Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression (BENEFIT) (BENEFIT)

• ClinicalTrials.gov Identifier: NCT00256750
• Recruitment Status: Completed
• First Posted: November 22, 2005
• Results First Posted: August 19, 2016
• Last Update Posted: August 19, 2016
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Study Description

Brief Summary:

The purpose of this study is to learn if Belatacept can provide protection from organ rejection following kidney transplantation while avoiding some of the toxic effects of standard immunosuppressive medications such as kidney damage. Effects on kidney function and patient survival as well as drug safety will also be studied.

Condition or disease	Intervention/treatment	Phase
Kidney Transplantation; Chronic Kidney Failure	Drug: Cyclosporine (CsA); Drug: Belatacept LI (less intensive); Drug: Belatacept MI (more intensive)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 738 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT)
• Study Start Date: March 2005
• Actual Primary Completion Date: June 2008
• Actual Study Completion Date: April 2015

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cyclosporine (CsA)	Drug: Cyclosporine (CsA); tablet, oral, 1st month target: 150-300 ng/mL, after 1st month target: 100-250 ng/mL, daily, 36 months (ST), 100-250 ng/mL, daily, 24 months (LT)
Experimental: Belatacept LI (less intensive)	Drug: Belatacept LI (less intensive); 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 (ST), 5 mg/kg every 4 weeks, q 4 weeks, 24 months (LT)
Experimental: Belatacept MI (more intensive)	Drug: Belatacept MI (more intensive); 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 (ST), 5 mg/kg every 4 weeks, q 4 weeks, 24 months (LT)

Outcome Measures

Primary Outcome Measures :

1. Percent of Participants Surviving With a Functioning Graft by Month 12 [ Time Frame: Day 1 to Month 12 ]
   Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss was defined as a sustained level of serum creatinine (SCr) ≥ 6.0 milligrams per deciliter (mg/dL) or 530 micromolar per liter (μmol/L) as determined by the central laboratory for ≥ 4 weeks or ≥ 56 consecutive days of dialysis or impairment of renal function to such a degree that the participant underwent retransplant.
2. Percent of Participants With a Composite of Measured Glomerular Filtration Rate (mGFR) Less Than 60 mL/Min/1.73 m^2 at Month 12 or With a Decrease in mGFR Greater Than or Equal to 10 mL/Min/1.73m^2 From Month 3 to Month 12 [ Time Frame: Month 12; Month 3 to Month 12 ]
   Measured glomerular filtration rate (mGFR) is the direct measurement of renal function and was assessed by measurement of the clearance of a true glomerular filtration marker (non-radiolabeled iothalamate) using a validated procedure. A GFR of 60 mL/min/1.73 m^2 was used as the approximate equal of the threshold values of serum creatinine (SCr) of 1.5 mg/dL. A change in GFR of at least 10 mL/min/1.73 m^2 was used as the approximate change in SCr of at least 0.3 mg/dL. The change component of the composite renal endpoint was assessed from Month 3 to Month 12, since post-transplant renal function is largely stable by Month 3.
3. Percent of Participants Experiencing Acute Rejection (AR) Post-transplant by Month 12 [ Time Frame: Day 1 to Month 12 ]
   Acute rejection was defined as a clinico-pathological event requiring clinical evidence and biopsy confirmation. Clinical evidence was defined if either a or b was satisfied: a: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b: an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists. Allograft biopsies were evaluated by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology. Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. AR was defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Only the episode with the highest Banff grade for each participant was counted.

Secondary Outcome Measures :

1. Mean Value of the Measured Glomerular Filtration Rate (mGFR) [ Time Frame: Months 3, 12, 24 ]
   Measured glomerular filtration rate (mGFR) is the direct measurement of renal function and was assessed by measurement of the clearance of a true glomerular filtration marker (non-radiolabeled iothalamate) using a validated procedure. Missing mGRF assessments were imputed to assess renal function. The overall imputation strategy involved a primary imputation method (linear extrapolation and quartile method) followed by 2 secondary imputation methods (regression method and graded quartile method) to assess the robustness of conclusions obtained from the application of the primary imputation method. All imputation methods entailed replacing a missing value with a value drawn from a plausible distribution incorporating theoretical and observed aspects of the data. GFR was measured as mL/min/1.73 m^2.
2. Percent of Participants With Prevalence of Chronic Allograft Nephropathy (CAN) at Month 12 [ Time Frame: Month 12 ]
   Prevalence of CAN = if participant met any of the following conditions: a: CAN observed in a biopsy either prior to 12 months (including baseline biopsy) or first post 12 months biopsy; b: participant had graft loss during the first year post transplant; c: no biopsy was available post 12 months and CAN not observed in biopsies prior to 12 months, but the measured GFR from Month 3 to Month 12 decreased at least 10 mL/min/1.73m^2; d: no biopsy available either prior to or post 12 months, and the measured GFR (incorporated missing data imputation) from Month 3 to Month 12 decreased at least 10 mL/min/1.73m^2. CAN = All allograft biopsies evaluated for presence and severity of CAN by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology. Onset of CAN determined by the biopsy date when it was observed.
3. Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events by Month 84 [ Time Frame: Randomization to Month 84 ]
   Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
4. Number of Participants With Adverse Events of Special Interest by Month 84 [ Time Frame: Randomization to Month 84 ]
   Prospectively identified events of special interest which were a subset of all AEs, and were either SAEs or non-serious AEs, included the following categories: Serious Infections and Infestations, Thrombolic/embolic events, and Malignancy. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/ abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Time frame is from randomization to the event date, or to the last dose date+56, or to Month 84 (Day 2548), whichever is the earliest.
5. Mean Blood Pressure at Month 84 [ Time Frame: Month 84 ]
   Blood pressure was measured in millimeters of mercury (mmHg). Blood pressure was measured soon after the participant arrived and sat quietly at rest for 10 minutes. 3 consecutive seated blood pressure readings were made at least 1 minute apart.
6. Number of Participants Meeting Marked Laboratory Abnormality Criteria Post-transplant by Month 36 [ Time Frame: Baseline to Month 36 ]

