Phase IIIB Subcutaneous Missed Dose Study

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00533897
• Other study ID #: IM101-167
• Status: Completed
• Phase: Phase 3
• First received: September 20, 2007
• Last updated: April 22, 2015
• Start date: November 2007
• Est. completion date: February 2014

Study information

• Verified date: April 2015
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 270
• Est. completion date: February 2014
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Abatacept
Solution in pre-filled syringes, Subcutaneously, 125 mg, Weekly, (Short Term (3 periods - 12 weeks each; Long Term)
• Placebo
Solution in pre-filled syringes, Subcutaneously, 0 mg, Weekly, Period II 12 weeks (Short Term)

Locations

Country	Name	City	State
Argentina	Local Institution	Capital Federal	Buenos Aires
Argentina	Local Institution	Cordoba
Argentina	Local Institution	Rosario	Santa Fe
Argentina	Local Institution	Santa Fe
Canada	Local Institution	Trois-Rivieres	Quebec
Mexico	Local Institution	Leon	Guanajuato
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Metepec	Estado De Mexico
Mexico	Local Institution	Mexico City	Distrito Federal
South Africa	Local Institution	Berea	Kwa Zulu Natal
South Africa	Local Institution	Bloemfontein	Free State
South Africa	Local Institution	Muckleneuk	Gauteng
South Africa	Local Institution	Panorama	Western Cape
South Africa	Local Institution	Pretoria	Gauteng
United States	Albuquerque Clinical Trials, Inc.	Albuquerque	New Mexico
United States	East Penn Rheumatology Associates	Bethlehem	Pennsylvania
United States	Mountain State Clinical Research	Clarksburg	West Virginia
United States	Columbia Arthritis Center	Columbia	South Carolina
United States	Klein And Associates, M.D., Pa	Cumberland	Maryland
United States	Altoona Center For Clinical Research	Duncansville	Pennsylvania
United States	St. Paul Rheumatology, P.A.	Eagan	Minnesota
United States	Center For Assessment And Research Of Erie	Erie	Pennsylvania
United States	Diagnostic Rheumatology And Research,Pc	Indianapolis	Indiana
United States	Wallace Rheumatic Study Center	Los Angeles	California
United States	Sarasota Arthritis Research Center	Sarasota	Florida
United States	New England Research Associates, Llc	Trumbull	Connecticut
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Mexico,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 Immunosorbent Assay (ELISA) at Day 169	Serum samples from all treated adult participants with active rheumatoid arthritis (RA) were screened for the presence of drug-specific antibodies using an enzyme-linked immunosorbent assay (ELISA). Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody.	Day 169	No
Primary	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	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.	Day 253 (short term)	No
Secondary	RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Day 253, by DBW Period Placebo Group	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.	Day 253 (short term)	No
Secondary	Lead-in (LI) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time	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.	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	No
Secondary	LI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by Electrochemiluminescence (ECL) Over Time	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.	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	No
Secondary	DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time	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. Samples were obtained during treatment (TRT) visits.	Days 86-169, includes =21 Days after last dose or up to 1st dose of RI Period	No
Secondary	DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Post Visits	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.	Day 22 after last dose of drug to Day 85 after last dose of drug	No
Secondary	DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time	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.	Days 86-169, includes =21 Days after last dose or up to 1st dose of RI Period	No
Secondary	DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL At Post Visits	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.	Day 22 after last dose of drug to Day 85 after last dose of drug	No
Secondary	RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time by DBW Treatment Group	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.	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	No
Secondary	RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time by DBW Treatment Group	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.	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	No
Secondary	Short Term (ST); Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 ELISA Antibody Responses by DBW Treatment Groups	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. ST was defined as the LI Period, the DBW Period, and the RI Period (Days 1-253).	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	No
Secondary	Short Term: Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 ECL Antibody Responses by DBW Treatment Groups	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.	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	No
Secondary	Short Term: Mean Change in Disease Activity Score (DAS) 28 (Using C-Reactive Protein [CRP]) From Baseline Over Time by DBW Treatment Groups	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.	Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)	No
