Belatacept Pharmacokinetic Trial in Renal Transplantation

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00578448
• Collaborator: (none)
• Enrollment: 14
• Locations: 5
• Arms: 2
• Duration (Months): 54
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the pharmacokinetics and safety of belatacept in de novo renal transplant subjects treated with belatacept-based immunosuppressant medication

Condition or Disease	Intervention/Treatment	Phase
Renal Transplantation	Drug: Belatacept	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Pharmacokinetic Study in De Novo Renal Transplant Subjects Receiving a Belatacept Based Immunosuppressant Regimen
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A 10mg/kg 6 doses (Day 1, 5, week 2, 4, 8 and 12) for 12 weeks	Drug: Belatacept; IV infusion; Other Names: BMS-224818
Active Comparator: B 5mg/kg 33 doses (every 4 weeks) for 144 weeks	Drug: Belatacept; IV infusion; Other Names: BMS-224818

Outcome Measures

Primary Outcome Measures

1. Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population [Day 84 to Day 112]

   Pharmacokinetic (PK) sampling started from pre-dose (0 hour) on Day 84 and ended at 672 hour (h) on Day 112 (between Weeks 12 to 16). The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method and measured as nanograms/milliliter (ng/mL). Less than the lower limit of quantification (LLQ), 3.000 ng/mL concentration value was treated as missing.

2. Maximum Observed Serum Concentration (Cmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept and Trough Serum Concentration Prior to Dosing (Cmin) - Pharmacokinetic Population [Day 84 to Day 112]

   Cmax, Cmin are measured in micrograms per milliliter (µg/mL). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. Serum samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. The Cmax, and the Cmin were recorded directly from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria, which is also referred to as adjusted R-squared. Values below lower limits of quantification (LLQ), 0.003 µg/mL, were set to 0.0015 for computation of summary statistics.

3. Time of Maximum Observed Serum Concentration (Tmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population [Day 84 to Day 112]

   Tmax measured in hours (h). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 (h) on Day 112 . The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations.

4. Area Under the Concentration Time Curve Within a Dosing Interval (AUC) (TAU) Between Weeks 12 and 16 Following 10 mg/kg IV Belatacept - Pharmacokinetic Population [Day 82 to Day 112]

   At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). The area under the concentration-time curve in one dose interval [AUC(TAU), where TAU = 4 weeks] were calculated using the mixed log-linear trapezoidal algorithm in Kinetica. Actual sampling times were used for PK calculations. AUC (TAU) was measured as micrograms multiplied by time(h) per milliliter (µg*h/mL).

5. Total Body Clearance (CLT) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population [Day 84 to Day 112]

   At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. CLT was calculated by dividing the dose by AUC(TAU) and was adjusted to body weight. CLT was measured as milliliter per time per kg body weight (mL/h/kg).

6. Steady-state Volume Distribution (Vss) Following 10mg/kg IV Belatacept Between Weeks 12 and 16 - Pharmacokinetic Population [Day 84 to Day 112]

   At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. Vss was calculated by dividing the dose by AUC and multiply the mean residence time (MRT). Vss was adjusted to body weight and measured as liter per kilogram body weight (l/kg).

7. Serum Half Life (T-HALF) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population [Day 84 to Day 112]

   At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. T-HALF was calculated as ln2/Lz, where Lz is the absolute value of the slope of the terminal log-linear phase. T-HALF is measured in hours (h).

Secondary Outcome Measures

1. Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population [Day 1 to Day 1092]

   Blood samples were obtained pre and post dose at designated time points up to Day 112 and thereafter, pre-dose samples were obtained at Days 168 and 364, and then once yearly up to end of Year 3. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. The trough serum concentration (Cmin), was recorded directly from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria, which is also referred to as adjusted R-squared. Cmin was measured as micrograms per milliliter (µg/mL).

2. Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants [Day 1 up to 4 years post transplantation]

   Acute rejection of transplant defined as a clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. Graft loss was defined as either functional loss or physical loss. Day 1 is day of transplantation.

3. Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants [Baseline to Day 364]

   Indoleamine 2,3 dioxygenase (IDO) is a tryptophan catabolizing enzyme that can be induced in antigen-presenting cells by the engagement of B7 by cytotoxic lymphocyte antigen 4 (CTLA-4). Tryptophan depletion in cellular microenvironments has an inhibitory effect on T cells and may be part of a broader immuno-regulatory effect of IDO induction. The IDO activity was determined by measuring the quantity of tryptophan and its metabolite, kynurenine, in serum samples using a validated high performance liquid chromatography (HPLC) method. Baseline is defined as pre-dose. Tryptophan was measured in micromoles (µM)

4. Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants [Day 1 to Day 364]

   Indoleamine 2,3 dioxygenase (IDO) is a tryptophan catabolizing enzyme that can be induced in antigen-presenting cells by the engagement of B7 by CTLA-4. Tryptophan depletion in cellular microenvironments has an inhibitory effect on T cells and may be part of a broader immuno-regulatory effect of IDO induction. The IDO activity was determined by measuring the quantity of tryptophan and its metabolite, kynurenine, in serum samples using a validated high performance liquid chromatography (HPLC) method. Baseline is defined as pre-dose. Kynurenine was measured in micromoles (µM).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Recipient of a living or deceased donor kidney

• First or second transplant

• Men and women, including women of childbearing potential, 18 years and older

Exclusion Criteria:

• Panel reactive antibodies ≥ 30%

• Significant infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western New England Renal & Transplant	Springfield	Massachusetts	United States	01107
2	Henry Ford Hospital	Detriot	Michigan	United States	48202
3	Local Institution	Capital Federal	Buenos Aires	Argentina	1425
4	Local Institution	Cuernavaca	Morelos	Mexico	62448
5	Local Institution	Aguascalientes		Mexico	20219

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00578448
• Other Study ID Numbers: IM103-047
• First Posted: Dec 21, 2007
• Last Update Posted: Jan 17, 2014
• Last Verified: Dec 1, 2013

• Additional relevant MeSH terms: Abatacept

Study Results

Participant Flow

Recruitment Details	First participant, first visit: 3 March 2008. Last subject, last visit 6 September 2012. Participants had received a renal transplant from a living or deceased donor with an anticipated cold ischemia time of less than (<) 24 hours (h)
Pre-assignment Detail	14 participants enrolled; 12 received study drug; 2 not treated due to: kidney damage (1) and prolonged cold ischemia (1). Study continued for up to 3 years until drug approval in participant's country. Participants continued in a 1 year extension after conclusion of the 3rd year.

Arm/Group Title	Belatacept 10mg/kg; 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 4 (Weeks 8 and 12). After 4 months, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the trial (3 years and then a 1 year extension was available for those who completed the 3rd year).
Period Title: Day 1 up to 3 Years of Planned Study
STARTED	12
COMPLETED	9
NOT COMPLETED	3
Period Title: Day 1 up to 3 Years of Planned Study
STARTED	9
COMPLETED	8
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	IV Belatacept 10mg/kg With 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 4 (Weeks 8 and 12). After 4 months, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the trial.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 83.3%
>=65 years	2 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.7 (19.05)
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%
Region of Enrollment (participants) [Number]
United States	4 33.3%
Mexico	6 50%
Argentina	2 16.7%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	74.90 (17.735)

Outcome Measures

1. Primary Outcome

Title	Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population
Description	Pharmacokinetic (PK) sampling started from pre-dose (0 hour) on Day 84 and ended at 672 hour (h) on Day 112 (between Weeks 12 to 16). The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method and measured as nanograms/milliliter (ng/mL). Less than the lower limit of quantification (LLQ), 3.000 ng/mL concentration value was treated as missing.
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

Number (N) of participants analyzed for each collection time was 10, except for time 0.50 h, which was missing 1 participant. Therefore Number (N) for Time 0.50 h = 9.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
0.00 h	8491.00 (5175.97)
0.50 h	242667 (64459.3)
2.00 h	212800 (62467.4)
72.00 h	55970.0 (12989.7)
168.00 h	36890.0 (16426.8)
336.00 h	19063.0 (7803.41)
504.00 h	11587.0 (6282.26)
672 h	7613.00 (4698.61)

