Study Comparing the Safety and Efficacy of Belatacept With That of Cyclosporine in Patients With a Transplanted Kidney

Phase II/III, Open-Label, Randomized, Controlled, Multiple-Dose Study of Efficacy and Safety of BMS-224818 (Belatacept) as Part of a Quadruple Drug Regimen in First Renal Transplant Recipients

The purpose of this study is to determine whether treatment with Belatacept (BMS-224818) is as efficacious as treatment with cyclosporine at preventing acute rejection and with a superior safety/tolerability profile (better kidney function and blood pressure, fewer lipid problems, less diabetes mellitus).

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation; Graft Rejection; Renal Transplantation
• Intervention / Treatment: Drug: Belatacept; Drug: Mycophenolate mofetil (MMF); Drug: Corticosteroids; Drug: Cyclosporine

• Study Type: Interventional
• Enrollment (Actual): 230
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143-0001
      • Univ. of Calif. - San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Univ. School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198-1002
      • Univ. of Nebraska Medical Center
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • New York
    • New York, New York, United States, 10029-6574
      • Mount Sinai Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univ. of Pennsylvania
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical Univ. of South Carolina
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Univ. Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-7375
      • Univ. of Wisconsin

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

Key inclusion criteria

• Recipients of first kidney transplant

Key exclusion criteria

• Those at high risk for acute allograft rejection, including those who receive a second or more renal transplant, those with a history of panel reactive antibody levels >20%, and those considered by investigators to be at relatively higher risk for acute rejection
• Human leukocyte antigen-identical donor-recipient pairs
• Cold ischemia time >36 hours (donor kidney)
• Participants who are positive for hepatitis C antibody, on polymerase chain reaction, for hepatitis B surface antigen, and for human immunodeficiency virus
• A positive purified protein derivative tuberculosis test (test performed within 1 year of enrollment), unless previously vaccinated with Bacille-Calmette-Guérin or those who had a history of adequate chemoprophylaxis
• Any active infection that would normally exclude transplantation
• Recipients of multiple organ transplants
• Donor age >60 or <6 years or donors whose hearts were not beating
• Recipients with underlying renal disease of (due to risk of rapid disease recurrence in the allograft): focal segmental glomerulosclerosis, Type I or II membranoproliferative glomerulonephritis, or hemolytic uremic syndrome/ thrombotic thrombocytopenic purpura
• A positive T-cell lymphocytoxic crossmatch using donor lymphocytes and recipient serum
• A history of true allergy to intravenous iodinated roentgenographic contrast agents
• Participants with life expectancy severely limited by disease state or other underlying medical condition
• A history of cancer (other than nonmelanoma skin cell cancers cured by local resection) within the last 5 years
• Mammogram film with any clinically significant abnormality requiring further investigation or biopsies
• History of substance abuse (drug or alcohol) or psychotic disorders that were not compatible with adequate study follow-up
• A currently functioning, nonrenal transplant
• Previous treatment with basiliximab for any reason
• Active peptic ulcer disease, chronic diarrhea, or gastrointestinal malabsorption
• Those who had used any investigational drug within 30 days before the Day 1 visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belatacept: More intensive (MI) regimen; The MI regimen was designed to achieve projected serum trough concentrations of belatacept of approximately 20 μg/mL through Day 99, and approximately 5 μg/mL through Day 183 (10 mg/kg on Days 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, and 169). After Day 169, patients were reallocated and dosed to achieve projected trough serum concentrations of approximately 2 or 0.25 μg/mL (5 mg/kg every 4 or 8 weeks starting on Day 197). Those patients who received belatacept every 8 weeks received placebo infusions on scheduled treatment dates between infusions of active drug to maintain the blind between treatment regimens. Patients initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the patient was able to tolerate medications by mouth. Corticosteroids given daily.	Drug: Belatacept; Solution, intravenous; Other Names: LEA29Y, BMS-224818; Drug: Mycophenolate mofetil (MMF); Oral, capsule; Drug: Corticosteroids; Corticosteroids given daily, orally or intravenously (IV). Day of transplant (Day 1): methylprednisolone, 500 mg, given IV on arrival in operating room; Day 2: methylprednisolone, 250 mg, given IV once daily; Day 3: prednisone, 100 mg, given orally once daily; Day 4: prednisone, 50 mg, given orally once daily; Days 5 through 30: prednisone, 25 mg, given orally once daily; Days 31-44: prednisone, 22.5 mg, given orally once daily; Days 45-58: prednisone, 20 mg, given orally once daily
Experimental: Belatacept: Less intensive (LI) regimen; The LI regimen was designed to achieve projected trough serum concentrations of belatacept of approximately 20 μg/mL through Day 29, and approximately 5 μg/mL through Day 99 (10 mg/kg on Days 1, 15, 29, 57 and 85). After Day 85, these subjects were reallocated and dosed to achieve projected trough serum concentrations of either approximately 2 or 0.25 μg/mL (5 mg/kg every 4 or 8 weeks starting on Day 113). Participants initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the participant was able to tolerate medications by mouth. Corticosteroids given daily.	Drug: Belatacept; Solution, intravenous; Other Names: LEA29Y, BMS-224818; Drug: Mycophenolate mofetil (MMF); Oral, capsule; Drug: Corticosteroids; Corticosteroids given daily, orally or intravenously (IV). Day of transplant (Day 1): methylprednisolone, 500 mg, given IV on arrival in operating room; Day 2: methylprednisolone, 250 mg, given IV once daily; Day 3: prednisone, 100 mg, given orally once daily; Day 4: prednisone, 50 mg, given orally once daily; Days 5 through 30: prednisone, 25 mg, given orally once daily; Days 31-44: prednisone, 22.5 mg, given orally once daily; Days 45-58: prednisone, 20 mg, given orally once daily