   Upper limit of normal (ULN). Units per Liter (U/L). Cells per microliter (c/µL). Grams per deciliter (g/dL). Milligrams per deciliter (mg/dL).Cells per Liter (c/L). Milliequivalents/Liter (mEq/L).

   Hemoglobin (low): <8.0 g/dL; Platelet count: <50*10^9 c/L; Leukocytes: <2*10^3 c/µL; Alkaline phosphatase (ALP): >5.0*ULN U/L; Alanine aminotransferase (ALT): >5.0*ULN U/L; Asparate aminotransferase (AST): >5.0*ULN U/L; Bilirubin Total: >3.0*ULN mg/dL; Creatinine: >3.0*ULN mg/dL; Calcium Total: low if <7.0 mg/dL or high if >12.5 mg/dL; Bicarbonate: <11.0 mEq/L; Potassium serum: low if <3.0 mEq/L or high if >6.0 mEq/L; Magnesium serum: low is <0.8 mEq/L or high if >2.46 mEq/L; Sodium serum: low if <130.0 mEq/L or high if >155.0 mEq/L; Phosphorus inorganic: <2.0 mg/dL; Albumin: <2 g/dL; Uric acid: >10 mg/dL; Protein urine: >=3+

7. Percent of Participants With Development of Anti-Donor HLA Positive Antibodies by Month 84 [ Time Frame: Randomization to Month 84 ]
   Only participants who had non-missing test result for Class I or Class II anti-donor HLA antibodies were included in analysis and only participants who had at least one non-NA test result or finding were counted. This was a cumulative summary (excluding baseline) and once a participant was positive, that participant remained positive for the later time point. Acute rejection (AR) defined: a clinico-pathological event requiring clinical evidence and biopsy confirmation. Clinical evidence defined: if either a or b was satisfied: a: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b: an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists. AR defined as allograft biopsies of Banff 97 classification Grade IA or greater (higher scores indicate more severe rejection). Evaluated by blinded central independent pathologist.
8. Mean Change of the Measured Glomerular Filtration Rate (mGFR) From Month 3 to Month 12 and From Month 3 to Month 24 [ Time Frame: Month 3 to Month 12; Month 3 to Month 24 ]
   Measured glomerular filtration rate (mGFR) is the direct measurement of renal function and was assessed by measurement of the clearance of a true glomerular filtration marker (non-radiolabeled iothalamate) using a validated procedure. Missing mGRF assessments were imputed to assess renal function. The overall imputation strategy involved a primary imputation method (linear extrapolation and quartile method) followed by 2 secondary imputation methods (regression method and graded quartile method) to assess the robustness of conclusions obtained from the application of the primary imputation method. All imputation methods entailed replacing a missing value with a value drawn from a plausible distribution incorporating theoretical and observed aspects of the data. GFR was measured as mL/min/1.73 m^2.
9. Percent of Participants With a Decrease in Measured Glomerular Filtration Rate (mGFR) Greater Than or Equal to 10mL/Min/1.73m^2 From Month 3 to Month 12 [ Time Frame: Month 3 to Month 12 ]
   Measured glomerular filtration rate (mGFR) is the direct measurement of renal function and was assessed by measurement of the clearance of a true glomerular filtration marker (non-radiolabeled iothalamate) using a validated procedure. A change in GFR of at least 10 mL/min/1.73 m^2 was used as the approximate change in serum creatinine (SCr) of at least 0.3 mg/dL. The change component of the composite renal endpoint was assessed from Month 3 to Month 12, since post-transplant renal function is largely stable by Month 3. Month 3 = baseline
10. Percent of Participants With a Measured Glomerular Filtration Rate (mGFR) Less Than 60 mL/Min/1.73 m^2 at Month 12 [ Time Frame: Month 12 ]
    Measured glomerular filtration rate (mGFR) is the direct measurement of renal function and was assessed by measurement of the clearance of a true glomerular filtration marker (non-radiolabeled iothalamate) using a validated procedure. A GFR of 60 mL/min/1.73 m^2 was used as the approximate equal of the threshold values of serum creatinine (SCr) of 1.5 milligrams per deciliter (mg/dL).
11. Mean Value of the Calculated Glomerular Filtration Rate (cGFR) With Imputation [ Time Frame: Months 6, 12, 24, 36 ]
    Calculated glomerular filtration rate (cGFR) was used to assess renal function (as measured by the estimated creatinine clearance) using the following modification of diet in renal disease (MDRD) formula: MDRD: GFR = 170 x [SCr/0.95]^(-0.999) x [Age]^(-0.176) x [0.762 if participant is female] x [1.180 if participant is black] x [BUN]^(-0.170) x [Alb]^(+0.318); Age in years; Alb = Albumin in g/dL; SCr = Serum creatinine in mg/dL; BUN = Blood urea nitrogen in mg/dL; cGFR = mL/min/1.73m2
12. Mean Change in Calculated Glomerular Filtration Rate (cGFR) From Month 6 to Month 12 [ Time Frame: Month 6 to Month 12 ]
    Calculated glomerular filtration rate (cGFR) was used to assess renal function (as measured by the estimated creatinine clearance) using the following modification of diet in renal disease (MDRD) formula: MDRD: GFR = 170 x [SCr/0.95]^(-0.999) x [Age]^(-0.176) x [0.762 if participant is female] x [1.180 if participant is black] x [BUN]^(-0.170) x [Alb]^(+0.318); Age in years; Alb = Albumin in g/dL; SCr = Serum creatinine in mg/dL; BUN = Blood urea nitrogen in mg/dL; cGFR = mL/min/1.73m^2
13. Percent of Participants With Incidence of New Onset Diabetes Mellitus by Month 36 [ Time Frame: Week 4 post-transplantation to Month 36 ]
    The incidence of new onset diabetes mellitus defined as participants who developed diabetes mellitus after randomization and transplantation. Participants that did not have diabetes prior to randomization were determined to have new onset diabetes mellitus if (i) the participant received an anti-diabetic medication for a duration of at least 30 days or (ii) at least two fasting plasma glucose (FPG) tests indicate that FPG is >=126 mg/dL (7.0 mmol/L). New onset diabetes mellitus (NODM) = post-transplant diabetes mellitus (PTDM)
