Rheumatoid Arthritis
Conditions
Brief summary
The purpose of this study is to determine whether the blood levels of Abatacept (BMS-188667) drug product manufactured at Lonza Biologics and the Devens, MA facility of Bristol-Myers Squibb are comparable in healthy subjects
Detailed description
Primary Purpose of this study is to compare the pharmacokinetic (PK) of Abatacept (BMS-188667) manufactured at Lonza relative to Abatacept (BMS-188667) manufactured at Devens, MA facility following a single intravenous infusion of 750 mg in healthy subjects
Interventions
BIOLOGICALAbatacept (BMS-188667)
Solution for injection, Intravenous, 750 mg, Single dose, 1 day,
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations * Body weight will be between 60 and 100 kg, inclusive
Exclusion criteria
* Any significant acute or chronic medical illness * Any major surgery within 4 weeks of study drug administration * Smoking more than 10 cigarettes per day * Recent (within 6 months of study drug administration) drug or alcohol abuse. * Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or Human Immunodeficiency Virus-1, Human Immunodeficiency Virus-2 antibody * History of any significant drug allergy or asthma * Women who are pregnant or breastfeeding and/or unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Vss was measured in liters per kg body weight (L/kg). |
| Time to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Tmax was measured in hours (h). |
| Area Under the Concentration-time Curve (AUC) From Time Zero to 28 Days [AUC(0-28 Days)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | AUC (0 - 28) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - 28) was measured in micro grams\*hours per milliliter (µg\*h/mL). |
| Area Under the Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration [AUC(0-T)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | AUC (0 - T) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - T) was measured in micro grams\*hour per milliliter (µg\*h/mL). |
| Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(0 - INF)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | AUC (0 - INF) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - INF) was measured in µg\*h/mL. |
| Terminal Phase Elimination Half-life (T-HALF) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). T-HALF was measured in hours (h). |
| Total Body Clearance (CLT) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Day 1 to Day 71 | 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). CLT was measured in milliliters per hours per kilogram of body weight (mL/h/kg). |
| Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | Days 1 to 71 | 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Cmax was measured in micro grams per milliliter (µg/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Day 2 to Day 71 | Blood samples obtained: Days 1, 2, 4, 8, 15, 22, 29, 43, 57 and 71. International Units per liter (U/L); milligram per deciliter (mg/dL); Male(M); Female (F). Reference ranges (low/high) for laboratories for which participants were identified with marked abnormalities during the study: Blood Urea Nitrogen (M/F) 10-20mg/dL ; Creatine Kinase (F) 21-21 U/L,(M) 32-294 U/L; Direct Bilirubin (M/F) 0.1-0.4 mg/dL ; Fasting Glucose (M/F) 70-110 mg/dL; Lactate Dehydrogenase (M/F) 110-209 U/L. |
| Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Day 2 to Day 72 | Blood samples obtained: Days 2, 4, 8, 15, 22, 29, 43, 57 and 71. Male(M); Female (F). Reference ranges (low/high) for laboratory parameters for which participants were identified with marked abnormalities during the study: Leukocytes (quantitative White blood cells) (M/F) 4-11\*10\^3/microliters (µL); Neutrophils (absolute)(M/F) 1.4- 8.2\*10\^3/µL. |
| Change From Baseline in Systolic Blood Pressure - Safety Population | Day 1 to Day 71 | Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71. |
| Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 1 to Day 71 | Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71. |
| Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Day 1 to Day 71 | 12-lead electrocardiograms were performed on a supine participant (5 minutes supine) at baseline (baseline = screening; Days -21 to -2) and at Day 71. QT interval and QTc were measured in mille seconds (msec). A change from baseline QT and QTc (corrected for heart rate by Fridericia formula) greater than (\>) 30 msec or less than (\<) 60 msec were presented, as well as values over 450 and 500 msec. QT interval on ECG image defined as: time from the beginning of the QRS (complex consisting of Q, R and S waves) to the end of the T wave. |
| Number of Participants With Positive Abatacept-induced Immunogenicity Response | Days 29, 57, 71 | Immunogenicity determination was based on titers of anti-abatacept and anti- cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4-T) antibodies in serum over time. A participant had a positive abatacept-induced immunogenicity if 1 of the following criteria were met: missing baseline measurement and a positive response after baseline; negative baseline response and positive response after baseline; a baseline response and a positive response after baseline that has a titer value strictly greater than the baseline titer value. A validated, sensitive, electrochemiluminescence assay (ECL) method was used to analyze the antibodies in serum. Samples confirmed positive with ECL and with abatacept serum concentrations of less than equal to 1 µg/mL were further analyzed with a validated, in vitro, cell-based bioassay to analyze the sera containing the abatacept neutralizing activity. Samples obtained on Days 29, 57 and 71 post dose of abatacept on Day 1 (baseline). |
Countries
United States
Participant flow
Recruitment details
10 October 2011 to 11 Feb 2012. Participants who were randomized to an arm were admitted to a clinical facility the day prior to dosing (Day -1) and confined until 24 hours post the single dose; participants followed to Day 71.
