Clinical trial NCT00555321: Belatacept in Liver Transplant Recipients
Official title: Evaluation of Belatacept as First Line Immunosuppression in De Novo Liver Transplant Recipients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Immunosuppression in Solid Organ Transplant
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2007-11-08
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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


Eligibility 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

Primary outcomes:
measure: Percentage of Participants Who Experienced at Least One Episode of Acute Rejection (AR), Graft Loss, or Death by 6 Months Post-transplant
timeFrame: At 6 months posttransplant
measure: Number of Participants Who Had Adverse Events (AEs), Death, Serious AEs (SAEs) or Were Discontinued Due to AEs (Includes Long Term Extension [LTE] Data)
timeFrame: Day 1 (randomization) to Week 104 + within 56 Days after the last infusion/dose, Deaths were monitored up to database lock (20-June-2011)
measure: Number of Participants Who Had AEs of Special Interest During the LTE
timeFrame: Day 1 (randomization) through database lock (20-June-2011)
measure: Number of Participants With Marked Hematology Abnormalities During the LTE
timeFrame: Every 4 weeks from Week 53 to Week 104.
measure: Number of Participants With Marked Liver and Kidney Function Abnormalities During the LTE
timeFrame: Every 4 weeks from Week 53 to Week 104.
measure: Number of Participants With Marked Electrolytes, Protein and Metabolic Test Abnormalities During the LTE
timeFrame: Every 4 weeks from Week 53 to Week 104.
Secondary outcomes:
measure: Percentage of Participants Surviving With Functional Graft: 12-month Treatment Phase
timeFrame: At 6 and 12 months
measure: Percentage of Participants Surviving With Functional Graft by End of Study (Includes LTE Data)
timeFrame: Day 1 (randomization) through database lock (20-June-2011)
measure: Percentage of Participants Who Experienced at Least One Episode of Acute Rejection, Graft Loss, or Death by 12 Months
timeFrame: At 12 months posttransplant
measure: Percentage of Participants Who Experienced at Least One Episode of Acute Rejection, Graft Loss, or Death by End of Study (Includes LTE Data)
timeFrame: Day 1 (randomization) through database lock (20-June-2011)
measure: Number of Participants Having Acute Rejections: 12-month Treatment Phase
timeFrame: 3 , 6, and 12 months
measure: Number of Participants Having Acute Rejections During the LTE
timeFrame: Day 1 (randomization) through database lock (20-June-2011)
measure: Number of Participants With Central Biopsy Proven Acute Rejection by Treatment Type by 12 Months
timeFrame: 3, 6 and 12 months posttransplant
measure: Number of Participants With Central Biopsy Proven Acute Rejection by Treatment Type During the LTE
timeFrame: Day 1 (randomization) through database lock (20-June-2011)
measure: Number of Participants Who Had Acute Rejection by Banff Grade by 12 Months
timeFrame: 3, 6 and 12 months posttransplant
measure: Number of Participants With Acute Rejections by Rejection Activity Index (RAI) by 12 Months
timeFrame: 3, 6 and 12 months posttransplant
measure: Number of Participants Having Acute Rejection by Rejection Activity Index During the LTE
timeFrame: Day 1 (randomization) through End of study (database lock of 20-June-2011)
measure: Number of Participants at Risk of First Acute Rejection as Determined by Kaplan-Meier Method by 12 Months
timeFrame: 3, 6, 9 and 12 months posttransplant
measure: Mean Change From Baseline in Measured Glomerular Filtration Rate (GFR): 12-month Treatment Phase
timeFrame: Baseline (2 month), 12 months posttransplant
measure: Mean Change From Baseline in Calculated GFR, by Modification of Diet in Renal Disease (MDRD) Equation: 12-month Treatment Phase
timeFrame: Baseline [BL] (pretransplant time point), 1, 2, 3, 6 and 12 months posttransplant
measure: Mean Change From Baseline in Calculated GFR During the LTE
timeFrame: Baseline (pretransplant time point), 1, 2, 3, 6,12, 18, 24, 30, 36 months posttransplant
measure: Mean Change From Baseline Serum Creatinine at Months 1, 2, 3, 6 and 12
timeFrame: Baseline (pretransplant time point), 1, 2, 3, 6 and 12 months posttransplant
measure: Mean Change in Baseline Values of Cystatin C at 2 and 12 Months
timeFrame: Baseline (pretransplant), 2, and 12 months posttransplant
measure: Belatacept Pharmacokinetic (PK) Parameter: Maximum Serum Concentration
timeFrame: 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.
