Renal Transplantation
Conditions
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
Interventions
DRUGBelatacept
IV infusion
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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). |
| 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). |
| 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). |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) |
| 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). |
| 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). |
Countries
Argentina, Mexico, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| IV Belatacept 10mg/kg With 5mg/kg Maintenance 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. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 1 Year Long Term Extension (LTE) | Adverse Event | 1 |
| Day 1 up to 3 Years of Planned Study | Adverse Event | 1 |
| Day 1 up to 3 Years of Planned Study | Death | 1 |
| Day 1 up to 3 Years of Planned Study | started marketed Cellcept and Prograf | 1 |
Baseline characteristics
| Characteristic | IV Belatacept 10mg/kg With 5mg/kg Maintenance |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 48.7 years STANDARD_DEVIATION 19.05 |
| Region of Enrollment Argentina | 2 participants |
| Region of Enrollment Mexico | 6 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
| Weight | 74.90 kilograms STANDARD_DEVIATION 17.735 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 6 / 12 |
Outcome results
Primary
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
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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | 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 | 21241 µg*h/mL | Geometric Coefficient of Variation 35 |
Primary
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
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | 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 | Cmin | 7.29 µg/mL | Geometric Coefficient of Variation 61 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | 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 | Cmax | 238.33 µg/mL | Geometric Coefficient of Variation 27 |
Primary
Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 0.00 h | 8491.00 ng/mL | Standard Deviation 5175.97 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 0.50 h | 242667 ng/mL | Standard Deviation 64459.3 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 2.00 h | 212800 ng/mL | Standard Deviation 62467.4 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 72.00 h | 55970.0 ng/mL | Standard Deviation 12989.7 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 168.00 h | 36890.0 ng/mL | Standard Deviation 16426.8 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 336.00 h | 19063.0 ng/mL | Standard Deviation 7803.41 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 504.00 h | 11587.0 ng/mL | Standard Deviation 6282.26 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 672 h | 7613.00 ng/mL | Standard Deviation 4698.61 |
Primary
Serum Half Life (T-HALF) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Serum Half Life (T-HALF) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 235.43 hours | Standard Deviation 76.414 |
Primary
Steady-state Volume Distribution (Vss) Following 10mg/kg IV Belatacept Between Weeks 12 and 16 - Pharmacokinetic Population
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Steady-state Volume Distribution (Vss) Following 10mg/kg IV Belatacept Between Weeks 12 and 16 - Pharmacokinetic Population | 0.11 l/kg | Standard Deviation 0.033 |
Primary
Time of Maximum Observed Serum Concentration (Tmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Time of Maximum Observed Serum Concentration (Tmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 0.60 hours |
Primary
Total Body Clearance (CLT) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population
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
Population: Participants who were treated and had PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Total Body Clearance (CLT) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population | 0.47 mL/h/kg | Geometric Coefficient of Variation 27 |
Secondary
Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants | Acute rejection of transplant | 4 participants |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants | Death | 1 participants |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants | Graft Loss | 1 participants |
Secondary
Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants
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
Population: Number analyzed for Baseline, Days 5, 28, 112, 168, 364 = 12, 11, 11, 10, 10, and 10, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants | Day 5 Post Transplantation | -7.276 µM | Standard Deviation 9.307 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants | Day 28 Post Transplantation | -8.486 µM | Standard Deviation 9.188 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants | Day 112 Post Transplantation | -7.936 µM | Standard Deviation 9.663 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants | Day 168 Post Transplantation | -7.589 µM | Standard Deviation 9.6115 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Kynurenine - All Treated Participants | Day 364 Post Transplantation | -7.279 µM | Standard Deviation 9.7117 |
Secondary
Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants
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
Population: Number analyzed for Baseline, Days 5, 28, 112, 168, 364 = 12, 11, 11, 10, 10, and 10, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants | Day 364 Post Transplantation | -24.610 µM | Standard Deviation 41.4859 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants | Day 5 Post Transplantation | -27.375 µM | Standard Deviation 38.9151 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants | Day 28 Post Transplantation | -22.765 µM | Standard Deviation 39.0174 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants | Day 112 Post Transplantation | -27.331 µM | Standard Deviation 39.2819 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Mean Change From Baseline to Days 5, 28, 112, 168, and 364 in Tryptophan - All Treated Participants | Day 168 Post Transplantation | -18.627 µM | Standard Deviation 37.901 |
Secondary
Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 5 Post Transplantation | 33.499 µg/mL | Geometric Coefficient of Variation 25.02 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 14 Post Transplantation | 24.558 µg/mL | Geometric Coefficient of Variation 40.605 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 28 Post Transplantation | 21.375 µg/mL | Geometric Coefficient of Variation 39.224 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 56 Post Transplantation (N=12) | 8.574 µg/mL | Geometric Coefficient of Variation 58.386 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 84 Post Transplantation | 7.289 µg/mL | Geometric Coefficient of Variation 60.959 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 112 Post Transplantation | 6.391 µg/mL | Geometric Coefficient of Variation 61.718 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 168 Post Transplantation | 3.189 µg/mL | Geometric Coefficient of Variation 47.797 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 364 Post Transplantation | 3.704 µg/mL | Geometric Coefficient of Variation 42.236 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 728 Post Transplantation | 4.383 µg/mL | Geometric Coefficient of Variation 43.209 |
| Belatacept 10mg/kg(3 Months); 5mg/kg Maintenance | Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population | Day 1092 Post Transplantation | 4.996 µg/mL | Geometric Coefficient of Variation 55.892 |