2. Primary Outcome

Title	Maximum Observed Serum Concentration (Cmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept and Trough Serum Concentration Prior to Dosing (Cmin) - Pharmacokinetic Population
Description	Cmax, Cmin are measured in micrograms per milliliter (µg/mL). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. Serum samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. The Cmax, and the Cmin were recorded directly from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria, which is also referred to as adjusted R-squared. Values below lower limits of quantification (LLQ), 0.003 µg/mL, were set to 0.0015 for computation of summary statistics.
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

One participant excluded from analysis of Cmax and Tmax due to a very high concentration value (it was considered an outlier) therefore, for Cmax, Number of participants analyzed (N)=9.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
Cmin	7.29 (61)
Cmax	238.33 (27)

3. Primary Outcome

Title	Time of Maximum Observed Serum Concentration (Tmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
Description	Tmax measured in hours (h). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 (h) on Day 112 . The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations.
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

1 participant excluded from analysis of Cmax and Tmax due to a very high concentration value (it was considered an outlier) therefore, for Tmax, Number of participants analyzed (N)=9.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	9
Median (Full Range) [hours]	0.60

4. Primary Outcome

Title	Area Under the Concentration Time Curve Within a Dosing Interval (AUC) (TAU) Between Weeks 12 and 16 Following 10 mg/kg IV Belatacept - Pharmacokinetic Population
Description	At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). The area under the concentration-time curve in one dose interval [AUC(TAU), where TAU = 4 weeks] were calculated using the mixed log-linear trapezoidal algorithm in Kinetica. Actual sampling times were used for PK calculations. AUC (TAU) was measured as micrograms multiplied by time(h) per milliliter (µg*h/mL).
Time Frame	Day 82 to Day 112

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [µg*h/mL]	21241 (35)

5. Secondary Outcome

Title	Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population
Description	Blood samples were obtained pre and post dose at designated time points up to Day 112 and thereafter, pre-dose samples were obtained at Days 168 and 364, and then once yearly up to end of Year 3. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. The trough serum concentration (Cmin), was recorded directly from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria, which is also referred to as adjusted R-squared. Cmin was measured as micrograms per milliliter (µg/mL).
Time Frame	Day 1 to Day 1092

Outcome Measure Data

Analysis Population Description

Number of participants (N) analyzed = 11 for Days 5, 14,and 28; and 12 for Day 56. Days 84, 112, 168, 364 N=10.

Arm/Group Title	10mg/kg IV Belatacept
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	11
Day 5 Post Transplantation	33.499 (25.020)
Day 14 Post Transplantation	24.558 (40.605)
Day 28 Post Transplantation	21.375 (39.224)
Day 56 Post Transplantation (N=12)	8.574 (58.386)
Day 84 Post Transplantation	7.289 (60.959)
Day 112 Post Transplantation	6.391 (61.718)
Day 168 Post Transplantation	3.189 (47.797)
Day 364 Post Transplantation	3.704 (42.236)
Day 728 Post Transplantation	4.383 (43.209)
Day 1092 Post Transplantation	4.996 (55.892)

6. Primary Outcome

Title	Total Body Clearance (CLT) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
Description	At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. CLT was calculated by dividing the dose by AUC(TAU) and was adjusted to body weight. CLT was measured as milliliter per time per kg body weight (mL/h/kg).
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

Participants who were treated and had PK data.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [mL/h/kg]	0.47 (27)

7. Primary Outcome

Title	Steady-state Volume Distribution (Vss) Following 10mg/kg IV Belatacept Between Weeks 12 and 16 - Pharmacokinetic Population
Description	At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. Vss was calculated by dividing the dose by AUC and multiply the mean residence time (MRT). Vss was adjusted to body weight and measured as liter per kilogram body weight (l/kg).
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
Mean (Standard Deviation) [l/kg]	0.11 (0.033)

8. Primary Outcome

Title	Serum Half Life (T-HALF) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
Description	At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox [version 2.6.1]). Actual sampling times were used for PK calculations. T-HALF was calculated as ln2/Lz, where Lz is the absolute value of the slope of the terminal log-linear phase. T-HALF is measured in hours (h).
Time Frame	Day 84 to Day 112

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	10
Mean (Standard Deviation) [hours]	235.43 (76.414)

9. Secondary Outcome

Title	Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants
Description	Acute rejection of transplant defined as a clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. Graft loss was defined as either functional loss or physical loss. Day 1 is day of transplantation.
Time Frame	Day 1 up to 4 years post transplantation

Outcome Measure Data

Analysis Population Description

All treated participants were analyzed during the planned 3 year study N=12. Only 9 participants entered the LTE so N=9 for LTE.

