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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase IIIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Comparative Study of Abatacept or Infliximab in Combination With Methotrexate in Controlling Disease Activity in Subjects With Rheumatoid Arthritis Having an Inadequate Clinical Response to Methotrexate

Conditions
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Rheumatoid Arthritis

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Abatacept (ABA) + Methotrexate (MTX) (double-blind [DB])<br>Days 1-365 | Drug: Abatacept (ABA) + Methotrexate (MTX), double-blind (DB)<br>* Abatacept, intravenous (IV) Solution, Infusion, Depends on participant weight, Monthly, 12 months.<br>* Other names: Orencia;|
| Active Comparator: Infliximab + MTX (DB)<br>Days 1-365 | Drug: Infliximab (INF) + MTX, DB<br>* Infliximab, IV Solution, Infusion, Depends on participant weight, Every 2 Months, 12 months.<br>|
| Placebo Comparator: Placebo + MTX (DB)<br>Days 1-197 | Drug: Placebo (PLA) + MTX, DB<br>* Placebo, IV Solution, Infusion, Depends on participant weight, Monthly, 6 months.<br>|
| Experimental: Placebo + MTX switched to abatacept + MTX (DB)<br>Participants received placebo plus methotrexate for days 1-197, and abatacept plus methotrexate for days 198-365 | Drug: PLA + MTX switched to ABA+ MTX, DB<br>* Placebo=IV Solution, Infusion, Depends on participant weight, Monthly, 6 months. Abatacept=IV Solution, Infusion, Depends on participant weight, Monthly, 6 months<br>* Other names: Orencia;|
| Experimental: Abatacept (open-label)<br>Days 365 to 729 All participants receive Active Drug | Drug: ABA, open-label (OL)<br>* Abatacept, IV solution, Infusion. Depends on participant weight, Monthly, 12+ months<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | Baseline (Day 1), 6 months (Day 197) | 
| 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 | 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 beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months) | 
| OL; Number of Participants With AEs of Special Interest | 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). | From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months) | 
| OL; Number of Participants With Select Hematologic Laboratory Abnormalities | 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; | From Day 366 through end of OL (range from 1.9 months to 42.3 months) | 
| OL; Number of Participants With Select Blood Chemistry Laboratory Abnormalities | 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 | From Day 366 through end of OL (range from 1.9 months to 42.3 months) | 
| OL; Mean Change From Baseline to Day 365 in Hemoglobin, Total Protein, and Albumin | Hemoglobin (HGB): >3 g/dL decrease from BL; total protein: < 0.9 x LLN, >1.1 x ULN; albumin:<0.9 x LLN | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Platelets | Platelets (PLT): <0.67 x LLN, >1.5 x ULN | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Hematocrit | Hematocrit: <0.75 x BL | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in White Blood Cells | 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. | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Erythrocytes | Erythrocytes: <0.75 x BL | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Electrolytes | 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 | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid | 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; | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 365 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase | 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 | Baseline (Day 1), Day 365 | 
| OL; Mean Change From Baseline to Day 729 in Hemoglobin, Total Protein, and Albumin | Hemoglobin (HGB): >3 g/dL decrease from BL; total protein: < 0.9 x LLN, >1.1 x ULN; albumin:<0.9 x LLN | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Platelets | Platelets (PLT): <0.67 x LLN, >1.5 x ULN | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Hematocrit | Hematocrit: <0.75 x BL | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in White Blood Cells | 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. | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Erythrocytes | Erythrocytes: <0.75 x BL | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Electrolytes | 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 | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid | 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; | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 729 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase | 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 | Baseline (Day 1), Day 729 | 
| OL; Mean Change From Baseline to Day 1121 in Hemoglobin, Total Protein, and Albumin | Hemoglobin (HGB): >3 g/dL decrease from BL; total protein: < 0.9 x LLN, >1.1 x ULN; albumin:<0.9 x LLN | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Platelets | Platelets (PLT): <0.67 x LLN, >1.5 x ULN | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Hematocrit | Hematocrit: <0.75 x BL | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in White Blood Cells | 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. | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Erythrocytes | Erythrocytes: <0.75 x BL | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Electrolytes | 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 | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid | 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; | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1121 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase | 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 | Baseline (Day 1), Day 1121 | 
| OL; Mean Change From Baseline to Day 1513 in Hemoglobin, Total Protein, and Albumin | Hemoglobin (HGB): >3 g/dL decrease from BL; total protein: < 0.9 x LLN, >1.1 x ULN; albumin:<0.9 x LLN | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Platelets | Platelets (PLT): <0.67 x LLN, >1.5 x ULN | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Hematocrit | Hematocrit: <0.75 x BL | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in White Blood Cells | 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. | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Erythrocytes | Erythrocytes: <0.75 x BL | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Electrolytes | 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 | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid | 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; | Baseline (Day 1), Day 1513 | 
