Study of Belatacept in Subjects Who Are Undergoing a Renal Transplant

Study Overview
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Brief Summary
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The purpose of this trial is to learn if Belatacept is effective and safe as a first line of immunosuppression treatment in patients undergoing a renal transplant where the donor kidney is obtained in patients with extended criteria.

Official Title
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Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial - Extended Criteria Donors (BENEFIT-EXT)

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Cyclosporin A
* Drug: Belatacept Less Intensive Regimen (LI)
* Drug: Belatacept More Intensive Regimen (MI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is a first-time recipient of a kidney transplant from a deceased donor. Specific donor criteria Exclusion Criteria: Donor age <10 years Subjects receiving a concurrent solid organ or cell transplant (lung, heart, etc.) Subjects with a positive T-cell lymphocytotoxic crossmatch. Subjects who are positive for Hepatitis B or C, or HIV Active tuberculosis History of cancer in the last 5 years History of substance abuse Specific laboratory results are exclusionary Mammography suspicious for cancer Allergy to iodine For Long-term extension study-Subjects who have completed three years of study treatment (through Week 156)

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclosporin A<br> | Drug: Cyclosporin A<br>* tablet, oral, 1st month target: 150-300 ng/mL, after 1st month target: 100-250 ng/mL, daily, 36 months, 100-250 ng/mL, daily, 84 months<br>* Other names: CsA;|
| Experimental: Belatacept Less Intensive Regimen (LI)<br> | Drug: Belatacept Less Intensive Regimen (LI)<br>* solution, IV, 10mg/kg: Days 1 and 5, Weeks 2, 4, 8 and 12, then 5 mg/kg every 4 weeks, q 4 weeks, 36 months months, 5 mg/kg every 4 weeks, q 4 weeks, 84 months<br>|
| Experimental: Belatacept More Intensive Regimen (MI)<br> | Drug: Belatacept More Intensive Regimen (MI)<br>* solution, IV, 10mg/kg: Days 1 and 5, Weeks 2, 4, 6, 8, 10,12, 16, 20, and 24, then 5 mg/kg every 4 weeks, q 4 weeks, 36 months, 5 mg/kg every 4 weeks, q 4 weeks, 84 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Survived With a Graft at 12 Months Post-Transplant | Participant and graft survival at 12 months was summarized within each treatment group. Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss was defined as a sustained level of serum creatinine ≥ 6.0 mg/dL (530 μmol/L) as determined by central laboratory for ≥4 weeks or 56 or more consecutive days of dialysis. | Month 12 post-transplant | 
| Percentage of Participants With a Measured Glomerular Filtration Rate (GFR) <60 mL/Min Per 1.73 m^2 at Month 12 or a Decrease in Measured GFR >=10 mL/Min Per 1.73 m^2 From Month 3 to Month 12 | GFR was assessed using a true measure of glomerular filtration via non-radiolabeled iothalamate clearance test using a validated procedure. | From Month 3 to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured Glomerular Filtration Rate (GFR) by Month 12 and 24 | GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here, 'n' signifies the number of evaluable participants for the reporting arm at the given time point. Missing measured GFR assessments were imputed to a GFR of zero. | At Month 12 and Month 24 | 
| Percentage of Participants With Chronic Allograft Nephropathy (CAN) at Month 12 | Biopsy-proven CAN was determined by a blinded central histopathologist using the Banff 97 working classification of kidney transplant pathology. Onset of CAN was determined by the biopsy date when it was observed. Participants were considered as having CAN at 12 months if: CAN observed in a biopsy either prior to 12 months (including baseline biopsy) or first post 12 months biopsy; Participant had graft loss during the first year post transplant; no biopsy available post 12 months and CAN not observed in biopsies prior to 12 months; no biopsy available either prior to or post 12 months; and the measured glomerular filtration rate from Month 3 to Month 12 decreases at least 10 mL/min/1.73m^2. All other participants with missing 12 month biopsy were considered having no CAN observed at 12 months. | At Month 12 | 
| Percentage of Participants Who Survived With a Graft at 24 and 36 Months Post-Transplant | Participant and graft survival at 12 months was summarized within each treatment group. Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss will be defined as a sustained level of serum creatinine ≥ 6.0 mg/dL (530 μmol/L) as determined by central laboratory for ≥ 4 weeks or 56 or more consecutive days of dialysis. | Month 24 and Month 36 post-transplant | 
| Calculated Glomerular Filtration Rate (GFR) at 6, 12, 24, 36 and 84 Months | GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Months 6, 12, 24, 36 and 84 | 
| Change in Calculated GFR at Months 12, 24, 36 and 84 | GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Baseline and Months 12, 24, 36 and 84 | 
| Number of Participants With Anti-Hypertensive Medications Used to Control Hypertension at 12, 24 and 36 Months | Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or participant had received an antihypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Baseline and Months 12, 24 and 36 | 
| Percentage of Subjects Who Used Anti-Hypertensive Medications to Control Hypertension at Months 12, 24 and 36 | Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or subject had received an anti-hypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Months 12, 24 and 36 | 
