Belatacept in Liver Transplant Recipients

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00555321
First received: November 7, 2007
Last updated: September 17, 2012
Last verified: September 2012
  Purpose

The purpose of this clinical research study is to evaluate the effects of belatacept, relative to tacrolimus, on the incidence of rejection, graft loss and death in subjects receiving a liver transplant


Condition Intervention Phase
Immunosuppression in Solid Organ Transplant
Drug: Tacrolimus
Drug: Basiliximab
Drug: Belatacept More Intensive (MI)
Drug: Belatacept Less Intensive (LI)
Drug: Mycophenolate Mofetil (MMF)
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: Evaluation of Belatacept as First Line Immunosuppression in De Novo Liver Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percentage of Participants Who Experienced at Least One Episode of Acute Rejection (AR), Graft Loss, or Death by 6 Months Post-transplant [ Time Frame: At 6 months posttransplant ] [ Designated as safety issue: No ]
    Any AR that was clinically suspected and biopsy proven (by central pathologist) was included in this triple composite end point. All biopsies for suspected AR were assessed by a blinded central histopathologist using Banff grading schema. Graft loss was defined as impairment of liver function to such a degree that the participant died or underwent re-transplantation. For 95% (confidence interval) CI within each group, normal approximation is used if N>=5, otherwise exact method is used.

  • Number of Participants Who Had Adverse Events (AEs), Death, Serious AEs (SAEs) or Were Discontinued Due to AEs (Includes Long Term Extension [LTE] Data) [ Time Frame: Day 1 (randomization) to Week 104 + within 56 Days after the last infusion/dose, Deaths were monitored up to database lock (20-June-2011) ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.

  • Number of Participants Who Had AEs of Special Interest During the LTE [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ] [ Designated as safety issue: Yes ]
    AE of special interest included malignancies (including skin carcinomas), infections (viral, cytomegalovirus, herpes, fungal, and bacterial).

  • Number of Participants With Marked Hematology Abnormalities During the LTE [ Time Frame: Every 4 weeks from Week 53 to Week 104. ] [ Designated as safety issue: Yes ]
    Low platelet count: <50*10^9 c/µl; Low leukocytes: <2.0*10^3 c/µl; Low lymphocytes (absolute): <0.5*10^3 c/µl; Low neutrophils (absolute): <1.0*10^3 c/µl.

  • Number of Participants With Marked Liver and Kidney Function Abnormalities During the LTE [ Time Frame: Every 4 weeks from Week 53 to Week 104. ] [ Designated as safety issue: Yes ]
    ULN= upper limit of normal; Normal ranges are provided by the Central Laboratory and may vary according to sex and age. High alanine aminotransferase (ALT): >5.0*ULN U/L; High aspartate aminotransferase (AST): >5.0*ULN U/L; High direct bilirubin: >3.0*ULN mg/dL; High g-glutamyl transferase (GGT): >5.0*ULN U/L; High total bilirubin: >3.0*ULN mg/dL; High creatinine: > 3.0*ULN mg/dL

  • Number of Participants With Marked Electrolytes, Protein and Metabolic Test Abnormalities During the LTE [ Time Frame: Every 4 weeks from Week 53 to Week 104. ] [ Designated as safety issue: Yes ]
    Low Serum Potassium: <3.0 meq/L; High serum potassium:>6.0 mEq/L; Low serum magnesium:<0.8 mEq/L; Low serum sodium: <130 mEq/L; High serum sodium: >155 mEq/L; Low inorganic phosphorus: <2.0 mg/dL; High uric acid: >10 mg/dL


Secondary Outcome Measures:
  • Percentage of Participants Surviving With Functional Graft: 12-month Treatment Phase [ Time Frame: At 6 and 12 months ] [ Designated as safety issue: No ]
    For 95% CI within each group, normal approximation was used if N>=5. Otherwise exact method was used.

  • Percentage of Participants Surviving With Functional Graft by End of Study (Includes LTE Data) [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ] [ Designated as safety issue: No ]
    For 95% CI within each group, normal approximation was used if N>=5, otherwise exact method was used.