Arm/Group Title	Belatacept 10mg/kg; 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study (3 years planned study; 1 year extension allowed to those who completed 3rd year).
Measure Participants	12
Acute rejection of transplant	4 33.3%
Death	1 8.3%
Graft Loss	1 8.3%

10. Secondary Outcome

Title	Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants
Description	Indoleamine 2,3 dioxygenase (IDO) is a tryptophan catabolizing enzyme that can be induced in antigen-presenting cells by the engagement of B7 by cytotoxic lymphocyte antigen 4 (CTLA-4). Tryptophan depletion in cellular microenvironments has an inhibitory effect on T cells and may be part of a broader immuno-regulatory effect of IDO induction. The IDO activity was determined by measuring the quantity of tryptophan and its metabolite, kynurenine, in serum samples using a validated high performance liquid chromatography (HPLC) method. Baseline is defined as pre-dose. Tryptophan was measured in micromoles (µM)
Time Frame	Baseline to Day 364

Outcome Measure Data

Analysis Population Description

Number analyzed for Baseline, Days 5, 28, 112, 168, 364 = 12, 11, 11, 10, 10, and 10, respectively.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	12
Day 5 Post Transplantation	-27.375 (38.9151)
Day 28 Post Transplantation	-22.765 (39.0174)
Day 112 Post Transplantation	-27.331 (39.2819)
Day 168 Post Transplantation	-18.627 (37.9010)
Day 364 Post Transplantation	-24.610 (41.4859)

11. Secondary Outcome

Title	Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants
Description	Indoleamine 2,3 dioxygenase (IDO) is a tryptophan catabolizing enzyme that can be induced in antigen-presenting cells by the engagement of B7 by CTLA-4. Tryptophan depletion in cellular microenvironments has an inhibitory effect on T cells and may be part of a broader immuno-regulatory effect of IDO induction. The IDO activity was determined by measuring the quantity of tryptophan and its metabolite, kynurenine, in serum samples using a validated high performance liquid chromatography (HPLC) method. Baseline is defined as pre-dose. Kynurenine was measured in micromoles (µM).
Time Frame	Day 1 to Day 364

Outcome Measure Data

Analysis Population Description

Number analyzed for Baseline, Days 5, 28, 112, 168, 364 = 12, 11, 11, 10, 10, and 10, respectively.

Arm/Group Title	Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance
Arm/Group Description	Participants received intravenous (IV) belatacept (10 milligram per kilogram body weight (mg/kg) on Days 1 and 5, and then every 2 weeks through Month 1 (Weeks 2 and 4), and then every 4 weeks through Month 3. After Day 112, participants received a maintenance dose of 5 mg/kg belatacept administered every 4 weeks until completion of the study.
Measure Participants	12
Day 5 Post Transplantation	-7.276 (9.3070)
Day 28 Post Transplantation	-8.486 (9.1880)
Day 112 Post Transplantation	-7.936 (9.6630)
Day 168 Post Transplantation	-7.589 (9.6115)
Day 364 Post Transplantation	-7.279 (9.7117)