Secondary	Short Term: 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	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.	Days 85, 169, and 253 (short term)	No
Secondary	Short Term; Mean Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline Over Time by DBW Treatment Groups	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.	Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)	No
Secondary	Short Term; Percentage of Participants With HAQ-DI Response Over Time by DBW Treatment Groups	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.	Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)	No
Secondary	LI; Mean Change in DAS 28 (CRP) From Baseline Over Time	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.	Days 1 (Baseline), 15, 29, 57, 78, 85	No
Secondary	LI; Percentage of Participants With Clinically Meaningful Improvement in DAS (CRP) Over Time	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.	Days 15, 29, 57, 78, 85	No
Secondary	DBW Period; Mean Change in DAS 28 (CRP) From DBW Period Baseline (Day 85) Over Time	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.	Days 85 (Period 2 Baseline), 113, 141, and 169	No
Secondary	DBW Period; Percentage of Participants With Rheumatoid Arthritis (RA) Flare Over Time	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 2) and continued to Re-introduction Period (Period 3)	Days 85, 113, 141, and 169	No
Secondary	RI Period; Mean Change in DAS 28 (CRP) From RI Period Baseline (Day 169) Over Time	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.	Days 169 (Period III Baseline), 197, 225, and 253	No
Secondary	LI; Number of Participants With Deaths, Serious Adverse Events (SAEs), SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, or AEs Leading to Discontinuation	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.	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	Yes
Secondary	LI Period; Number of Participants With AEs of Special Interest	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)	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	Yes
Secondary	LI; Number of Participants With Hematology Values Meeting the Marked Abnormality (MA) Criteria	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	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	Yes
Secondary	LI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria	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	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	Yes
Secondary	LI; Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria	Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL	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	Yes
Secondary	LI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria	MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*upper limits of normal (ULN),or if BL< lower limits of normal (LLN) then use 0.8*BL or > upper limits of normal (ULN),or if BL>ULN then use >2.0*BL or	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	Yes
Secondary	LI Period; Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Blood pressure was taken in participants while seated and measured in millimeters of mercury (mmHg). Pressures were assessed at screening, at baseline on Day 1 prior to infusion of IV abatacept, at 30 and 60 minutes after IV infusion of abatacept on Day 1, and at all office visits prior to SC injection of abatacept. Vital signs were also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 1, 15, 29, 57, 78, and 85	Yes
Secondary	LI Period; Mean Heart Rate (HR)	Heart rate was taken in participants while seated and measured in beats per minute (bpm). Heart rate was assessed at screening, at baseline on Day 1 prior to infusion of IV abatacept, at 30 and 60 minutes after IV infusion of abatacept on Day 1, and at all office visits prior to SC injection of abatacept. Heart rate was also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 1, 15, 29, 57, 78, and 85	Yes
Secondary	LI Period; Mean Temperature (T)	Temperature was taken in participants while seated and measured in degrees celsius. Temperature was assessed at screening, at baseline on Day 1 prior to infusion of IV abatacept, at 30 and 60 minutes after IV infusion of abatacept on Day 1, and at all office visits prior to SC injection of abatacept. Temperature was also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 1, 15, 29, 57, 78, and 85	Yes
Secondary	DBW; Number of Participants With Death, Serious SAEs, Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation	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.	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	Yes
Secondary	DBW; Number of Participants With AEs of Special Interest	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)	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	Yes
Secondary	DBW; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria	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	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	Yes
Secondary	DBW; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria	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	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	Yes
Secondary	DBW; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria	Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL	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	Yes
Secondary	DBW; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria	MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL	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	Yes
