Subcutaneous Pharmacokinetics of Belatacept

Study Overview
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Brief Summary
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Pharmacokinetics, Bioavailability, Safety and Immunogenicity of Single Doses of Belatacept Administered Subcutaneously to Healthy Subjects

Official Title
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Pharmacokinetics, Safety and Immunogenicity of Single Doses of Belatacept Administered Subcutaneously to Healthy Subjects

Conditions
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Transplantation

Intervention / Treatment
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* Drug: belatacept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ages 18 to 65 years old Subjects must weigh less than or equal to 100 kg Exclusion Criteria: Inability to tolerate injections or IV infusions autoimmune disorders TB herpes HCV HBV HIV bacterial or viral infection history of cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Belatacept 50 mg Subcutaneous Injection<br>Belatacept 50 mg subcutaneous (SC) injection | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 100 mg Subcutaneous Injection<br>Belatacept 100 mg SC injection | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 125 mg Subcutaneous Injection<br>Belatacept 125 mg SC injection | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 150 mg Subcutaneous Injections<br>2 SC injections of 75 mg Belatacept | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 200 mg Subcutaneous Injections<br>2 SC injections of 100 mg Belatacept | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 250 mg Subcutaneous Injections<br>2 SC injections of 125 mg Belatacept | Drug: belatacept<br>* single dose, 116 days<br>|
| Active Comparator: Belatacept 125 mg Intravenous Infusion<br>125 mg Belatacept intravenous (IV) injection | Drug: belatacept<br>* single dose, 116 days<br>|
| Placebo Comparator: Placebo<br>SC injection of placebo solution | Drug: Placebo<br>* Subcutaneous injection of placebo solution (product ID: 224818-N000- 029)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of Belatacept | Maximum observed serum concentration (Cmax) values were derived from serum concentration versus time data and reported in micrograms per milliliter (ug/mL). | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Time of Maximum Observed Serum Concentration (Tmax) of Belatacept | Time of maximum observed serum concentration (Tmax) values were derived from serum concentration versus time data for all participants treated with Belatacept. | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Adjusted Geometric Means of Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-T)) for Belatacept | Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUC(0-T)) was derived from serum concentration versus time data. Adjusted geometric means were reported in microgram hours per milliliter (ug*h/mL). | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Adjusted Geometric Means of Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC(INF)) for Belatacept | Area under the serum concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) was derived from serum concentration versus time data. Adjusted geometric means were reported in microgram hours per milliliter (ug*h/mL) | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Serum Half-life (T-HALF) of Belatacept | Serum half-life (T-HALF) was determined from serum concentration versus time data and was reported in hours. | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Apparent Total Body Clearance (CLT/F) of SC Belatacept | Apparent total body clearance (CLT/F) was derived from serum concentration versus time data for all participants who received subcutaneous (SC) Belatacept injections. Units reported in milliliters per hour (mL/h). | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Total Body Clearance (CLT) of IV Belatacept | Total body clearance (CLT) was derived from serum concentration versus time data for all participants that were treated with IV Belatacept. Units reported in milliliters per hour (mL/h) | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Volume of Distribution at Steady State (VSS) for IV Belatacept | Volume of distribution at steady state (VSS) was derived from serum concentration versus time data for all participants treated with IV Belatacept. | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Apparent Volume of Distribution at Steady State (Vss/F) for SC