Pre-assignment details
Healthy participants who weighed between 60 and 100 kilograms, inclusive. 223 enrolled; 72 randomized to an arm. Reasons for not being randomized: 24 withdrew consent, 5 poor/non-compliance, 111 no longer met study criteria, 11 other. Participants were age and sex matched between treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| 750 mg Abatacept From Lonza, NH A single dose of abatacept 750 mg, manufactured at Lonza, New Hampshire facility, was administered intravenously (IV) using a calibrated, constant rate infusion pump over approximately 30 minutes. | 36 |
| 750 mg Abatacept From Devens, MA A single dose of abatacept 750 mg, manufactured at Devens, Massachusetts facility, was administered intravenously (IV) using a calibrated, constant rate infusion pump over approximately 30 minutes. | 36 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | No longer meets study criteria | 1 | 0 |
| Overall Study | poor/non-compliance | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | 750 mg Abatacept From Lonza, NH | 750 mg Abatacept From Devens, MA | Total |
|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 10.02 | 31.2 years STANDARD_DEVIATION 8.9 | 31.4 years STANDARD_DEVIATION 9.41 |
| Body Weight | 78.93 kg STANDARD_DEVIATION 11.472 | 79.39 kg STANDARD_DEVIATION 11.057 | 79.16 kg STANDARD_DEVIATION 11.189 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 30 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 36 participants | 36 participants | 72 participants |
| Sex: Female, Male Female | 22 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 36 | 12 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Area Under the Concentration-time Curve (AUC) From Time Zero to 28 Days [AUC(0-28 Days)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population
AUC (0 - 28) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - 28) was measured in micro grams\*hours per milliliter (µg\*h/mL).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Area Under the Concentration-time Curve (AUC) From Time Zero to 28 Days [AUC(0-28 Days)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 33195 µg*h/mL | Geometric Coefficient of Variation 26 |
| 750 mg Abatacept From Devens, MA | Area Under the Concentration-time Curve (AUC) From Time Zero to 28 Days [AUC(0-28 Days)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 35255 µg*h/mL | Geometric Coefficient of Variation 23 |
Primary
Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(0 - INF)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population
AUC (0 - INF) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - INF) was measured in µg\*h/mL.
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(0 - INF)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 40385 µg*h/mL | Geometric Coefficient of Variation 23 |
| 750 mg Abatacept From Devens, MA | Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity [AUC(0 - INF)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 43229 µg*h/mL | Geometric Coefficient of Variation 27 |
Primary
Area Under the Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration [AUC(0-T)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population
AUC (0 - T) 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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). AUC (0 - T) was measured in micro grams\*hour per milliliter (µg\*h/mL).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Area Under the Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration [AUC(0-T)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 39295 µg*h/mL | Geometric Coefficient of Variation 23 |
| 750 mg Abatacept From Devens, MA | Area Under the Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration [AUC(0-T)] of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 41916 µg*h/mL | Geometric Coefficient of Variation 25 |
Primary
Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population
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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Cmax was measured in micro grams per milliliter (µg/mL).