14. Percent of Participants Using At Least One Anti-Hypertensive Medication to Control Hypertension at Month 36 [ Time Frame: Month 36 ]
    This analysis was based on all participants who had been followed up at least 1092 days after transplantation. Hypertension was defined in according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for participants with chronic kidney disease. This definition was based upon SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg. In addition, all participants who had a SBP < 130 mm Hg and a DBP < 80 mm Hg who received an antihypertensive medication(s) for the indication of hypertension or with a medical history of hypertension were included in this definition. Systolic blood pressure = SBP; Diastolic blood pressure = DBP
15. Percent of Participants With Incidence of Hypertension Post-Transplantation at Month 12 [ Time Frame: Month 12 ]
    The incidence of hypertension was defined as the proportion of participants who developed hypertension after randomization and transplantation. Specifically, the incidence of hypertension was assessed only after the Week 4 visit. This period allowed for adequate stabilization and resolution of transient changes. If participants received antihypertensive medication for the indication of hypertension at this (or later) time point, they were considered to have developed hypertension. Hypertension was defined according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for subjects with chronic kidney disease. This definition was based upon SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg. Systolic blood pressure = SBP; Diastolic blood pressure = DBP
16. Percent of Participants With Prevalence of Hypertension Post-Transplantation at Month 12 [ Time Frame: Month 12 ]
    The prevalence of hypertension was defined as the proportion of participants at any given time who meet the definition of hypertension. Hypertension defined according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for participants with chronic kidney disease. This definition is based upon SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg. Systolic blood pressure = SBP; Diastolic blood pressure = DBP
17. Mean Systolic Blood Pressure and Diastolic Blood Pressure [ Time Frame: Months 12, 24, 36 ]
    Blood pressure was measured in millimeters of mercury (mmHg). Blood pressure was measured soon after the participant arrived and sat quietly at rest for 10 minutes. 3 consecutive seated blood pressure readings were made at least 1 minute apart.
18. Percent of Participants at Baseline With Controlled Hypertension Post Transplantation by Month 12 [ Time Frame: Day 1 to Month 12 ]
    Controlled hypertension was defined as a SBP < 130 mm Hg and a DBP < 80 mm Hg while receiving an antihypertensive medication for the indication of hypertension or receiving an antihypertensive medication for another indication with a medical history of hypertension. Participants with a SBP < 130 mm Hg and a DBP < 80 mm Hg who were prescribed an antihypertensive medication(s) for an indication(s) other than hypertension (eg, beta blockers for migraine prophylaxis) with no medical history of hypertension were not considered to have either hypertension or controlled hypertension. Systolic blood pressure = SBP; Diastolic blood pressure = DBP
19. Percent of Participants With Prevalence of Controlled Hypertension at Month 12 [ Time Frame: Month 12 ]
    The prevalence of controlled hypertension was defined as the proportion of participants at any given time who met the definition of controlled hypertension. Controlled hypertension was defined as a SBP < 130 mm Hg and a DBP < 80 mm Hg while receiving an antihypertensive medication for the indication of hypertension or receiving an antihypertensive medication for another indication with a medical history of hypertension. Participants with a SBP < 130 mm Hg and a DBP < 80 mm Hg who were prescribed an antihypertensive medication(s) for an indication(s) other than hypertension (eg, beta blockers for migraine prophylaxis) with no medical history of hypertension were not considered to have either hypertension or controlled hypertension. Systolic blood pressure = SBP; Diastolic blood pressure = DBP
20. Percent of Non-dyslipidemic Participants With Incidence of Dyslipidemia Post-Transplantation by Month 12 [ Time Frame: Randomization to Month 12 ]
    Incidence of dyslipidemia was defined as the proportion of participants who developed dyslipidemia after randomization and transplantation. Dyslipidemia was defined in accordance with recent guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Dyslipidemia = hypertriglyceridemia (TGs >= 500 milligrams/deciliter (mg/dL) [5.65 mmol/L]), hypercholesterolemia (LDL >= 100 mg/dL [2.59 mmol/L]), or elevated non-HDL (non-HDL >= 130 mg/dL [3.36 mmol/L]) in the presence of high TGs (TGs >= 200 mg/dL [2.26 mmol/L]). The TG = triglyceride; LDL = low density lipoprotein; HDL = high density lipoprotein; millimole/Liter (mmol/L). For 95% CI within each group, normal approximation is used if N >=5. Otherwise exact method is used.
21. Percent of Participants With Prevalence of Dyslipidemia at Month 12 [ Time Frame: Month 12 ]