Belatacept | Apparent volume of distribution at steady state (Vss/F) was derived from concentration versus time data for all participants treated with subcutaneous (SC) Belatacept. | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Number of Injection Sites on Subcutaneous Belatacept Absorption | AUC(0-T) and AUC(INF) for Belatacept were derived from serum concentration versus time data to assess the effect of number of injection sites on the subcutaneous absorption of Belatacept. All treatments were dose-normalized to 50mg. Adjusted geometric means reported in microgram hours per milliliter (ug*h/mL). AUC(0-T) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration. AUC(INF) = Area Under the Serum Concentration-time Curve From Time Zero Extrapolated to Infinite Time. | Immediately before dose, 0.5, 2, 6, 12, 24, 36, 48, 60, 72, 84 hours post-dose, Days 5, 6, 7, 8, 14, 21, 28, 35, 42, 56, 86 and 116 | 
| Number of Participants With Vital Sign Abnormalities | Vital signs (body temperature, respiratory rate, seated blood pressure, and heart rate) were recorded at screening. All significant findings were evaluated by the investigator, and all abnormalities were listed. | 1 day pre-dose, Days 1, 2, 5, 14, 28, 42, 86 and 116 | 
| Number of Participants With Injection Site Reactions | Participants were assessed for erythema, heat, pain, pruritis and swelling at the injection sites and were characterized by the investigator as mild, moderate or severe reactions. | 0.5, 2, 6 and 24 hours post-dose, Days 3, 4, 5, 6, 7, 8, 14, 21 and 116 | 
| Number of Participants With Physical Examination Abnormalities | All clinically significant deviations from normal physical examinations were reported. | Days 1, 2, 5, 14, 28, 42, 86, 116 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Participants underwent a 12-lead ECG assessment at Screening (Day 1) and Study Discharge (Day 116). All investigator-assessed ECG abnormalities were reported. | Days 1 and 116 | 
| Number of Participants With Marked Hematology Laboratory Abnormalities | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Hemoglobin (grams per deciliter:g/dL): <0.85*Pre-Rx. Hematocrit (%): <0.85*Pre-Rx. Platelet Count (*10^9 cells per liter:c/L): <0.85*LLN or >1.5*ULN (if Pre-Rx<LLN, use <0.85*Pre-Rx). Leukocytes (*10^3 cells per microliter: c/uL): <0.9*LLN, >1.2*ULN (if Pre-Rx<LLN, use <0.85*Pre-Rx or >ULN, if Pre-Rx>ULN, use >1.15*Pre-Rx or <LLN) Neutrophils+Bands (*10^3 c/uL): <=1.500. Lymphocytes (*10^3 c/uL): <0.750 or >7.500. Monocytes (*10^3 c/uL): >2.000. Basophils (*10^3 c/uL): >0.400. Eosinophils (*10^3 c/uL): >0.750. | Day 1 Pre-dose, Days 2, 5, 14, 28, 42, 86, 116 | 
| Number of Participants With Marked Serum Chemistry Abnormalities | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Alkaline Phosphatase (units per liter: U/L), Aspartate Aminotransferase (U/L), Alanine Aminotransferase (U/L): >1.25*ULN (if Pre-Rx>ULN, use >1.25*Pre-Rx). Bilirubin (milligrams per deciliter: mg/dL): >1.1*ULN (if Pre-Rx>ULN, use >1.25*Pre-Rx). Blood Urea Nitrogen (mg/dL): >1.1*ULN (if Pre-Rx>ULN, use >1.2*Pre-Rx). Creatinine (mg/dL): >1.33*Pre-Rx. Sodium (milliequivalents per Liter: mEq/L): <0.95*LLN, >1.05*ULN (if Pre-Rx<LLN: <0.95*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.05*Pre-Rx, <LLN). Potassium(mEq/L), Chloride (mEq/L), Calcium(mg/dL): <0.9*LLN, >1.1*ULN (if Pre-Rx<LLN: <0.9*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.1*Pre-Rx, <LLN). Phosphorus (mg/dL): <0.85*LLN, >1.25*ULN (if Pre-Rx<LLN, <0.85*Pre-Rx, >ULN. if Pre-Rx>ULN: >1.25*Pre-Rx, <LLN). | Day 1 Pre-dose, Days 2, 5, 14, 28, 42, 86, 116 | 
| Number of Participants With Marked Laboratory Abnormalities | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Glucose (mg/dL): <0.8*LLN, >1.5*ULN (if Pre-Rx<LLN: <0.8*Pre-Rx, >ULN. If Pre-Rx>ULN: >2.0*Pre-Rx, <LLN). Protein (grams per deciliter: g/dL): <0.9*LLN, >1.1*ULN (if Pre-Rx<LLN: <0.9*Pre-Rx, >ULN. If Pre-Rx>ULN: >1.1*Pre-Rx, <LLN). Albumin (g/dL): <0.9*LLN (if Pre-Rx<LLN: <0.9*Pre-Rx). Uric Acid (mg.dL): >1.2*ULN (if Pre-Rx>ULN: >1.25*Pre-Rx). Lactate Dehydrogenase (U/L): >1.25*ULN (if Pre-Rx>ULN: >1.5*Pre-Rx) | Day 1 Pre-dose, Days 2, 5, 14, 28, 42, 86, 116 | 
| Number of Participants With Positive Immunogenicity to Belatacept | The number of participants with positive immunogenicity to Belatacept was reported for each arm. Positive immunogenicity was defined as the presence of a positive antibody response generated against Belatacept. | Days 1, 14, 28, 42, 56, 86, 116 |