Combination Drug Therapy Followed by Single Drug Steroid Free Therapy to Prevent Organ Rejection in Kidney Transplantation
Condition: Kidney Transplantation
Intervention: Sirolimus; Tacrolimus
Intervention MeSH terms: Sirolimus; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Healthy volunteers: No
Keywords: Tolerance; Kidney; Transplant; Polyclonal; Antibody; Kidney Transplant

Summary:

      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           is withdrawn through a catheter in an arm vein or through the central line and directed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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Candidates for a kidney transplant at the 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 (human leukocyte antigen)-specific antibodies.

        HLA (human leukocyte antigen) 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.