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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00035555
First received: May 3, 2002
Last updated: November 27, 2013
Last verified: November 2013
  Purpose

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).


Condition Intervention Phase
Graft Rejection
Kidney Transplantation
Renal Transplantation
Drug: Belatacept
Drug: Cyclosporine
Drug: Mycophenolate mofetil (MMF)
Drug: Corticosteroids
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Number of Participants With an Episode of Clinically-suspected and Biopsy-proven Acute Rejection (CSPAR) [ Time Frame: By Month 6 posttransplant (From Day 1 to Month 6) ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants With Biopsy-proven Acute Rejection (BPAR) Through Months 6 and 12 [ Time Frame: Through Months 6 and 12 posttransplant (From Day 1 to Months 6 and 12) ] [ Designated as safety issue: Yes ]
    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.

  • Percentage of Participants With Biopsy-proven Acute Rejection (BPAR) or Who Received Treatment for Acute Rejection [ Time Frame: By Months 3, 6, and 12 posttransplant (Day 1 to Months 3, 6, and 12) ] [ Designated as safety issue: Yes ]
    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).

  • Percentage of Participants With Acute Rejection or Presumed Acute Rejection (PAR) [ Time Frame: By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12) ] [ Designated as safety issue: Yes ]
    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.

  • Percentage of Participants Who Had Chronic Allograft Nephropathy [ Time Frame: By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12) ] [ Designated as safety issue: Yes ]
    Based on postbaseline biopsies

  • Mean Iohexol Clearance [ Time Frame: By Months 1, 6, and 12 posttransplant (Day 1 to Months 1, 6, and 12) ] [ Designated as safety issue: Yes ]
    Iohexol, a true glomerular filtration marker, is used to measure glomerular filtration rate.

  • Percentage of Participants Who Used Antihypertensive Medication [ Time Frame: By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12) ] [ Designated as safety issue: Yes ]
    Hypertension is defined as diastolic blood pressure ≥90 mm Hg and/or systolic blood pressure ≥140 mm Hg

  • Number of Participants With Hypertension [ Time Frame: By Months 6 and 12 posttransplant (Day 1 to Months 6 and 12) ] [ Designated as safety issue: Yes ]
    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.

  • Mean LDL Cholesterol, HDL Cholesterol, Total Cholesterol, Triglyceride, and Non-HDL Levels [ Time Frame: By Months 1, 6, and 12 posttransplant (Day 1 to Months 1, 6, and 12) ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Posttransplant Diabetes Mellitus [ Time Frame: By Months 1, 3, 6, 9, and 12 posttransplant (Day 1 to Months 1, 3, 6, 9, and 12 ) ] [ Designated as safety issue: No ]
    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


Other Outcome Measures:
  • 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 [ Time Frame: Day 1 (posttransplant) continuously to 56 days following last dose of study medication ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants Meeting Marked Abnormality Criteria for Select Hemolytic, Blood Chemistry, and Urinalysis Laboratory Test Results [ Time Frame: Days 8 and Months 1, 3, 6, 9, and 12 posttransplant (from Day 1) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 230
Study Start Date: March 2001
Study Completion Date: July 2012
Primary Completion Date: January 2004 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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: Cyclosporine
Oral, capsule
Other Name: The cyclosporine used in this study will be in the modified formulation with enhanced bioavailability.
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT00035555

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

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00035555     History of Changes
Other Study ID Numbers: IM103-100
Study First Received: May 3, 2002
Results First Received: September 4, 2013
Last Updated: November 27, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
kidney
transplant
rejection

Additional relevant MeSH terms:
Mycophenolic Acid
Mycophenolate mofetil
Cyclosporins
Cyclosporine
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 19, 2014