Time frame: Days 1 to 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles. All completers had evaluable PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 262 µg/mL | Geometric Coefficient of Variation 27 |
| 750 mg Abatacept From Devens, MA | Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 255 µg/mL | Geometric Coefficient of Variation 21 |
Primary
Terminal Phase Elimination Half-life (T-HALF) of Single Dose Abatacept - Pharmacokinetic Evaluable Population
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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). T-HALF was measured in hours (h).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Terminal Phase Elimination Half-life (T-HALF) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 344 h | Standard Deviation 87.6 |
| 750 mg Abatacept From Devens, MA | Terminal Phase Elimination Half-life (T-HALF) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 364 h | Standard Deviation 106 |
Primary
Time to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population
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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Tmax was measured in hours (h).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 750 mg Abatacept From Lonza, NH | Time to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 1.00 h |
| 750 mg Abatacept From Devens, MA | Time to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 1.00 h |
Primary
Total Body Clearance (CLT) of Single Dose Abatacept - Pharmacokinetic Evaluable Population
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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). CLT was measured in milliliters per hours per kilogram of body weight (mL/h/kg).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Total Body Clearance (CLT) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 0.237 mL/h/kg | Geometric Coefficient of Variation 24 |
| 750 mg Abatacept From Devens, MA | Total Body Clearance (CLT) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 0.219 mL/h/kg | Geometric Coefficient of Variation 24 |
Primary
Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population
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: predose (0 hours), 0.25 hours (h), 0.5, 1, 2, 6, 12, 24, 72, 168, 336, 504, 672, 1008, 1344, and 1688 h post dose (Days 1 to 71). The results were summarized. The lower limit of assay quantitation (LLOQ) was 1.00 nanograms per milliliter (ng/mL). Vss was measured in liters per kg body weight (L/kg).
Time frame: Day 1 to Day 71
Population: Pharmacokinetic (PK) population: all participants who received study drug and had adequate PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 0.088 L/kg | Geometric Coefficient of Variation 33 |
| 750 mg Abatacept From Devens, MA | Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population | 0.083 L/kg | Geometric Coefficient of Variation 22 |
Secondary
Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population
Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71.
Time frame: Day 1 to Day 71
Population: All participants who received study drug (safety population) and had diastolic assessment were included in the analysis. Day 2 N=36 both arms; Day 15 (Lonza arm N=36; Devens arm N=34; Day 29 (N=33 in both arms); Day 57 (Lonza arm N=31; Devens arm N=33); Day 71 (Lonza arm N=36; Devens arm N=34).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 1 (1 hour post dose) N=36 | -4.9 mmHg | Standard Deviation 5.91 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 2 (N=36) | -2.3 mmHg | Standard Deviation 8.98 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 15 (N=36,34) | -1.4 mmHg | Standard Deviation 7.45 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 29 (N=33) | -1.9 mmHg | Standard Deviation 6.37 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 57 (N=31,33) | 0.4 mmHg | Standard Deviation 7.48 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 71 (N=36,34) | 1.6 mmHg | Standard Deviation 8.59 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 57 (N=31,33) | 3.5 mmHg | Standard Deviation 7.56 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 1 (1 hour post dose) N=36 | -4.1 mmHg | Standard Deviation 5.78 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 29 (N=33) | 0.9 mmHg | Standard Deviation 7.08 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 2 (N=36) | -0.6 mmHg | Standard Deviation 6.02 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 71 (N=36,34) | 4.0 mmHg | Standard Deviation 5.78 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Diastolic Blood Pressure on Days 1, 2, 15, 29, 57, and 71 - Safety Population | Day 15 (N=36,34) | 1.0 mmHg | Standard Deviation 7.29 |
Secondary
Change From Baseline in Systolic Blood Pressure - Safety Population
Blood pressure was obtained while the participant had been quietly seated for at least 5 minutes. Baseline was the 0 hour measurement on Day 1 (day of dosing) or if this value was missing, the last measurement before dosing. Blood pressure was measured in millimeters of mercury (mmHg) on Days 1, 2, 15, 29, 57, and 71.
