Open-Label Phase 2 Trial of a Steroid-Free, CNI-Free, Belatacept-Based Immunosuppressive Regimen

Phase 2

Terminated

Conditions: Kidney Transplantation
Primary Renal Allograft Candidate

Interventions: Biological: Anti-thymocyte Globulin (Rabbit)
Biological: belatacept
Drug: methylprednisolone
Biological: basiliximab
Drug: mycophenolate mofetil
Drug: tacrolimus

Registration Number: NCT01856257

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The primary objective is to evaluate a NULOJIX® (belatacept) based regimens as a means of improving long-term graft function without increasing the risks of immunologic graft injury by avoiding both calcineurin inhibitors (CNIs) and corticosteroids.

Detailed Description: Taking standard anti-rejection medications for a long time can cause serious side effects, including kidney damage. Transplant recipients have to take anti-rejection medications to prevent their immune system (the body's natural defense system against illness) from rejecting their new kidney. Most patients who receive a kidney transplant must take these anti-rejection medications for the rest of their lives, or for as long as the kidney continues to work.

The purpose of this study is to determine if NULOJIX® (belatacept), will minimize serious long term side effects seen with anti-rejection medications while still protecting the transplanted kidney from damage. The researchers also want to learn more about the safety of this treatment and the long term health of the transplanted kidney.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 71

Inclusion Criteria

Male or Female, 18-65 years of age at the time of enrollment;
Ability to understand and provide written informed consent;
Candidate for primary renal allograft from either living or deceased donor;
No known contraindications to study therapy using NULOJIX® (belatacept);
Female participants of childbearing potential must have a negative pregnancy test upon study entry;
Participants with reproductive potential must agree to use an appropriate method(s) of birth control as outlined in the CellCept® , Myfortic® or generic package labeling during participation in the study and for 4 months following completion of the study;
No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator;
Negative crossmatch or Panel Reactive Antibodies (PRA) of 0% on historic and current sera, as determined by each participating study center;
A documented negative tuberculosis (TB) test within the 6 months prior to transplant. If documentation is not present at the time of transplantation, and the subject does not have any risk factors for TB, a TB-specific interferon gamma release assay (IGRA) may be performed.

Exclusion Criteria

Need for multi-organ transplant;
Recipient of previous organ transplant;
Epstein-Barr Virus (EBV) seronegative (or unknown) recipients;
Active infection including hepatitis B, hepatitis C, or human Immunodeficiency Virus (HIV);
Individuals who have required treatment with prednisone or other immunosuppressive drugs within 1 year prior to transplant;
Individuals undergoing transplant using organs from extended criteria donor (ECD) or donation after cardiac death (DCD) donors;
Histocompatibility antigen (HLA) identical living donors;
Individuals at significant risk of early recurrence of the primary renal disease including focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) type 2 or any other disease that in the opinion of the investigator is at increased likelihood of recurrence and which may result in rapid decline in renal function;
Known history of thrombotic events or risk factors, including any of the following:
- Factor V Leiden, elevated homocysteine, positive lupus anticoagulant, elevated anticardiolipin antibody, heparin-induced thrombocytopenia,
- A family history of a heritable thrombotic condition,
- Recurrent deep vein thrombosis (DVT) or pulmonary emboli (PE),
- Unexplained stillborn infant or recurrent spontaneous abortion or other congenital or acquired thrombotic disorder.

At the discretion of the investigator, a history of thrombosis of a dialysis access graft, fistula, or indwelling catheter/device may not be considered an exclusion criterion.

