Phase IIIB Subcutaneous Abatacept Monotherapy Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00547521
First received: October 19, 2007
Last updated: February 7, 2012
Last verified: February 2012
  Purpose

To evaluate safety and immunogenicity of abatacept when used with or without methotrexate in the absence of an IV loading dose of abatacept


Condition Intervention Phase
Rheumatoid Arthritis (RA)
Drug: abatacept
Drug: Methotrexate (MTX)
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IIIb, Multi-center, Stratified, Open-Label Study to Evaluate the Immunogenicity, Steady State Trough Level, and Safety of Subcutaneous Abatacept (BMS-188667) in Subjects With Rheumatoid Arthritis Administered With or Without Background Methotrexate

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (Enzyme-linked Immunosorbent Assay [ELISA] Method) at Day 113 of the ST Study [ Time Frame: Day 113 ] [ Designated as safety issue: No ]
    ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.

  • Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses (ELISA Method) Over Time During the ST Study [ Time Frame: Day 15, 29, 43, 57, 85,113 and 28, 56 and 85 days post last dose. ] [ Designated as safety issue: No ]
    ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.

  • Number of Participants With Positive Anti-abatacept Responses to Abatacept (Meso-Scale Discovery [MSD] Electrochemiluminescence [ECL] Assay Method) Over Time During the ST Study [ Time Frame: Day 15, 29, 43, 57, 85,113 and 28, 56 and 85 days post last dose. ] [ Designated as safety issue: No ]
    The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. It is more sensitive and has a higher drug tolerance than ELISA method. For the anti-abatacept antibody ECL (MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.

  • Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for ELISA Results) [ Time Frame: Day 113. ] [ Designated as safety issue: No ]
    ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.

  • Immunogenicity in MTX Naive and MTX-previous Users in Cohort 1 at Day 113 of the ST Study (for MSD Results) [ Time Frame: Day 113. ] [ Designated as safety issue: No ]
    The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. It is more sensitive and has a higher drug tolerance than the ELISA method. For anti-abatacept antibody ECL (MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.

  • Cross Tabulations of the Number of Participants With Positive and Negative Immunogenicity Status at Baseline and Each Visit During the ST Study (for ELISA Results) [ Time Frame: Baseline and on day 15, 29, 43, 57, 85 and 113 ] [ Designated as safety issue: No ]
    ELISA is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum. For anti-abatacept antibody ELISA, a sample was considered seropositive if it had a titer of 400 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 400. A sample was considered positive in CTLA4-T antibody ELISA if it had a titer of 25 or greater and if immunodepletion was observed. The responses that were negative in initial screen were reported as seronegative with a value of < 25.

  • Cross Tabulations of the Number of Participants With Positive and Negative Immunogenicity Status at Baseline and Each Visit During the ST Study (for MSD Results) [ Time Frame: Baseline and day 15, 29, 43, 57, 85 and 113. ] [ Designated as safety issue: No ]
    The ECL (MSD) assay method is a validated, sensitive assay technique used to analyze presence of abatacept-specific antibodies in serum . It is more sensitive and has a higher drug tolerance than the ELISA method. For anti-abatacept antibody ECL(MSD) assay, a sample was considered seropositive if it had a titer of 10 or greater and if immunodepletion was observed with abatacept, or abatacept and CTLA4-T. Those responses that were not positive in the initial screen or were not confirmed to be positive based on immunodepletion were reported as seronegative and were assigned a value of < 10.


Secondary Outcome Measures:
  • Change From Baseline in DAS28-CRP Score at End of 4-month (Day 113) of the ST Study [ Time Frame: Baseline and Month 4 (Day113). ] [ Designated as safety issue: No ]
    DAS28-CRP is a continuous variable which is a composite of 4 variables: the number of tender joint out of 28, the number of swollen joint out of 28, C-reactive protein (CRP) in miligrams/Liter (mg/L) and subject assessment of disease activity measure on a VAS of 100mm. DAS 28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * VAS + 0.96.

  • Number of Participants With Clinically Meaningful Improvement at End of 4-month (Day 113) of the ST Study [ Time Frame: Day 113. ] [ Designated as safety issue: No ]
    A clinically meaningful improvement is defined as a greater than or equal to 1.2 reduction in DAS28-CRP score from baseline.

  • Change From Baseline in Physical Functioning (HAQ-DI) at End of the 4-month Treatment Period (Day 113) of the ST Study [ Time Frame: Baseline and Month 4 (Day 113). ] [ Designated as safety issue: No ]
    HAQ-DI takes into account participant's use of aids or devices or assistance in scoring algorithm for a disability category. The questionnaire includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The questions are evaluated on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score is calculated by summing worst scores in each domain and dividing by the number of domains answered.

