Phase IIIB Subcutaneous Missed Dose Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00533897
First received: September 20, 2007
Last updated: June 26, 2012
Last verified: June 2012
  Purpose

The purpose of the study is to determine whether subcutaneous abatacept administered to patients with rheumatoid arthritis is associated with increased immunogenicity or increased safety events upon withdrawal and reintroduction.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Abatacept
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase IIIb, Multi-Center, Randomized, Withdrawal Study to Evaluate the Immunogenicity and Safety of Subcutaneous Administered Abatacept in Adults With Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Double-blind Withdrawal (DBW) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Antibody Responses by Enzyme-Linked Immunosorbant Assay (ELISA) at Day 169 [ Time Frame: Day 169 ] [ Designated as safety issue: No ]
    Serum samples from all treated adult participants with active rheumatoid arthritis (RA) were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • Re-introduction (RI) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Day 253, by DBW Period Groups [ Time Frame: Day 253 (short term) ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.


Secondary Outcome Measures:
  • RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Day 253, by DBW Period Placebo Group [ Time Frame: Day 253 (short term) ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • Lead-in (LI) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time [ Time Frame: For on-treatment visits: Day 1-Day 85, includes ≤21 Days after last dose or up to 1st dose of DBW Period. For follow-up post visits for participants who discontinued drug in LI: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • LI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by Electrochemiluminescence (ECL) Over Time [ Time Frame: For on-treatment visits: Day 1-Day 85, includes ≤21 Days after last dose or up to 1st dose of DBW Period. For follow-up post visits for participants who discontinued drug in LI: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNC) Category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing or negative.

  • DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time [ Time Frame: Days 86-169, includes ≤21 Days after last dose or up to 1st dose of RI Period ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Post Visits [ Time Frame: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time [ Time Frame: Days 86-169, includes ≤21 Days after last dose or up to 1st dose of RI Period ] [ Designated as safety issue: No ]
    ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNC) Category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing or negative.

  • DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL At Post Visits [ Time Frame: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNC) Category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing or negative.

  • RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time [ Time Frame: For on-treatment visits: Days 170-253, includes ≤21 Days after last dose or up to 1st dose of LTE Period. For follow-up post visits for participants who discontinued drug in RI: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.

  • RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time [ Time Frame: For on-treatment visits: Days 170-253, includes ≤21 Days after last dose or up to 1st dose of LTE Period. For follow-up post visits for participants who discontinued drug in RI: Day 22 after last dose of drug to Day 85 after last dose of drug ] [ Designated as safety issue: No ]
    ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNC) Category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing or negative.

  • Short Term Period (ST); Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 ELISA Antibody Responses by DBW Treatment Groups [ Time Frame: For on-TRT visits: Days 1-253 (ST). For follow-up post visits for participants who discontinued drug in the ST: Day 22 after last dose of ST drug to Day 85 after last dose of ST drug ] [ Designated as safety issue: No ]
    Serum samples from Abatacept-treated adult participants with active rheumatoid arthritis (RA) were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody. The ST was defined as the LI Period, the DBW Period, and the RI Period (Days 1-253).

  • Short Term Period; Number of Participants With Positive Anti-Abatacept or Anti-CTLA4 ECL Antibody Responses by DBW Treatment Groups [ Time Frame: For on-TRT visits: Days 1-253 (ST). For follow-up post visits for participants who discontinued drug in the ST: Day 22 after last dose of ST drug to Day 85 after last dose of ST drug ] [ Designated as safety issue: No ]
    ECL screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. Cytotoxic leukocyte antigen 4 (CTLA4) and Possibly Immunoglobulin (Ig) Category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNC) Category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing or negative.

  • Short Term Period; Mean Change in Disease Activity Score (DAS) 28 (Using C-Reactive Protein [CRP]) From Baseline Over Time by DBW Treatment Groups [ Time Frame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term period) ] [ Designated as safety issue: No ]
    The DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • Short Term Period; Percentage of Participants Achieving Clinically Meaningful Improvement (CMI) in DAS 28 (CRP), Low Disease Activity (LDAS), or Clinical Remission Over Time by DBW Treatment Groups [ Time Frame: Days 85, 169, and 253 (short term period) ] [ Designated as safety issue: No ]
    DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • Short Term Period; Mean Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline Over Time by DBW Treatment Groups [ Time Frame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term period) ] [ Designated as safety issue: No ]
    The disability section of the full HAQ includes 20 questions to assess physical functions 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= greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ response=an improvement of at least 0.3 units from baseline in HAQ disability Index.

  • Short Term Period; Percentage of Participants With HAQ-DI Response Over Time by DBW Treatment Groups [ Time Frame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term period) ] [ Designated as safety issue: No ]
    The disability section of the full HAQ includes 20 questions to assess physical functions 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= greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ response=an improvement of at least 0.3 units from baseline in HAQ disability Index.

