Belatacept in Liver Transplant Recipients

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Group 1: Basiliximab+Belatacept (MI) + MMF	Basiliximab- Intravenous (IV), 20 mg, on Day 1 and Day 5; Belatacept More Intensive (MI)-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]), and 5 mg/kg, every 4 weeks, 4 years (Long-term extension [LTE]); Mycophenolate Mofetil (MMF)-IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 2: Belatacept (MI) + MMF	Belatacept MI- 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 (ST), and 5 mg/kg, every 4 weeks, 4 years (LTE); MMF-IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 3: Belatacept (LI) + MMF	Belatacept Less Intensive (LI)- 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 (ST]), 5 mg/kg, every 4 weeks, 4 years (LTE); MMF, Intravenous (IV)/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), ≤ 1 g/Day, 4 years (LTE)
Group 4: Tacrolimus + MMF	Tacrolimus, Capsules, Oral, 6-12 ng/mL trough level, twice daily, 52 weeks (ST), in accordance with local practice and the package insert, 4 years (LTE); MMF, IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 5: Tacrolimus	Tacrolimus, Capsules, Oral, 6-12 ng/mL trough level, twice daily, 52 weeks (ST), in accordance with local practice and the package insert, and 4 years (LTE)

Participant Flow for 2 periods

Period 1:   Treatment Phase up to 12-months

	Group 1: Basiliximab+Belatacept (MI) + MMF	Group 2: Belatacept (MI) + MMF	Group 3: Belatacept (LI) + MMF	Group 4: Tacrolimus + MMF	Group 5: Tacrolimus
STARTED	52	51	50	53	54
Received Transplant and Treated	50	48	49	53	50
COMPLETED	31	29	26	46	32
NOT COMPLETED	21	22	24	7	22
Adverse Event	6	7	11	7	18
Withdrawal by Subject	1	0	1	0	0
Death	2	1	4	0	0
Lack of Efficacy	9	8	5	0	0
Other Reason	1	3	2	0	0
Never treated	2	3	1	0	4

Period 2:   Long-term Extension Phase

	Group 1: Basiliximab+Belatacept (MI) + MMF	Group 2: Belatacept (MI) + MMF	Group 3: Belatacept (LI) + MMF	Group 4: Tacrolimus + MMF	Group 5: Tacrolimus
STARTED	30 [1]	27 [2]	24 [2]	38 [3]	26 [4]
COMPLETED	0	0	0	0	0
NOT COMPLETED	30	27	24	38	26
Adverse Event	2	5	2	1	0
Withdrawal by Subject	2	1	2	3	2
Administrative reason by sponsor	23	21	18	31	23
Death	2	0	0	3	0
Participant did not meet study criteria	0	0	0	0	1
Other Reason	1	0	2	0	0

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Group 1: Basiliximab+Belatacept (MI) + MMF	Basiliximab- Intravenous (IV), 20 mg, on Day 1 and Day 5; Belatacept More Intensive (MI)-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]), and 5 mg/kg, every 4 weeks, 4 years (Long-term extension [LTE]); Mycophenolate Mofetil (MMF)-IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 2: Belatacept (MI) + MMF	Belatacept MI- 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 (ST), and 5 mg/kg, every 4 weeks, 4 years (LTE); MMF-IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 3: Belatacept (LI) + MMF	Belatacept Less Intensive (LI)- 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 (ST]), 5 mg/kg, every 4 weeks, 4 years (LTE); MMF, Intravenous (IV)/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), ≤ 1 g/Day, 4 years (LTE)
Group 4: Tacrolimus + MMF	Tacrolimus, Capsules, Oral, 6-12 ng/mL trough level, twice daily, 52 weeks (ST), in accordance with local practice and the package insert, 4 years (LTE); MMF, IV/Capsules, IV/Oral, 1-2g/Day, 52 weeks (ST), and ≤ 1 g/Day, 4 years (LTE)
Group 5: Tacrolimus	Tacrolimus, Capsules, Oral, 6-12 ng/mL trough level, twice daily, 52 weeks (ST), in accordance with local practice and the package insert, and 4 years (LTE)
Total	Total of all reporting groups

