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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01791491

Enrollment

Registered

2013-02-15

Start date

2013-05-09

Completion date

2016-12-06

Last updated

2017-07-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Kidney Transplant

Brief summary

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.

Interventions

DRUGBelatacept

Single intravenous infusion of belatacept, 7.5 mg/kg

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to 17 Years

Healthy volunteers

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
Volume of Distribution at Steady-state (Vss) of Belatacept	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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).
Half-Life of Elimination (T-Half) of Belatacept	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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).
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	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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).
Total Body Clearance (CLT) of Belatacept	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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).
Maximum Observed Serum Concentration (Cmax) of Belatacept	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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.
Time of Maximum Observed Plasma Concentration (Tmax) of Belatacept	Pre-dose (0), 0.5hr and 2hr from the start of infusion on Day 1, Day 29, and Day 57	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).

Secondary

Measure	Time frame	Description
Number of Participants With Positive Belatacept-induced Immunogenicity Response	Baseline/Day 1, Days 15, 29, and 57	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.
Percentage of CD86 Receptor Occupancy	0.5 hours post dose on Day 1, Day 29 and Day 57	Blood samples collected following the single dose belatacept infusion were assessed for CD86 receptor occupancy (CD86 RO).
Number of Participants With Death, Serious Adverse Events (SAEs), and Treatment-related Adverse Event (AE)	Date of First Dose to 24 weeks post the last dose; approximately 26 weeks	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.

Countries

United States

Participant flow

Recruitment details

16 participants were enrolled and 9 were treated. Reasons for non-treatment: 1 withdrew consent and 6 no longer met study criteria.

Participants by arm

Arm	Count
Belatacept A single dose of 7.5 mg/kg Belatacept was given intravenously on study Day 1 over approximately 30 minutes.	9
Total	9

Baseline characteristics

Characteristic	Belatacept
Age, Continuous	15.1 years STANDARD_DEVIATION 1.17
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	4 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	5 Participants
Sex: Female, Male Female	4 Participants
Sex: Female, Male Male	5 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	3 / 9
serious Total, serious adverse events	4 / 9

Outcome results

Primary

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).