Adverse Events

Time Frame	Day 1 (day of transplant) up to 3 years post transplant for the study and 1 additional year for the 1 year extension for those participants who entered the extension.
Arm/Group Title	Bela 10-5mg/kg
Arm/Group Description
All Cause Mortality
	Bela 10-5mg/kg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bela 10-5mg/kg
	Affected / at Risk (%)	# Events
Total	6/12 (50%)
Congenital, familial and genetic disorders
Congenital cystic kidney disease	1/12 (8.3%)
Gastrointestinal disorders
Nausea	1/12 (8.3%)
Gastritis	1/12 (8.3%)
Vomiting	1/12 (8.3%)
Gastritis haemorrhagic	1/12 (8.3%)
Retroperitoneal haematoma	1/12 (8.3%)
General disorders
Pyrexia	1/12 (8.3%)
Infections and infestations
Cellulitis	1/12 (8.3%)
Meningitis viral	1/12 (8.3%)
Urinary tract infection	2/12 (16.7%)
Septic shock	1/12 (8.3%)
Pneumonia	1/12 (8.3%)
Investigations
Blood creatine increased	1/12 (8.3%)
Metabolism and nutrition disorders
Dehydration	1/12 (8.3%)
Nervous system disorders
Myelopathy	1/12 (8.3%)
Intracranial aneurysm	1/12 (8.3%)
Renal and urinary disorders
Ureteral necrosis	1/12 (8.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Bela 10-5mg/kg
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anaemia	4/12 (33.3%)
Thrombocytopenia	2/12 (16.7%)
Polycythaemia	1/12 (8.3%)
Leukopenia	2/12 (16.7%)
Neutropenia	1/12 (8.3%)
Cardiac disorders
Arrhythmia	1/12 (8.3%)
Tachycardia	3/12 (25%)
Palpitations	1/12 (8.3%)
Ear and labyrinth disorders
Vertigo	1/12 (8.3%)
Endocrine disorders
Hypothyroidism	1/12 (8.3%)
Eye disorders
Eye pain	1/12 (8.3%)
Eye haemorrhage	1/12 (8.3%)
Chalazion	1/12 (8.3%)
Retinal haemorrhage	1/12 (8.3%)
Gastrointestinal disorders
Nausea	1/12 (8.3%)
Abdominal distension	2/12 (16.7%)
Abdominal pain upper	1/12 (8.3%)
Colitis	1/12 (8.3%)
Food poisoning	1/12 (8.3%)
Gastritis	2/12 (16.7%)
Abdominal pain	4/12 (33.3%)
Haematochezia	1/12 (8.3%)
Mouth ulceration	1/12 (8.3%)
Flatulence	1/12 (8.3%)
Gastrointestinal sounds abnormal	1/12 (8.3%)
Dyspepsia	1/12 (8.3%)
Vomiting	1/12 (8.3%)
Diarrhoea	4/12 (33.3%)
Dry mouth	1/12 (8.3%)
Gastrooesophageal reflux disease	1/12 (8.3%)
Odynophagia	1/12 (8.3%)
Abdominal discomfort	1/12 (8.3%)
Abdominal pain lower	1/12 (8.3%)
Constipation	4/12 (33.3%)
Hiatus hernia	2/12 (16.7%)
Oesophagitis	2/12 (16.7%)
General disorders
Chest pain	1/12 (8.3%)
Oedema peripheral	4/12 (33.3%)
Malaise	2/12 (16.7%)
Influenza like illness	1/12 (8.3%)
Pyrexia	3/12 (25%)
Chills	1/12 (8.3%)
Fatigue	3/12 (25%)
Cyst	1/12 (8.3%)
Oedema	2/12 (16.7%)
Ischaemic ulcer	1/12 (8.3%)
Infections and infestations
Onychomycosis	2/12 (16.7%)
Pharyngotonsillitis	1/12 (8.3%)
Pyelonephritis acute	1/12 (8.3%)
Respiratory tract infection	1/12 (8.3%)
Herpes zoster	3/12 (25%)
Oral candidiasis	2/12 (16.7%)
Pharyngitis	3/12 (25%)
Tinea versicolour	1/12 (8.3%)
Candidiasis	1/12 (8.3%)
Herpes simplex	1/12 (8.3%)
Molluscum contagiosum	1/12 (8.3%)
BK virus infection	2/12 (16.7%)
Infected cyst	1/12 (8.3%)
Nasopharyngitis	3/12 (25%)
Postoperative wound infection	1/12 (8.3%)
Staphylococcal infection	1/12 (8.3%)
Body tinea	1/12 (8.3%)
Cellulitis	1/12 (8.3%)
Sinusitis	1/12 (8.3%)
Urinary tract infection	7/12 (58.3%)