Baseline Measures

	Group 1: Basiliximab+Belatacept (MI) + MMF	Group 2: Belatacept (MI) + MMF	Group 3: Belatacept (LI) + MMF	Group 4: Tacrolimus + MMF	Group 5: Tacrolimus	Total
Overall Participants Analyzed  [Units: Participants]	50	48	49	53	50	250
Age, Customized  [Units: Participants]
18 to 45 years	7	7	4	11	4	33
46 to 65 years	41	40	43	37	42	203
Above 65 years	2	1	2	5	4	14
Gender  [Units: Participants]
Female	11	14	18	7	8	58
Male	39	34	31	46	42	192
Race/Ethnicity, Customized  [Units: Participants]
White	44	40	46	49	43	222
Black / African American	4	3	1	3	2	13
American Indian / Alaska native	0	1	0	0	0	1
Asian	1	0	2	0	0	3
Other	1	4	0	1	5	11
Race/Ethnicity, Customized [1]  [Units: Participants]
Hispanic or Latino (US sites)	5	7	3	3	4	22
Not Hispanic or Latino (US sites)	28	16	11	22	23	100
Unknown (Non- US sites)	17	25	35	28	23	128
[1] Ethnicity data collected in compliance with the 2005 Food and Drug Administration (FDA) Guidance for Industry for subjects enrolled in the United States (US) only.
Model for End-Stage Liver Disease (MELD) score [1]  [Units: Units on a scale] Median (Full Range)	22.0   (6.0 to 40.0)	22.0   (8.0 to 42.0)	22.0   (7.0 to 31.0)	24.0   (9.0 to 40.0)	22.0   (9.0 to 40.0)	22.0   (6.0 to 42.0)
[1] The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease. MELD uses the participant's values for serum bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. 100% mortality= 3 month mortality is ≥ 40; 83% mortality= 3 month mortality 30-39; 76% mortality= 3 month mortality 20-29; 27% mortality= 3 month mortality 10-19; 4% mortality= 3 month mortality <10.
Primary cause of End Stage Liver Disease (ESLD)  [Units: Participants]
Non-cholestatic cirrhosis	38	33	33	39	41	184
Cholestatic liver disease cirrhosis	0	3	3	1	2	9
Biliary atresia	0	0	0	1	0	1
Acute hepatic necrosis	4	0	3	1	0	8
Metabolic disease	0	2	0	1	0	3
Malignant neoplasms	4	7	5	6	3	25
Other	4	3	5	4	4	20
United Network for Organ Sharing (UNOS) Status [1]  [Units: Participants]
Status 1	0	1	0	0	0	1
Status 2A	1	1	2	3	0	7
Status 2B	3	2	5	1	2	13
Status 3	2	2	2	1	1	8
Not available	44	42	40	48	47	221
[1] Participant's status category is determined by a point system, using objective and subjective factors. Status 1: critical, sudden liver failure, or newly transplanted liver not functioning; Status 2A: with chronic liver disease and are in the hospital's critical care unit. Status 1 and 2A have a life expectancy of less than 7 days without a liver transplant; Status 2B: with chronic liver disease, but do not meet the criteria for Status 2A; Status 3: with chronic liver disease, under continuous medical care, but not hospitalized, not meet the criteria for Status 2B.
Participants on Anti-Hypertensive Medications  [Units: Participants]
No	41	39	41	42	40	203
Yes	9	9	8	11	10	47
Participants on Lipid Lowering Medications  [Units: Participants]
No	46	43	48	51	44	232
Yes	4	5	1	2	6	18
Participants on Anti-diabetic Medications  [Units: Participants]
No	35	35	40	41	38	189
Yes	15	13	9	12	12	61

1.  Primary:

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 ]

2.  Primary:

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) ]

3.  Primary:

Number of Participants Who Had AEs of Special Interest During the LTE   [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ]

4.  Primary:

Number of Participants With Marked Hematology Abnormalities During the LTE   [ Time Frame: Every 4 weeks from Week 53 to Week 104. ]

5.  Primary:

Number of Participants With Marked Liver and Kidney Function Abnormalities During the LTE   [ Time Frame: Every 4 weeks from Week 53 to Week 104. ]

6.  Primary:

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. ]

7.  Secondary:

Percentage of Participants Surviving With Functional Graft: 12-month Treatment Phase   [ Time Frame: At 6 and 12 months ]

8.  Secondary:

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) ]

9.  Secondary:

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 ]

10.  Secondary:

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) ]

11.  Secondary:

Number of Participants Having Acute Rejections: 12-month Treatment Phase   [ Time Frame: 3 , 6, and 12 months ]

12.  Secondary:

Number of Participants Having Acute Rejections During the LTE   [ Time Frame: Day 1 (randomization) through database lock (20-June-2011) ]

13.  Secondary:

Number of Participants With Central Biopsy Proven Acute Rejection by Treatment Type by 12 Months   [ Time Frame: 3, 6 and 12 months posttransplant ]