measure: Belatacept Pharmacokinetic (PK) Parameter: Time to Achieve the Maximum Plasma Concentration
timeFrame: 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.
measure: Belatacept PK Parameter: Area Under the Serum Concentration-time Curve to the End of the Dosing Period (AUCtau)
timeFrame: 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.
measure: Belatacept PK Parameter: Minimum Plasma Concentration
timeFrame: 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.
measure: Belatacept PK Parameter: Terminal Half-life
timeFrame: 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.
measure: Belatacept PK Parameter: Total Body Clearance
timeFrame: 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.
measure: Belatacept PK Parameter: Volume of Distribution
timeFrame: 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.
measure: Belatacept PK Parameter: Amount Excreted in Ascites Fluid Over Days 1 to 14
timeFrame: Days 1 to 14
measure: Belatacept PK Parameter: Clearance From Ascites Fluid
timeFrame: Days 1 to 14
measure: Belatacept Trough Concentration Before Each Infusion During the LTE
timeFrame: 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.
measure: Percentage of Participants (Who Were Hepatitis C Virus [HCV] Positive at Baseline) With HCV Recurrence (Assessed by Central Pathologist) by 12 Months
timeFrame: 6 and 12 months posttransplant
measure: Percentage of Participants (Who Were Hepatitis C Virus [HCV] Positive at Baseline) With HCV Recurrence (Assessed by Central Pathologist) During the LTE
timeFrame: 12 months posttransplant, end of study (database lock, 20-June-2011)
measure: 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
timeFrame: Baseline (pretransplant), 6 and 12 months (mo) posttransplant
measure: 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
timeFrame: BL (pretransplant), 12, 18, 24, 30 months (mo) posttransplant
measure: Percentage of Participants Who Develop Dyslipidemia, Hypertriglyceridemia and Hypercholesterolemia After Randomization and Transplantation: 12-month Treatment Phase
timeFrame: 6 and 12 months posttransplant
measure: Percentage of Participants Meeting the Definition of Dyslipidemia, Hypertriglyceridemia or Hypercholesterolemia at Any Given Time: 12-month Treatment Phase
timeFrame: 6 and 12 months posttransplant
measure: Summary Statistics for Lipid Parameters-Serum Total Non-High Density Lipoprotein (Non-HDL) Cholesterol: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 6, 12 months posttransplant
measure: Summary Statistics for Lipid Parameters; Serum HDL Cholesterol: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 6, 12 months posttransplant
measure: Summary Statistics for Lipid Parameters- Serum Low Density Lipoprotein Cholesterol (LDL): 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 6, 12 months posttransplant
measure: Summary Statistics for Lipid Parameters- Serum Cholesterol: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 6, 12 months posttransplant
measure: Summary Statistics for Lipid Parameters - Serum Triglyceride: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 6, 12 months posttransplant
measure: Summary Statistics for Systolic Blood Pressure: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 1, 3, 6, 9, 12 months posttransplant
measure: Summary Statistics for Diastolic Blood Pressure: 12-month Treatment Phase
timeFrame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant
measure: Summary Statistics for Mean Arterial Pressure: 12-month Treatment Phase
timeFrame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant
measure: Percentage of Participants Who Developed Hypertension in 12-month Treatment Phase
timeFrame: 6 and 12 months posttransplant
measure: Percentage of Participants Who Have Hypertension at Any Given Time During the 12-month Treatment Phase
timeFrame: 6 and 12 months posttransplant
measure: Number of Participants Who Received Anti-hypertensive Therapy at Month 12
timeFrame: 12 months posttransplant
measure: Percentage of Participants With New Onset Diabetes Mellitus (NODM): 12-month Treatment Phase
timeFrame: 6 and 12 months posttransplant
measure: Glycosylated Hemoglobin (HbA1C) Values: 12-month Treatment Phase