    The prevalence of dyslipidemia was defined as the proportion of participants at any given time who met the definition of dyslipidemia. Dyslipidemia defined in accordance with recent guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Dyslipidemia defined as hypertriglyceridemia (TGs >= 500 milligrams/deciliter (mg/dL) [5.65 mmol/L]), hypercholesterolemia (LDL >= 100 mg/dL [2.59 mmol/L]), or elevated non-HDL (non-HDL >= 130 mg/dL [3.36 mmol/L]) in the presence of high TGs (TGs >= 200 mg/dL [2.26 mmol/L]). TG = triglyceride; LDL = low density lipoprotein; HDL = high density lipoprotein; millimole/Liter (mmol/L). For 95% CI within each group, normal approximation is used if N >=5. Otherwise exact method is used.
22. Percent of Participants With Controlled Dyslipidemia at Month 12 [ Time Frame: Month 12 ]
    Prevalence of controlled dyslipidemia = the proportion of participants at any given time who met the stated definition of dyslipidemia. Dyslipidemia defined in accordance with recent guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Dyslipidemia defined as hypertriglyceridemia (TGs >= 500 milligrams/deciliter (mg/dL) [5.65 mmol/L]), hypercholesterolemia (LDL >= 100 mg/dL [2.59 mmol/L]), or elevated non-HDL (non-HDL >= 130 mg/dL [3.36 mmol/L]) in the presence of high TGs (TGs >= 200 mg/dL [2.26 mmol/L]). Controlled dyslipidemia defined as participants who received successful pharmacologic treatment for 1 of the above stated dyslipidemias, and their lipid values fell below the thresholds described. TG = triglyceride; LDL = low density lipoprotein; HDL = high density lipoprotein; millimole/Liter (mmol/L). For 95% CI within each group, normal approximation is used if N >=5. Otherwise exact method is used.
23. Number of Participants With Antihyperlipidemic Medication by Intensity Level [ Time Frame: Month 36 ]
    An intensity level was associated with the dose level of the statin based anti-hyperlipidemic agent. Any other agent (i.e., non-statin therapy) used as an antihyperlipidemic were considered Level I treatment intensity. Multiple daily dose levels during a period were averaged to compute the daily dose during that period. Level I = 20 mg fluvastatin (flu), 10 mg lovastatin (lova), 10 mg pravastatin (prav), 5-10 mg simvastatin (sim); Level II = 10 mg atorvastatin (atorv), 40 mg flu, 20 mg lova, 20 mg prav, 5 mg rosuvastatin (rosu), 20 mg sim, 10/10 vytorin; Level III = 20 mg atorv, 80 mg flu, 40 mg lova, 40 mg prav, 10 mg rosu, 40 mg sim, 10/20 vytorin; Level IV = 40 mg atorv, 80 mg lova, 80 mg prav, 20 mg rosu, 80 mg sim, 10/40 vytorin; Level V = 80 mg atorv, 40 mg rosu, 10/80 vytorin. Concomitant use of a statin and an agent of another class elevated the intensity level of the statin therapy by 1 level; therefore, an intensity level of greater than V was possible.
24. Percent of Participants Using At Least One Anti-Hyperlipidemic Medication [ Time Frame: Month 36 ]
    This analysis is based on all participants who were followed up at least 1092 days after transplantation.
25. Mean Value of Lipid Parameters [ Time Frame: Months 12, 24, 36 ]
    Lipid parameters included total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and triglycerides (TGs).
26. Percent of Participants With Prevalence of Acute Rejection (AR) by Month 36 [ Time Frame: Randomization to Month 36 ]
    Prevalence of AR = participants with the stated definition of AR at any given time. AR defined as a clinico-pathological event requiring clinical evidence and renal biopsy confirmation demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Only the episode with the highest Banff grade for each participant was counted. Clinical evidence = if either a or b was satisfied: a: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b: an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists. Allograft biopsies were evaluated by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology. Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification.
27. Number of Participants With Acute Rejection (AR) Post-transplant in Terms of Severity Using Banff Grades by Month 36 [ Time Frame: Randomization to Month 36 ]
    Acute rejection was defined as a clinico-pathological event requiring clinical evidence and renal biopsy confirmation demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Clinical evidence defined: if either a or b was satisfied: a) an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b) an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists. Allograft biopsies were evaluated by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology. Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Only the episode with the highest Banff grade for each participant was counted.
28. Percent of Participants Using Polyclonal Antilymphocyte Preparations for Impaired Renal Function and Anticipated Delayed Graft Function by Month 12 [ Time Frame: Randomization to Month 12 ]
    A participant was considered to have delayed graft function (DGF), if treated with dialysis within the first week (Day 1 - 8) after transplantation. The use of polyclonal antilymphocyte preparations (LDT) was permitted only for participants randomized to cyclosporine (CsA) who experienced impaired renal allograft function and anticipated DGF following transplantation and were not permitted in belatacept-treated participants, except for the treatment of acute rejection. Participants treated with LDT began CsA at the discretion of the investigator by Day 7. LDT could also have been used in participants who met >= 1 of the following criteria, observed in the presence of a transplant artery and vein and no evidence of hydronephrosis by sonogram: Urine output < 250 mL/12 hours, no significant improvement (< 1 milligram per deciliter (mg/dL)) in serum creatinine from baseline value over the first 24 - 72 hours post-transplant, or dialysis treatment.
29. Percent of Participants Using Lymphocyte Depleting Therapy (LDT) for the Initial Treatment of Acute Rejection (AR) by Month 36 [ Time Frame: Randomization to Month 36 ]
