A Trial of Two Steroid-Free Approaches Toward Mycophenolate Mofetil-Based Monotherapy Immunosuppression
Condition: Kidney Transplant Failure and Rejection
Intervention: Tacrolimus (TAC); Sirolimus; Alemtuzumab; Mycophenolate mofetil (MMF)
Intervention description: Tacrolimus (TAC) will be given standard of care by prescription twice a day (2.0 mg), orally. Doses will be adjusted by serum levels. The dose will be modified to achieve 12 hour trough concentrations of 5-8 ng/mL.; Sirolimus will be given standard of care by prescription, dosed at 5mg daily. The dosage will be adjusted by serum level to achieve 24 hour trough concentrations of 8-12 ng/mL by HPLC assay.; Patients receiving alemtuzumab will be premedicated with 50mg of diphenhydramine hydrochloride, and 650mg of acetaminophen 30-60 minutes to the first Alemtuzumab infusion. The of 30mg will be diluted in 100cc sterile 0.9% normal saline and infused over 2 hours. The infusion line must contain an in-line 0.22-micron filter. Alemtuzumab will be administered on the day of transplant (intraoperatively), and on post-operative day 2. Both doses will be administered while the patient is in the hospital. Alemtuzumab is supplied in single-use clear glass ampoules containing 30mg of alemtuzumab in 3mL of solution.; MMF will be given at 1.0-1.5gm, twice daily, orally. The first dose will be given pre-transplant, open label fashion.
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Alemtuzumab; Tacrolimus
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Kidney Transplant; Living Donor Kidney Transplant Recipients

Summary:

      This is an open label, single-center, randomized phase IV pilot study of steroid and
      calcineurin inhibitor avoidance in renal transplant recipients. All patients will receive two
      doses of alemtuzumab to achieve peripheral T-cell depletion. Intravenous glucocorticoids will
      be administered prior to alemtuzumab administration to limit cytokine release syndrome in
      association with this monoclonal antibody, and continued for the first two days
      post-transplant. Thereafter, steroids will not be used for immunosuppression. All transplant
      recipients will be started on oral immunosuppressive therapy with mycophenolate mofetil (MMF)
      prior to transplant. Pretransplant, these patients will be randomized to receive, in
      addition, either tacrolimus (Tac) or sirolimus.

      After six months, patients in the tacrolimus arm who do not experience rejection will be
      randomized to continue on tacrolimus or to be converted to the combination of sirolimus and
      MMF. Individuals in this arm of the study who do not experience acute rejection, and
      demonstrate evidence of donor specific hyporesponsiveness at 9 months post-transplant (those
      staying on Tac + MMF) or 3 months post-conversion (those converted from Tac + MMF to
      sirolimus + MMF) will be weaned to MMF monotherapy.

      Individuals in the sirolimus + MMF arm who do not experience acute rejection and demonstrate
      evidence of donor specific hyporesponsiveness at 6 months post-transplant will be weaned to
      MMF monotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients who are male or female age 18-65 years

          2. Donor age 18-65 years

          3. Patients who are single-organ recipients (kidney only)

          4. Women who are of childbearing potential must have a negative serum pregnancy test
             before transplantation and agree to use a medically acceptable method of contraception
             throughout the treatment period.

          5. Subject (recipient) is able to understand the consent form and give written informed
             consent

        Exclusion Criteria:

          1. Known sensitivity or contraindication to sirolimus, tacrolimus or MMF

          2. Patient with significant or active infection

          3. Patients with a positive lymphocytotoxic crossmatch using donor lymphocytes and
             recipient serum

          4. Patients with PRA > 20%

          5. Patients who are pregnant or nursing mothers

          6. Patients whose life expectancy is severely limited by diseases other than renal
             disease

          7. Ongoing active substance abuse, drug or alcohol

          8. Major ongoing psychiatric illness or recent history of noncompliance

          9. Significant cardiovascular disease (e.g.):

               -  Significant non-correctable coronary artery disease

               -  Ejection fraction below 30%

               -  History of recent myocardial infarction

         10. Malignancy within 3 years, excluding non-melanoma skin cancers

         11. Serologic evidence of infection with HIV or HBVsAg positive

         12. Patients with a screening/baseline total white blood cell count < 4,000/mm3; platelet
             count < 100,000/mm3; triglycerides > 400 mg/dl; total cholesterol > 300 mg/dl

         13. Investigational drug within 30 days prior to transplant surgery

         14. Anti-T cell therapy within 30 days prior to transplant surgery

         15. Patients using Prednisone

         16. Patients who are ABO incompatible