Effectiveness of the Investigational Drug Campath-1H in Preventing Rejection of Transplanted Kidneys
Condition: Graft Rejection; Kidney Disease
MeSH terms: Kidney Diseases
Intervention: Alemtuzumab and DSG
Intervention description: Alemtuzumab was administered intravenously at 0.3 mg/kg/dose over 3 hr. Patients received one dose on each of days -1,+1,+3 and +5 relative to transplantation (total dose 1.2 mg/kg). Methylprednisolone was given prior to each dose to limit the cytokine release: 500 mg prior to dose 1, 125 mg prior to dose 2, and 60 mg prior to doses 3 and 4. Deoxyspergualin was dosed as follows. The first two patients received 4 mg/kg as a loading dose on the day of transplant and 2.5 mg/kg daily for 13 additional days (14 days of treatment; 36.5 mg/kg total dose). The next three patients received the same dosing regimen but it was initiated on postoperative day 12 to coincide with the resurgence of monocytes on days 12- 25.
Intervention MeSH terms: Alemtuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Healthy volunteers: No
Keywords: Immunosuppression; Tolerance; DSG; Alemtuzumab

Summary:

      This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability
      to induce a state of permanent allograft acceptance, or tolerance, when administered in
      combination with a brief course of the immunosuppressive drug deoxyspergualin (DSG) at the
      time of human renal allotransplantation. Campath-1H is specific for the common lymphocyte and
      monocyte antigen CD52. Its administration temporarily depletes mature lymphocytes and some
      monocytes without altering neutrophils or hematopoietic stem cells. Deoxyspergualin inhibits
      the NFkB pathway thus preventing monocyte and macrophage activation.

      Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H
      prior to transplantation to insure that peripheral depletion is achieved at the time of graft
      reperfusion. Three subsequent doses of Campath-1H will be administered on the first, third
      and fifth days after the transplant to deplete passenger donor leukocytes and residual
      recipient cells that mobilize in response to the allograft. In addition, patients will be
      treated with DSG for 14 days beginning on the day prior to surgery. This trial expands on
      pilot studies at the NIH of 15 patients in which Campath was given alone at the time of
      transplantation. In those studies, excellent peripheral depletion occurred after just one
      dose of Campath though central depletion required additional dosing. This allowed for greatly
      reduced immunosuppression to be used to prevent rejection, but to date, all patients have
      required some immunosuppressive medication. It is hoped that the addition of DSG will
      eliminate the need for long-term immunosuppression.

      Patients will be followed closely in the post transplant period. If patients experience
      rejection, they will be treated with methylprednisolone and have immunosuppression added
      using sirolimus as the predominant immunosuppressive agent. In the previous phase of this
      study without DSG, this maneuver has in all cases been successful in returning the allograft
      to normal function.

      In addition to evaluating graft function following transplantation, this protocol will also
      characterize and evaluate the function of the immune system and the composition of the T cell
      repertoire following the administration of Campath-1H and DSG, and during immune system
      recovery after transplantation.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Candidates for a kidney transplant performed at the Warren G. Magnuson Clinical Center.

        Willingness and legal ability to give informed consent, or permission from a legal
        guardian.

        Willingness to travel to the Clinical Center for protocol specific samples to be taken, or
        in some cases, the ability to send samples via overnight mail.

        Availability of donor tissue for testing. This could include splenic or peripheral blood
        lymphocytes from a cadaveric donor or a willing living donor enrolled on the Clinic Center
        Living Donor Protocol 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 must not be taking prednisone, cyclosporine, tacrolimus,
        azathioprine, mycophenolate mofetil, antilymphocyte agents, cyclophosphamide, methotrexate,
        or other agents whose therapeutic effect is immunosuppressive.

        Any condition that precludes serial follow-up.

        Any active malignancy or any history of a 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.

        Significant coagulopathy or requirement for anticoagulation therapy that would
        contraindicate protocol allograft biopsies.

        Platelet count less than 100,000/mm(3).

        Hemoglobin less than 9.0 mg/dl. Patients may be on erythropoietin therapy, but will not be
        placed on therapy solely to facilitate research sample acquisition.

        Any known immunodeficiency syndrome.

        HLA identical status with a living donor.

        Any history of uncompensated cardiac insufficiency, major vascular disease, or symptomatic
        coronary artery disease.

        Systemic or pulmonary edema.

        Inability to be effectively dialyzed.

        Chronic hypotension (SBP less than 100 mmHg).

        Any condition that would likely increase the risk of protocol participation or confound the
        interpretation of the data.

        CMV negative status receiving an organ from a known CMV positive donor.

        EBV negative status receiving an organ from a known EBV positive donor.

        Panel reactive antibody greater than 20% due to HLA antibodies.