Belatacept Pharmacokinetic Trial in Renal Transplantation

Study Overview
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Brief Summary
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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

Official Title
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An Open-label Pharmacokinetic Study in De Novo Renal Transplant Subjects Receiving a Belatacept Based Immunosuppressant Regimen

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Belatacept


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 84 to Day 112 | 
| 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. | Day 84 to Day 112 | 
| 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. | Day 84 to Day 112 | 
| 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). | Day 82 to Day 112 | 
| 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). | Day 84 to Day 112 | 
| 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). | Day 84 to Day 112 | 
| 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). | Day 84 to Day 112 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 1 to Day 1092 | 
| 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. | Day 1 up to 4 years post transplantation | 
| 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) | Baseline to Day 364 | 
| 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). | Day 1 to Day 364 |