Abatacept and Infliximab in Combination With Methotrexate in Subjects With Rheumatoid Arthritis

Phase 3

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Infliximab (INF) + MTX, DB
Drug: Abatacept (ABA) + Methotrexate (MTX), double-blind (DB)
Drug: Placebo (PLA) + MTX, DB
Drug: PLA + MTX switched to ABA+ MTX, DB
Drug: ABA, open-label (OL)

Registration Number: NCT00095147

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: The purpose of this clinical research study is to learn if Abatacept or Infliximab in combination with Methotrexate demonstrate a greater reduction in disease activity over placebo.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 431

Inclusion Criteria

Diagnosis of Rheumatoid Arthritis
At least 3 months prior treatment with Methotrexate (MTX)
At least 10 swollen joints and 12 tender joints and C-Reactive Protein of at least 1 mg/dl
Washout required for other disease modifying anti-rheumatic drugs (DMARDS)

Exclusion Criteria

participants who have failed more than 3 DMARDs
participants previously treated with an approved biologic drug
History of cancer in the last 5 years
Severe or recurrent bacterial infection
Any previous or current medical conditions that are contraindications to the use of TNF blocking agents
Women of Child Bearing Potential

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Infliximab + MTX (DB)	Infliximab (INF) + MTX, DB	Days 1-365
Abatacept (ABA) + Methotrexate (MTX) (double-blind [DB])	Abatacept (ABA) + Methotrexate (MTX), double-blind (DB)	Days 1-365
Placebo + MTX (DB)	Placebo (PLA) + MTX, DB	Days 1-197
Placebo + MTX switched to abatacept + MTX (DB)	PLA + MTX switched to ABA+ MTX, DB	Participants received placebo plus methotrexate for days 1-197, and abatacept plus methotrexate for days 198-365
Abatacept (open-label)	ABA, open-label (OL)	Days 365 to 729 All participants receive Active Drug

