Belatacept Early Steroid Withdrawal Trial
Condition: Renal Transplantation
Intervention: Alemtuzumab; rabbit antithymocyte globulin; Belatacept; Tacrolimus; Mycophenolate mofetil; early cessation of steroids
Intervention description: Alemtuzumab will be dosed on day of transplant (Study Day 1) at dose of 30 mg given intravenously (IV) over a period of 2 hours after induction of anesthesia. Methylprednisolone IV will be administered 30-60 minutes prior to the administration of alemtuzumab.; Rabbit antithymocyte globulin will be dosed post-operatively at a total cumulative dose of 4.0-6.0mg/kg given by days 5-10 post-transplant. It will be administered by local standards of care with the following recommendations. The initial intravenous intra-operative dose will be administered approximately one hour after the methylprednisolone dose. The first dose will be administered so that approximately 25% of the dose is infused prior to revascularization of the graft. Subsequent doses will be administered over a minimum of 4 hours. Premedication with acetaminophen 650mg p.o. and diphenhydramine 25mg p.o. prior to rabbit antithymocyte globulin dose will be given to reduce the incidence of infusion reactions.; Belatacept will be administered via intravenous (IV) infusion according to the FDA approved dosage recommendations. Subjects randomized to belatacept arms will receive the first dose of IV belatacept (10 mg/kg) within 12-24 hours post reperfusion. The second dose will be given between post-transplant days 4 -6 (Study Days 5-7), and then study days 14, 28, 56, and 84 (12 weeks) and then subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial at 24 months (104 weeks). Study Day 1 is defined as the day of transplant.; Tacrolimus will be administered orally twice daily (BID). The recommended total initial dose of tacrolimus is 0.1 mg/kg/day in two divided doses orally. Tacrolimus should be started post-transplant within 48 hours or when serum creatinine drops lower than 4mg/dL, whichever comes first. The initial targeted trough level of tacrolimus will be 8 - 12 ng/mL for Days 1 through 30, with dose reduction to achieve a 12-hour trough target of 5 - 10 ng/mL thereafter.; The first dose of mycophenolate mofetil/EC mycophenolate sodium will be administered pre-operatively. Patients receiving mycophenolate mofetil will be dosed 1000 mg twice daily (2000mg/day). Patients receiving EC mycophenolate sodium will be dosed 720 mg twice daily (1440 mg/day). Dose may be increased for African American transplant recipients to mycophenolate mofetil 1500 mg twice daily (3000mg/day) or EC mycophenolate sodium 1080 mg twice daily (2160 mg/day).; Glucocorticoid therapy will be administered as described. Methylprednisolone will be administered on Days 1 through 3. Additional tapering doses of glucocorticoids will continue to be given until Day 5 as below:
Day 1 (day of transplant): 500mg IV prior to alemtuzumab (Group A) or rabbit antithymocyte globulin (Groups B and C) Day 2: 250mg IV Day 3: 125mg IV Day 4: 80mg p.o. Day 5: 60mg p.o. No further steroids
Intervention MeSH terms: Mycophenolic Acid; Prednisone; Alemtuzumab; Abatacept; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 316.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: belatacept; rabbit antithymocyte globulin; alemtuzumab; corticosteroid withdrawal

Summary:

      The study purpose is to determine the safety and efficacy of a belatacept-based
      immunosuppressive regimen (calcineurin inhibitor free) with alemtuzumab or rabbit
      antithymocyte globulin (rATG) induction and early glucocorticoid withdrawal (CSWD) and a
      belatacept-based immunosuppressive regimen with tacrolimus-based regimen with rabbit
      antithymocyte globulin induction and early glucocorticoid withdrawal in renal transplant
      recipients.

      The hypothesis is that a belatacept-based immunosuppressive regimen with alemtuzumab
      induction, mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and early glucocorticoid
      withdrawal (Group A) in renal transplant recipients or Belatacept-based immunosuppressive
      regimen with rabbit antithymocyte globulin induction, MMF/MPA and early glucocorticoid
      withdrawal (Group B) will lead to less risk of graft loss, patient death, or reduced renal
      function at 12 months as compared to a tacrolimus-based immunosuppressive regimen with rabbit
      antithymocyte globulin, MMF/MPA, and early glucocorticoid withdrawal in renal transplant
      recipients (Group C).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and female patients > 18 years of age.

