Belatacept Early Steroid Withdrawal Trial

Renal Transplantation Clinical 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01729494
• Other study ID #: BEST
• Status: Completed
• Phase: Phase 4
• Start date: September 2012
• Est. completion date: December 2019

Study information

• Verified date: August 2020
• Source: University of Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 316
• Est. completion date: December 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Renal Transplantation

Intervention

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.
• 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.
• 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.
• 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.
• 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).
• 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

Locations

Country	Name	City	State
United States	University of Illinois Medical Center at Chicago	Chicago	Illinois
United States	The Christ Hospital	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio
United States	University of Colorado Denver	Denver	Colorado
United States	University of Wisconsin-Madison	Madison	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	California Pacific Medical Center	San Francisco	California
United States	Tampa General Hospital	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Cincinnati

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Requirement of T-cell Depleting Therapy for Biopsy Proven Acute Rejection (BPAR)	Number of patients requiring anti-lymphocyte therapy for the treatment of BPAR rejection	24 months
Other	New Onset Diabetes After Transplantation (NODAT)	Number of patients developing New Onset Diabetes Mellitus after Transplant by one of 5 definitions; only patients without preexisting diabetes were included	24 months
Other	Time to First BPAR	Mean Time to first episode of BPAR (days)	24 months
Other	# Patients Experiencing a First Biopsy-proven ACR With Severity Banff > or = 2a Grade	Number of patients with their First BPACR with a Banff grade >= Banff 2a using the Banff 2007 classification system for biopsy grading. Banff grade 2a and above is considered severe cellular rejection and includes grades of Banff 2a, Banff 2b, and Banff 3.	24 months
Other	Delayed Graft Function	Number of patients experiencing Delayed graft function (DGF) within first week after transplant. DGF is defined as need for dialysis within the first week after transplant.	24 months
Other	Leukopenia (WBC < 2000/mm3)	Number of patients developing leukopenia defined as WBC < 2000/mm3	24 months
Other	Steroid Therapy	Number of patients on treatment with corticosteroids at 2 years	24 months
Other	Discontinuation of Mycophenolate	Number of patients who were discontinued from mycophenolate treatment at 2 years	24 months
Other	Discontinuation of Study Treatment (Belatacept or Tacrolimus)	Number of patients who had to Discontinue study treatment (belatacept or tacrolimus) at 2 years	24 months
Primary	# Patients With Composite Endpoint of Experiencing Either Death, Graft Loss, or eGFR < 45ml/Min	Number of Patients that experienced patient Death or Graft Loss or had an estimated GFR (eGFR) (MDRD) < 45 mL/min	12 months
Secondary	# Patients Experiencing a Graft Loss But Not Including Patients Who Died With Functioning Graft (Death-censored Graft Loss)	Number of patient who experienced Graft loss, not including (censored) patients who lost graft due to death	24 months
Secondary	# Patients With Composite Endpoint of Either Experiencing Death, Graft Loss, or eGFR < 45ml/Min at 24 Months	Composite Endpoint of number of patients who experienced either patient death, allograft loss, or had an eGFR < 45 ml/min/1.73m2	24 months
Secondary	eGFR (MRDRD) < 45 ml/Min/1.73m2	Patients with reduced Renal function measured by estimated GFR MDRD < 45 ml/min at 24 months	24 months
Secondary	Biopsy Proven Acute Rejection	Incidence of all biopsy proven acute rejection whether clinically relevant or clinically silent.	24 months
Secondary	Biopsy Proven Acute Cellular Rejection	Biopsy proven acute cellular rejection (BPACR)	24 months
Secondary	Biopsy Proven Acute Antibody Mediated Rejection	Incidence of patients experiencing a Biopsy proven acute antibody mediated rejection (BPAMR)	24 months
Secondary	Biopsy Proven Mixed Acute Rejection	Incidence of patients experiencing a Biopsy proven acute cellular rejection with either DSA positive or C4d staining positive indicating antibody rejection	24 months
Secondary	# of Patients Developing Denovo Donor Specific Antibody (DSA) Post-transplant	Number of patients (%) with development of denovo DSA after transplant	24 months
Secondary	Mean eGFR (MDRD) (ml/Min/1.73m2)	Mean eGFR (MDRD) (ml/min/1.73m2) measured for all patients reaching 2 year endpoint	24 months
Secondary	Proteinuria UPC Ratio > 0.8	Number of Patients with a Urine protein/creatinine (UPC) ratio > 0.8	24 months
Secondary	Patient Death	Number of Patients who experienced death, all causes	24 months