Primary Outcome Measures

Name	Time	Method
OL; Mean Change From Baseline to Day 365 in Hematocrit	Baseline (Day 1), Day 365	Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 365 in Platelets	Baseline (Day 1), Day 365	Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, and AEs Leading to Discontinuation	From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months)	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.
OL; Mean Change From Baseline to Day 365 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase	Baseline (Day 1), Day 365	alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
DB; Adjusted Mean Change From Baseline to Day 197 in Disease Activity Score (DAS) 28 Score (Erythrocyte Sedimentation Rate [ESR]) For ABA Versus PLA (Last Observation Carried Forward [LOCF] Analysis)	Baseline (Day 1), 6 months (Day 197)	The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or C-reactive protein (CRP), and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). A clinically significant response is a decrease in DAS28 score of \>1.2 from baseline.
OL; Mean Change From Baseline to Day 729 in White Blood Cells	Baseline (Day 1), Day 729	Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 729 in Electrolytes	Baseline (Day 1), Day 729	Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 729 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid	Baseline (Day 1), Day 729	Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Number of Participants With AEs of Special Interest	From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months)	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. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, autoimmune disorders; malignancies; and acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion).
OL; Number of Participants With Select Hematologic Laboratory Abnormalities	From Day 366 through end of OL (range from 1.9 months to 42.3 months)	High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Hemoglobin (HGB): \>3 g/dL decrease from Baseline (BL); Hematocrit: \<0.75 x BL; Erythrocytes: \<0.75 x BL; Platelets (PLT): \<0.67 x LLN/\>1.5 x ULN; Leukocytes: \<0.75 x LLN/ \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; lymphocytes: \<0.750 x 10\^3 c/uL/ \>7.50 x 10\^3 c/uL; monocytes: \>2000 mm3; eosinophils: \>0.750 x 10\^3 c/uL;
OL; Number of Participants With Select Blood Chemistry Laboratory Abnormalities	From Day 366 through end of OL (range from 1.9 months to 42.3 months)	Low=lower than LLN, High=greater than ULN. LLN/ULN= Alkaline phosphatase (ALP): \>2 x ULN; aspartate aminotransferase (AST): \>3 x ULN; alanine aminotransferase (ALT): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL
OL; Mean Change From Baseline to Day 365 in Hemoglobin, Total Protein, and Albumin	Baseline (Day 1), Day 365	Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 365 in Erythrocytes	Baseline (Day 1), Day 365	Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 365 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid	Baseline (Day 1), Day 365	Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Change From Baseline to Day 729 in Hemoglobin, Total Protein, and Albumin	Baseline (Day 1), Day 729	Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 729 in Platelets	Baseline (Day 1), Day 729	Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 729 in Hematocrit	Baseline (Day 1), Day 729	Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 729 in Erythrocytes	Baseline (Day 1), Day 729	Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1121 in Hemoglobin, Total Protein, and Albumin	Baseline (Day 1), Day 1121	Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 365 in White Blood Cells	Baseline (Day 1), Day 365	Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 365 in Electrolytes	Baseline (Day 1), Day 365	Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 1121 in Platelets	Baseline (Day 1), Day 1121	Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 1121 in Hematocrit	Baseline (Day 1), Day 1121	Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 1121 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase	Baseline (Day 1), Day 1121	alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Change From Baseline to Day 1513 in Hemoglobin, Total Protein, and Albumin	Baseline (Day 1), Day 1513	Hemoglobin (HGB): \>3 g/dL decrease from BL; total protein: \< 0.9 x LLN, \>1.1 x ULN; albumin:\<0.9 x LLN
OL; Mean Change From Baseline to Day 1513 in Erythrocytes	Baseline (Day 1), Day 1513	Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in Electrolytes	Baseline (Day 1), Day 1513	Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Change From Baseline to Day 729 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase	Baseline (Day 1), Day 729	alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Change From Baseline to Day 1121 in White Blood Cells	Baseline (Day 1), Day 1121	Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 1121 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid	Baseline (Day 1), Day 1121	Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Change From Baseline to Day 1513 in Platelets	Baseline (Day 1), Day 1513	Platelets (PLT): \<0.67 x LLN, \>1.5 x ULN
OL; Mean Change From Baseline to Day 1513 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid	Baseline (Day 1), Day 1513	Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; calcium (Ca): \<0.8 x LLN, \>1.2 x ULN; phosphorous (P): \<0.75 x LLN, \>1.2 5 x ULN; serum glucose (Glu): \<65 mg/dL, \>220 mg/dL; fasting serum Glu: \<0.8 x LLN, \>1.5 x ULN; uric acid: \>1.5 x ULN;
OL; Mean Temperature (T) During Open Label Period	Days 365, 729, 1121, and 1513	Temperature (T), units=degrees Celcius
OL; Mean Change From Baseline to Day 1121 in Erythrocytes	Baseline (Day 1), Day 1121	Erythrocytes: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in Hematocrit	Baseline (Day 1), Day 1513	Hematocrit: \<0.75 x BL
OL; Mean Change From Baseline to Day 1513 in White Blood Cells	Baseline (Day 1), Day 1513	Leukocytes: \<0.75 x LLN, \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; basophils: \> 400 mm3; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL, \>7.50 x 10\^3 c/uL.
OL; Mean Change From Baseline to Day 1513 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase	Baseline (Day 1), Day 1513	alanine aminotransferase (ALT): \>3 x ULN; aspartate aminotransferase (AST): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Alkaline phosphatase (ALP): \>2 x ULN
OL; Mean Heart Rate (HR) During Open Label Period	Days 365, 729, 1121, and 1513	Heart Rate (HR), units=beats per minute (bpm)
OL; Mean Change From Baseline to Day 1121 in Electrolytes	Baseline (Day 1), Day 1121	Sodium (Na): \<0.95 x LLN, \>1.05 x ULN; potassium (K): \<0.9 x LLN, \>1.1 x ULN; chloride (Cl): \<0.9 x LLN, \>1.1 x ULN
OL; Mean Systolic (SBP) and Diastolic (DBP) Blood Pressure During Open Label Period	Days 365, 729, 1121, and 1513	Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), units=mm mercury (Hg)