  • LI; Mean Change in DAS 28 (CRP) From Baseline Over Time [ Time Frame: Days 1 (Baseline), 15, 29, 57, 78, 85 ] [ Designated as safety issue: No ]
    DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • LI; Percentage of Participants With Clinically Meaningful Improvement in DAS (CRP) Over Time [ Time Frame: Days 15, 29, 57, 78, 85 ] [ Designated as safety issue: No ]
    DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • DBW Period; Mean Change in DAS 28 (CRP) From DBW Period Baseline (Day 85) Over Time [ Time Frame: Days 85 (Period II Baseline), 113, 141, and 169 ] [ Designated as safety issue: No ]
    DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • DBW Period; Percentage of Participants With Rheumatoid Arthritis (RA) Flare Over Time [ Time Frame: Days 85, 113, 141, and 169 ] [ Designated as safety issue: No ]

    A participant had an RA flare if at least 2 of the following criteria were met:

    • Doubling of tender and swollen joint count from Day 78
    • Increase in DAS28-CRP score ≥ 1.2 from Day 78
    • Prematurely discontinued from Double-blind Withdrawal Period (Period II) and continued to Re-introduction Period (Period III)

  • RI Period; Mean Change in DAS 28 (CRP) From RI Period Baseline (Day 169) Over Time [ Time Frame: Days 169 (Period III Baseline), 197, 225, and 253 ] [ Designated as safety issue: No ]
    DAS28 is a continuous disease measure composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, the level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. DAS28 has numeric thresholds defining high disease activity (> 5.1), low disease activity (≤ 3.2) and remission (< 2.6). Clinically meaningful improvement= decrease in DAS28 score of ≥1.2 from baseline.

  • LI; Number of Participants With Deaths, Serious Adverse Events (SAEs), SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, or AEs Leading to Discontinuation [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

  • LI; Number of Participants With AEs of Special Interest [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion), peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion),local injection site reaction (pre-specified AEs occurring at the site of SC injection)and systemic injection site reactions (pre-specified systemic AEs such as hypersensitivity reactions occurring within 24 hours of SC injection)

  • LI; Number of Participants With Hematology Values Meeting the Marked Abnormality (MA) Criteria [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Upper Normal Limit (ULN), Lower Normal Limit (LLN), Baseline (BL). Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 cells/uL; eosinophils: >0.750 * 10^3 cells/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 cells/uL/ >7.50 * 10^3 cells/uL.

  • LI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL

  • LI; Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN

  • LI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3

  • LI; Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period I [ Time Frame: Days 1, 15, 29, 57, 78, and 85 ] [ Designated as safety issue: Yes ]
  • LI; Mean Heart Rate (HR) During Period I [ Time Frame: Days 1, 15, 29, 57, 78, and 85 ] [ Designated as safety issue: Yes ]
  • LI; Mean Temperature (T) During Period I [ Time Frame: Days 1, 15, 29, 57, 78, and 85 ] [ Designated as safety issue: Yes ]
  • DBW; Number of Participants With Death, Serious SAEs, Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

  • DBW; Number of Participants With AEs of Special Interest [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion), peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion),local injection site reaction (pre-specified AEs occurring at the site of SC injection)and systemic injection site reactions (pre-specified systemic AEs such as hypersensitivity reactions occurring within 24 hours of SC injection)

  • DBW; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 cells/uL; eosinophils: >0.750 * 10^3 cells/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 cells/uL/ >7.50 * 10^3 cells/uL.

  • DBW; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL

  • DBW; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN

  • DBW; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier ] [ Designated as safety issue: Yes ]
    MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3

  • DBW Period; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period II [ Time Frame: Days 113, 141, and 169 ] [ Designated as safety issue: Yes ]
  • DBW Period; Mean Heart Rate (HR) During Period II [ Time Frame: Days 113, 141, and 169 ] [ Designated as safety issue: Yes ]
  • DBW Period; Mean Temperature (T) During Period II [ Time Frame: Days 113, 141, and 169 ] [ Designated as safety issue: Yes ]
  • RI; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

  • RI; Number of Participants With AEs of Special Interest [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion), peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion),local injection site reaction (pre-specified AEs occurring at the site of SC injection)and systemic injection site reactions (pre-specified systemic AEs such as hypersensitivity reactions occurring within 24 hours of SC injection)

  • RI; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 cells/uL; eosinophils: >0.750 * 10^3 cells/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 cells/uL/ >7.50 * 10^3 cells/uL.