    The use of LDT (thymoglobulin or antithymocyte gamma globulin [ATGAM]) was permitted only for participants randomized to cyclosporine (CsA) who experienced impaired renal allograft function and anticipated delayed graft function following transplantation. Acute rejection (AR) defined as a clinico-pathological event requiring clinical evidence (an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remained elevated within 14 days post-transplantation and clinical suspicion of acute rejection existed) and biopsy confirmation. AR defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Only the episode with the highest Banff grade for each participant was counted.
30. Percent of Participants With Corticosteroid Resistant Acute Rejection (AR) by Month 36 [ Time Frame: Randomization to Month 36 ]
    Steroid-resistant acute rejection (AR) defined as the use of lymphocyte-depletion therapy following treatment with corticosteroids. AR defined as a clinico-pathological event requiring clinical evidence and renal biopsy confirmation demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Clinical evidence defined: either a or b was satisfied: a) an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b) an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remained elevated within 14 days post-transplantation and clinical suspicion of acute rejection existed. Allograft biopsies were evaluated by a blinded central independent pathologist using Banff 97 international standardized histopathological working classification of kidney transplant pathology. Only the episode with the highest Banff grade for each participant was counted.
31. Number of Participants Who Recovered Completely From an Episode of Acute Rejection (AR) by Month 12 [ Time Frame: Randomization to Month 12 ]
    Acute rejection (AR) = a clinico-pathological event requiring clinical evidence and renal biopsy confirmation demonstrating a Banff 97 classification of Grade IA or greater. Clinical evidence = if either a or b was satisfied: a: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b: an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists. Complete recovery following AR defined as serum creatinine [SCr] levels returned to baseline. Recovery calculated using 2 algorithms: Algorithm 1 = last laboratory measurement prior to onset of AR (baseline and first laboratory measurement after 84 days since onset of AR = resolution); Algorithm 2 = lowest laboratory measurement on or after transplantation and prior to onset day of AR (baseline and lowest laboratory measurement after onset on first AR up to Month 12 = resolution)
32. Percent of Participants With Subclinical Rejection at Month 12 [ Time Frame: Month 12 ]
    Subclinical rejection defined as histological findings by the central pathologist consistent with acute rejection, but lacking its clinical correlate. Acute rejection defined as a clinico-pathological event requiring clinical evidence and renal biopsy confirmation demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection. Only the episode with the highest Banff grade for each participant was counted. Clinical evidence defined if either a or b was satisfied: a) an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; b) an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remained elevated within 14 days post-transplantation and clinical suspicion of acute rejection existed. Allograft biopsies were evaluated by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology.
33. Number of Participants Treated for Acute Rejection (AR) Regardless of Histological Findings by Month 36 [ Time Frame: Randomization to Month 36 ]
    Allograft rejection includes any episode of rejection including: clinically suspected rejection, treated rejection, any central biopsy-proven acute rejection (BPAR), and acute rejection (AR: a subset of BPAR) defined as central biopsy-proven rejection that was either clinically suspected by protocol-defined reasons or by other reasons and was treated. Acute rejection (AR) defined as a clinico-pathological event requiring clinical evidence ( either an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output; or fever and graft tenderness; or a serum creatinine that remained elevated within 14 days post-transplantation and clinical suspicion of AR) and renal biopsy confirmation biopsy demonstrating a Banff 97 working classification of kidney transplant pathology classification of Grade IA or greater, with higher scores indicating more severe rejection. Only the highest Banff grade for each participant was counted.
34. Mean Value of Physical and Mental Components Using SF-36 Questionnaire [ Time Frame: Months 6, 12, 24, 36 ]
    SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire measuring health-related quality of life (HRQL) covering 2 scale measures: physical component summary (PCS) and mental component summary (MCS). PCS represented by 4 domains: physical function, role limitations due to physical problems, pain, and general health perception. MCS represented by 4 domains: vitality, social function, role limitations due to emotional problems, and mental health. Their scores were computed based on weighted combinations of the 8 domain scores, which were transformed to a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Higher scores reflect better health-related functional status. Scoring is standardized using the norm-based scoring method where data is scored in relation to the U.S. general population having a mean of 50 and a standard deviation of 10. Scores below 50 are below the U.S. general population norm and above 50 are above the U.S. general population norm.
35. Mean Value of the Eight Domain Scores of Quality of Life Using SF-36 Questionnaire [ Time Frame: Months 6, 12, 24, 36 ]
    SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire measuring health-related quality of life (HRQL) covering 2 scale measures: physical component summary (PCS) and mental component summary (MCS). PCS represented by 4 domains: physical function, role limitations due to physical problems, pain, and general health perception. MCS represented by 4 domains: vitality, social function, role limitations due to emotional problems, and mental health. Their scores were computed based on weighted combinations of the 8 domain scores, which were transformed to a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Higher scores reflect better health-related functional status. Scoring is standardized using the norm-based scoring method where data is scored in relation to the U.S. general population having a mean of 50 and a standard deviation of 10. Scores below 50 are below the U.S. general population norm and above 50 are above the U.S. general population norm.
36. Mean Relative to an Identified Distribution (Ridit) Value of Symptom Occurrence and Symptom Distress Using Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSDS-59R) [ Time Frame: Months 6, 12, 24, 36 ]
    The Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) was used to assess the occurrence (never, occasionally, regularly, almost always, always) and distress (0=no distress to 4=terrible distress) of symptoms associated with immunosuppressive therapies. Ridit (relative to an identified distribution) analysis (Fleiss JL. Statistical methods for rates and proportions. New York: John Wiley & Sons, Inc. 1991) was used. Ridit scores were calculated at baseline and at 6, 12, 24, and 36 months for overall symptom occurrence score and overall symptom distress. The Ridit score reflects the probability that a score observed for an individual randomly selected from a group would be higher (worse symptom) than a score observed for a randomly selected individual from the reference group. The reference group was constituted by the frequency distribution of the responses of all participants on all items at baseline. The ridit of the reference group is by definition, 0.5.
37. Mean Changes in the Value of Physical and Mental Components Using SF-36 From Baseline Up To Months 6, 12, 24, and 36 [ Time Frame: Baseline to Months 6, 12, 24,and 36 ]
    SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire measuring health-related quality of life (HRQL) covering 2 scale measures: physical component summary (PCS) and mental component summary (MCS). PCS represented by 4 domains: physical function, role limitations due to physical problems, pain, and general health perception. MCS represented by 4 domains: vitality, social function, role limitations due to emotional problems, and mental health. Their scores were computed based on weighted combinations of the 8 domain scores, which were transformed to a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Higher scores reflect better health-related functional status. Scoring is standardized using the norm-based scoring method where data is scored in relation to the U.S. general population having a mean of 50 and a standard deviation of 10. Scores below 50 are below the U.S. general population norm and above 50 are above the U.S. general population norm.
38. Mean Change in the Value of the Eight Domain Scores Using SF-36 From Baseline Up To Months 6, 12, 24, and 36 [ Time Frame: Baseline to Months 6, 12, 24, and 36 ]
    SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire measuring health-related quality of life (HRQL) covering 2 scale measures: physical component summary (PCS) and mental component summary (MCS). PCS represented by 4 domains: physical function, role limitations due to physical problems, pain, and general health perception. MCS represented by 4 domains: vitality, social function, role limitations due to emotional problems, and mental health. Their scores were computed based on weighted combinations of the 8 domain scores, which were transformed to a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Higher scores reflect better health-related functional status. Scoring is standardized using the norm-based scoring method where data is scored in relation to the U.S. general population having a mean of 50 and a standard deviation of 10. Scores below 50 are below the U.S. general population norm and above 50 are above the U.S. general population norm.
39. Percent of Participants Surviving With a Functioning Graft [ Time Frame: Months 24, 36 ]
    Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss was defined as a sustained level of serum creatinine (SCr) ≥ 6.0 milligrams per deciliter (mg/dL) or 530 micromoles per liter (μmol/L) as determined by the central laboratory for ≥ 4 weeks or ≥ 56 consecutive days of dialysis or impairment of renal function to such a degree that the participant underwent retransplant.
40. Percent of Participants With Composite Endpoint or Death, Graft Loss or Acute Rejection by Month 36 [ Time Frame: Randomization to Month 36 ]
    Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss was defined as a sustained level of serum creatinine (SCr) ≥ 6.0 milligrams per deciliter (mg/dL) or 530 micromoles per liter (μmol/L) as determined by the central laboratory for ≥ 4 weeks or ≥ 56 consecutive days of dialysis or impairment of renal function to such a degree that the participant underwent retransplant. Acute rejection was defined as central biopsy proven rejection that was either (1) clinically suspected by protocol defined reasons or (2) clinically suspected by other reasons and treated. Death and graft loss were not imputed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The subject is a recipient of a living donor or deceased donor kidney transplant.
• Male or Female, 18 or older

