3 to 7 days after transplant, followed by other exams scheduled no sooner than 5 days prior to being assigned to a study group.

Patients will be assigned to a treatment group at random (as in the flip of a coin). There is a 2 out of 3 chance that the patient will be assigned to one of the two study groups using everolimus.

Patients will be randomized at Day 30 ± 5 days after transplant to one of the three study groups:
• Group 1 – Patients will be started on everolimus plus low dose tacrolimus and steroids (until Month 4, when tacrolimus is stopped).
• Group 2 – Patients will be started on everolimus plus low dose tacrolimus and steroids.
• Group 3 – Patients will be started and remain on tacrolimus and steroids.

Steroids are to be used for the duration of the study but may not be stopped sooner than 180 days after transplant.

Patients will be treated in the study for 24 months, and will be required to attend the clinic for 16 study visits.

Screening Period (Visit 1):
This is the period before the liver transplant and before starting the study. During this period, the study nurse will check to make sure the patient can be in the study. The patient will be asked to sign this consent form before any part of the study is done. The following procedures will be done:
• The study doctor will ask about the patient’s health and medical and psychiatric history.
• Patients will be asked about any other drugs they have been taking.
• Blood samples (about 5 teaspoons) will be taken for lab testing to assess general health. This will be done for research purposes.
• Urine samples will be obtained to measure glucose, protein and creatinine. This will be done for research purposes.
• Tests will also be done for HIV and Hepatitis B, Hepatitis C, viral load and type for HCV positive patients, and other common viruses such as CMV and EBV. Test results that show that the patient does not have HIV, Hepatitis B and C done 6 months prior to the date the patient is assigned to a study group at random will be OK.
• If the patient is female, a urine or blood sample will be obtained to test whether she is pregnant.
• If the patient is male, a blood test to check the level of male sex hormones will be done.

Baseline Period (Visit 2):
Three to seven days after having liver transplant, the study doctor will assess how the patient is doing and decide if he can be enrolled into the study. The following procedures will be done:
• The patient will have a few tests which include a physical exam, a review of medical history, vital signs (blood pressure, pulse, and weight) and blood tests (about 5 teaspoons) and a urine test to check general health. Blood and urine tests will be done for research purposes.
• Details on the background of the transplant will be obtained.
• If blood tests show that the patient had hepatitis C before receiving the new liver, a biopsy of the new liver will be performed by the doctor most likely at the time of the transplant procedure in the operating room. This sample will be checked for any early or late signs of damage to the new liver.

Week 2 (Visit 3):
Two weeks after liver transplant, the following procedures will be done:
• The patient will have a few tests which include a physical exam, vital signs (blood pressure, pulse, and weight), blood tests (about 5 teaspoons) and urine tests to check general health. Blood and urine tests will be done for research purposes.

Week 4 (Visit 4):
No later than one month after liver transplant (Week 4), the following procedures will be done:
• The patient will have a few tests which include vital signs (blood pressure, pulse, weight) and blood tests (about 5 teaspoons) to check general health as well for hepatitis C and CMV. Blood tests will be done for research purposes.
• If female, a urine or blood sample will be obtained to test whether the patient is pregnant.
• Urine samples will be obtained to measure glucose, protein and creatinine as well as for urine biomarkers. This will be done for research purposes.
• A Doppler ultrasound of the liver will be performed up to 5 days prior to the Week 4 Visit to detect any blood clots in the blood vessels of the new liver. This will be done for research purposes.
• The patient will be asked to provide data on any times he was ill after the liver transplant and on any drugs the patient is now taking.

If the patient is still eligible to be in the study, he will be assigned to a study group at random. The patient will receive the first dose right after it is known which study group he is in.

Weeks 5, 6, 8, 12, 16 and 18, and Months 5, 6, 9, 12, 18, and 24:
The following procedures will be done:
• Blood samples (about 5 teaspoons at each visit) will be drawn for routine lab tests as well as everolimus and tacrolimus levels in the blood just before the morning everolimus and tacrolimus doses. This will be done at Weeks 5 (Visit 5), 6 (Visit 6), 8 (Visit 7), 12 (Visit 8), 16 (Visit 9), and 18 (Visit 10), and Months 5 (Visit 11), 6 (Visit 12), 9 (Visit 13), 12 (Visit 14), 18 (Visit 15), and 24 (Visit 16). The blood draws are being done for research purposes.
• Urine samples will be obtained to measure glucose, protein and creatinine. This will be done for research purposes.
• Data on any side effects to everolimus, other drugs the patient is also taking as well as any health events that occurred since the previous visit will be collected.
• At Month 4 (Week 16), if assigned to Group 1, tacrolimus will be stopped.
• A physical exam will be performed at Months 4, 5 and 24 at the end of the study.
• Vital signs (blood pressure, pulse, weight) will be done at all visits except Weeks 5, 6 and 18.
• Blood test for hepatitis C and CMV will be done at Months 3, 4, 6, 12 and 24.
• If female, a urine or blood sample to learn whether patient is pregnant will be obtained at Month 24. This will be done for research purposes.
• If male, blood tests will be done to check the level of male sex hormones at Months 6, 9, 18, and 24. This will be done for research purposes.
• If the patient tests positive for hepatitis C before receiving the new liver, a biopsy of the liver will be performed by the Doctor at Months 12 and 24. The sample will be taken with a long, thin needle. This sample will be checked for any early or late signs of damage to the new liver.
• Urine samples for urine biomarkers (urine proteins) will be taken at Months 2, 3, 5, 6, 9,12,18, and 24. These samples will be used to look at how well the kidneys are working. This will be done for research purposes.
• A biopsy of the liver will also be done in case the doctor is concerned about clinical signs of rejection. This is a routine procedure done as part of normal care.