This study will test the safety and effectiveness of a combination of three drugs followed by long-term treatment with just one drug in preventing organ rejection in kidney transplant patients. Current anti-rejection medicines are not completely effective in preventing rejection. This trial will test how well Thymoglobulin, Tacrolimus, and Sirolimus work together post-transplant and if the treatment can be reduced over time to control rejection with either Tacrolimus or Sirolimus alone.

Candidates for kidney transplantation at the National Institutes of Health Clinical Center may participate in this 5-year study. Patients will be screened for eligibility with a medical history, physical examination, and blood tests.

Participants will undergo the following tests and procedures:

- Central line placement: A large intravenous catheter (plastic tube, or IV line) is placed in a vein in the chest or neck under local anesthesia before the transplant surgery. The line remains in place for some time during the hospitalization to administer Thymoglobulin, antibiotics, and blood, if needed. The line is also used to collect blood samples.

- Leukapheresis: This procedure for collecting white blood cells is done before the transplant. The cells are studied to evaluate the patient's immune system. Whole blood is withdrawn through a catheter in an arm vein or through the central line and directed into a machine that separates the blood components by spinning. The white cells are removed and the red cells and plasma are returned to the body.

- Kidney transplant: Patients undergo kidney transplant surgery under general anesthesia.

- Immunosuppressive therapy: Patients receive thymoglobulin by vein for 4 days starting 1 day before the transplant. They also take Tylenol, Benadryl and a steroid (methylprednisolone) to help reduce the side effects of the Thymoglobulin. After the transplant, patients receive Tacrolimus and Sirolimus by mouth once a day for 6 months and then either Tacrolimus or Sirolimus alone indefinitely. In addition, they take medicines to help prevent viral and fungal infections for 6 months because the immunosuppressive therapy leaves them vulnerable to infection.

- Follow-up visits: After hospital discharge, patients return to the Clinical Center twice a week for 4 weeks, then every 6 months for 1 year, and then yearly for another 4 years. At each visit, the patient's vital signs are checked and blood and urine samples are collected. Periodically, patients are also questioned about how they feel and how the transplant has affected their quality of life. Kidney biopsies (removal of a small amount of kidney tissue through a thin needle) are done when the patient begins single-drug immunosuppression (generally 6 months after transplantation) and 1 year after that. The biopsied tissue is examined to evaluate how well the kidney is responding to the treatment and to determine how to proceed with therapy.

- Routine laboratory tests: Routine tests, coordinated by the patient's local physician, are done 2 to 3 times a week for the first 2 to 3 months after transplantation, then weekly for several more months, and at least monthly for life.

Condition	Phase
Kidney Transplantation	Phase II

This protocol will test a novel combination of three FDA-approved immunosuppressive agents for its ability to prevent human renal allograft rejection, and eventually allow for a single agent to be used for chronic maintenance immunosuppression. It will test two variations of the therapy to determine if one is better tolerated or superior for the prevention of rejection. It will also evaluate the two variations for their ability to induce donor-specific hyporesponsiveness over time. All patients will receive rabbit anti-thymocyte globulin (RATG, Thymoglobulin, Sangstat Medical Corporation) for four consecutive days beginning within 24 hours prior to allograft reperfusion to achieve perioperative T-cell depletion. Glucocorticosteroids will be given as premedication for the RATG treatment to limit the cytokine release syndrome associated with this antibody preparation. However, thereafter, steroids will not be used for immunosuppression. Beginning on the first post-operative day all patients will be started on oral therapy with sirolimus (Rapamune, Wyeth), and tacrolimus (Prograf, Fujisawa). These two agents have been shown to synergistically inhibit allograft rejection. Patients will remain on these agents for 6 months. After 6 months, patients who have been rejection-free will undergo a protocol surveillance biopsy and then be weaned from either sirolimus or tacrolimus in a randomized fashion. Patients will be followed to determine if this monotherapy approach prevents rejection, and if either agent is significantly more efficacious in including a state of donor-specific hyporesponsiveness. A follow-up biopsy will be performed on each patient 1 year after he or she has been weaned to monotherapy immunosuppression.

A total of sixty non-sensitized (peak Panel Reactive Antibody less than 20%), non-HLA identical recipients of first living donor or cadaveric kidney allografts will be enrolled and followed for five years. In addition to standard measures of allograft and patient survival, assays will be performed to evaluate potential mechanisms of donor-specific hyporesponsiveness.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Candidates for a kidney transplant at the Warren G. Magnuson Clinical Center.
Willingness and legal ability to give informed consent.
Availability of donor tissue for testing. This could include splenic or peripheral blood lymphocytes from a cadaveric donor or a willing living donor who consents to periodic phlebotomy for peripheral blood lymphocyte isolation.
EXCLUSION CRITERIA:
Immunosuppressive drug therapy at the time of or 2 months prior to enrollment. Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive.
Any active malignancy or any history of any hematogenous malignancy or lymphoma. Patients with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the lesions are appropriately treated prior to transplant.
Any known immunodeficiency syndrome, or other condition that, in the opinion of the investigators, would likely increase the risk of protocol participation or confound the interpretation of the data.
Any history of sensitization to rabbits or extensive exposure to rabbits, as defined by symptomatic allergic response upon exposure to rabbits.
Inability or unwillingness to comply with protocol monitoring and therapy including, among others, a history of noncompliance, circumstances where compliance with protocol requirements is not feasible due to living conditions, travel restrictions, access to urgent medical services, or access to anti-rejection drugs after the research protocol is completed.
Peak Panel Reactive Antibody greater than 20%, or historically positive crossmatch due to HLA-specific antibodies.
HLA identity between the donor and recipient.
Pregnancy or unwillingness to practice an approved method of birth control. Acceptable methods of birth control may include barrier methods (condom and/or diaphragm with spermicide), oral contraceptives, Norplant, Depo-Provera or partner sterility.

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040099; 04-DK-0099
Record last reviewed:  January 13, 2004
Last Updated:  January 13, 2004
Record first received:  January 26, 2004
ClinicalTrials.gov Identifier:  NCT00076570
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-08