Experimental: Cyclosporine regimen; The initial daily dose was 7±3 mg/kg. Subsequent doses were adjusted to maintain a predefined range of serum concentrations: 1st month, target level 150-400 ng/mL; after 1st month, target level of 150-300 ng/mL. Participants initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the participant was able to tolerate medications by mouth. Corticosteroids given daily.	Drug: Mycophenolate mofetil (MMF); Oral, capsule; Drug: Corticosteroids; Corticosteroids given daily, orally or intravenously (IV). Day of transplant (Day 1): methylprednisolone, 500 mg, given IV on arrival in operating room; Day 2: methylprednisolone, 250 mg, given IV once daily; Day 3: prednisone, 100 mg, given orally once daily; Day 4: prednisone, 50 mg, given orally once daily; Days 5 through 30: prednisone, 25 mg, given orally once daily; Days 31-44: prednisone, 22.5 mg, given orally once daily; Days 45-58: prednisone, 20 mg, given orally once daily; Drug: Cyclosporine; Oral, capsule; Other Names: The cyclosporine used in this study will be in the modified formulation with enhanced bioavailability.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With an Episode of Clinically-suspected and Biopsy-proven Acute Rejection (CSPAR)	No participant was to receive treatment for acute rejection without a biopsy to confirm the diagnosis. CSPAR=Clinically-suspected rejection, defined as an increase in serum creatinine ≥0.5 mg/dL compared with the baseline value in the absence of other factors known to adversely affect renal function, and biopsy-proven rejection, which includes all cases in which a biopsy was read by the central pathologist as demonstrating acute rejection regardless of the reason why the biopsy was performed.	By Month 6 posttransplant (From Day 1 to Month 6)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Biopsy-proven Acute Rejection (BPAR) Through Months 6 and 12	BPAR includes all cases in which a biopsy read by the central pathologist demonstrates acute rejection, regardless of the reason that the biopsy was performed.	Through Months 6 and 12 posttransplant (From Day 1 to Months 6 and 12)
Percentage of Participants With Biopsy-proven Acute Rejection (BPAR) or Who Received Treatment for Acute Rejection	BPAR includes all cases in which a biopsy read by the central pathologist demonstrates acute rejection, regardless of the reason that the biopsy was performed. A participant was reported as having had an episode of treated acute rejection if he or she received antirejection therapy during an episode of rejection (clinically-suspected or biopsy-proven rejection).	By Months 3, 6, and 12 posttransplant (Day 1 to Months 3, 6, and 12)
Percentage of Participants With Acute Rejection or Presumed Acute Rejection (PAR)	Throughout this study, acute rejection=clinically-suspected and biopsy-proven acute rejection (BPAR). Clinically-suspected rejection is defined as an increase in serum creatinine ≥0.5 mg/dL compared with the baseline value in the absence of other factors known to adversely affect renal function. BPAR includes all cases in which a biopsy was read by the central pathologist as demonstrating acute rejection regardless of the reason why the biopsy was performed. PAR is defined as an elevation in SCr ≥0.5 mg/dL compared with the baseline value in the absence of other factors known to adversely affect renal function that led the investigator to suspect that the participant had experienced acute rejection, and in whom either the biopsy did not confirm acute rejection and the participant received treatment for acute rejection or the participant received treatment for acute rejection without a biopsy to confirm the diagnosis.	By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12)
Percentage of Participants Who Had Chronic Allograft Nephropathy	Based on postbaseline biopsies	By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12)
Mean Iohexol Clearance	Iohexol, a true glomerular filtration marker, is used to measure glomerular filtration rate.	By Months 1, 6, and 12 posttransplant (Day 1 to Months 1, 6, and 12)
Percentage of Participants Who Used Antihypertensive Medication	Hypertension is defined as diastolic blood pressure ≥90 mm Hg and/or systolic blood pressure ≥140 mm Hg	By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12)
Number of Participants With Hypertension	Hypertension is defined as diastolic blood pressure ≥90 mm Hg and/or systolic blood pressure ≥140 mm Hg or, the use of any antihypertensive medication.	By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12)
Mean LDL Cholesterol, HDL Cholesterol, Total Cholesterol, Triglyceride, and Non-HDL Levels	LDL=low-density lipoprotein; HDL=high-density lipoprotein. Total cholesterol=LDL + HDL + very low-density (VLDL) cholesterol. VLDL=triglycerides divided by 5. Non-HDL cholesterol=Total cholesterol minus HDL cholesterol.	By Months 1, 6, and 12 posttransplant (Day 1 to Months 1, 6, and 12)
Number of Participants With Posttransplant Diabetes Mellitus	Posttransplant diabetes mellitus is defined as the need for treatment of hyperglycemia with either an oral agent or insulin for a total of >4 weeks or hemoglobin A1c (HbA1c) >7% in a participant not known to be diabetic prior to transplantation	By Months 1, 3, 6, 9, and 12 posttransplant (Day 1 to Months 1, 3, 6, 9, and 12 )

