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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

Phase 4
18 Years
Open (Enrolling)
Renal Transplantation

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Trial Information

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

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

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

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 HLA identical living donor transplant.

3. Patient who is a recipient of a multiple organ transplant.

4. Patient has a most recent PRA of > 25%.

5. Patient with a positive T or B cell crossmatch.

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 an 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 + SCr > 1.5 mg/dL OR

- CVA + hypertension OR

- CVA + SCr > 1.5 mg/dL OR

- Hypertension + SCr > 1.5 mg/dL OR

- 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 or donor is known to be seropositive for hepatitis C virus (HCV) or B virus
(HBV) except for hepatitis B surface antibody positive. HCV seropositive patients
with a negative HCV viral load testing may be included

12. Recipient or donor is known to be seropositive for human immunodeficiency virus

13. Recipient who is seronegative for Epstein Barr virus (EBV).

14. Patient has uncontrolled concomitant infection or any other unstable medical
condition that could interfere with the study objectives.

15. Patients with thrombocytopenia (PLT < 75,000/mm3), and/or leucopoenia (WBC <
2,000/mm3), or anemia (hemoglobin < 6 g/dL) prior to study inclusion.

16. Patient is taking or has been taking an investigational drug in the 30 days prior to

17. Patient who has undergone desensitization therapy within 6 months prior to

18. Patient has a known hypersensitivity to belatacept, tacrolimus, mycophenolate
mofetil, alemtuzumab, rabbit anti-thymocyte globulin, or glucocorticoids.

19. Patient is receiving chronic steroid therapy at the time of transplant.

20. 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%.

21. 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.

22. Women of childbearing potential must use reliable contraception simultaneously,
unless they are status post bilateral tubal ligation, bilateral oophorectomy, or

23. 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.

24. Inability to cooperate or communicate with the investigator.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Composite endpoint

Outcome Description:

Patient Death or Graft Loss or estimated GFR (eGFR) (MDRD) < 45 mL/min

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

E. Steve Woodle, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Cincinnati


United States: Food and Drug Administration

Study ID:




Start Date:

September 2012

Completion Date:

December 2015

Related Keywords:

  • Renal Transplantation
  • belatacept
  • rabbit antithymocyte globulin
  • alemtuzumab
  • corticosteroid withdrawal



University of Minnesota Minneapolis, Minnesota  55455
California Pacific Medical Center San Francisco, California  94115
University of Cincinnati Cincinnati, Ohio  45267-0502
The Christ Hospital Cincinnati, Ohio  45219
University of Wisconsin-Madison Madison, Wisconsin  53792