  • Percentage of Participants Who Experienced at Least One Episode of Acute Rejection, Graft Loss, or Death by 12 Months [ Time Frame: At 12 months posttransplant ] [ Designated as safety issue: No ]
    Any AR that was clinically suspected and biopsy proven (by central pathologist) was included in this triple composite end point. All biopsies for suspected AR were assessed by a blinded central histopathologist using Banff grading. Graft loss was defined as impairment of liver function to such a degree that the participant died or underwent re-transplantation. For 95% CI within each group, normal approximation is used if N>=5. Otherwise exact method is used. For 95% CI of difference, adjustment is made for randomization strata if N >= 5 in each treatment arm.

  • Percentage of Participants Who Experienced at Least One Episode of Acute Rejection, Graft Loss, or Death by End of Study (Includes LTE Data) [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ] [ Designated as safety issue: No ]
    Any AR that was clinically suspected and biopsy proven (by central pathologist) was included in this triple composite end point. All biopsies for suspected AR were assessed by a central histopathologist using Banff criteria. For 95% CI within each group, normal approximation was used if N>=5, otherwise exact method was used.

  • Number of Participants Having Acute Rejections: 12-month Treatment Phase [ Time Frame: 3 , 6, and 12 months ] [ Designated as safety issue: No ]
    Acute rejections were clinically suspected and biopsy proven by central pathologist. The number of episodes of AR was counted.

  • Number of Participants Having Acute Rejections During the LTE [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ] [ Designated as safety issue: No ]
    Acute rejections were clinically suspected and biopsy proven by central pathologist. The number of episodes of AR was counted.

  • Number of Participants With Central Biopsy Proven Acute Rejection by Treatment Type by 12 Months [ Time Frame: 3, 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Acute rejections were clinically suspected and biopsy proven by central pathologist. Corticosteroid-resistant rejection = Continued rejection, as documented by liver biopsy, after the completion of 2 days of corticosteroids and requiring use of T-cell depleting agent. Refractory rejection=Continued rejection, as documented by liver biopsy, after use of corticosteroids and T cell depletion therapy. Increase in the dose of TAC was monitored in participants who were assigned to one of the TAC-based regimens. TRT= treatment

  • Number of Participants With Central Biopsy Proven Acute Rejection by Treatment Type During the LTE [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ] [ Designated as safety issue: No ]
    Acute rejections were clinically suspected and biopsy proven by central pathologist. Corticosteroid-resistant rejection = Continued rejection, as documented by liver biopsy, after the completion of 2 days of corticosteroids and requiring use of T-cell depleting agent. Refractory rejection=Continued rejection, as documented by liver biopsy, after use of corticosteroids and T cell depletion therapy. Increase in the dose of TAC was monitored in participants who were assigned to one of the TAC-based regimens. DBL=database lock, TRT=treatment

  • Number of Participants Who Had Acute Rejection by Banff Grade by 12 Months [ Time Frame: 3, 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Acute Rejections (AR) were clinically suspected and biopsy proven by central pathologist. The Banff grading is a classification of renal allograft pathology and AR. Grade I: AR requiring moderate (>25%) to severe mononuclear cell interstitial infiltrate and moderate tubulitis; Grade II: AR requiring severe tubulitis and/or intimal arteritis; Grade III: AR requiring transmural arteritis. Only the episode with highest Banff grade for each participant was counted.

  • Number of Participants With Acute Rejections by Rejection Activity Index (RAI) by 12 Months [ Time Frame: 3, 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Acute Rejections were clinically suspected and biopsy proven by central pathologist. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI). An overall score of 0-2 is considered indeterminate, score of 3-4 is mild, score of 5-6 is moderate, and score of 7-9 is severe. Only the episode with the highest total RAI score for each participant was counted.

  • Number of Participants Having Acute Rejection by Rejection Activity Index During the LTE [ Time Frame: Day 1 (randomization) through End of study (database lock of 20-June-2011) ] [ Designated as safety issue: No ]
    Acute Rejections were clinically suspected and biopsy proven by central pathologist. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI). An overall score of 0-2 is considered indeterminate, score of 3-4 is mild, score of 5-6 is moderate, and score of 7-9 is severe. Only the episode with the highest total RAI score for each participant was counted.

