Regimen Optimization Study

Study Overview
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Brief Summary
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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.

Detailed Description
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Calcineurin inhibitor (CNI)

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

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Thymoglobulin
* Drug: Belatacept
* Drug: mycophenolate mofetil(MMF)
* Drug: Corticosteroids
* Drug: Everolimus(EVL)
* Drug: Tacrolimus(TAC)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belatacept + Everolimus<br>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<br> <br> * Other names: ATG;Drug: Belatacept<br> <br> * Other names: Nulojix;Drug: Corticosteroids<br> <br> * Other names: Prednisone;Drug: Everolimus(EVL)<br> <br> * Other names: Zortress®;|
| Experimental: Tacrolimus + Mycophenolate mofetil<br>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<br> <br> * Other names: ATG;Drug: mycophenolate mofetil(MMF)<br> <br> * Other names: CellCept;Drug: Corticosteroids<br> <br> * Other names: Prednisone;Drug: Tacrolimus(TAC)<br> <br> * Other names: Prograf;|

What is the study measuring?
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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 |