Exclusion Criteria:

• First time recipient, PRA >- 50% or for retransplantation PRA >- 30%.
• If retransplantation, previous graft loss cannot be due to acute rejection.
• Positive cross match.
• Subject receiving extended criteria donor (ECD) organ
• For Long-term extension study-Subjects who have completed three years of study treatment (through Week 156)

Contacts and Locations

Locations

United States, Alabama

University Of Alabama At Birmingham

Birmingham, Alabama, United States, 35294

United States, California

Loma Linda University Medical Center-Transplantation Institu

Loma Linda, California, United States, 92354

Cedars Sinai Medical Center

Los Angeles, California, United States, 90048

California Institute Of Renal Research

San Diego, California, United States, 92123

University Of California San Francisco Medical Center

San Francisco, California, United States, 94143

United States, Colorado

University Of Colorado Health Sciences Center

Aurora, Colorado, United States, 80045

United States, Connecticut

Yale University School Of Medicine-Yale New Haven Hospital

New Haven, Connecticut, United States, 06520

United States, Georgia

Piedmont Hospital

Atlanta, Georgia, United States, 30309

Emory University Hospital

Atlanta, Georgia, United States, 30322

Medical College Of Georgia

Augusta, Georgia, United States, 30912

United States, Illinois

University Of Chicago Hospitals

Chicago, Illinois, United States, 60637

United States, Indiana

University Of Iowa Hospitals And Clinics

Iowa City, Indiana, United States, 52242

United States, Kentucky

University Of Kentucky

Lexington, Kentucky, United States, 40536

United States, Maine

Maine Tranplant Program

Portland, Maine, United States, 04102

United States, Massachusetts

Western New England Renal & Transplant Associates, Pc

Springfield, Massachusetts, United States, 01107

United States, Michigan

Henry Ford Hospital, Transplant Institute

Detriot, Michigan, United States, 48202

United States, Minnesota

University Of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Washington University School Of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Recanati/Miller Transplantation Institute