Folliculitis	2/12 (16.7%)
Gastroenteritis	2/12 (16.7%)
Incision site cellulitis	1/12 (8.3%)
Furuncle	2/12 (16.7%)
Influenza	4/12 (33.3%)
Tinea cruris	1/12 (8.3%)
Upper respiratory tract infection	1/12 (8.3%)
Vaginal infection	1/12 (8.3%)
Injury, poisoning and procedural complications
Contusion	1/12 (8.3%)
Foot fracture	1/12 (8.3%)
Skin injury	1/12 (8.3%)
Wrist fracture	1/12 (8.3%)
Traumatic renal injury	1/12 (8.3%)
Graft dysfunction	1/12 (8.3%)
Incision site pain	1/12 (8.3%)
Road traffic accident	1/12 (8.3%)
Wound evisceration	1/12 (8.3%)
Procedural pain	2/12 (16.7%)
Ligament sprain	1/12 (8.3%)
Investigations
Blood creatine phosphokinase increased	1/12 (8.3%)
White blood cell count decreased	2/12 (16.7%)
Liver function test abnormal	1/12 (8.3%)
Body temperature increased	1/12 (8.3%)
Blood creatinine increased	1/12 (8.3%)
Troponin increased	2/12 (16.7%)
Urine output increased	1/12 (8.3%)
Metabolism and nutrition disorders
Hypokalaemia	3/12 (25%)
Hypomagnesaemia	1/12 (8.3%)
Vitamin D deficiency	1/12 (8.3%)
Glucose tolerance impaired	1/12 (8.3%)
Fluid overload	1/12 (8.3%)
Hypocalcaemia	3/12 (25%)
Hypocholesterolaemia	1/12 (8.3%)
Overweight	1/12 (8.3%)
Dehydration	1/12 (8.3%)
Hyperlipidaemia	2/12 (16.7%)
Dyslipidaemia	5/12 (41.7%)
Hypophosphataemia	3/12 (25%)
Metabolic acidosis	1/12 (8.3%)
Hypoglycaemia	1/12 (8.3%)
Decreased appetite	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/12 (8.3%)
Arthralgia	2/12 (16.7%)
Scoliosis	1/12 (8.3%)
Spinal osteoarthritis	1/12 (8.3%)
Back pain	1/12 (8.3%)
Musculoskeletal chest pain	1/12 (8.3%)
Muscular weakness	1/12 (8.3%)
Pain in extremity	2/12 (16.7%)
Exostosis	1/12 (8.3%)
Intervertebral disc protrusion	1/12 (8.3%)
Osteopenia	1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	1/12 (8.3%)
Neoplasm	1/12 (8.3%)
Seborrhoeic keratosis	1/12 (8.3%)
Nervous system disorders
Myelopathy	1/12 (8.3%)
Neuropathy peripheral	1/12 (8.3%)
Cerebral infarction	1/12 (8.3%)
Cervicobrachial syndrome	1/12 (8.3%)
Headache	4/12 (33.3%)
Hypoaesthesia	1/12 (8.3%)
Amnesia	1/12 (8.3%)
Paraesthesia	2/12 (16.7%)
Dizziness	3/12 (25%)
Psychiatric disorders
Insomnia	2/12 (16.7%)
Depression	2/12 (16.7%)
Anxiety	1/12 (8.3%)
Renal and urinary disorders
Hydronephrosis	2/12 (16.7%)
Perinephric effusion	1/12 (8.3%)
Proteinuria	1/12 (8.3%)
Renal vein thrombosis	1/12 (8.3%)
Leukocyturia	2/12 (16.7%)
Renal haemorrhage	1/12 (8.3%)
Dysuria	2/12 (16.7%)
Urethral stenosis	1/12 (8.3%)
Urinary retention	1/12 (8.3%)
Nocturia	1/12 (8.3%)
Reproductive system and breast disorders
Genital discharge	1/12 (8.3%)
Genital lesion	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/12 (8.3%)
Cough	2/12 (16.7%)
Oropharyngeal pain	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Petechiae	1/12 (8.3%)
Alopecia	2/12 (16.7%)
Ingrowing nail	1/12 (8.3%)
Rash	1/12 (8.3%)
Actinic keratosis	1/12 (8.3%)
Urticaria	1/12 (8.3%)
Acne	1/12 (8.3%)
Pruritus	1/12 (8.3%)
Ecchymosis	2/12 (16.7%)
Papule	1/12 (8.3%)
Skin ulcer	1/12 (8.3%)
Vascular disorders
Aneurysm	1/12 (8.3%)
Arterial spasm	1/12 (8.3%)
Hypertension	4/12 (33.3%)
Peripheral arterial occlusive disease	1/12 (8.3%)
Hypotension	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.