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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00256750
First received: November 15, 2005
Last updated: July 12, 2016
Last verified: July 2016
  Purpose
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 Intervention Phase
Kidney Transplantation
Chronic Kidney Failure
Drug: Cyclosporine (CsA)
Drug: Belatacept LI (less intensive)
Drug: Belatacept MI (more intensive)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT)

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percent of Participants Surviving With a Functioning Graft by Month 12 [ Time Frame: Day 1 to Month 12 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants Experiencing Acute Rejection (AR) Post-transplant by Month 12 [ Time Frame: Day 1 to Month 12 ] [ Designated as safety issue: No ]
    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:
  • Mean Value of the Measured Glomerular Filtration Rate (mGFR) [ Time Frame: Months 3, 12, 24 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Prevalence of Chronic Allograft Nephropathy (CAN) at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events by Month 84 [ Time Frame: Randomization to Month 84 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Adverse Events of Special Interest by Month 84 [ Time Frame: Randomization to Month 84 ] [ Designated as safety issue: Yes ]
    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.

  • Mean Blood Pressure at Month 84 [ Time Frame: Month 84 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants Meeting Marked Laboratory Abnormality Criteria Post-transplant by Month 36 [ Time Frame: Baseline to Month 36 ] [ Designated as safety issue: Yes ]

    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+


  • Percent of Participants With Development of Anti-Donor HLA Positive Antibodies by Month 84 [ Time Frame: Randomization to Month 84 ] [ Designated as safety issue: Yes ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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).

  • Mean Value of the Calculated Glomerular Filtration Rate (cGFR) With Imputation [ Time Frame: Months 6, 12, 24, 36 ] [ Designated as safety issue: No ]
    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

  • Mean Change in Calculated Glomerular Filtration Rate (cGFR) From Month 6 to Month 12 [ Time Frame: Month 6 to Month 12 ] [ Designated as safety issue: No ]
    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

  • Percent of Participants With Incidence of New Onset Diabetes Mellitus by Month 36 [ Time Frame: Week 4 post-transplantation to Month 36 ] [ Designated as safety issue: No ]
    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)

  • Percent of Participants Using At Least One Anti-Hypertensive Medication to Control Hypertension at Month 36 [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    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

  • Percent of Participants With Incidence of Hypertension Post-Transplantation at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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

  • Percent of Participants With Prevalence of Hypertension Post-Transplantation at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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

  • Mean Systolic Blood Pressure and Diastolic Blood Pressure [ Time Frame: Months 12, 24, 36 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants at Baseline With Controlled Hypertension Post Transplantation by Month 12 [ Time Frame: Day 1 to Month 12 ] [ Designated as safety issue: No ]
    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

  • Percent of Participants With Prevalence of Controlled Hypertension at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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

  • Percent of Non-dyslipidemic Participants With Incidence of Dyslipidemia Post-Transplantation by Month 12 [ Time Frame: Randomization to Month 12 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Prevalence of Dyslipidemia at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Controlled Dyslipidemia at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Antihyperlipidemic Medication by Intensity Level [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants Using At Least One Anti-Hyperlipidemic Medication [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    This analysis is based on all participants who were followed up at least 1092 days after transplantation.

  • Mean Value of Lipid Parameters [ Time Frame: Months 12, 24, 36 ] [ Designated as safety issue: No ]
    Lipid parameters included total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and triglycerides (TGs).

  • Percent of Participants With Prevalence of Acute Rejection (AR) by Month 36 [ Time Frame: Randomization to Month 36 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Corticosteroid Resistant Acute Rejection (AR) by Month 36 [ Time Frame: Randomization to Month 36 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Who Recovered Completely From an Episode of Acute Rejection (AR) by Month 12 [ Time Frame: Randomization to Month 12 ] [ Designated as safety issue: No ]
    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)

  • Percent of Participants With Subclinical Rejection at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Treated for Acute Rejection (AR) Regardless of Histological Findings by Month 36 [ Time Frame: Randomization to Month 36 ] [ Designated as safety issue: No ]
    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.

  • Mean Value of Physical and Mental Components Using SF-36 Questionnaire [ Time Frame: Months 6, 12, 24, 36 ] [ Designated as safety issue: No ]
    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.

  • Mean Value of the Eight Domain Scores of Quality of Life Using SF-36 Questionnaire [ Time Frame: Months 6, 12, 24, 36 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants Surviving With a Functioning Graft [ Time Frame: Months 24, 36 ] [ Designated as safety issue: No ]
    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.

  • Percent of Participants With Composite Endpoint or Death, Graft Loss or Acute Rejection by Month 36 [ Time Frame: Randomization to Month 36 ] [ Designated as safety issue: No ]
    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.


Enrollment: 738
Study Start Date: March 2005
Study Completion Date: April 2015
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00256750

  Hide Study 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:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00256750     History of Changes
Obsolete Identifiers: NCT00432497
Other Study ID Numbers: IM103-008 
Study First Received: November 15, 2005
Results First Received: May 24, 2016
Last Updated: July 12, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Cyclosporins
Cyclosporine
Abatacept
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

ClinicalTrials.gov processed this record on August 25, 2016