Clinical trial NCT01729494: Belatacept Early Steroid Withdrawal Trial
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Transplantation
Keywords: belatacept
rabbit antithymocyte globulin
alemtuzumab
corticosteroid withdrawal
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
First posted: 2012-11-20
Enrollment: 316
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: # Patients With Composite Endpoint of Experiencing Either Death, Graft Loss, or eGFR < 45ml/Min
timeFrame: 12 months
Secondary outcomes:
measure: # Patients Experiencing a Graft Loss But Not Including Patients Who Died With Functioning Graft (Death-censored Graft Loss)
timeFrame: 24 months
measure: # Patients With Composite Endpoint of Either Experiencing Death, Graft Loss, or eGFR < 45ml/Min at 24 Months
timeFrame: 24 months
measure: eGFR (MRDRD) < 45 ml/Min/1.73m2
timeFrame: 24 months
measure: Biopsy Proven Acute Rejection
timeFrame: 24 months
measure: Biopsy Proven Acute Cellular Rejection
timeFrame: 24 months
measure: Biopsy Proven Acute Antibody Mediated Rejection
timeFrame: 24 months
measure: Biopsy Proven Mixed Acute Rejection
timeFrame: 24 months
measure: # of Patients Developing Denovo Donor Specific Antibody (DSA) Post-transplant
timeFrame: 24 months
measure: Mean eGFR (MDRD) (ml/Min/1.73m2)
timeFrame: 24 months
measure: Proteinuria UPC Ratio > 0.8
timeFrame: 24 months
measure: Patient Death
timeFrame: 24 months
Other outcomes:
measure: Requirement of T-cell Depleting Therapy for Biopsy Proven Acute Rejection (BPAR)
timeFrame: 24 months
measure: New Onset Diabetes After Transplantation (NODAT)
timeFrame: 24 months
measure: Time to First BPAR
timeFrame: 24 months
measure: # Patients Experiencing a First Biopsy-proven ACR With Severity Banff > or = 2a Grade
timeFrame: 24 months
measure: Delayed Graft Function
timeFrame: 24 months
measure: Leukopenia (WBC < 2000/mm3)
timeFrame: 24 months
measure: Steroid Therapy
timeFrame: 24 months
measure: Discontinuation of Mycophenolate
timeFrame: 24 months
measure: Discontinuation of Study Treatment (Belatacept or Tacrolimus)
timeFrame: 24 months
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Chicago
country: United States
facility: University of Illinois Medical Center at Chicago
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: University of Cincinnati
name: E. Steve Woodle, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kaufman DB, Woodle ES, Shields AR, Leone J, Matas A, Wiseman A, West-Thielke P, Sa T, King EC, Alloway RR; BEST Study Group. Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. Clin J Am Soc Nephrol. 2021 Sep;16(9):1387-1397. doi: 10.2215/CJN.13100820. Epub 2021 Jul 7.
citation: Castro-Rojas CM, Godarova A, Shi T, Hummel SA, Shields A, Tremblay S, Alloway RR, Jordan MB, Woodle ES, Hildeman DA. mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28- Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-refractory Renal Allograft Rejection. Transplantation. 2020 May;104(5):1058-1069. doi: 10.1097/TP.0000000000002917.