New York, New York, United States, 10029

Columbia University College Of Physicians & Surgeons

New York, New York, United States, 10032

University Of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

University Of North Carolina At Chapel Hill

Chapel Hill, North Carolina, United States, 27599

Carolinas Medical Center

Charlotte, North Carolina, United States, 28203

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Pennsylvania

Div Of Multi-Organ Trans, Hepato-Biliary-Pancreatic Surgery

Philadelphia, Pennsylvania, United States, 19102

United States, South Carolina

Musc

Charleston, South Carolina, United States, 29425

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 27232

United States, Texas

Baylor University Medical Center

Dallas, Texas, United States, 75246

United States, Vermont

Fletcher Allen Health Care

Burlington, Vermont, United States, 05401

United States, Virginia

Inova Transplant Center

Fairfax, Virginia, United States, 22031

United States, Washington

Swedish Medical Center

Seattle, Washington, United States, 98104

Sacred Heart Medical Ctr Providence Medical Research Ctr

Spokane, Washington, United States, 99204

United States, Wisconsin

University Of Wisconsin

Madison, Wisconsin, United States, 53792

Froedtert Memorial Lutheran Hospital

Milwaukee, Wisconsin, United States, 53226

Argentina

Local Institution

Capital Federal, Buenos Aires, Argentina, C1425APQ

Local Institution

La Plata, Buenos Aires, Argentina, 1900

Local Institution

Cordoba, Crd, Cordoba, Argentina, X5016KEH

Local Institution

Rosario, Santa Fe, Argentina, 2000

Local Institution

Buenos Aires, Argentina, C1155APP

Local Institution

Santa Fe, Argentina, S3000EPV

Australia, New South Wales

Local Institution

Camperdown, New South Wales, Australia, 2050

Local Institution

Westmead, New South Wales, Australia, 2145

Australia, South Australia

Local Institution

Adelaide, South Australia, Australia, 5000

Australia, Victoria

Local Institution

Parkville, Victoria, Australia, 3052

Austria

Local Institution

Innsbuck, Austria, 6020

Local Institution

Vienna, Austria, 1090

Belgium

Local Institution

Gent, Belgium, 9000

Local Institution

Leuven, Belgium, 3000

Brazil

Local Institution

Rio De Janeiro / Rj, Rio De Janeiro, Brazil, 21041

Local Institution

Porto Alegre/rs, Rio Grande Do Sul, Brazil, 90035

Local Institution

Porto Alegre, Rio Grande Do Sul, Brazil, 90035

Local Institution

Campinas, Sao Paulo, Brazil, 13033

Local Institution

Sao Paulo/sp, Sao Paulo, Brazil, 04038

Local Institution

Sao Paulo, Brazil, 05403

Canada, Alberta

Local Institution

Edmonton, Alberta, Canada, T6G 2S2

Canada, Nova Scotia

Local Institution

Halifax, Nova Scotia, Canada, B3H 2Y9

Canada, Quebec

Local Institution

Montreal, Quebec, Canada, H1T 2M4

Local Institution

Montreal, Quebec, Canada, H2L 2W5

Local Institution

Montreal, Quebec, Canada, H3A 1A1

Canada, Saskatchewan

Local Institution

Saskatoon, Saskatchewan, Canada, S7M 0Z9

Czech Republic

Local Institution

Praha 4, Czech Republic, 140 21

France

Local Institution

Bordeaux, France, 33076

Local Institution

Brest Cedex, France, 29609

Local Institution

Creteil, France, 94000

Local Institution

Grenoble Cedex 9, France, 38043

Local Institution

Nante Cedex 01, France, 44093

Local Institution

Paris, France, 75015

Local Institution

Toulouse, France, 31054

Germany

Local Institution

Berlin, Germany, 13353

Local Institution

Erlangen, Germany, 91054

Local Institution

Essen, Germany, 45122

Local Institution

Hannover, Germany, 30625

Hungary

Local Institution

Szeged, Hungary, H-6720

India

Local Institution

Gujarat, Ahmedabad, India, 380016

Local Institution

Nadiad, Gujarat, India, 387001

Local Institution

Ahmedabad, Gujrat, India, 380052

Local Institution

Cochin, Kerala, India, 682304

Local Institution

Mumbai, Maharashtra, India, 400 026

Local Institution

Mumbai, Maharashtra, India, 400016

Local Institution

Chandigarh, India, 160012

Local Institution

Chennai, India, 600 006

Local Institution

Lucknow, India, 226000

Local Institution

New Delhi, India, 110076

Israel

Local Institution

Petah Tikva, Israel, 49100

Italy

Local Institution

Milano, Italy, 20162

Local Institution

Padova, Italy, 35128

Local Institution

Roma, Italy, 00168

Mexico

Local Institution

Mexico, Distrito Federal, Mexico, 14080

Local Institution

Cuernavaca, Morelos, Mexico, 62448

Local Institution

Monterrey, Nuevo Leon, Mexico, 64460

Local Institution

Aguascalientes, Mexico, 20000

Local Institution

Distrito Federal, Mexico, 14080

Local Institution

San Luis Potosi, Mexico, 78240

Poland

Local Institution

Poznan, Poland, 60-479

Local Institution

Szczecin, Poland, 70-111

South Africa

Local Institution

Observatory, Cape Town, South Africa, 7925

Local Institution

Pretoria, Gauteng, South Africa, 0002

Local Institution

Durban, Kwa Zulu Natal, South Africa, 4001

Spain

Local Institution

Barcelona, Spain, 08907

Local Institution

Madrid, Spain, 28040

Local Institution

Malaga, Spain, 29010

Sweden

Local Institution

Goteborg, Sweden, SE-413 45

Switzerland

Local Institution

Bern, Switzerland, 3010

Local Institution

Zurich, Switzerland, 8091

Turkey

Local Institution

Antalya, Turkey, 07059

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

More Information

Additional Information:

BMS clinical trial educational resource 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, Moal MC, Mondragon-Ramirez GA, Kothari J, Polinsky MS, Meier-Kriesche HU, Munier S, Larsen CP. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43. doi: 10.1056/NEJMoa1506027. Erratum In: N Engl J Med. 2016 Feb 18;374(7):698.

Dobbels F, Wong S, Min Y, Sam J, Kalsekar A. Beneficial effect of belatacept on health-related quality of life and perceived side effects: results from the BENEFIT and BENEFIT-EXT trials. Transplantation. 2014 Nov 15;98(9):960-8. doi: 10.1097/TP.0000000000000159.

Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari J, Lang P, Urrea EM, Massari P, Mondragon-Ramirez G, Reyes-Acevedo R, Rice K, Rostaing L, Steinberg S, Xing J, Agarwal M, Harler MB, Charpentier B. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012 Jan;12(1):210-7. doi: 10.1111/j.1600-6143.2011.03785.x. Epub 2011 Oct 12.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00256750
• Obsolete Identifiers: NCT00432497
• Other Study ID Numbers: IM103-008
• First Posted: November 22, 2005
• Results First Posted: August 19, 2016
• Last Update Posted: August 19, 2016
• Last Verified: July 2016

Additional relevant MeSH terms:

Renal Insufficiency; Kidney Failure, Chronic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Cyclosporine; Abatacept; Cyclosporins; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Calcineurin Inhibitors; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Agents