Any condition that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements;
Use of investigational drugs within 4 weeks of enrollment;
Known hypersensitivity to mycophenolate mofetil (MMF)or any of the drug's components;
Administration of live attenuated vaccine(s) within 8 weeks of enrollment;
Blood type A2 and A2B donors into blood type B recipients.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Thymoglobulin®+tacrolimus+MMF	Anti-thymocyte Globulin (Rabbit)	Induction with Thymoglobulin®, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)
Basiliximab+20 weeks of tacrolimus+MMF + belatacept	basiliximab	Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent. Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.
Thymoglobulin®+belatacept+MMF	belatacept	Induction with Thymoglobulin®, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)
Thymoglobulin®+belatacept+MMF	Anti-thymocyte Globulin (Rabbit)	Induction with Thymoglobulin®, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)
Basiliximab+20 weeks of tacrolimus+MMF + belatacept	belatacept	Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent. Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.
Thymoglobulin®+tacrolimus+MMF	methylprednisolone	Induction with Thymoglobulin®, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)
Thymoglobulin®+tacrolimus+MMF	mycophenolate mofetil	Induction with Thymoglobulin®, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)
Thymoglobulin®+tacrolimus+MMF	tacrolimus	Induction with Thymoglobulin®, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)
Thymoglobulin®+belatacept+MMF	mycophenolate mofetil	Induction with Thymoglobulin®, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)
Basiliximab+20 weeks of tacrolimus+MMF + belatacept	tacrolimus	Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent. Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.
Basiliximab+20 weeks of tacrolimus+MMF + belatacept	mycophenolate mofetil	Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent. Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.
Thymoglobulin®+belatacept+MMF	methylprednisolone	Induction with Thymoglobulin®, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)
Basiliximab+20 weeks of tacrolimus+MMF + belatacept	methylprednisolone	Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent. Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.

Primary Outcome Measures

Name	Time	Method
Mean Estimated Glomerular Filtration Rate (eGFR) Calculated for Each Treatment Group Using the CKD-EPI Equation at Wk 52 Post-Transplant	Week 52	eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI): * A score of ≥90 means kidney function is normal. * A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. * Scores between 30 and 59 indicates moderately reduced kidney function. * Scores between 15 and 29 indicate severely reduced kidney function. * Scores below 15 indicate very severe or end stage kidney failure.