  • Change From Baseline in All HAQ-DI Components at End of the 4-month Treatment Period (Day 113) of the ST Study [ Time Frame: Baseline and Month 4 (Day113). ] [ Designated as safety issue: No ]
    HAQ-DI takes into account participant's use of aids or devices or assistance in scoring algorithm for a disability category. The questionnaire includes 20 questions assessing physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The questions are evaluated on a 4-point scale: 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty and 3 = unable to do. Higher scores indicate greater dysfunction. The score is calculated by summing worst scores in each domain and dividing by the number of domains answered.

  • Cross Tabulations of Number of Participants With Positive and Negative Status for RF at Day 113 With Baseline, in the ST Study [ Time Frame: Baseline and Day 113. ] [ Designated as safety issue: No ]
    RF is an autoantibody that is usually present in the serum of people with rheumatoid arthritis. The cut-point value for seroconversion was 15 IU/mL (>= 15 IU/mL resulted in a positive result). Cross-tabulation of frequency of seroconversion of RF at Day 113 with baseline, in the ST period, was provided.

  • Number of Participants Who Died, Experienced SAEs, Experienced AEs or Who Discontinued Due to AEs During the ST Study [ Time Frame: Continuously through ST period (upto Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first. ] [ Designated as safety issue: Yes ]
    AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs or SAEs were recorded.

  • Number of Participants Who Experienced Drug-related SAEs and Drug-related AEs During the ST Study [ Time Frame: Continuously through ST period (upto Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first. ] [ Designated as safety issue: Yes ]
    Drug-related AEs are those events with a relationship to the study therapy of certain; probable; possible; or missing. Drug-related SAEs are those events with any relationship to the study therapy.

  • Number of Participants With AEs of Special Interest During the ST Study [ Time Frame: Continuously through ST period (upto Day 113). Includes the data from start of study drug therapy up to 56 days after the last dose (Day 113) or start of the long-term period whichever occurred first. ] [ Designated as safety issue: Yes ]
    An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, AEs of particular importance were associated with the use of immunomodulatory agents: infections, autoimmune disorders, malignancies, and injection reaction AEs (systemic AEs occurring within 24 hours of SC injection and local injection site reactions) were recorded.

  • Number of Participants With Marked Abnormalities (MAs) in Hematology During the ST Study: Hemoglobin, Hematocrit, Platelet Count, Erythrocytes and Leukocytes [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin: >3 g/dL decrease from pre-treatment (pre Rx); hematocrit: <0.75 * pre-Rx value; platelet count: <0.67 * (LLN -lower limit of normal) (or, if pre-Rx value <LLN, then <0.5 * pre-Rx value and <100,000/mm^3); leukocytes: <0.75 * LLN or >1.25 * ULN (or, if pre-Rx value <LLN, then <0.8 * pre-Rx or >(ULN -upper limit of normal) ; erythrocytes: <0.75 * pre Rx.

  • Number of Participants With MAs in Hematology During the ST Study: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils + bands (absolute): <1.00 * 10^3cells/microlitre (uL); lymphocytes (absolute): <0.75 * 10^3 cells/uL or >7.50 * 10^3 cells/uL; monocytes (absolute): >2.00 * 10^3 cells/uL; basophils (absolute): >0.40 * 10^3 cells/uL; eosinophils (absolute): >0.75 * 10^3 cells/uL.

  • Number of Participants With MAs in Serum Chemistry During the ST Study: Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Bilirubin (Total), G-Glutamyl Transferase (G-GT) and Blood Urea Nitrogen (BUN) [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP: >2.0 * ULN (if pre-Rx > ULN, then >3 * pre-Rx); AST, ALT: > 3 * ULN (if pre-Rx > ULN, then > 4 * pre-Rx); bilirubin (total): >2 * ULN, or if pre Rx > ULN then >4 * Pre Rx; BUN : >2 * pre Rx; GGT : >2 * ULN, or if pre Rx > ULN then >3 * pre Rx.

  • Number of Participants With MAs in Serum Chemistry During the ST Study: Creatinine, Sodium (Serum), Potassium (Serum), Chloride (Serum), Calcium (Total) and Protein (Total) [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs= laboratory measurements marked as abnormal: creatinine: >1.5 * pre-Rx; sodium (serum):<0.95 * LLN or >1.05 * ULN (if pre-Rx < LLN, then <0.95 * pre-Rx or >1.05 * ULN. If pre-Rx > ULN, then >0.95 * pre-Rx or < ULN); potassium (serum):<0.9 * LLN or >1.1 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN; chloride (serum),protein (total):<0.9 * LLN or >1.1 8 ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >1.1 * pre-Rx or < LLN); calcium (total): <0.8 * LLN or >1.2 * ULN (if pre-Rx < LLN, then <0.9 * pre-Rx or > ULN. If pre-Rx > ULN, then >0.75 * pre-Rx or < ULN).