  • Number of Participants at Risk of First Acute Rejection as Determined by Kaplan-Meier Method by 12 Months [ Time Frame: 3, 6, 9 and 12 months posttransplant ] [ Designated as safety issue: No ]
    The time from transplantation to the first AR episode in each treatment arm was summarized using Kaplan-Meier curves. Acute Rejections were clinically suspected and biopsy proven by central pathologist.

  • Mean Change From Baseline in Measured Glomerular Filtration Rate (GFR): 12-month Treatment Phase [ Time Frame: Baseline (2 month), 12 months posttransplant ] [ Designated as safety issue: No ]
    GFR was assessed using a true measure of glomerular filtration via iothalamate clearance test. The month 2 time point was selected as the "baseline" time point with respect to measured GFR due to logistical difficulty in obtaining measured GFR at the time of liver transplant and post-transplant renal function largely stabilizing by 2 months. All Measured GFR > 200 were truncated at 200.

  • Mean Change From Baseline in Calculated GFR, by Modification of Diet in Renal Disease (MDRD) Equation: 12-month Treatment Phase [ Time Frame: Baseline [BL] (pretransplant time point), 1, 2, 3, 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    GFR is a measure of the rate at which blood is filtered by the kidney. MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine (ScR), age, race, gender, blood urea nitrogen (BUN), and albumin (Alb). GFR (mL/min/1.73 m^2) = 170*(Scr)^-0.999*(Age)^-0.176*(0.762 if female)*(1.180 if African American)*(BUN)^-0.170*(Alb)^+0.318. ). BL= baseline, mL= milliliters; min= minute; m^2= meters squared.

  • Mean Change From Baseline in Calculated GFR During the LTE [ Time Frame: Baseline (pretransplant time point), 1, 2, 3, 6,12, 18, 24, 30, 36 months posttransplant ] [ Designated as safety issue: No ]
    GFR is a measure of the rate at which blood is filtered by the kidney. MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine (ScR), age, race, gender, blood urea nitrogen (BUN), and albumin (Alb). GFR (mL/min/1.73 m^2) = 170*(Scr)^-0.999*(Age)^-0.176*(0.762 if female)*(1.180 if African American)*(BUN)^-0.170*(Alb)^+0.318. ). BL= baseline, mL= milliliters; min= minute; m^2= meters squared.

  • Mean Change From Baseline Serum Creatinine at Months 1, 2, 3, 6 and 12 [ Time Frame: Baseline (pretransplant time point), 1, 2, 3, 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Measurement of SCr is commonly used as an indicator of renal function. High creatinine blood level is an indicator of deficient filtering by the kidney. SCr was determined at baseline and various post-baseline time points.

  • Mean Change in Baseline Values of Cystatin C at 2 and 12 Months [ Time Frame: Baseline (pretransplant), 2, and 12 months posttransplant ] [ Designated as safety issue: No ]
    Cystatin C is a protein encoded by the CST3 gene, which is mainly used as a biomarker of kidney function. If kidney function and glomerular filtration rate decline, the blood levels of cystatin C rise.

  • Belatacept Pharmacokinetic (PK) Parameter: Maximum Serum Concentration [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Maximum Plasma Concentration (Cmax) is the maximum observed serum drug concentration.

  • Belatacept Pharmacokinetic (PK) Parameter: Time to Achieve the Maximum Plasma Concentration [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Maximum Plasma Concentration (Tmax) is the time taken to reach the maximum observed plasma concentration.

  • Belatacept PK Parameter: Area Under the Serum Concentration-time Curve to the End of the Dosing Period (AUCtau) [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve for each dosing interval is determined using the linear trapezoidal rule. The AUC(TAU) of belatacept from the MI regimens and LI regimens were calculated over 2 and 4 weeks respectively.