  • RI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL

  • RI; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN

  • RI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria [ Time Frame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier. ] [ Designated as safety issue: Yes ]
    MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3

  • RI Period; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period III [ Time Frame: Days 169, 197, 225, and 253 ] [ Designated as safety issue: Yes ]
  • RI Period; Mean Heart Rate (HR) During Period III [ Time Frame: Days 169, 197, 225, and 253 ] [ Designated as safety issue: Yes ]
  • RI Period; Mean Temperature (T) During Period III [ Time Frame: Days 169, 197, 225, and 253 ] [ Designated as safety issue: Yes ]
  • Long Term Extension (LTE); Number of Participants With Death, SAEs, Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

  • LTE; Number of Participants With AEs of Special Interest [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion), peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion),local injection site reaction (pre-specified AEs occurring at the site of SC injection)and systemic injection site reactions (pre-specified systemic AEs such as hypersensitivity reactions occurring within 24 hours of SC injection)

  • LTE; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria are: Hemoglobin (HGB): >3 g/dL decrease from BL; Hematocrit: <0.75 * BL; Erythrocytes: <0.75 * BL; Platelets (PLT): <0.67 * LLN/>1.5 * ULN, or if BL < LLN then use <0.5 * BL and <100,000 mm^3; Leukocytes: <0.75 * LLN/ >1.25 * ULN, or if BL<LLN then use <0.8 * BL or >ULN, or if BL>ULN then use >1.2 * BL or <LLN; neutrophils+bands: <1.0 * 10^3 cells/uL; eosinophils: >0.750 * 10^3 cells/uL; basophils: > 400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750 * 10^3 cells/uL/ >7.50 * 10^3 cells/uL.

  • LTE; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL

  • LTE; Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN

  • LTE; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria [ Time Frame: For Period I non-responders: as of Day 85 and up to data cut-off for database lock (15Dec09). For Period II completers: as of Day 253 and up to data cut-off for database lock (15Dec09). Data included up to 56 days post last dose. ] [ Designated as safety issue: Yes ]
    MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3

  • LTE; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period LTE [ Time Frame: Days 337, 365, and 449 ] [ Designated as safety issue: Yes ]
  • LTE; Mean Heart Rate (HR) During Period LTE [ Time Frame: Days 337, 365, and 449 ] [ Designated as safety issue: Yes ]
  • LTE; Mean Temperature (T) During Period LTE [ Time Frame: Days 337, 365, and 449 ] [ Designated as safety issue: Yes ]
  • Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ELISA by RI Treatment Groups [ Time Frame: Day 197 through Day 253 ] [ Designated as safety issue: No ]
    Pharmacokinetics is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Cmin=minimum observed plasma concentration of single-dose abatacept. Cmin for each participant was listed by study visit and immunogenicity status (seropositive vs. seronegative) was determined by ELISA.

  • Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ECL by RI Treatment Groups [ Time Frame: Day 197 through Day 253 ] [ Designated as safety issue: No ]
    Pharmacokinetics is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Cmin=minimum observed plasma concentration of single-dose abatacept. Cmin for each participant was listed by study visit and immunogenicity status (seropositive vs. seronegative) was determined by ECL.

  • ST; Number of Participants Positive for Anti-nuclear Antibody (ANA), Anti-double Stranded DNA Antibody (dsDNA), or Rheumatoid Factor (RF) at Day 253 According to Baseline Status (Negative at Baseline or Positive at Baseline) by DBW Treatment Groups [ Time Frame: Baseline, Day 253 ] [ Designated as safety issue: No ]
    Venous blood was collected and tested for anti-nuclear antibodies, anti-dsDNA antibodies, and rheumatoid factor. ANA were detected by means of immunofluorescent antibodies. An anti-DNA radioimmunoassay was used for detection of anti-dsDNA antibodies (Diagnostic Products Corporation). RF was measured by an immunoturbidimetric assay (Roche Tina-Quant). Determinations of antibody or RF status were made at baseline and Day 253.


Enrollment: 270
Study Start Date: November 2007
Study Completion Date: January 2012
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abatacept Drug: Abatacept
Solution in pre-filled syringes, Subcutaneously, 125 mg, Weekly, (Short Term (3 periods - 12 weeks each; Long Term)
Other Names:
  • Orencia
  • BMS-188667
Placebo Comparator: Placebo Drug: Placebo
Solution in pre-filled syringes, Subcutaneously, 0 mg, Weekly, Period II 12 weeks (Short Term)

  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
  • Disease Activity Score (DAS)28-C-Reactive Protein (CRP) score ≥ 3.2 and ≤5.1
  • On background methotrexate at least 3 months (≥10mg weekly)
  • Must be able to self injection or allow a care giver to do it for them
  • Discontinue all Biologics and Disease-Modifying Anti-rheumatic Drugs (DMARDs) except for methotrexate

Exclusion Criteria:

  • Participants who had prior exposure to abatacept or CTLA-4 Ig
  • Received treatment with rituximab.
  • Participants who have received treatment with leflunomide within 1 year of screening
  • Participants who have received treatment with immunoadsorption 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: NCT00533897

  Show 27 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: NCT00533897     History of Changes
Other Study ID Numbers: IM101-167
Study First Received: September 20, 2007
Results First Received: January 10, 2011
Last Updated: June 26, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
Rheumatoid Arthritis (RA)

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
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 October 21, 2014