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, Discontinuations Due to SAEs, Adverse Events (AEs), Treatment-related AEs, and Discontinuations Due to AEs	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. Treatment-related=having certain, probable, possible, or missing relationship to study drug.	Day 1 (posttransplant) continuously to 56 days following last dose of study medication
Number of Participants Meeting Marked Abnormality Criteria for Select Hemolytic, Blood Chemistry, and Urinalysis Laboratory Test Results	Normal laboratory values: Hemoglobin (g/dL): Males (18-64 years) 13.8-17, (65 years and older) 11.8-16.8; Females (18-64 years) 12.0-15.6, F (65 years and older) 11.1-15.5. Platelets (per mm^3) 130,000-400,000. Leukocytes (18 years and older) 3.8-10.8 1000/uL. ALT (u/L)(13 years and older) 0-48.	Days 8 and Months 1, 3, 6, 9, and 12 posttransplant (from Day 1)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: March 1, 2001
• Primary Completion (Actual): January 1, 2004
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: May 3, 2002
• First Submitted That Met QC Criteria: May 3, 2002
• First Posted (Estimate): May 6, 2002

Study Record Updates

• Last Update Posted (Estimate): January 13, 2014
• Last Update Submitted That Met QC Criteria: November 27, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: transplant; rejection; kidney
• 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; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Immune Checkpoint Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Abatacept; Cyclosporine; Cyclosporins
• Other Study ID Numbers: IM103-100