Time frame: Day 1 to Day 71
Population: All participants who received study drug (safety population) and had systolic assessment were included in the analysis. Days 1 and 2 N=36 both arms; Day 15 (Lonza arm N=36; Devens arm N=34; Day 29 (N=33 in both arms); Day 57 (Lonza arm N=31; Devens arm N=33); Day 71 (Lonza arm N=36; Devens arm N=34).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 15 (N=36,34) | -1.1 mmHg | Standard Deviation 12.09 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 1 (1 hour post dose) (N=36) | -6.3 mmHg | Standard Deviation 9.73 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 2 (N=36) | -3.0 mmHg | Standard Deviation 12.31 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 29 (N=33) | -2.3 mmHg | Standard Deviation 10.94 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 57 (N=31,33) | 1.0 mmHg | Standard Deviation 11.96 |
| 750 mg Abatacept From Lonza, NH | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 71 (N=36,34) | 2.2 mmHg | Standard Deviation 12.09 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 57 (N=31,33) | 3.4 mmHg | Standard Deviation 9.48 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 15 (N=36,34) | 0.3 mmHg | Standard Deviation 8.12 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 29 (N=33) | -0.2 mmHg | Standard Deviation 9.65 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 1 (1 hour post dose) (N=36) | -4.5 mmHg | Standard Deviation 9.06 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 71 (N=36,34) | 2.9 mmHg | Standard Deviation 9.87 |
| 750 mg Abatacept From Devens, MA | Change From Baseline in Systolic Blood Pressure - Safety Population | Day 2 (N=36) | -1.4 mmHg | Standard Deviation 10.35 |
Secondary
Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population
12-lead electrocardiograms were performed on a supine participant (5 minutes supine) at baseline (baseline = screening; Days -21 to -2) and at Day 71. QT interval and QTc were measured in mille seconds (msec). A change from baseline QT and QTc (corrected for heart rate by Fridericia formula) greater than (\>) 30 msec or less than (\<) 60 msec were presented, as well as values over 450 and 500 msec. QT interval on ECG image defined as: time from the beginning of the QRS (complex consisting of Q, R and S waves) to the end of the T wave.
Time frame: Day 1 to Day 71
Population: All participants who received study drug and had at least one ECG value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QTc >30 msec < 60 msec | 2 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QT >60 msec | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QT > 500 msec | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QTc >60 msec | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QT > 450 msec | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QTcF >450 msec | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QT >30 msec < 60 msec | 5 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QTcF >450 msec | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QT >60 msec | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QT >30 msec < 60 msec | 4 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QTc >60 msec | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | Change from baseline in QTc >30 msec < 60 msec | 2 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QT > 500 msec | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With a Change From Baseline in QT Interval and Corrected (Fridericia) QT Interval (QTcF) - Safety Population | QT > 450 msec | 1 participants |
Secondary
Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population
Blood samples obtained: Days 2, 4, 8, 15, 22, 29, 43, 57 and 71. Male(M); Female (F). Reference ranges (low/high) for laboratory parameters for which participants were identified with marked abnormalities during the study: Leukocytes (quantitative White blood cells) (M/F) 4-11\*10\^3/microliters (µL); Neutrophils (absolute)(M/F) 1.4- 8.2\*10\^3/µL.