timeFrame: 6, 12 months (mth) posttransplant
measure: Number of Participants Who Had AEs, Death, SAEs or Were Discontinued Due to AEs: 12-month Treatment Phase
timeFrame: Day 1 (randomization) to 12 m + 8 week follow-up or ≤ 56 days after discontinuation of study medication
measure: Number of Participants Who Had Adverse Events of Special Interest During 12-month Treatment Phase
timeFrame: Day 1 (randomization) to 12 months or ≤ 56 days after discontinuation of study medication
measure: Number of Participants With Marked Hematology Abnormalities: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 2, 4, 8, 12 weeks, and every 4 weeks for week 16 to 52
measure: Number of Participants With Marked Liver and Kidney Function Abnormalities: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), 4, 12, 24, 52 weeks
measure: Number of Participants With Marked Electrolytes, Protein and Metabolic Test Abnormalities: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), Weeks 4, 12, 24, and 52
measure: Number of Participants Who Had Abnormalities in Electrocardiograms: 12-month Treatment Phase
timeFrame: Baseline (pretransplant), Week 52
measure: Change in Protein to Creatinine Ratio From Month 3 to Month 12.
timeFrame: Month 3 and 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Usc University Hospital
state: California
city: San Francisco
country: United States
facility: University Of California San Francisco Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Transplant Department
state: Florida
city: Tampa
country: United States
facility: Lifelink Healthcare Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School Of Medicine
state: Illinois
city: New Orleans
country: United States
facility: Tulane Center For Abdominal Transplant
state: Louisiana
city: Detriot
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University Of Minnesota
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School Of Medicine
state: Missouri
city: New York
country: United States
facility: Nyu School Of Medicine
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. Of Cin. Coll. Of Med.
state: Ohio
city: Oklahoma City
country: United States
facility: Integris-Baptist Medical Ctr.
state: Oklahoma
city: Philadelphia
country: United States
facility: Hospital Of The University Of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
city: Ciudad De Buenos Aires
country: Argentina
facility: Local Institution
state: Buenos Aires
city: Wien
country: Austria
facility: Local Institution
city: Curitiba
country: Brazil
facility: Local Institution
state: Parana
city: Centro-Porto Alegre
country: Brazil
facility: Local Institution
state: Rio Grande Do Sul
city: Rio De Janeiro
country: Brazil
facility: Local Institution
city: Edmonton
country: Canada
facility: Local Institution
state: Alberta
city: Toronto
country: Canada
facility: Local Institution
state: Ontario
city: Clichy Cedex
country: France
facility: Local Institution
city: Lyon
country: France
facility: Local Institution
city: Montpellier
country: France
facility: Local Institution
city: Paris
country: France
facility: Local Institution
city: Toulouse Cedex 9
country: France
facility: Local Institution
city: Villejuif
country: France
facility: Local Institution
city: Berlin
country: Germany
facility: Local Institution
city: Hamburg
country: Germany
facility: Local Institution
city: Hannover
country: Germany
facility: Local Institution
city: Heidelberg
country: Germany
facility: Local Institution
city: Tuebingen
country: Germany
facility: Local Institution
city: Bergamo
country: Italy
facility: Local Institution
city: Padova
country: Italy
facility: Local Institution
city: Pisa
country: Italy
facility: Local Institution
city: Roma
country: Italy
facility: Local Institution
city: Barcelona
country: Spain
facility: Local Institution
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Klintmalm GB, Feng S, Lake JR, Vargas HE, Wekerle T, Agnes S, Brown KA, Nashan B, Rostaing L, Meadows-Shropshire S, Agarwal M, Harler MB, Garcia-Valdecasas JC. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study. Am J Transplant. 2014 Aug;14(8):1817-27. doi: 10.1111/ajt.12810.