| Percentage of Participants With New Onset Diabetes Mellitus (NODM) at 12, 24 and 36 Months. | NODM was defined as participant who did not have diabetes prior to randomization. Participants were determined for NODM if the participant received an antidiabetic medication for a duration of at least 30 days, or at least two fasting plasma glucose (FPG) tests indicate that FPG is ≥ 126 mg/dL (7.0 mmol/L). | Months 12, 24 and 36 | 
| Systolic and Diastolic Blood Pressure (BP) at 12, 24 and 36 Months | Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or participant had received an anti-hypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Months 12, 24 and 36 | 
| Mean Framingham Risk Score From Baseline to Months 12, 24 and 36 | The risk score was calculated based on the total points from six variables: Age, Level of LDL-cholesterol, Level of HDL-cholesterol, Presence and severity of systolic or diastolic hypertension, Presence or absence of a history of diabetes mellitus and Presence or absence of a history recent cigarette smoking. Total scores can range from <-3 to >14, which translate to a 1% to 56% risk of developing coronary heart disease in 10 years. Totals in the 4 to 6 point range translate to a 7 to 11% risk and 8 to 10 point range translate to a 18 to 27% risk. | Baseline and Months 12, 24 and 36 | 
| Percentage of Participants Using Lipid-Lowering Therapy at 12, 24, and 36 Months | Dyslipidemia was defined as triglyceride ≥ 500 mg/dL [5.65 mmol/L], low density lipoprotein (LDL) ≥ 100 mg/dL [2.59 mmol/L], and non-elevated high density lipoprotein (HDL) ≥ 130 mg/dL [3.36 mmol/L]. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Months 12, 24 and 36 | 
| Change in Total Cholesterol (TC), Non-HDL, LDL and HDL Cholesterol and Triglycerides at 12, 24 and 36 | Dyslipidemia was defined as triglyceride ≥ 500 mg/dL [5.65 mmol/L], low density lipoprotein (LDL) ≥ 100 mg/dL [2.59 mmol/L], and elevated non-high density lipoprotein (HDL) ≥ 130 mg/dL [3.36 mmol/L]. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively. | Months 12, 24 and 36 | 
| Percentage of Participants Who Have an Acute Rejection by Months 6, 12, 24, 36 and 84 | Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Clinically suspected acute rejection was defined as an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output or fever and graft tenderness or serum creatinine that remains elevated within 14 days post--transplantation and clinical suspicion of acute rejection exists. | Months 6, 12, 24, 36 and 84 | 
| Number of Participants Using Lymphocyte Depleting Therapy and Steroid-Resistant for Acute Rejection by Months 6, 12, 24, and 36. | Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Lymphocyte -depletion therapy for treatment of an episode of acute was defined as a participant treated with therapy and provided not treated with steroids earlier while steroid resistant acute rejection was defined as participants initially treated with steroids alone for suspected acute rejection for at least 2 days and then followed by the start of lymphocyte -depletion therapy. | Months 6, 12, 24 and 36 | 
| Number of Participants Based on Severity of Acute Rejection Based on Banff Grade Level by Months 6, 12, 24, 36 and 84 | Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Clinically suspected acute rejection was defined as an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output or fever and graft tenderness or serum creatinine that remains elevated within 14 days post--transplantation and clinical suspicion of acute rejection exists. | Months 6, 12, 24, 36 and 84 | 
| Mean Changes in Mental Component and Physical Component Health-Related Quality of Life (SF-36) From Baseline to Months 12, 24 and 36 | The SF-36 is a 36-item self-administered questionnaire developed to assess health-related quality of life (QOL) and comprises 8 domains, including 4 physical (physical health, bodily pain, physical functioning and physical role limitations) and 4 mental (mental health, vitality, social functioning, and emotional role limitation) subscales. Responses are used to derive physical and mental component summary scores, ranging from 0 to 100, with higher scores indicating better QOL (0=Poorest Health; 100=Best Health). Mean change from baseline = post-baseline value - baseline value; a higher value signifies improvement. | Baseline and Months 12, 24 and 36 | 
| Number of Participants With Clinically Significant Changes in Vital Signs up to 36 Months | Participants with abnormal blood pressure, body weight and body temperature outside the defined normal range were graded as clinically significant vital signs by the investigator. | Day 1 to Month 36 | 
| Number of Participants With Laboratory Test Abnormalities up to 36 Months | Participants with laboratory values outside the defined normal range were graded as clinically significant laboratory abnormalities by the investigator. Subjects were analyzed for Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase(AST), Hemoglobin, Platelet Count, Leukocytes, Bilirubin, Creatinine, Calcium, Bicarbonate, Potassium, Magnesium, Sodium, Phosphorus, Albumin, Uric Acid and Protein. Laboratory abnormalities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3. Here 'n' signifies those subjects evaluable for this measure at specified time points for each arm, respectively. | Day 1 to Month 36 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Related AEs and SAEs, AEs Leading to Discontinuation and Who Died up to Month 36 | AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | Day 1 to Month 36 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Related AEs and SAEs, AEs Leading to Discontinuation and Who Died up to Month 84 | AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | Day 1 to Month 84 | 
| Percentage of Participants With Graft Loss or Death to Month 84 | Participant and graft survival at 84 months was summarized within each treatment group. | Randomization to date of death, up to 84 months |