Secondary	DBW; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Double Blind Period	Blood pressures were taken in participants while seated, just prior to study drug injection, and measured in millimeters of mercury (mmHg).	Days 113, 141, and 169	Yes
Secondary	DBW Period; Mean Heart Rate (HR) During Period 2	Heart Rate was taken in participants while seated, just prior to study drug injection, and measured in beats per minute (bpm)	Days 113, 141, and 169	Yes
Secondary	DBW Period; Mean Temperature (T) During Period II	Participants were seated and temperature taken just prior to study drug injection.	Days 113, 141, and 169	Yes
Secondary	RI; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation	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.	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.	Yes
Secondary	RI; Number of Participants With AEs of Special Interest	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)	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.	Yes
Secondary	RI; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria	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	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.	Yes
Secondary	RI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria	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	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.	Yes
Secondary	RI; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria	Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL	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.	Yes
Secondary	RI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria	MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL	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.	Yes
Secondary	RI Period; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period III		Days 169, 197, 225, and 253	Yes
Secondary	RI Period; Mean Heart Rate (HR) During Period III		Days 169, 197, 225, and 253	Yes
Secondary	RI Period; Mean Temperature (T) During Period III		Days 169, 197, 225, and 253	Yes
Secondary	Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ELISA by RI Treatment Groups	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.	Day 197 through Day 253	No
Secondary	Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ECL by RI Treatment Groups	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.	Day 197 through Day 253	No
Secondary	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	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.	Baseline, Day 253	No
Secondary	LTE: DAS28-CRP Mean Change From Baseline (Day 1) Over Time - All Participants Treated in LTE	DAS28=continuous disease measure composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28, level of serum reactant protein CRP, and participant global assessment of disease activity measured on a visual analogue scale. DAS28-CRP has numeric thresholds defining high disease activity (> 5.1), low disease activity (= 3.2) and remission (< 2.6). Last day of ST is Day 85 for Period I Nonresponders and Day 253 for ST Completers . Data are not available(NA) for the period from Day 113 to Day 253 for Period 1 non-responders. Note: Day 85 and Day 337 assessments for the Period I Nonresponder cohort in fact represent consecutive assessments with an interval of approximately 1 month. For Period I nonresponder, study days do not represent treatment days. Study Day 337 for a Period I nonresponder actually corresponds to that participant's Treatment Day 169.	For Period 1 non-responders: as of Study Day 85 and up to Day 1821. For ST completers: as of Study Day 253 and up to Day 1821.	No
Secondary	LTE: Percent of Participants Who Achieved Clinical Remission in the Long Term Extension - All Participants Treated in LTE	DAS28=continuous disease measure composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28, level of serum reactant protein CRP, and participant global assessment of disease activity measured on a visual analogue scale. Clinical remission=DAS28-CRP score<2.6. Percent=Number of participants meeting remission divided by number of participants evaluated. Last day of ST is Day 85 for Period I Nonresponders and Day 253 for ST Completers . Data are not available (NA) for the period from Day 113 to Day 253 for Period 1 non-responders. Note: Day 85 and Day 337 assessments for the Period I Nonresponder cohort in fact represent consecutive assessments with an interval of approximately 1 month. For Period I nonresponder, study days do not represent treatment days. Study Day 337 for a Period I nonresponder actually corresponds to that participant's Treatment Day 169.	For Period I non-responders: as of Study Day 85 and up to Study Day 1821. For ST completers: as of Study Day 253 and up to Study Day 1821	No
Secondary	LTE: Percent of Participants With Low Disease Activity in Long Term Extension: All Participants Treated in LTE	DAS28:continuous disease measure composite of 4 variables: number of tender joints out of 28 joints, number of swollen joints out of 28 joints, level of the serum reactant protein CRP, and participant global assessment of disease activity measure on a visual analogue scale. Low disease activity score: = 3.2. Percent=Number of participants with Low Disease Activity divided by number of participants evaluated. Last day of ST is Day 85 for Period I Nonresponders and Day 253 for ST Completers . Data are not available(NA) for the period from Day 113 to Day 253 for Period 1 non-responders. Note: Day 85 and Day 337 assessments for the Period I Nonresponder cohort in fact represent consecutive assessments with an interval of approximately 1 month. For Period I nonresponder, study days do not represent treatment days. Study Day 337 for a Period I nonresponder actually corresponds to that participant's Treatment Day 169.	For Period 1 non-responders: as of Study Day 85 and up to Day 1821. For ST completers: as of Study Day 253 and up to Day 1821.	No