  • Belatacept PK Parameter: Minimum Plasma Concentration [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Minimum Plasma Concentration (Cmin) is the minimum observed serum drug concentration.

  • Belatacept PK Parameter: Terminal Half-life [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Terminal Half-life (T 1/2) is the time a drug takes for the concentration levels to fall to 50% of their value.

  • Belatacept PK Parameter: Total Body Clearance [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Total body clearance is the rate and extent at which the drug is eliminated from the body. The clearance of a drug is used to understand the processes involved in drug elimination, distribution and metabolism. CLT was estimated from AUC (TAU) between Weeks 12 and 16, assuming steady state.

  • Belatacept PK Parameter: Volume of Distribution [ Time Frame: Samples were collected at Pre dose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105. ] [ Designated as safety issue: No ]
    Volume of distribution (Vss) is the volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration. . Vss was estimated from AUC (TAU) between Weeks 12 and 16, assuming steady state.

  • Belatacept PK Parameter: Amount Excreted in Ascites Fluid Over Days 1 to 14 [ Time Frame: Days 1 to 14 ] [ Designated as safety issue: No ]
    Amount Excreted in Ascites (Ae,asc) was estimated from the ascites drug concentrations and volumes within a dosing interval.

  • Belatacept PK Parameter: Clearance From Ascites Fluid [ Time Frame: Days 1 to 14 ] [ Designated as safety issue: No ]
    Clearance from ascites fluid was determined by amount excreted in ascites fluid (Ae, asc)[0-T] / AUC[0-T], where 0-T is the same duration relative to a belatacept infusion.

  • Belatacept Trough Concentration Before Each Infusion During the LTE [ Time Frame: Samples were collected predose on Days 5, 14, 28, 56, 84, 112, 168, 252, 336, 364; after end of infusion on Days 1, 5, 84, 112, 196, 336; and on Days 9, 85, 91, 98, 105, 532, 728. ] [ Designated as safety issue: No ]
    Minimum Plasma Concentration (Cmin) is the minimum observed serum drug concentration.

  • Percentage of Participants (Who Were Hepatitis C Virus [HCV] Positive at Baseline) With HCV Recurrence (Assessed by Central Pathologist) by 12 Months [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    HCV Recurrence is defined as Histological confirmation on liver biopsy by the Ishak (modified Knodell) system and required both a score >= 5 out of 18 on modified Histological Activity Index grading and a fibrosis Score >= 2 out of 6 on modified staging. All biopsies, including Week 52 biopsies, were considered. Only the first HCV recurrence episode for each participant was counted. For 95% CI within each group, normal approximation was used if N>=5, otherwise exact method was used. For 95% CI of difference, normal approximation was used if N>=5 in both arms, otherwise exact method was used.

  • Percentage of Participants (Who Were Hepatitis C Virus [HCV] Positive at Baseline) With HCV Recurrence (Assessed by Central Pathologist) During the LTE [ Time Frame: 12 months posttransplant, end of study (database lock, 20-June-2011) ] [ Designated as safety issue: No ]
    HCV Recurrence is defined as Histological confirmation on liver biopsy by the Ishak (modified Knodell) system and required both a score >= 5 out of 18 on modified Histological Activity Index grading and a fibrosis Score >= 2 out of 6 on modified staging. All biopsies, including Week 52 biopsies, were considered. Only the first HCV recurrence episode for each participant was counted. For 95% CI within each group, normal approximation was used if N>=5, otherwise exact method was used. For 95% CI of difference, normal approximation was used if N>=5 in both arms, otherwise exact method was used.

  • Number of Participants (Who Were HCV Positive at Baseline) With HCV Ribonucleic Acid (RNA) Levels >2.4*10^6 U/mL and >4.7*10^6 U/mL: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 6 and 12 months (mo) posttransplant ] [ Designated as safety issue: No ]
    Recurrent hepatitis C infection of the allograft following liver transplantation can be detected by monitoring HCV RNA levels. In HCV positive participants, quantitative HCV RNA levels > 2.4 * 10^6 U/mL and > 4.7 * 10^6 U/mL were descriptively summarized by treatment group. BL=baseline

  • Number of Participants (Who Were HCV Positive at Baseline) With HCV RNA Levels >2.4 * 10^6 U/mL and >4.7 * 10^6 U/mL During the LTE [ Time Frame: BL (pretransplant), 12, 18, 24, 30 months (mo) posttransplant ] [ Designated as safety issue: No ]
    Recurrent hepatitis C infection of the allograft following liver transplantation can be detected by monitoring HCV RNA levels. In HCV positive participants, quantitative HCV RNA levels > 2.4 x 10^6 U/mL and > 4.7 x 10^6 U/mL were descriptively summarized by treatment group. BL = baseline

  • Percentage of Participants Who Develop Dyslipidemia, Hypertriglyceridemia and Hypercholesterolemia After Randomization and Transplantation: 12-month Treatment Phase [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Percentage of participants who develop dyslipidemia, defined as hypertriglyceridemia (triglycerides [TGs] ≥ 500 mg/dL [5.65 mmol/L]), hypercholesterolemia (Low density lipoprotein [LDL] ≥ 100 mg/dL [2.59 mmol/L]), or elevated non-high density lipoprotein (non- high density lipoprotein [HDL] ≥ 130 mg/dL [3.36 mmol/L]) in the presence of high TGs (TGs ≥ 200 mg/dL [2.26 mmol/L]).

  • Percentage of Participants Meeting the Definition of Dyslipidemia, Hypertriglyceridemia or Hypercholesterolemia at Any Given Time: 12-month Treatment Phase [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Percentage of participants at any given time (at Month 6 and Month 12) who met the definition of dyslipidemia.Dyslipidemia is defined as hypertriglyceridemia (TGs ≥ 500 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]).

  • Summary Statistics for Lipid Parameters-Serum Total Non-High Density Lipoprotein (Non-HDL) Cholesterol: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Lipid Parameters; Serum HDL Cholesterol: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Lipid Parameters- Serum Low Density Lipoprotein Cholesterol (LDL): 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Lipid Parameters- Serum Cholesterol: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Lipid Parameters - Serum Triglyceride: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Systolic Blood Pressure: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 1, 3, 6, 9, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Summary Statistics for Diastolic Blood Pressure: 12-month Treatment Phase [ Time Frame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant ] [ Designated as safety issue: No ]
    Participants were considered to have hypertension if they had Diastolic Blood Pressure (SBP) ≥ 80 mmHg.

  • Summary Statistics for Mean Arterial Pressure: 12-month Treatment Phase [ Time Frame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Developed Hypertension in 12-month Treatment Phase [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Percentage of participants who develop hypertension after randomization and transplantation. Transient post-operative increases in BP were not to be counted as new onset hypertension. Hypertension was to be assessed only at or after the Week 4 visit. Participants were considered to have hypertension when either of the following criteria were met: (1) SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg or (2) participant received an antihypertensive medication(s) for the indication of hypertension or due to medical history of hypertension.

  • Percentage of Participants Who Have Hypertension at Any Given Time During the 12-month Treatment Phase [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    Percentage of participants at any given time who meet the definition of hypertension. Participants were considered to have hypertension when either of the following criteria were met: (1) SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg or (2) participant received an antihypertensive medication(s) for the indication of hypertension or due to medical history of hypertension.

  • Number of Participants Who Received Anti-hypertensive Therapy at Month 12 [ Time Frame: 12 months posttransplant ] [ Designated as safety issue: No ]
  • Percentage of Participants With New Onset Diabetes Mellitus (NODM): 12-month Treatment Phase [ Time Frame: 6 and 12 months posttransplant ] [ Designated as safety issue: No ]
    A participant who did not have diabetes prior to randomization was determined to have NODM if(i) the participant received an antidiabetic 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). For 95% CI within each group, normal approximation is used if N>=5. For 95% CI of difference, adjustment is made for randomization strata (HCV-Infection status at baseline) if N >= 5 in each treatment arm.