Time frame: Day 2 to Day 72
Population: All participants who received study drug (safety population) and had a laboratory assessment were included in the analysis. Day 2 N=36 both arms; Day 15 (Lonza arm N=36; Devens arm N=34; Day 29 (Lonza arm N=34; Devens arm N=33); Day 57 (Lonza arm N=31; Devens arm N=33); Day 71 (Lonza arm N=36; Devens arm N=34).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 57 (N=31,33) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 29 (N=34,33) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Any marked abnormalities Day 15 (n=36,34) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Neutrophils (absolute) (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Any marked abnormalities Day 2 (N=36) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Neutrophils (absolute) (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Any marked abnormalities Day 2 (N=36) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 29 (N=34,33) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Any marked abnormalities Day 15 (n=36,34) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Hematology Abnormalities on Days 2, 15, 29, 57, and 71 - Safety Population | Leukocytes (high) Day 57 (N=31,33) | 1 participants |
Secondary
Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population
Blood samples obtained: Days 1, 2, 4, 8, 15, 22, 29, 43, 57 and 71. International Units per liter (U/L); milligram per deciliter (mg/dL); Male(M); Female (F). Reference ranges (low/high) for laboratories for which participants were identified with marked abnormalities during the study: Blood Urea Nitrogen (M/F) 10-20mg/dL ; Creatine Kinase (F) 21-21 U/L,(M) 32-294 U/L; Direct Bilirubin (M/F) 0.1-0.4 mg/dL ; Fasting Glucose (M/F) 70-110 mg/dL; Lactate Dehydrogenase (M/F) 110-209 U/L.
Time frame: Day 2 to Day 71
Population: All participants who received study drug (safety population) and had a laboratory assessment were included in the analysis. Day 2 N=36 both arms; Day 15 (Lonza arm N=36; Devens arm N=34; Day 29 (Lonza arm N=34; Devens arm N=33); Day 57 (Lonza arm N=31; Devens arm N=33); Day 71 (Lonza arm N=36; Devens arm N=34).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 2 (N=36) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 15 (N=36,34) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 29 (N=34,33) | 2 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 57 (N=31,33) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Lactate Dehydrogenase (high) Day 2 (N=36) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 15 (N=36,34) | 1 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 29 (N=34) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 71 (N=36,34) | 2 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Bilirubin Direct (high) Day 29 (N=34) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Bilirubin Direct (high) Day 71 (N=36,34) | 0 participants |
| 750 mg Abatacept From Lonza, NH | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Fasting Glucose (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 71 (N=36,34) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 2 (N=36) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 15 (N=36,34) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 15 (N=36,34) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Fasting Glucose (high) Day 71 (N=36,34) | 0 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 29 (N=34,33) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Bilirubin Direct (high) Day 71 (N=36,34) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 57 (N=31,33) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Blood urea nitrogen (high) Day 29 (N=34) | 1 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Creatine Kinase (high) Day 71 (N=36,34) | 2 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Bilirubin Direct (high) Day 29 (N=34) | 3 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population | Lactate Dehydrogenase (high) Day 2 (N=36) | 1 participants |
Secondary
Number of Participants With Positive Abatacept-induced Immunogenicity Response
Immunogenicity determination was based on titers of anti-abatacept and anti- cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4-T) antibodies in serum over time. A participant had a positive abatacept-induced immunogenicity if 1 of the following criteria were met: missing baseline measurement and a positive response after baseline; negative baseline response and positive response after baseline; a baseline response and a positive response after baseline that has a titer value strictly greater than the baseline titer value. A validated, sensitive, electrochemiluminescence assay (ECL) method was used to analyze the antibodies in serum. Samples confirmed positive with ECL and with abatacept serum concentrations of less than equal to 1 µg/mL were further analyzed with a validated, in vitro, cell-based bioassay to analyze the sera containing the abatacept neutralizing activity. Samples obtained on Days 29, 57 and 71 post dose of abatacept on Day 1 (baseline).
Time frame: Days 29, 57, 71
Population: Immunogenicity Data Set: All participants with at least 1 postdose visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 750 mg Abatacept From Lonza, NH | Number of Participants With Positive Abatacept-induced Immunogenicity Response | 4 participants |
| 750 mg Abatacept From Devens, MA | Number of Participants With Positive Abatacept-induced Immunogenicity Response | 1 participants |