Secondary	LTE: Percent of Participants With HAQ Response Over Time - All Participants Treated in LTE	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 (DI) 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 DI. Percent=number of participants with HAQ response divided by number of participants in the analysis. Since Period I Non-responders proceeded directly to the LTE at the end of Period I (Day 85), study days do not represent treatment days.	Study Days 1 (Baseline),15, 29, 57, 78, 85, 253, 337, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541,1625,1709,1821,1905,1989, 2073	No
Secondary	LTE: Overall Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses (ECL Method) for On-Treatment Visits, Post Last Dose Visits, and Overall Study - All Participants Treated in LTE	Serum samples from Abatacept-treated adult participants with active RA were screened for the presence of drug-specific antibodies using electrochemiluminescence (ECL). The percent of participants with a positive abatacept induced immunogenicity response against cytotoxic T-lymphocyte antigen 4 (CTLA4) and possibly immunoglobulin (Ig), or against Ig and/or Junction Region was calculated by number of participants with a positive response divided by number of participants evaluated. Overall for on-treatment includes treatment visits on Days 337, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1457, 1625, 1821, and 1989.	Days 337, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1457, 1625, 1821, 1989 and 28, 56, 85, 168 days post last dose in LTE	No
Secondary	LTE: Number of Participants With Death, Related SAEs, SAEs Leading to Discontinuation, Related AEs, or AEs Leading to Discontinuation During Long Term Extension (LTE)	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. SAEs include hospitalizations for elective surgical procedures.All deaths reported during the LTE including those that occurred > 56 days after the last dose. Related AE or SAE defined as AE or SAE with Certain, Probable, Possible, or Missing relationship to study medication. All participants who completed the ST period could enter the open label LTE on Day 253; LI Period 1 non-responders could directly enter the LTE.	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014), up to 56 days post last dose. For ST completers: as of Day 253 and up to completion of LTE (FEB 2014) up to 56 days post last dose.	Yes
Secondary	LTE: Number of Participants With AEs of Special Interest During LTE	AEs of special interest in LTE are those AEs that may be associated with the use of immunomodulatory drugs, including all infections and opportunistic infections; autoimmune disorders; malignancies, 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)	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014) up to 56 days post last dose. For ST completers: as of Day 253 and up to completion of LTE (FEB 2014) up to 56 days post last dose.	Yes
Secondary	LTE: Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria During LTE	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	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.	Yes
Secondary	LTE: Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria During LTE	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	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.	Yes
Secondary	LTE: Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria During LTE	Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.	Yes
Secondary	LTE: Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria During LTE	MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL	For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.	Yes
Secondary	LTE: Mean Seated Systolic Blood Pressure (SBP) During LTE	During LTE, blood pressure was taken in participants while seated, measured in millimeters of mercury (mmHg) and were assessed at all office visits prior to SC injection of abatacept. Vital signs were also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261,1345, 1457,1541,1625,1709,1821,1905,1989,2073	Yes
Secondary	LTE: Mean Seated Diastolic Blood Pressure (DBP) During LTE	During LTE, blood pressure was taken in participants while seated, measured in millimeters of mercury (mmHg) and were assessed at all office visits prior to SC injection of abatacept. Vital signs were also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073	Yes
Secondary	LTE: Mean Heart Rate (HR) During LTE	During LTE, heart rate was taken in participants while seated, measured in beats per minute (bpm) and was assessed at all office visits prior to SC injection of abatacept. Heart rate was also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073	Yes
Secondary	LTE: Mean Temperature (T) During LTE	During LTE, temperature was taken in participants while seated, measured in degrees celsius and was assessed at all office visits prior to SC injection of abatacept. Temperature was also assessed 7 days after the last injection of abatacept for participants who were withdrawn prematurely.	Days 337, 365, 449,533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm