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Pharmacokinetic Study to Compare the Blood Levels of Abatacept Manufactured at Lonza Biologics to the Blood Levels of Abatacept Manufactured at the Devens, Massachusetts (MA) Facility of Bristol-Myers Squibb

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01439204
First received: September 21, 2011
Last updated: February 21, 2014
Last verified: February 2014
  Purpose

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


Condition Intervention Phase
Rheumatoid Arthritis
Biological: Abatacept (BMS-188667)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: A Randomized, Open-label, Parallel-Group, Single-dose, Biocomparability Study of the Pharmacokinetics of Abatacept (BMS-188667) Drug Products Using Active Pharmaceutical Ingredient Manufactured at Devens, MA Site Relative to Active Pharmaceutical Ingredient Manufactured at Lonza, New Hampshire (NH) in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Maximum Observed Concentration (Cmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population [ Time Frame: Days 1 to 71 ] [ Designated as safety issue: No ]
    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 to Reach Maximum Concentration (Tmax) of Single Dose Abatacept - Pharmacokinetic Evaluable Population [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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).

  • Volume of Distribution at Steady-state (Vss) of Single Dose Abatacept - Pharmacokinetic Evaluable Population [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Number of Participants With Positive Abatacept-induced Immunogenicity Response [ Time Frame: Days 29, 57, 71 ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With Marked Serum Chemistry Abnormalities on Days 2, 15, 29, 57 and 71 - Safety Population [ Time Frame: Day 2 to Day 71 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 2 to Day 72 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 to Day 71 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 223
Study Start Date: October 2011
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Abatacept (BMS-188667) manufactured at Lonza, NH facility Biological: Abatacept (BMS-188667)
Solution for injection, Intravenous, 750 mg, Single dose, 1 day,
Other Name: BMS-188667
Experimental: Abatacept (BMS-188667) manufactured at Devens, MA facility Biological: Abatacept (BMS-188667)
Solution for injection, Intravenous, 750 mg, Single dose, 1 day,
Other Name: BMS-188667

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

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  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: NCT01439204

Locations
United States, Nebraska
Icon Clinical Pharmacology Unit, Llc
Omaha, Nebraska, United States, 68154
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: NCT01439204     History of Changes
Other Study ID Numbers: IM101-292
Study First Received: September 21, 2011
Results First Received: November 4, 2013
Last Updated: February 21, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Arthritis, Rheumatoid
Arthritis
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Abatacept
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014