Secondary Outcome Measures

Name	Time	Method
DB; Adjusted Mean Change From Baseline to Day 197 in DAS 28 Score (ESR) For INF Versus PLA (LOCF Analysis)	Baseline (Day 1), 6 months (Day 197)	The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). A clinically significant response is a decrease in DAS28 score of \>1.2 from baseline.
DB; Adjusted Mean Change From Baseline to Day 197 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)	Baseline (Day 1), 6 months (Day 197)	The SF-36 is a validated instrument measuring health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores (1) physical component summary=physical functioning, role-physical, bodily pain, and general health; (2) mental component summary=vitality, social functioning, role-emotional, and mental health. There is no total overall score; scoring is done for both subscores and summary scores. For subscores and summary scores, 0 =worst score (or quality of life) and 100=best score. Change from Baseline= post-Baseline - Baseline value.
DB; Adjusted Mean Change From Baseline to Day 365 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)	Baseline (Day 1), 12 months (Day 365)	The SF-36 is a validated instrument measuring health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores (1) physical component summary=physical functioning, role-physical, bodily pain, and general health; (2) mental component summary=vitality, social functioning, role-emotional, and mental health. There is no total overall score; scoring is done for both subscores and summary scores. For subscores and summary scores, 0 =worst score (or quality of life) and 100=best score. Change from Baseline= post-Baseline - Baseline value.
DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 365	From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study	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. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, autoimmune disorders; malignancies; and acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion).
DB; DAS 28 (ESR) Area Under The Curve (AUC) Over 12 Months For ABA Versus INF	From Day 1 through Day 365 (12 months)	The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). Clinically significant response= decrease in DAS28 score of \>1.2 from baseline. DAS28 AUC can be calculated from the DAS28 score versus time curve, which provides an assessment of changes in disease activity over time.
DB; Adjusted Mean Change From Baseline to Day 197 in HAQ-DI (LOCF Analysis)	Baseline (Day 1), 6 months (Day 197)	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.
DB; Adjusted Mean Change From Baseline to Day 365 in HAQ-DI (LOCF Analysis)	Baseline (Day 1), 12 months (Day 365)	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.
DB; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) at Day 365	DB Day 365	The DAS28 is a continuous disease measure composite of 4 variables: 28 tender joint count, 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. High disease activity= \> 5.1, low disease activity= \< 3.2, and remission= \< 2.6. Clinically significant response= decrease of \>1.2 from baseline. Utilizing EULAR response criteria, DAS28 categorical responses define a good (absolute: \<3.2 or \>1.2 improvement from baseline \[BL\]), moderate (absolute: 3.2-5.1 or 0.6-1.2 change from BL), or no response (absolute: \>5.1 or \<0.6 change from BL)
DB; Number of Participants With AEs of Special Interest From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept	From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study	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. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, autoimmune disorders; malignancies; and acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion).
DB; Number of Participants With Significant Changes in Mean Heart Rate During Days 1 Through 197 and Days 1 Through 365	From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study	Heart Rate (HR) was assessed as clinically significant or relevant at the discretion of the Clinical Investigator. Criteria may have varied between institutions.
DB; Percentage of Participants With Antibodies Against Infliximab (Human Anti-chimeric Antibody [HACA]) From Day 1 Through Day 365	Day 1 through day 365	Infliximab levels were measured using a microplate enzyme-linked immunosorbant assay (ELISA) with infliximab bound to immobilized recombinant tumor necrosis factor (TNF)-alpha. Bound infliximab is detected utilizing a horseradish peroxidase-conjugated anti-human IgG Fc(fragment, crystallizable region)-specific). The enzyme turns over the substrate O-phenlenediamine to a chromogenic product that is measured at 490 nm. The cut-off value was 1.40 ug/mL; this was based on the mean (+ 3 SD) value in serum samples from 40 participants who had never received infliximab.
OL; Mean Change From Baseline Over Time in DAS 28 (ESR) Score	Baseline (Day 1), Day 365, Day 533, Day 729	The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). A clinically significant response is a decrease in DAS28 score of \>1.2 from baseline.
DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 197	DB Day 197	The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joint counts, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein \[CRP\]). The evaluation for 50% improvement (ACR 50) and 70% improvement (ACR 70) follow similarly.
DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 365	DB Day 365	The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joint counts, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein \[CRP\]). The evaluation for 50% improvement (ACR 50) and 70% improvement (ACR 70) follow similarly.
DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 365	From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study	High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Hemoglobin (HGB): \>3 g/dL decrease from Baseline (BL); Hematocrit: \<0.75 x BL; Platelets (PLT): \<0.67 x LLN/\>1.5 x ULN; Leukocytes: \<0.75 x LLN/ \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; aspartate aminotransferase (AST): \>3 x ULN; alanine aminotransferase (ALT): \>3 x ULN; creatinine: \>4 x BL
DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 197	DB Day 197	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.
DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 365	DB Day 365	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.
DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 197	From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study	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. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, autoimmune disorders; malignancies; and acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion).
DB; Number of Participants With Significant Changes in Mean Temperature During Days 1 Through 197 and Days 1 Through 365	From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study	Temperature (T) was assessed as clinically significant or relevant at the discretion of the Clinical Investigator. Criteria may have varied between institutions.
DB; Number of Participants With Anti-Abatacept Antibodies From Day 1 Through Day 365 (Electrochemiluminescent [ECL] Immunoassay)	Day 1 through day 365	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 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.
OL; Percentage of Participants With American College of Rheumatology (ACR) Responses Over Time	DB Day 197, Day 365, Day 533, Day 729	The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joint counts, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function and acute phase reactant value (C-reactive protein \[CRP\]). The evaluation for 50% improvement (ACR 50) and 70% improvement (ACR 70) follow similarly.
OL; Percentage of Participants Who Achieved Major Clinical Response	Defined from the date of achieving ACR 70 response to 6 months post response	Major Clinical Response was defined as a continuous ACR 70 for six months.
DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 197	From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study	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.
DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 365	From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study	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.
DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept	From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study	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.
DB; Number of Participants With Significant Changes in Mean Systolic and Diastolic Blood Pressure During Days 1 Through 197 and Days 1 Through 365	From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study	Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) were assessed as clinically significant or relevant at the discretion of the Clinical Investigator. Criteria may have varied between institutions.
DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 197	From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study	High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Hemoglobin (HGB): \>3 g/dL decrease from Baseline (BL); Hematocrit: \<0.75 x BL; Platelets (PLT): \<0.67 x LLN/\>1.5 x ULN; Leukocytes: \<0.75 x LLN/ \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; aspartate aminotransferase (AST): \>3 x ULN; alanine aminotransferase (ALT): \>3 x ULN; creatinine: \>4 x BL
OL; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) Over Time	DB Days 365, 533, and 729	The DAS28 is a continuous disease measure composite of 4 variables: 28 tender joint count, 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. High disease activity= \> 5.1, low disease activity= \< 3.2, and remission= \< 2.6. Clinically significant response= decrease of \>1.2 from baseline. Utilizing EULAR response criteria, DAS28 categorical responses define a good (absolute \<3.2 or \>1.2 improvement from baseline \[BL\]), moderate (absolute 3.2-5.1 or 0.6-1.2 change from BL), or no response (absolute \>5.1 or \<0.6 change from BL)
OL; Percentage of Participants With DAS28 (ESR) Remission and Low Disease Activity (LDAS) Over Time	Baseline (Day 1), Day 365, Day 533, Day 729	The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or CRP, and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (\> 5.1), low disease activity (\< 3.2) and remission (\< 2.6). A clinically significant response is a decrease in DAS28 score of \>1.2 from baseline.
OL; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Over Time	OL Days 197, 253, 281, 309, 337, 365, 449, 533, 617, and 729	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.
OL; Adjusted Mean Change From Baseline to Day 729 in HAQ-DI	Day 1 (Baseline), Day 729	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.