Secondary Outcome Measures

Name	Time	Method
Count of Participants With Biopsy Proven Acute Rejection By Wk 52 Post-Transplant	Transplantation through Week 52	Biopsy proven acute rejection definition: histologic evidence of a Banff grade of ≥1A per local pathologist.
Count of Participants With eGFR < 60 mL/Min/1.73 m^2 Measured by CKD-EPI at Wk 52 Post-Transplant	Week 52	eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI): * A score of ≥90 means kidney function is normal. * A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. * Scores between 30 and 59 indicates moderately reduced kidney function. * Scores between 15 and 29 indicate severely reduced kidney function. * Scores below 15 indicate very severe or end stage kidney failure.
Count of Participants by CKD Stage at Wk 52	Week 52	The stages of Chronic Kidney Disease are defined using the participant's GFR value: * Stage 1 if GFR value is ≥90 ( kidney function is normal) * Stage 2 if 60 ≤ GFR \< 90 (mildly reduced kidney function, pointing to kidney disease) * Stage 3A if 45 ≤ GFR \< 60\* * Stage 3B if 30 ≤ GFR \< 45\* * Stage 4 if 15 ≤ GFR \< 30 (severely reduced kidney function) * Stage 5 if GFR \< 15 (severe or end stage kidney failure). Stages 3A and 3B indicate moderately reduced kidney function.\*
Count of Participants With Defined CKD Stage 4 or 5 at Wk 52 Post-Transplant	Week 52	The stages of Chronic Kidney Disease (CKD) are defined using the participant's GFR value: * Stage 1 if GFR value is ≥ 90 (kidney function is normal) * Stage 2 if 60 ≤ GFR \< 90 (mildly reduced kidney function, pointing to kidney disease) * Stage 3A if 45 \<= GFR \< 60\* * Stage 3B if 30 \<= GFR \< 45\* * Stage 4 if 15 ≤ GFR \< 30 (severely reduced kidney function) * Stage 5 if GFR \< 15 (severe or end stage kidney failure). Stages 3A abd 3B indicate moderately reduced kidney function.\*
Mean Calculated eGFR Using MDRD 4 Variable Model at Wk 52 Post-Transplant	Week 52	The estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation (MDRD): * A score of ≥ 90 means kidney function is normal. * A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. * Scores between 30 and 59 indicates moderately reduced kidney function. * Scores between 15 and 29 indicate severely reduced kidney function. * Scores below 15 indicate severe or endstage kidney failure.
The Slope of eGFR by CKD-EPI Over Time Based on Serum Creatinine Post-Transplant	Day 28 through Week 52 Post-Transplant	The estimated Glomerular Filtration Rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI): * A score of ≥ 90 means kidney function is normal. * A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. * Scores between 30 and 59 indicates moderately reduced kidney function. * Scores between 15 and 29 indicate severely reduced kidney function. * Scores below 15 indicate very severe or endstage kidney failure. An estimate of the slope, or change over time, in eGFR was produced using standard statistical linear modeling procedures. The estimate was then re-scaled so that it could be interpreted as a change in eGFR per month. Positive numbers indicate increasing kidney function. Larger numbers indicate greater change in kidney function.
Count of Participants With Delayed Graft Function at Wk 52 Post-Transplant	Transplantation through Week 52	Delayed grafted function is defined as dialysis in the first week on one or more occasions for any indication other than the treatment of acute hyperkalemia in the setting of otherwise acceptable renal function.
Count of Participants With Acute Cellular Rejection Grade ≥ IA Defined by Banff 2007 Criteria By Wk 52 Post-Transplant	Transplantation through Week 52	Acute cellular rejection occurs when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade equal to or greater than IA by Banff 2007 criteria as determined by local pathology.
Count of Participants by Severity of First Acute Cellular Rejection by Wk 52 Post-Transplant	Transplantation through Week 52	Acute cellular rejection occurs when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade equal to or greater than IA by Banff 2007 criteria as determined by local pathology. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection. Originally it was 2 endpoints but all participants' highest grade was also their first grade so only reporting their first grade.
Count of Participants With Antibody Mediated Rejection by Wk 52 Post-Transplant	Transplantation through Week 52	Antibody mediated rejection is defined by diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury and was determined by local pathology.
Type of Rejection Classified by Pathologist - For Cause Kidney Biopsies	Transplantation through Week 52	Upon having a biopsy performed, persons often receive treatment for rejection based on the results of the biopsy, which may or may not have shown signs of rejection. Details of local biopsy findings are presented here for rejection. Acronyms and abbreviations are defined as follows: * ACR= Acute T-Cell Mediated rejection * AMR= Acute Antibody-mediated rejection * Chr. AMR=Chronic Antibody Mediated Rejection * Gd.=Grade * IFTA=Interstitial Fibrosis and Tubular Atrophy
Type of Treatment for Detected Graft Rejection	Transplantation through Week 52	Upon having a biopsy performed, persons often receive treatment for rejection based on the results of the biopsy, which may or may not have shown signs of rejection. Details of treatment are presented here for rejection. Acronyms and abbreviations are defined below. ATG=Thymoglobulin
Count of Participants With De Novo Anti-Donor Histocompatibility Antigen (HLA) Antibodies at Wk 52 Post-Transplant	Week 52	The presence of antibodies reactive to Histocompatibility Antigen (HLA) molecules expressed on the renal allograft have been associated with both acute and chronic injury to the transplanted kidney. The development of de novo anti donor HLA antibodies may mean a person is more likely to reject the graft. No data available.
Count of Participants With Either New Onset Diabetes After Transplant (NODAT) or Impaired Fasting Glucose (IFG) at Week 52 Post-Transplant -Based on Criteria Specified by the ADA and WHO	Transplantation through Week 52	New onset diabetes is the development of diabetes post-kidney transplant. It was identified by the clinical sites caring for each participant and reported directly in the clinical database. Impaired fasting glucose (IFG) is a determination made by referencing glucose measurements obtained from a standard chemistry panel. Any fasting glucose measure that is between 110 and 125 mg/dL is classified as IFG. Acronyms: American Diabetes Association (ADA); World Health Organization (WHO).
