Belatacept Pharmacokinetic Trial in Renal Transplantation

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00578448
First received: December 19, 2007
Last updated: December 16, 2013
Last verified: December 2013
  Purpose

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 Intervention Phase
Renal Transplantation
Drug: Belatacept
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Pharmacokinetic Study in De Novo Renal Transplant Subjects Receiving a Belatacept Based Immunosuppressant Regimen

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Mean Belatacept Serum Concentrations Between Weeks 12 and 16 by Nominal Collection Time, Following 10mg/kg IV Belatacept - Pharmacokinetic Population [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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 of Maximum Observed Serum Concentration (Tmax) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 82 to Day 112 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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).

  • Serum Half Life (T-HALF) Between Weeks 12 and 16 Following 10mg/kg IV Belatacept - Pharmacokinetic Population [ Time Frame: Day 84 to Day 112 ] [ Designated as safety issue: No ]
    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:
  • Summary of Trough Serum Concentration of Belatacept Prior to Dosing up to 3 Years Post Transplantation - Pharmacokinetic Population [ Time Frame: Day 1 to Day 1092 ] [ Designated as safety issue: No ]
    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).

  • Acute Rejection, Graft Loss, and Death up to 3 Years Post Transplantation in Planned Study and 1 Year Long Term Extension - All Treated Participants [ Time Frame: Day 1 up to 4 years post transplantation ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to Day 364 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 364 ] [ Designated as safety issue: No ]
    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).


Enrollment: 14
Study Start Date: March 2008
Study Completion Date: September 2012
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: A

10mg/kg

6 doses (Day 1, 5, week 2, 4, 8 and 12) for 12 weeks

Drug: Belatacept
IV infusion
Other Name: BMS-224818
Active Comparator: B

5mg/kg

33 doses (every 4 weeks) for 144 weeks

Drug: Belatacept
IV infusion
Other Name: BMS-224818

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00578448

Locations
United States, Massachusetts
Western New England Renal & Transplant
Springfield, Massachusetts, United States, 01107
United States, Michigan
Henry Ford Hospital
Detriot, Michigan, United States, 48202
Argentina
Local Institution
Capital Federal, Buenos Aires, Argentina, 1425
Mexico
Local Institution
Cuernavaca, Morelos, Mexico, 62448
Local Institution
Aguascalientes, Mexico, 20219
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00578448     History of Changes
Other Study ID Numbers: IM103-047
Study First Received: December 19, 2007
Results First Received: October 28, 2013
Last Updated: December 16, 2013
Health Authority: United States: Food and Drug Administration
Mexico: Subsecretaria de Regulacion y Fomento Sanitario
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica

Additional relevant MeSH terms:
Immunosuppressive Agents
Abatacept
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014