14.  Secondary:

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) ]

15.  Secondary:

Number of Participants Who Had Acute Rejection by Banff Grade by 12 Months   [ Time Frame: 3, 6 and 12 months posttransplant ]

16.  Secondary:

Number of Participants With Acute Rejections by Rejection Activity Index (RAI) by 12 Months   [ Time Frame: 3, 6 and 12 months posttransplant ]

17.  Secondary:

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) ]

18.  Secondary:

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 ]

19.  Secondary:

Mean Change From Baseline in Measured Glomerular Filtration Rate (GFR): 12-month Treatment Phase   [ Time Frame: Baseline (2 month), 12 months posttransplant ]

20.  Secondary:

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 ]

21.  Secondary:

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 ]

22.  Secondary:

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 ]

23.  Secondary:

Mean Change in Baseline Values of Cystatin C at 2 and 12 Months   [ Time Frame: Baseline (pretransplant), 2, and 12 months posttransplant ]

24.  Secondary:

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. ]

25.  Secondary:

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. ]

26.  Secondary:

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. ]

27.  Secondary:

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. ]

28.  Secondary:

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. ]

29.  Secondary:

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. ]

30.  Secondary:

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. ]

31.  Secondary:

Belatacept PK Parameter: Amount Excreted in Ascites Fluid Over Days 1 to 14   [ Time Frame: Days 1 to 14 ]

32.  Secondary:

Belatacept PK Parameter: Clearance From Ascites Fluid   [ Time Frame: Days 1 to 14 ]

33.  Secondary:

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. ]

34.  Secondary:

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 ]

35.  Secondary:

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) ]

36.  Secondary:

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 ]

37.  Secondary:

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 ]

38.  Secondary:

Percentage of Participants Who Develop Dyslipidemia, Hypertriglyceridemia and Hypercholesterolemia After Randomization and Transplantation: 12-month Treatment Phase   [ Time Frame: 6 and 12 months posttransplant ]

39.  Secondary:

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 ]

40.  Secondary:

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 ]

41.  Secondary:

Summary Statistics for Lipid Parameters; Serum HDL Cholesterol: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ]

42.  Secondary:

Summary Statistics for Lipid Parameters- Serum Low Density Lipoprotein Cholesterol (LDL): 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ]

43.  Secondary:

Summary Statistics for Lipid Parameters- Serum Cholesterol: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ]

44.  Secondary:

Summary Statistics for Lipid Parameters - Serum Triglyceride: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 1, 6, 12 months posttransplant ]

45.  Secondary:

Summary Statistics for Systolic Blood Pressure: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 1, 3, 6, 9, 12 months posttransplant ]

46.  Secondary:

Summary Statistics for Diastolic Blood Pressure: 12-month Treatment Phase   [ Time Frame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant ]

47.  Secondary:

Summary Statistics for Mean Arterial Pressure: 12-month Treatment Phase   [ Time Frame: BL (pretransplant), 1, 3, 6, 9, 12 months posttransplant ]

48.  Secondary:

Percentage of Participants Who Developed Hypertension in 12-month Treatment Phase   [ Time Frame: 6 and 12 months posttransplant ]

49.  Secondary:

Percentage of Participants Who Have Hypertension at Any Given Time During the 12-month Treatment Phase   [ Time Frame: 6 and 12 months posttransplant ]

50.  Secondary:

Number of Participants Who Received Anti-hypertensive Therapy at Month 12   [ Time Frame: 12 months posttransplant ]

51.  Secondary:

Percentage of Participants With New Onset Diabetes Mellitus (NODM): 12-month Treatment Phase   [ Time Frame: 6 and 12 months posttransplant ]

52.  Secondary:

Glycosylated Hemoglobin (HbA1C) Values: 12-month Treatment Phase   [ Time Frame: 6, 12 months (mth) posttransplant ]

53.  Secondary:

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 ]

54.  Secondary:

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 ]

55.  Secondary:

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 ]

56.  Secondary:

Number of Participants With Marked Liver and Kidney Function Abnormalities: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), 4, 12, 24, 52 weeks ]

57.  Secondary:

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 ]

58.  Secondary:

Number of Participants Who Had Abnormalities in Electrocardiograms: 12-month Treatment Phase   [ Time Frame: Baseline (pretransplant), Week 52 ]

59.  Secondary:

Change in Protein to Creatinine Ratio From Month 3 to Month 12.   [ Time Frame: Month 3 and 12 ]

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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