NCT01729494

Belatacept Early Steroid Withdrawal Trial

Randomized, Open Label, Multicenter Study of Belatacept-based Early Steroid Withdrawal Regimen With Alemtuzumab or rATG Induction Compared to Tacrolimus-based Early Steroid Withdrawal Regimen With rATG Induction in Renal Transplantation

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 316 (actual)
• Sponsor: University of Cincinnati · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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).

Detailed description

Renal transplant is the most effective treatment for end-stage renal disease. It provides improved survival and quality of life. Maintenance of a functioning renal transplant mandates lifelong immunosuppressive therapy to prevent immune destruction of the graft. Current immunosuppressive regimens yield 1-year survival rates of 89% for cadaveric and 94% for living-donor grafts. Over time, however, there is progressive loss of both subjects and grafts. Five-year graft survival for cadaveric and living related donor renal transplants is 67% and 80%, respectively. The most common causes of long-term subject and graft loss in kidney transplant recipients are cardiovascular disease and chronic allograft nephropathy (CAN), respectively. Paradoxically, the principal immunosuppressive therapies for renal transplant, the calcineurin inhibitors (CNIs), cyclosporine (CsA) and tacrolimus, directly contribute to long-term allograft loss and subject death, since they are inherently nephrotoxic and can cause or exacerbate cardiovascular risks including hypertension, hypercholesterolemia, and diabetes mellitus. There is, therefore, a substantial unmet medical need for new therapies in renal transplant that can provide short-term subject and graft survival comparable to the CNIs without their long-term nephrotoxic, cardiovascular, and metabolic effects. Because belatacept can be administered at the time of engraftment rather than in a delayed fashion, as is frequently necessary with CNIs - especially in those allografts with initial impaired renal function-- it affords immunosuppression in a timely manner. Unlike CNIs, the targeted mechanism of action of belatacept should provide immunosuppression without nephrotoxicity or adverse effects on the cardiovascular/metabolic profile. Glucocorticoids have been a cornerstone of immunosuppressive therapy for six decades. Although glucocorticoids provide potent suppression of allo-immune responses in humans, their adverse effects including infection, diabetes, weight gain, hypertension, hyperlipidemia, bone disease, dermal thinning, collagen loss in multiple tissues, and cataracts, combined with a lack of available therapeutic monitoring all argue against their continued use in transplantation. Belatacept represents a potential new treatment option for renal transplant recipients, which addresses the current unmet need for an immunosuppressive treatment that provides short-term outcomes comparable to calcineurin inhibitors (CNIs) with the potential to avoid their renal, cardiovascular, and metabolic toxicities. However, the initial Phase 3 studies exhibited in higher rate of acute rejection and malignancy. The malignancies were associated with recipients who were EBV negative at the time of transplant. All EBV negative patients are precluded from treatment with Belatacept. Due to the limitations of Phase 3 trial designs and the required use of basilixumab induction, it is intuitive that the addition of a potent t cell depleting induction agent may decrease the overall acute rejection rate in patients treated with belatacept. The current study tests these assumptions with the following immunosuppressive regimens. Group A and B consist of potent T-cell depleting induction agents combined with belatacept. Group C represents the most common immunosuppressive regimen currently utilized in the United States. Each of these regimens include early withdrawal of glucocorticoids along with maintenance mycophenolate mofetil. Based upon the totality of available evidence, the current study offers a favorable benefit/risk profile to study subjects, and the potential to continue to provide important data for the development of new immunosuppressive regimens that address important unmet needs. The proposed Phase 4 study is designed to determine whether belatacept, in combination with other immunosuppressive agents (rabbit antithymocyte globulin or alemtuzumab, mycophenolate mofetil/EC mycophenolate sodium), may provide acceptable efficacy and safety in de novo kidney transplant recipients, in a regimen that provides simultaneous CNI freedom and early CSWD.

Conditions

• Renal Transplantation

Interventions

Type	Name	Description
DRUG	Alemtuzumab	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.
DRUG	rabbit antithymocyte globulin	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.
DRUG	Belatacept	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.
DRUG	Tacrolimus	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.
DRUG	Mycophenolate mofetil	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).
DRUG	early cessation of steroids	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

Timeline

• Start date: 2012-09-01
• Primary completion: 2018-12-01
• Completion: 2019-12-01
• First posted: 2012-11-20
• Last updated: 2021-07-28
• Results posted: 2021-07-28

Locations

8 sites across 1 country: United States