  • Glycosylated Hemoglobin (HbA1C) Values: 12-month Treatment Phase [ Time Frame: 6, 12 months (mth) posttransplant ] [ Designated as safety issue: No ]
    The HbA1c test is important in diabetes as a long-term measure of control over blood glucose, where the glucose bound to hemoglobin during the past 3-4 months is measured. A baseline diabetes participant was one who had a medical history of diabetes or being under anti-diabetic medication at the time of the transplantation. BL = baseline, DM = Diabetes mellitus.

  • Number of Participants Who Had AEs, Death, SAEs or Were Discontinued Due to AEs: 12-month Treatment Phase [ Time Frame: Day 1 (randomization) to 12 m + 8 week follow-up or ≤ 56 days after discontinuation of study medication ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event

  • Number of Participants Who Had Adverse Events of Special Interest During 12-month Treatment Phase [ Time Frame: Day 1 (randomization) to 12 months or ≤ 56 days after discontinuation of study medication ] [ Designated as safety issue: Yes ]
    AE of of special interest included malignancies (including skin carcinomas), infections (viral, cytomegalovirus, herpes, fungal, and bacterial), serious infections

  • Number of Participants With Marked Hematology Abnormalities: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 2, 4, 8, 12 weeks, and every 4 weeks for week 16 to 52 ] [ Designated as safety issue: Yes ]
    Low hemoglobin: <8 g/dL; Low platelet count: <50*10^9 C/L; Low leukocytes: <2.0 *10^3 c/µL; Low lymphocytes (absolute): <0.5*10^3 c/µL; Low neutrophils (absolute): <1.0*10^3 Cc/µL.

  • Number of Participants With Marked Liver and Kidney Function Abnormalities: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), 4, 12, 24, 52 weeks ] [ Designated as safety issue: Yes ]
    ULN= upper limit of normal; Normal ranges are provided by the central laboratory and may vary according to sex and age. High alkaline phosphatase (ALP): >5.0*ULN U/L; High alanine aminotransferase (ALT): >5.0*ULN U/L; High aspartate aminotransferase (AST): >5.0*ULN U/L; High direct bilirubin: >3.0 * ULN mg/dL; High g-glutamyl transferase (GGT): >5.0*ULN U/L; High total bilirubin: >3.0*ULN mg/dL; High creatinine: > 3.0*ULN mg/dL

  • Number of Participants With Marked Electrolytes, Protein and Metabolic Test Abnormalities: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), Weeks 4, 12, 24, and 52 ] [ Designated as safety issue: Yes ]
    Low total calcium: <7 mg/dL; High total calcium: >12.5 mg/dL ; Low bicarbonate: <11 mEq/L; Low serum potassium: <3.0 mEq/L; High serum potassium:>6.0 mEq/L; High serum magnesium: >2.46 mEq/L; Low serum magnesium:<0.8 mEq/L; Low serum sodium: <130 mEq/L; High serum sodium: >155 mEq/L; Low inorganic phosphorus: <2.0 mg/dL; Low albumin: <2 g/dL; High uric acid: >10 mg/dL

  • Number of Participants Who Had Abnormalities in Electrocardiograms: 12-month Treatment Phase [ Time Frame: Baseline (pretransplant), Week 52 ] [ Designated as safety issue: Yes ]
  • Change in Protein to Creatinine Ratio From Month 3 to Month 12. [ Time Frame: Month 3 and 12 ] [ Designated as safety issue: Yes ]

Enrollment: 260
Study Start Date: January 2008
Study Completion Date: June 2011
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1: Basiliximab+Belatacept (MI) + MMF Drug: Basiliximab
Intravenous (IV), 20 mg, Day1 and Day 5
Drug: Belatacept More Intensive (MI)

Intravenous (IV),

10 mg/kg on Days 1, 3 and 5, and at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24.