  • Number of Participants With MAs in Serum Chemistry During the ST Study: Glucose (Fasting Serum), Albumin, Glucose (Serum), Phosphorous (Inorganic) and Uric Acid [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 * LLN or >1.5 ULN (if pre-Rx <LLN, then <2.0 * pre-Rx or >ULN; albumin: <0.9 * LLN (if pre-Rx < LLN, then <0.75 * pre-Rx); uric acid: >1.5 * ULN (if pre-Rx > ULN, then >2.0 * pre-Rx); phosphorous (inorganic):<0.75 * LLN or >1.25 * ULN (if pre-Rx < ULN, then <0.67 * pre-Rx or < ULN. If pre-Rx > ULN, then >1.33 * re-Rx or < LLN); glucose (serum): <65 mg/dL or >220 mg/dL.

  • Number of Participants With MAs in Urinalysis During the ST Study: Protein, Glucose, Blood, Leukocyte Esterase, Red Blood Cells (RBC) and White Blood Cells (WBC) [ Time Frame: Continuously from start of ST period up to 56 days post the last dose in the short-term period or start of the long-term period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs in urinalysis: protein, glucose, blood, leukocyte esterase, RBC, WBC: >= 2+ (or, if value >= 4, or if pre-Rx value = 0 or 0.5, then >= 2x or if pre-Rx value =1, then >= 3, or if pre-Rx = 2 or 3, then >= 4).

  • Number of Participants With Anti-nuclear Antibody (ANA) Category at Day 113 of the ST Study [ Time Frame: Day 113. ] [ Designated as safety issue: Yes ]
    ANA status was categorized as negative or positive corresponding to the following dilutions: less than 1:160 and greater than equal to 1:160.

  • Number of Participants With Anti-double Stranded DNA (dsDNA) Category at Day 113 of the ST Study [ Time Frame: Day 113. ] [ Designated as safety issue: Yes ]
    Anti-dsDNA antibody status was categorized as negative or positive based upon assay-specific numeric cut-off values.

  • Number of Participants With Clinically Meaningful Vital Signs During the ST Study [ Time Frame: At screening and on days 1,15,29,43, 57, 85 and 113. ] [ Designated as safety issue: Yes ]
    Vital signs measurements (including seated blood pressure, heart rate and temperature) were recorded. The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs/physical examination were clinically meaningful.

  • Minimum Plasma Concentration (Cmin) at Each Visit During the 4 Month Treatment Period of the ST Study [ Time Frame: Days 1, 15, 29, 43, 57, 85 and 113. ] [ Designated as safety issue: No ]
    Cmin serum abatacept concentration was obtained directly from the concentration-time data.


Enrollment: 100
Study Start Date: December 2007
Study Completion Date: January 2012
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Subcutaneous (SC) Abatacept + Methotrexate (MTX) Cohort
In the ST period, participants were administered a dose of 125 mg abatacept SC, once weekly, for 4 months. Participants were also administered a stable MTX dose of greater than or equal to 10 mg once weekly for at least 4 weeks prior to first injection of SC abatacept.
Drug: abatacept
solution, subcutaneous injection, 125 mg/kg, weekly, 106 days in short term; long term is open
Other Names:
  • BMS-188667
  • Orencia®
Drug: Methotrexate (MTX)
Participants who were currently receiving methotrexate at a stable dose ≥ 10 mg for at least 4 weeks
Experimental: SC Abatacept Monotherapy Cohort
In the ST period, participants were administered a dose of 125 mg abatacept SC, once weekly, for 4 months. Participants did not receive MTX at screening i.e., MTX naive, or discontinued MTX due to lack of efficacy or tolerability at least 4 weeks prior to first injection of SC abatacept.
Drug: abatacept
solution, subcutaneous injection, 125 mg/kg, weekly, 106 days in short term; long term is open
Other Names:
  • BMS-188667
  • Orencia®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical diagnosis of Rheumatoid Arthritis
  • Subjects Global Disease Assessment of greater than equal to 20 mm on a visual analog scale
  • Discontinue all Biologics and Disease-modifying antirheumatic drugs (DMARDS) except for methotrexate

Exclusion Criteria:

  • Received treatment with rituximab
  • Subjects who have received treatment with immunoadsorbtion columns (such as Prosorba columns), mycophenolate mofetil (Cellcept®), cyclosporine A or other calcineurin inhibitors, or D-Penicillamine
  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: NCT00547521

  Show 22 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00547521     History of Changes
Other Study ID Numbers: IM101-173
Study First Received: October 19, 2007
Results First Received: October 15, 2010
Last Updated: February 7, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Abatacept
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 29, 2014