Belatacept Early Steroid Withdrawal Trial



Status:Active, not recruiting
Conditions:Renal Impairment / Chronic Kidney Disease
Therapuetic Areas:Nephrology / Urology
Healthy:No
Age Range:18 - Any
Updated:2/3/2018
Start Date:September 2012
End Date:December 2019

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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

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 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).

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.

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 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 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 + 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.
We found this trial at
8
sites
Chicago, Illinois 60612
Principal Investigator: Patricia West-Thielke, PharmD, BCPS
Phone: 312-996-5695
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Minneapolis, Minnesota 55455
(612) 625-5000
Phone: 612-625-6460
Univ of Minnesota With a flagship campus in the heart of the Twin Cities, and...
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1 Tampa General Cir
Tampa, Florida 33606
(813) 844-7000
Principal Investigator: John Leone, MD
Phone: 813-844-5660
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2139 Auburn Ave
Cincinnati, Ohio 45219
(513) 585-2000
Phone: 513-585-2145
The Christ Hospital For more than 120 years, The Christ Hospital has been a leader...
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2600 Clifton Ave
Cincinnati, Ohio 45267
(513) 556-6000
Phone: 513-558-1568
University of Cincinnati The University of Cincinnati offers students a balance of educational excellence and...
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Denver, Colorado 80291
Principal Investigator: Alexander Wiseman, Jr., MD
Phone: 720-848-0860
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Madison, Wisconsin 53706
(608) 263-2400
University of Wisconsin-Madison In achievement and prestige, the University of Wisconsin-Madison has long been recognized...
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45 Castro Street
San Francisco, California 94114
(415) 600-6000
California Pacific Medical Center California Pacific Medical Center is one of the largest private, not-for-profit,...
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