| OL; Mean Change From Baseline to Day 1513 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase | 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 | Baseline (Day 1), Day 1513 | 
| OL; Mean Systolic (SBP) and Diastolic (DBP) Blood Pressure During Open Label Period | Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), units=mm mercury (Hg) | Days 365, 729, 1121, and 1513 | 
| OL; Mean Heart Rate (HR) During Open Label Period | Heart Rate (HR), units=beats per minute (bpm) | Days 365, 729, 1121, and 1513 | 
| OL; Mean Temperature (T) During Open Label Period | Temperature (T), units=degrees Celcius | Days 365, 729, 1121, and 1513 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB; Adjusted Mean Change From Baseline to Day 197 in DAS 28 Score (ESR) For INF Versus PLA (LOCF Analysis) | 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. | Baseline (Day 1), 6 months (Day 197) | 
| DB; DAS 28 (ESR) Area Under The Curve (AUC) Over 12 Months For ABA Versus INF | 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. | From Day 1 through Day 365 (12 months) | 
| DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at 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 Day 197 | 
| DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at 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 Day 365 | 
| DB; Adjusted Mean Change From Baseline to Day 197 in HAQ-DI (LOCF Analysis) | 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. | Baseline (Day 1), 6 months (Day 197) | 
| DB; Adjusted Mean Change From Baseline to Day 365 in HAQ-DI (LOCF Analysis) | 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. | Baseline (Day 1), 12 months (Day 365) | 
| DB; Adjusted Mean Change From Baseline to Day 197 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) | 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. | Baseline (Day 1), 6 months (Day 197) | 
| DB; Adjusted Mean Change From Baseline to Day 365 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) | 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. | Baseline (Day 1), 12 months (Day 365) | 
| DB; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) at 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 Day 365 | 
| DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at 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 Day 197 | 
| DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at 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 Day 365 | 
| 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 | 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 Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 197 | 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). | From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study | 
| 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 | 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 Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study | 
| 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 | 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 198 through Day 365, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 365 | 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). | From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With AEs of Special Interest From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept | 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). | From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With Significant Changes in Mean Systolic and Diastolic Blood Pressure During Days 1 Through 197 and Days 1 Through 365 | 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. | 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 | 
| DB; Number of Participants With Significant Changes in Mean Heart Rate During Days 1 Through 197 and Days 1 Through 365 | Heart Rate (HR) was assessed as clinically significant or relevant at the discretion of the Clinical Investigator. Criteria may have varied between institutions. | 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 | 
| DB; Number of Participants With Significant Changes in Mean Temperature During Days 1 Through 197 and Days 1 Through 365 | Temperature (T) was assessed as clinically significant or relevant at the discretion of the Clinical Investigator. Criteria may have varied between institutions. | From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 197 | 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 | From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 365 | 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 | From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study | 
| DB; Number of Participants With Anti-Abatacept Antibodies From Day 1 Through Day 365 (Electrochemiluminescent [ECL] Immunoassay) | 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. | Day 1 through day 365 | 
| DB; Percentage of Participants With Antibodies Against Infliximab (Human Anti-chimeric Antibody [HACA]) From 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. | Day 1 through day 365 | 
| OL; Mean Change From Baseline Over Time in DAS 28 (ESR) Score | 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. | Baseline (Day 1), Day 365, Day 533, Day 729 | 
| OL; Percentage of Participants With DAS28 (ESR) Remission and Low Disease Activity (LDAS) Over Time | 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. | Baseline (Day 1), Day 365, Day 533, Day 729 | 
| OL; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) Over Time | 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 Days 365, 533, and 729 | 
| OL; Percentage of Participants With American College of Rheumatology (ACR) Responses Over Time | 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 Day 197, Day 365, Day 533, Day 729 | 
| OL; Percentage of Participants Who Achieved Major Clinical Response | Major Clinical Response was defined as a continuous ACR 70 for six months. | Defined from the date of achieving ACR 70 response to 6 months post response | 
| OL; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Over Time | 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 Days 197, 253, 281, 309, 337, 365, 449, 533, 617, and 729 | 
| OL; Adjusted Mean Change From Baseline to Day 729 in HAQ-DI | 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. | Day 1 (Baseline), Day 729 |