          2. Patient who is receiving a renal transplant from a living or deceased donor.

          3. Female patients of child bearing potential must have a negative urine or serum
             pregnancy test within the past 48 hours prior to study inclusion.

          4. The patient has given written informed consent to participate in the study.

        Exclusion Criteria:

          1. Patient has previously received an organ transplant other than a kidney.

          2. Patient is receiving an human leucocyte antigen (HLA) identical living donor
             transplant.

          3. Patient who is a recipient of a multiple organ transplant.

          4. Patient has a most recent cytotoxic panel reactive antibody (PRA) of >25% or
             calculated PRA of > 50% where multiple moderate level HLA antibodies exist and in the
             opinion of the PI represents substantial HLA sensitization.

          5. Patient with a positive T or B cell crossmatch that is primarily due to HLA
             antibodies.

          6. Patient with a donor specific antibody (DSA) as deemed by the local PI to be
             associated with significant risk of rejection.

          7. Patient has received a blood group (ABO) incompatible donor kidney.

          8. The donor and/or donor kidney meet any of the following extended criteria for organ
             donation (ECD):

               -  Donor age >/= 60 years OR

               -  Donor age 50-59 years and 1 of the following:

                    -  Cerebrovascular accident (CVA) + hypertension + serum creatinine (SCr) > 1.5
                       mg/dL OR

                    -  CVA + hypertension OR

                    -  CVA + SCr > 1.5 mg/dL OR

                    -  Hypertension + SCr > 1.5 mg/dL OR

               -  Cold ischemia time (CIT) > 24 hours, donor age > 10 years OR

               -  Donation after cardiac death (DCD)

          9. Recipients will be receiving a dual or en bloc kidney transplant.

         10. Donor anticipated cold ischemia is > 30 hours.

         11. Recipient that is seropositive for hepatitis C virus (HCV) with detectable Hepatitis C
             viral load are excluded. HCV seropositive patients with a negative HCV viral load
             testing may be included.

         12. Recipients who are Hepatitis B core antibody seropositive are eligible if their
             hepatitis B viral loads are negative. After transplant, their hepatitis B viral loads
             will be monitored every three months for the first year after transplant. If hepatitis
             B viral loads become positive, patients will be treated per institutional standard of
             care.

         13. Patients who are Hepatitis B surface antibody seropositive and who receive a kidney
             from a Hepatitis B core surface antibody positive donor may be included.

         14. Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV).

         15. Recipient who is seronegative for Epstein Barr virus (EBV).

         16. Patient has uncontrolled concomitant infection or any other unstable medical condition
             that could interfere with the study objectives.

         17. Patients with thrombocytopenia (PLT < 75,000/mm3), and/or leucopoenia (WBC <
             2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion.

         18. Patient is taking or has been taking an investigational drug in the 30 days prior to
             transplant.

         19. Patient who has undergone desensitization therapy within 6 months prior to transplant.

         20. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate mofetil,
             alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids.

         21. Patient is receiving chronic steroid therapy at the time of transplant.

         22. Patients with a history of cancer (other than non-melanoma skin cell cancers cured by
             local resection) within the last 5 years, unless they have an expected disease free
             survival of > 95%.

         23. Patient is pregnant, where pregnancy is defined as the state of a female after
             conception and until the termination of gestation, confirmed by positive human
             Chorionic Gonadotropin (hCG) laboratory test.

         24. Women of childbearing potential must use reliable contraception simultaneously, unless
             they are status post bilateral tubal ligation, bilateral oophorectomy, or
             hysterectomy.

         25. Patient has any form of substance abuse, psychiatric disorder or a condition that, in
             the opinion of the investigator, may invalidate communication with the investigator.

         26. Inability to cooperate or communicate with the investigator.