Regimen Optimization Study

Evaluation of Acute Rejection Rates in de Novo Renal Transplant Recipients Following Thymoglobulin Induction, CNI-free, Nulojix (Belatacept)-Based Immunosuppression

Patients who undergo a kidney transplant require prolonged therapy with drugs that suppress the immune system (called immunosuppressive regimens) to stop the immune system from attacking the transplanted kidney in order to limit damage to or the possibility of rejecting the transplanted kidney. The purpose of this study is to evaluate benefits and risks of two immunosuppressive regimens (belatacept with everolimus or tacrolimus with mycophenolate mofetil) following thymoglobulin induction and rapid corticosteroid withdrawal.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Thymoglobulin; Drug: Belatacept; Drug: Corticosteroids; Drug: Everolimus(EVL); Drug: mycophenolate mofetil(MMF); Drug: Tacrolimus(TAC)

Detailed Description

Calcineurin inhibitor (CNI)

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5016
    • Clínica Privada Velez Sarsfield
  • Sante Fe, Argentina, 3000
    • Clinica De Nefrologia, Urologia Y Enf. Cardiovasculares
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Sanatorio Parque S.A.
• United States
  • California
    • San Diego, California, United States, 92123
      • California Institute of Renal Research
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Univeristy
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • New York
    • Buffalo, New York, United States, 14215
      • Erie County Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University School of Medicine
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17104
      • Central PA Transplant Foundation
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0709
      • University of Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center - Swedish Colon and Rectal Clinic - First Hill (Northwest Colon and Rectal Cl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Men and women, aged 18 to 75
• Serologic test results are positive for past exposure to Epstein Barr Virus (EBV+)
• Diagnosed with end stage renal disease (ESRD) and scheduled to undergo transplantation of a non-HLA identical, living or standard criteria deceased donor kidney

Exclusion Criteria:

• Primary cause of ESRD is: primary focal segmental glomerulosclerosis; or Type I or II membranoproliferative glomerulonephritis; or Hemolytic Uremic Syndrome / Thrombotic Thrombocytopenic Purpura
• Had a previous graft loss due to acute rejection
• At increased immunologic risk of graft loss due to panel reactive antibodies (PRA) >20% or need for desensitization therapy
• Scheduled to receive a: kidney from identical twin; or paired kidney; or kidney from a Cytomegalovirus(CMV) positive donor when recipient is CMV negative; or kidney from an extended criteria donor
• Have a body mass index (BMI) of > 35 kg/m2 for nondiabetics or > 30 kg/m2 for diabetics
• Diagnosed as Hepatitis B positive; or Hepatitis C positive; or HIV positive; or currently or previously active or inadequately treated latent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belatacept + Everolimus; Thymoglobulin (i.v. infusion) induction, daily (or less frequently, as tolerated) not to exceed 10 days, to reach a total cumulative dose between 3.0 and 5.5 mg/kg; belatacept (infusion) regimen of 10 mg/kg i.v. on Day 1, Weeks 1, 2, 4, 8 and 12 post transplant and then a maintenance dose of 5 mg/kg every 4 weeks after 12 weeks post transplant; everolimus (tablet) daily dosing at 3.0 mg/day, 2 divided doses, starting on Day 3 dosing adjusted based on blood sample tests; methylprednisolone (infusion) prior to each Thymoglobulin infusion and prednisone (tablet), once methylprednisolone is no longer needed. (Corticosteroids to be discontinued by Day 7 or as soon thereafter as thymoglobulin infusions are completed)	Drug: Thymoglobulin; Other Names: ATG; Drug: Belatacept; Other Names: Nulojix; Drug: Corticosteroids; Other Names: Methylprednisolone; Prednisone; Drug: Everolimus(EVL); Other Names: Certican®; Zortress®
Experimental: Tacrolimus + Mycophenolate mofetil; Thymoglobulin (i.v. infusion) induction, daily (or less frequently, as tolerated) not to exceed 10 days, to reach a total cumulative dose between 3.0 and 5.5 mg/kg; tacrolimus (tablet) daily dosing beginning at 0.1 mg/kg/day, then adjusted based on blood sample tests; MMF (tablet) daily dosing between 0.5 to 2.0 g/day divided in 2 doses (up to 3 g/day if African Americans/Blacks); methylprednisolone (infusion) prior to each Thymoglobulin infusion and prednisone (tablet), once methylprednisolone is no longer needed. (Corticosteroids to be discontinued by Day 7 or as soon thereafter as thymoglobulin infusions are completed)	Drug: Thymoglobulin; Other Names: ATG; Drug: Corticosteroids; Other Names: Methylprednisolone; Prednisone; Drug: mycophenolate mofetil(MMF); Other Names: CellCept; Drug: Tacrolimus(TAC); Other Names: Prograf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Clinically-suspected Biopsy-proven Acute Rejection (CSBPAR) at 6 Months	Number of Participants with Clinically-suspected biopsy-proven acute rejection (CSBPAR) at 6 Months	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically-suspected Biopsy-proven Acute Rejection (CSBPAR) at 6, 12 and 24 Months	Clinically-suspected biopsy-proven acute rejection (CSBPAR) at 6, 12 and 24 Months Change in the incidence of CSBPAR at 6, 12 and 24 months post transplant, in the belatacept + EVL(Treatment A) as compared to TAC + MMF (Treatment B).	Up to 24 Months
Time to Clinically-suspected Biopsy-proven Acute Rejection (CSBPAR).	Time to Clinically suspected biopsy proven acute rejection	Up to 24 Months
Percentage of Participants With BANFF Grade by Severity Grades. BANFF Type (Grade) for Acute/Active Rejection	Treatment differences in the severity grades to treat all episodes of CSBPAR at 6, 12, and 24 months post-transplant. Type 1A - Cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of moderate tubulitis (>4 mononuclear cells/Tubular cross section or group of 10 Tubular cell). Type 1B - Cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of moderate tubulitis (>10 mononuclear cells/Tubular cross section or group of 10 Tubular cell).Type 2A - Cases with mild to moderate intimal arteritis.Type 2B - Cases with severe intimal arteritis comprising >25% of the luminal area. Type 3 - Cases with "transmural" arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (v3 with accompanying lymphocytic inflammation)	At 6, 12 and 24 Months
Treatment Differences in Therapeutic Modalities	Treatment Received for Biopsy Proven Acute Rejection (Banff Grade IA or Higher), or Humoral (Antibody Mediated) Rejection Treatment regimen: Categorical analysis of CSBPAR episodes by treatment received.	at 6, 12 and 24 Months
Number of Participants Who Survive With a Functioning Graft	Number of all participants who survive with a functioning graft at 6, 12 and 24 months post transplant	At 6, 12 and 24 months
Number of Participants Deaths Post Transplant	Number of participant deaths at 6, 12 and 24 months post transplant	up to 24 months
