Study of Belatacept in Subjects Who Are Undergoing a Renal Transplant (BENEFIT-EXT)

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

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

Study Overview

• Status: Completed
• Conditions: Renal Transplantation
• Intervention / Treatment: Drug: Cyclosporin A; Drug: Belatacept Less Intensive Regimen (LI); Drug: Belatacept More Intensive Regimen (MI)

• Study Type: Interventional
• Enrollment (Actual): 595
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Santa Fe, Argentina, S3000EPV
    • Local Institution
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, 1425
      • Local Institution
    • Capital Federal, Buenos Aires, Argentina, C1155APP
      • Local Institution
  • Cordoba
    • Cordoba, Crd, Cordoba, Argentina, X5016KEH
      • Local Institution
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Local Institution
• Australia
  • South Australia
    • Woodville, South Australia, Australia, 5011
      • Local Institution
• Austria
  • Innsbuck, Austria, 6020
    • Local Institution
  • Vienna, Austria, 1090
    • Local Institution
• Belgium
  • Leuven, Belgium, 3000
    • Local Institution
• Brazil
  • Rio De Janeiro, Brazil, 21041
    • Local Institution
  • Sao Paulo, Brazil, 05403
    • Local Institution
  • Sao Paulo, Brazil, 4038-002
    • Local Institution
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035
      • Local Institution
    • Porto Alegre/rs, Rio Grande Do Sul, Brazil, 90035
      • Local Institution
  • Sao Paulo
    • Campinas/sp, Sao Paulo, Brazil, 13083
      • Local Institution
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2S2
      • Local Institution
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Local Institution
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
      • Local Institution
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7M 0Z9
      • Local Institution
• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile
      • Local Institution
• Czechia
  • Prague 4, Czechia, 140 21
    • Local Institution
• France
  • Bordeaux, France, 33076
    • Local Institution
  • Brest, Cedex 29, France, 29609
    • Local Institution
  • Creteil, France, 94000
    • Local Institution
  • Le Kremlin Bicetre Cedex, France, 94275
    • Local Institution
  • Nante Cedex 01, France, 44093
    • Local Institution
  • Paris, France, 75015
    • Local Institution
  • Toulouse Cedex, France, 31054
    • Local Institution
  • Tours Cedex 09, France, 37044
    • Local Institution
  • Vandoeuvre Les Nancy Cedex, France, 54511
    • Local Institution
• Germany
  • Berlin, Germany, 13353
    • Local Institution
  • Berlin, Germany, 10117
    • Local Institution
  • Erlangen, Germany, 91054
    • Local Institution
  • Essen, Germany, 45147
    • Local Institution
  • Hannover, Germany, 30625
    • Local Institution
• Hungary
  • Budapest, Hungary, 1082
    • Local Institution
  • Szeged, Hungary, H-6720
    • Local Institution
• Italy
  • Milano, Italy, 20162
    • Local Institution
  • Padova, Italy, 35128
    • Local Institution
  • Roma, Italy, 00168
    • Local Institution
• Norway
  • Oslo, Norway, N-0027
    • Local Institution
• Poland
  • Poznan, Poland, 60-479
    • Local Institution
  • Warszawa, Poland, 02-006
    • Local Institution
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0181
      • Local Institution
• Spain
  • Barcelona, Spain, 08036
    • Local Institution
  • Barcelona, Spain, 08907
    • Local Institution
  • Madrid, Spain, 28041
    • Local Institution
  • Madrid, Spain, 28040
    • Local Institution
  • Malaga, Spain, 29010
    • Local Institution
• Sweden
  • Gothenburg, Sweden, 413 45
    • Local Institution
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Local Institution
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90057
      • National Institute of Transplantation
    • Los Angeles, California, United States, 90024
      • Ucla Kidney & Kidney-Pancreas Transplant Research Office
    • San Diego, California, United States, 92133
      • Sharp Memorial Hospital
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Sciences Center
  • Connecticut
    • New Haven, Connecticut, United States, 06540
      • Yale University School of Medicine
  • Florida
    • Tampa, Florida, United States, 33606
      • Lifelink Healthcare Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30309
      • Piedmont Transplant Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University-Feinberg School of Medicine
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospitals
  • Louisiana
    • New Iberia, Louisiana, United States, 70563
      • Acadiana Renal Physicians
    • New Orleans, Louisiana, United States, 70112
      • Tulane Abdominal Transplant Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Springfield, Massachusetts, United States, 01107
      • Western New England Renal & Transplant Associates, Pc
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital, Transplant Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10032
      • Columbia University College of Physicians & Surgeons
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College Of Medicine, Department Of Surgery
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subject is a first-time recipient of a kidney transplant from a deceased donor.
• Specific donor criteria

Exclusion Criteria:

• Donor age <10 years
• Subjects receiving a concurrent solid organ or cell transplant (lung, heart, etc.)
• Subjects with a positive T-cell lymphocytotoxic crossmatch.
• Subjects who are positive for Hepatitis B or C, or HIV
• Active tuberculosis
• History of cancer in the last 5 years
• History of substance abuse
• Specific laboratory results are exclusionary
• Mammography suspicious for cancer
• Allergy to iodine
• For Long-term extension study-Subjects who have completed three years of study treatment (through Week 156)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• 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.
• Pestana JO, Grinyo JM, Vanrenterghem Y, Becker T, Campistol JM, Florman S, Garcia VD, Kamar N, Lang P, Manfro RC, Massari P, Rial MD, Schnitzler MA, Vitko S, Duan T, Block A, Harler MB, Durrbach A. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012 Mar;12(3):630-9. doi: 10.1111/j.1600-6143.2011.03914.x. Epub 2012 Feb 2.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: June 17, 2005
• First Submitted That Met QC Criteria: June 17, 2005
• First Posted (Estimate): June 20, 2005

Study Record Updates

• Last Update Posted (Actual): July 7, 2017
• Last Update Submitted That Met QC Criteria: June 28, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Immune Checkpoint Inhibitors; Calcineurin Inhibitors; Abatacept; Cyclosporine; Cyclosporins
• Other Study ID Numbers: IM103-027