Belatacept Early Steroid Withdrawal Trial

NCT01729494 | Completed Phase 4 Results DMC

• 1 other identifier: BEST
• Study Type: interventional
• Target: 316
• Locations: 1 country
• Sites: 8

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).

Conditions

Renal Transplantation

Keywords

belatacept; rabbit antithymocyte globulin; alemtuzumab; corticosteroid withdrawal

Outcome Measures

Primary Outcomes (1)

• # 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 Outcomes (11)

• # Patients Experiencing a Graft Loss But Not Including Patients Who Died With Functioning Graft (Death-censored Graft Loss)

  24 months

• # Patients With Composite Endpoint of Either Experiencing Death, Graft Loss, or eGFR < 45ml/Min at 24 Months

  24 months

• eGFR (MRDRD) < 45 ml/Min/1.73m2

  24 months

• Biopsy Proven Acute Rejection

  24 months

• Biopsy Proven Acute Cellular Rejection

  24 months

Other Outcomes (9)

• Requirement of T-cell Depleting Therapy for Biopsy Proven Acute Rejection (BPAR)

  24 months

• New Onset Diabetes After Transplantation (NODAT)

  24 months

• Time to First BPAR

  24 months

Study Arms (3)

Group A

EXPERIMENTAL

Alemtuzumab + belatacept + mycophenolate mofetil /Enteric coated mycophenolate sodium + early cessation of steroids

Drug: Alemtuzumab; Drug: Belatacept; Drug: Mycophenolate mofetil; Drug: early cessation of steroids

Group B

EXPERIMENTAL

Rabbit antithymocyte globulin + belatacept + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids

Drug: rabbit antithymocyte globulin; Drug: Belatacept; Drug: Mycophenolate mofetil; Drug: early cessation of steroids

Group C

ACTIVE COMPARATOR

Rabbit antithymocyte globulin + tacrolimus + mycophenolate mofetil /Enteric coated (EC) mycophenolate sodium + early cessation of steroids

Drug: rabbit antithymocyte globulin; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: early cessation of steroids

Interventions

Alemtuzumab DRUG

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.

Also known as: Campath

Group A

rabbit antithymocyte globulin DRUG

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.

Also known as: Thymoglobulin

Group B; Group C

Belatacept DRUG

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.

Also known as: Nulojix

Group A; Group B

Tacrolimus DRUG

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.

Also known as: Prograf, various

Group C

Mycophenolate mofetil DRUG

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).

Also known as: Cellcept, various, Myfortic

Group A; Group B; Group C

early cessation of steroids DRUG

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

Also known as: prednisone, various

Group A; Group B; Group C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients \> 18 years of age.
• Patient who is receiving a renal transplant from a living or deceased donor.
• The patient has given written informed consent to participate in the study.

You may not qualify if:

• Patient has previously received an organ transplant other than a kidney.
• Patient is receiving an human leucocyte antigen (HLA) identical living donor transplant.
• Patient who is a recipient of a multiple organ transplant.
• 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.
• Patient with a positive T or B cell crossmatch that is primarily due to HLA antibodies.
• Patient with a donor specific antibody (DSA) as deemed by the local PI to be associated with significant risk of rejection.
• Patient has received a blood group (ABO) incompatible donor kidney.
• 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

Sponsors & Collaborators

• University of Cincinnati: lead

Study Sites (8)

California Pacific Medical Center

San Francisco, California, 94107, United States

Location

University of Colorado Denver

Denver, Colorado, 80045, United States

Location

Tampa General Hospital

Tampa, Florida, 33606, United States

Location

University of Illinois Medical Center at Chicago

Chicago, Illinois, 60612, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

The Christ Hospital

Cincinnati, Ohio, 45219, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45219, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53792, United States

Location

Related Publications (3)

• Pyatt A, McGowan M, Tanaka R, Miyagawa B, Mizuno T, Shields AR, Christianson A, West-Thielke P, Leone JP, Woodle ES, Kaufman D, Wiseman A, Matas AJ, Vinks AA, Alloway RR. Belatacept Pharmacokinetic Analysis of Belatacept Early Steroid Withdrawal Trial (BEST) to Clinical Outcomes and Compared With Reported BENEFIT and BENEFIT-EXT Pharmacokinetic Analysis. Clin Transplant. 2025 Aug;39(8):e70172. doi: 10.1111/ctr.70172.

  PMID: 40704545 DERIVED

• 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.

  PMID: 34233921 DERIVED

• 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.

  PMID: 31415033 DERIVED

MeSH Terms

Interventions

Alemtuzumab; thymoglobulin; Abatacept; Tacrolimus; Mycophenolic Acid; Prednisone

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoconjugates; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Rita R. Alloway, Pharm.D., Director of Clinical Trials
• Organization: University of Cincinnati

rita.alloway@uc.edu

513-558-1568

Study Officials

• E. Steve Woodle, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, FACS

Study Record Dates

• First Submitted: October 10, 2012
• First Posted: November 20, 2012
• Study Start: September 1, 2012
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2019
• Last Updated: July 28, 2021
• Results First Posted: July 28, 2021

Record last verified: 2020-08

Locations

US (8)