Count of Participants With Treated Diabetes Between Day 14 and Wk 52 Post-Transplant	Day 14 through week 52	Treated diabetes is defined as receipt of any oral medication or insulin for the treatment of diabetes for \>14 days.
Hemoglobin A1c (HbA1c) Measurements Over Time	Baseline (Pre-Transplant) and Days 28 and -84, and Weeks 28, -36, and -52 Post-Transplant	Hemoglobin A1c (HbA1c) measures the average blood glucose levels over 8-12 weeks, thus acting as a useful long-term gauge of blood glucose control: * A value below 6.0% reflects normal levels, * 6.0% to 6.4% reflects prediabetes, and * a value of ≥ 6.5% reflects diabetes.
Standardized Blood Pressure Measurement at Wk 52 Post-Transplant	Week 52	A blood pressure measurement consists of two numbers: the systolic and diastolic pressures. Systolic pressure measures the pressure in blood vessels when the heart beats. Diastolic pressure measures the pressure in blood vessels between beats of the heart. * Systolic measures of \<120 and diastolic measures of \<80 are considered normal. * Systolic measures of 120-139 and diastolic measures of 80-89 are considered at risk (or pre-hypertension). * Systolic measures of ≥140 and diastolic measures of ≥90 are considered high.
Count of Participants With Use of Anti-hypertensive Medication at Wk 52 Post-Transplant	Week 52	Anti-hypertensive medications are a class of drugs that are used to treat hypertension. The medications seek to prevent the complications of high blood pressure, such as stroke and myocardial infarction.
Fasting Lipid Profile at Baseline (Pre-Transplant)	Baseline	A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided: * Total cholesterol: 75-169 mg/dL if age ≤20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease * LDL cholesterol: \<70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; \<100 mg/dL for people considered high risk for cardiovascular disease; \<130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease * HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease * Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and * Triglycerides: \<150 mg/dL; high values indicate risk of cardiovascular disease.
Fasting Lipid Profile at Wk 28 Post-Transplant	Week 28	A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided: * Total cholesterol: 75-169 mg/dL if age ≤20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease * LDL cholesterol: \<70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; \<100 mg/dL for people considered high risk for cardiovascular disease; \<130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease * HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease * Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and * Triglycerides: \<150 mg/dL; high values indicate risk of cardiovascular disease.
Fasting Lipid Profile at Wk 52 Post-Transplant	Week 52	A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided: * Total cholesterol: 75-169 mg/dL if age ≤ 20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease * LDL cholesterol: \<70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; \<100 mg/dL for people considered high risk for cardiovascular disease; \<130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease * HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease * Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and * Triglycerides: \<150 mg/dL; high values indicate risk of cardiovascular disease.
Count of Participants With Use of Lipid Lowering Medications at Baseline and Wk 28 and Wk 52 Post-Transplant	Baseline (Pre-Transplant), Week 28, and Week 52	Lipid lowering medications are used in the treatment of high levels of fats (lipids), such as cholesterol in blood.
Total Daily Prescribed Pill Count	Day 28, Day 84, Week 28, Week 36, and Week 52	This is a measure of the total number of pills a participant was prescribed on a given day
Count of Participant Deaths or Graft Loss by Wk 52 Post-Transplant	Transplantation through Week 52	This measure counts deaths and graft loss occurring at any point post transplantation. Graft loss is defined as 90 days of dialysis dependency.
Count of Participants With Graft Rejection by Wk 52 Post-Transplant	Transplantation through Week 52	The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection of the transplanted kidney regardless of the presence of a biopsy.
Count of Participants Experiencing ≥ 1 Adverse Event (AEs) or Serious Adverse Events (SAEs) by Wk 52	Enrollment through Week 52	Adverse events were collected systematically from enrollment through Wk 52, the last study visit. Provided are numbers of participants with ≥ 1 adverse event (serious or non-serious adverse events) by treatment arm.
Count of Participants With Infections Requiring Hospitalization or Systemic Therapy by Wk 52 Post-Transplant	Transplantation through Week 52	Infections of certain types (i.e., excluding those identified in the protocol as occurring commonly in this study population) were required to be reported as a serious adverse event if they required either inpatient hospitalization or prolongation of a current hospitalization.
Count of Participants With BK Polyoma Virus (BKV) and Cytomegalovirus (CMV) Viremia (Local Center Monitoring) as Adverse Events by Wk 52 Post-Transplant	Transplantation through Week 52	Viral infections following renal transplantation is significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss. Specific viruses were monitored during the study, using participant blood samples. Displayed are counts of participants who experienced BKV and CMV viremia as adverse events by treatment arm.
Count of Participants With Epstein-Barr Virus (EBV) Infection as Reported on the Case Report Form as Adverse Events	Transplantation through Week 52	Viral infections following renal transplantation, including but not limited to EBV infection, is a significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss.
Count of Participants With Fever > 39 Degrees Celsius and Blood Pressure < 90 mmHg Within 24 Hours of Onset of Transplant Procedure	Within 24 Hours of transplant procedure	Temperature of \>39 degrees Celsius (e.g., 102.2 degrees Fahrenheit) would be an indication of fever most often in response to an infection or illness. Systolic blood pressure \<90mm Hg would be an indication of low blood pressure.

Trial Locations

Locations (3): Emory University
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Atlanta, Georgia, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
University of California, San Francisco
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San Francisco, California, United States