After 6 months (24 weeks) 5 mg/kg, every 4 weeks, 52 weeks (Short term [ST]), 5 mg/kg, every 4 weeks, 4 years (Long-term extension [LTE])

Drug: Mycophenolate Mofetil (MMF)
Intravenous (IV)/Capsules, IV/Oral, 1-2g/day, 52 weeks (Short term [ST]), ≤ 1 g/day, 4 years (Long-term extension [LTE])
Experimental: Group 2: Belatacept (MI) + MMF Drug: Belatacept More Intensive (MI)

Intravenous (IV),

10 mg/kg on Days 1, 3 and 5, and at Weeks 2, 4, 6, 8, 10, 12, 16, 20, and 24.

After 6 months (24 weeks) 5 mg/kg, every 4 weeks, 52 weeks (Short term [ST]), 5 mg/kg, every 4 weeks, 4 years (Long-term extension [LTE])

Drug: Mycophenolate Mofetil (MMF)
Intravenous (IV)/Capsules, IV/Oral, 1-2g/day, 52 weeks (Short term [ST]), ≤ 1 g/day, 4 years (Long-term extension [LTE])
Experimental: Group 3: Belatacept Less Intensive (LI) + MMF Drug: Belatacept Less Intensive (LI)

Intravenous (IV),

10 mg/kg on Days 1, 3 and 5, and at Weeks 2, 4, 8 and 12.

After 3 months (12 weeks) 5 mg/kg, every 4 weeks, 52 weeks (Short term [ST]), 5 mg/kg, every 4 weeks, 4 years (Long-Term Extension(LTE)

Drug: Mycophenolate Mofetil (MMF)
Intravenous (IV)/Capsules, IV/Oral, 1-2g/day, 52 weeks (Short term [ST]), ≤ 1 g/day, 4 years (Long-term extension [LTE])
Group 4: Tacrolimus + MMF
Other
Drug: Tacrolimus
Capsules, Oral, dosed to achieve 12 hour trough level of 6-12 ng/mL, twice daily, 52 weeks (Short Term [ST]), in accordance with local practice and the package insert, 4 years (Long-Term Extension [LTE])
Drug: Mycophenolate Mofetil (MMF)
Intravenous (IV)/Capsules, IV/Oral, 1-2g/day, 52 weeks (Short term [ST]), ≤ 1 g/day, 4 years (Long-term extension [LTE])
Active Comparator: Group 5: Tacrolimus Drug: Tacrolimus
Capsules, Oral, dosed to achieve 12 hour trough level of 6-12 ng/mL, twice daily, 52 weeks (Short Term [ST]), in accordance with local practice and the package insert, 4 years (Long-Term Extension [LTE])

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • First time recipient of deceased donor liver transplant
  • Age 18-70
  • Hepatitis C virus (HCV) positive recipients
  • For Long-term extension study-Subjects who have completed one year of study treatment (through Week 52)

Target Disease Exclusions:

Donor Exclusions a) Living donors b) ABO-incompatible donor recipient pairs c) Donor age < 12 or > 65 years d) Non heart-beating donors e) Anticipated cold ischemia time > 14 hours f) Donor Disease i) Known Human immunodeficiency virus (HIV) infection ii) Hepatitis B virus (HBV) surface antigen-positive or polymerase chain reaction (PCR)-positive donor if HBV negative recipient iii) HCV antibody-positive or PCR positive donor if HCV negative recipient

Recipient Exclusions g) Subjects with a history of hypercoagulable state h) Subjects with fulminant hepatic failure i) Subjects receiving a split or reduced liver j) Subjects who are Epstein-Barr virus (EBV) negative

Medical History and Concurrent Diseases

  1. Subjects who have received 2 or more consecutive weeks of dialysis 1 month prior to enrollment OR anticipated to have prolonged dialysis post-transplantation
  2. Subjects with known intrinsic renal disease (e.g., a urine protein/ creatinine ratio > 150 mg/g or the presence of an abnormal number of red blood cells (RBCs) or granular casts in the urine) AND calculated GFR < 40 ml/min/1.73 m^2 body surface area (BSA) (abbreviated Modification of Diet in Renal Disease [MDRD]). Subjects must have a calculated GFR assessment within 1 month prior to enrollment.
  3. Subjects with known HIV
  4. Subjects with any prior or concurrent solid organ (e.g., heart, kidney, pancreas) or cell (e.g., islet, bone marrow) transplant or subjects deemed likely to have a second solid organ or cell transplant (e.g., islet, bone marrow) within the next 3 years.
  5. Subjects with a history of cancer within the last 5 years