Number of Participants Who Experience Graft Loss Post Transplant	Number of all participants who experience graft loss at 6, 12 and 24 months post transplant	At 6, 12 and 24 months
Time to Event: Graft Loss and Death	The Number of days to participant Graft Loss and death for any reason	Up to 728 Days
Absolute Calculated Glomerular Filtration Rate (cGFR): Mean	Absolute (mean and median) cGFR values at 3, 6, 12 and 24 months post-transplant, as determined from the 4-variable Modification of Diet in Renal Disease (MDRD) formula	Up 24 Months post-transplant
Median Calculated Glomerular Filtration Rate (cGFR)	Median cGFR values at 3, 6, 12 and 24 months post-transplant, as determined from the 4-variable Modification of Diet in Renal Disease (MDRD) formula	Up 24 Months post-transplant
Mean Change From Month 3 in cGFR	The mean change from Month 3 cGFR at 3, 6, 12 and 24 months post-transplant	Up 24 Months post-transplant
Urine Protein Creatinine Ratio (UPr/Cr)	Urine protein to creatinine ratio (UPr/Cr) at 3, 6, 12 and 24 months post-transplant.	Up 24 Months post-transplant
Percentage of Participants With Donor Specific Anti-HLA Antibodies (DSA)	Percentage of participants with, and titers of pre-existing (pre-transplant) DSA on Day 1 (pre-transplant, pre-dose), and at Months 12 and 24 posttransplant	Up to 24 Months
Percentage of Participants With De Novo Donor Specific Anti-HLA Antibodies (DSA)	Characterization of any de novo DSA detected by IgM and IgG subclasses, and by the presence or absence of complement fixing properties.	Up to 24 Months
Percentage of Participants With Adverse Events (AEs)	Percentage of participants with AEs up to 24 months post-transplant	Up to 24 months Post-Transplant
Percentage of Participants With Serious Adverse Events (SAEs)	Percentage of participants with SAEs up to 24 months post-transplant	Up to 24 months Post-Transplant
Percentage of Participants With Events of Special Interest (ESIs)	Percentage of participants which have one of the following events of special interest: Serious Infections Post-Transplant Lymphoproliferative Disorder (PTLD) Progressive multifocal leukoencephalopathy (PML) Malignancies (Other than PTLD) including non-melanoma skin carcinomas (Malignancies) Tuberculosis Infections Central Nervous System (CNS) Infections Viral Infections Infusion Related reactions within 24 hours since belatacept infusion	Up to 24 Months
Percentage of Particpants With Laboratory Test Abnormalities (LTAs)	Percentage of participants with laboratory tests with marked laboratory abnormalities	At 24 Months
Mean and Mean Change From Baseline in Blood Glucose	Mean fasting blood glucose levels, and mean changes from baseline values at Months 6, 12 and 24 months post- transplant	Up to 24 months
Mean and Mean Change From Baseline in Whole Blood HbA1c	Mean whole blood HbA1C concentrations, and mean changes from baseline values at Months 6, 12 and 24 months post-transplant.	Up to 24 months
Percentage of Participants With New Onset Diabetes After Transplant	Percentage of participants with New Onset Diabetes After Transplantation (NODAT) at 6, 12, and 24 months post-transplant.	up to 24 months
Absolute Values of Blood Pressure: Mean	Absolute (mean and median) values for SBP and DBP at 3, 6, 12 and 24 months posttransplant;	Up to 24 Months
Absolute Values of Blood Pressure: Median	Absolute (mean and median) values for SBP and DBP at 3, 6, 12 and 24 months posttransplant;	Up to 24 Months
Mean Changes From Baseline Values for Blood Pressure	Mean changes from baseline values for SBP and DBP at 6, 12 and 24 months post-transplant	Up to 24 Months
Absolute Values of Fasting Lipid Values: Mean	Absolute (mean and median) values at 3, 6, 12 and 24 months post-transplant for the following: Serum total cholesterol (TC) Serum high density lipoprotein (HDL) cholesterol Serum low density lipoprotein (LDL) cholesterol Serum triglycerides (TG)	Up to 24 Months
Absolute Values of Fasting Lipid Values: Median	Absolute (mean and median) values at 3, 6, 12 and 24 months post-transplant for the following: Serum total cholesterol (TC) Serum high density lipoprotein (HDL) cholesterol Serum low density lipoprotein (LDL) cholesterol Serum triglycerides (TG)	Up to 24 Months
Mean Changes From Baseline Values of Lipid Values	Mean changes from baseline values in the following: Serum total cholesterol (TC) Serum high density lipoprotein (HDL) cholesterol Serum low density lipoprotein (LDL) cholesterol Serum triglycerides (TG)	at months 12 and 24

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2015
• Primary Completion (Actual): May 2, 2019
• Study Completion (Actual): May 2, 2019

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 12, 2014
• First Posted (Estimate): May 13, 2014

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone; Prednisone; Tacrolimus; Mycophenolic Acid; Everolimus; Abatacept; Thymoglobulin
• Other Study ID Numbers: IM103-177; 2013-002090-21 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No