Pharmacokinetics, Safety and Tolerability of Single-dose Belatacept in Adolescent Kidney Transplant Recipients

A Phase 2 Multi-Center, Randomized Conversion Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Belatacept Administered to Pediatric Subjects With a Stable Renal Transplant

The purpose of this study is to evaluate how well adolescent kidney transplant patients tolerate a single dose of belatacept they receive at least 6 months after transplant surgery, and how their body handles the drug.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant
• Intervention / Treatment: Drug: Belatacept

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90027
      • Childrens Hospital of LA
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20010
      • Childrens National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Male and Female subjects,12-17 years old
• Receiving CNI-based maintenance immunosuppression since the time of renal transplantation in accordance with local standard of care
• Stable renal function, in the opinion of the investigator, with a cGFR>45 mL/min/1.73m2 at the time of enrollment (per updated Schwartz Formula)
• Adolescent Recipients of a renal allograft from a living donor or a deceased donor at least 6 months prior to enrollment
• Subject must be receiving a calcineurin inhibitor (CNI)-based [cyclosporine (CsA) [any formulation] or Tacrolimus (TAC)] immunosuppressive regimen
• Subject must be receiving adjunctive background maintenance immunosuppression with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS)/mycophenolic acid (MPA)
• Subjects may be receiving maintenance corticosteroids in accordance with the local standard of care
• Negative Interferon Gamma Release Assay (IGRA) such as QuantiFERON-TB Gold test or T-Spot-TB
• FOCBP must have negative serum or urine pregnancy test within 24 hrs prior to start of study medication
• Subject must have stable estimated glomerular filtration rate (GFR) ≥45 mL/min/1.73m2 (updated Schwartz formula)

Exclusion Criteria:

• Epstein-Barr virus (EBV) serostatus negative or unknown at time of transplant and screening
• History of any treated or biopsy proven acute rejection (BPAR) within 3 months prior to enrollment
• Subjects who have experienced more than 1 episode of acute rejection (AR) of the current allograft or any antibody-mediated AR
• Subjects with any active infection [including, but not limited to, positive cytomegalovirus (CMV) or BK viral (BKV) loads, BKV associated nephropathy (BKVAN), CMV retinitis, CMV colitis, etc.]
• Urine albumin:creatinine ratio > 56.5 mg/mmol (> 0.5 mg albumin / mg creatinine) on a random voided urine specimen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Belatacept	Drug: Belatacept; Single intravenous infusion of belatacept, 7.5 mg/kg; Other Names: BMS-224818

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Serum Concentration (Cmax) of Belatacept	Cmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Cmax was measured in micrograms per milliliter.	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57
Time of Maximum Observed Plasma Concentration (Tmax) of Belatacept	Tmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Tmax was measured in hours (h).	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57
Half-Life of Elimination (T-Half) of Belatacept	T-HALF was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). T-HALF was measured in hours (h).	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57
Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC (0-T)) and Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) of Belatacept	AUC (0 - T) and AUC (0 - INF) were derived from serum concentration versus time data and measured in microgram hours per milliliter (µg*h/mL). Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL).	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57
Total Body Clearance (CLT) of Belatacept	CLT was the volume of abatacept cleared by the system, normalized by baseline body weight. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). CLT was measured in milliliters per hours per kilogram of body weight (mL/h/kg).	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57
Volume of Distribution at Steady-state (Vss) of Belatacept	Vss was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Vss was measured in liters per kg body weight (L/kg).	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Death, Serious Adverse Events (SAEs), and Treatment-related Adverse Event (AE)	Death was a fatal event leading to permanent cessations of all vital functions of the body. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment related=having certain, probable, possible, or missing relationship to study drug.	Date of First Dose to 24 weeks post the last dose; approximately 26 weeks
Number of Participants With Positive Belatacept-induced Immunogenicity Response	Serum samples were analyzed for anti-belatacept antibodies using a validated homogenous bridging assay. The assay followed a tiered approach consistent with health authority guidance: tier 1 for screening ADA responses, tier 2 for confirming drug specificity of the ADA-positive responses, and tier 3 for titer. A neutralizing antibody assay was used to test those samples positive to the LEA29Y portion of the molecule in tier 2 and for which drug concentrations are =>1 μg/mL. Lack of immunogenicity was defined as the absence of a positive response.	Baseline/Day 1, Days 15, 29, and 57
Percentage of CD86 Receptor Occupancy	Blood samples collected following the single dose belatacept infusion were assessed for CD86 receptor occupancy (CD86 RO).	0.5 hours post dose on Day 1, Day 29 and Day 57

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2013
• Primary Completion (Actual): December 6, 2016
• Study Completion (Actual): December 6, 2016

Study Registration Dates

• First Submitted: January 31, 2013
• First Submitted That Met QC Criteria: February 13, 2013
• First Posted (Estimate): February 15, 2013

Study Record Updates

• Last Update Posted (Actual): July 24, 2017
• Last Update Submitted That Met QC Criteria: June 23, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: IM103-144; 2011-005257-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No