Allergies and Adverse Drug Reactions

a) Hypersensitivity to any medications that will be used in the protocol

Prohibited Treatments and/or Therapies

  1. Subjects receiving immunosuppressive agent(s) (e.g., methotrexate, abatacept, infliximab, etanercept, chemotherapy, etc.) within the past 6 months for other indications such as an autoimmune disease
  2. Subjects who received maintenance corticosteroids at a dose of > 5 mg/day of prednisone (or equivalent) for at least 7 consecutive days within the prior year for an underlying chronic inflammatory or autoimmune disease
  3. Subjects who have used any investigational drug within 30 days prior to the Day 1 visit
  4. Subjects previously treated with belatacept
  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: NCT00555321

  Hide Study Locations
Locations
United States, Arizona
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
United States, California
Usc University Hospital
Los Angeles, California, United States, 90033
University Of California San Francisco Medical Center
San Francisco, California, United States, 94143
United States, Florida
Mayo Clinic Transplant Department
Jacksonville, Florida, United States, 32224
Lifelink Healthcare Institute
Tampa, Florida, United States, 33606
United States, Georgia
Emory University Hospital
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University Feinberg School Of Medicine
Chicago, Illinois, United States, 60611
United States, Louisiana
Tulane Center For Abdominal Transplant
New Orleans, Louisiana, United States, 70112
United States, Michigan
Henry Ford Hospital
Detriot, Michigan, United States, 48202
United States, Minnesota
University Of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School Of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Nyu School Of Medicine
New York, New York, United States, 10016
Westchester Medical Center
Valhalla, New York, United States, 10595
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28203
United States, Ohio
Univ. Of Cin. Coll. Of Med.
Cincinnati, Ohio, United States, 45267
United States, Oklahoma
Integris-Baptist Medical Ctr.
Oklahoma City, Oklahoma, United States, 73112
United States, Pennsylvania
Hospital Of The University Of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
United States, Wisconsin
Froedtert Memorial Lutheran Hospital
Milwaukee, Wisconsin, United States, 53226
Argentina
Local Institution
Ciudad De Buenos Aires, Buenos Aires, Argentina, C1181ACH
Austria
Local Institution
Wien, Austria, 1090
Brazil
Local Institution
Curitiba, Parana, Brazil, 80060
Local Institution
Centro-Porto Alegre, Rio Grande Do Sul, Brazil, 90020
Local Institution
Rio De Janeiro, Brazil, 21041
Canada, Alberta
Local Institution
Edmonton, Alberta, Canada, T6G 2B7
Canada, Ontario
Local Institution
Toronto, Ontario, Canada, M5G 2N2
France
Local Institution
Clichy Cedex, France, 92118
Local Institution
Lyon, France, 69437
Local Institution
Montpellier, France, 34295
Local Institution
Paris, France, 75014
Local Institution
Toulouse Cedex 9, France, 31059
Local Institution
Villejuif, France, 94800
Germany
Local Institution
Berlin, Germany, 13353
Local Institution
Hamburg, Germany, 20246
Local Institution
Hannover, Germany, 30625
Local Institution
Heidelberg, Germany, 69120
Local Institution
Tuebingen, Germany, 72076
Italy
Local Institution
Bergamo, Italy, 24128
Local Institution
Padova, Italy, 35128
Local Institution
Pisa, Italy, 56124
Local Institution
Roma, Italy, 00168
Spain
Local Institution
Barcelona, Spain, 08036
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00555321     History of Changes
Other Study ID Numbers: IM103-045
Study First Received: November 7, 2007
Results First Received: September 17, 2012
Last Updated: September 17, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Mycophenolic Acid
Mycophenolate mofetil
Tacrolimus
Basiliximab
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 19, 2014