Methotrexate-Inadequate Response Study

Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI

The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI ranges from 0 to a maximum overall score of 3.0.

Time frame: Baseline to Day 169

Double-blind Period: Number of Participants Achieving Clinically Meaningful HAQ-DI Response at Day 169

The disability section of the full HAQ-DI 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-DI response=an improvement of at least 0.3 units from baseline in HAQ-DI.

Time frame: Day 169

Double-blind Period: Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

AE=any new untoward medical event or worsening of a preexisting medical condition that 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. Treatment-related SAE=possibly, probably, or certainly related to study drug

Time frame: Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.

Anti-TNF Failure Sub-study Double-blind Period: Number of Participants With SAEs, AEs Leading to Discontinuation or Who Died

AE=any new untoward medical event or worsening of a preexisting medical condition that 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.

Time frame: Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.

Double-blind Period: Number of Participants With AEs of Special Interest

AE=any new untoward medical occurrence or worsening of a preexisting medical condition that 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: all infections,serious infections,and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (prespecified AEs occurring within 1 hr of start of infusion), peri-infusional AEs (prespecified AEs occurring within 24 hrs of the start of infusion), system injection reactions, and local injection site reactions

Time frame: Day 1 up to 56 days post last dose in short- term period or first dose in the long -term period, whichever occurs first.

Double-blind Period: Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements

Vital sign measurements were performed for participants before and after infusion/subcutaneous injection of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator.

Time frame: Day 1 through end of short-term period (Day 169)

Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality

ULN=upper limit of normal; LLN=lower limit of normal; BL= baseline. Marked abnormality criteria: Hemoglobin: \>3 g/dL decrease from BL; hematocrit: \<0.75\*BL; erythrocytes: \<0.75\*BL; platelets: \<0.67\*LLN/\>1.5\*ULN, or if BL\<LLN, use \<0.5\*BL and \<100,000 mm\^3; leukocytes: \<0.75\*LLN/\>1.25\*ULN, or if BL\<LLN use \<0.8\*BL or \>ULN, or if BL\>ULN, use \>1.2\*BL or \<LLN; neutrophils+bands: \<1.0\*10\^3 c/uL; eosinophils: \>0.750\*10\^3 c/uL; basophils: \>400 mm\^3; monocytes: \>2000 mm\^3; lymphocytes: \<0.750\*10\^3 c/uL/\>7.50\*10\^3 c/uL.

Time frame: Day 1 through end of short-term period (Day 169)

Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality

Marked abnormality criteria: Alkaline phosphatase (ALP): \>2\*ULN, or if BL\>ULN, use \>3\*BL; aspartate aminotransferase (AST): \>3\*ULN, or if BL\>ULN, use \>4\*BL; alanine aminotransferase (ALT): \>3\*ULN, or if BL\>ULN, use \>4\*BL; G-glutamyl transferase (GGT): \>2\* ULN, or if BL\>ULN, use \>3\*BL; bilirubin: \>2\* ULN, or if BL\>ULN, use \>4\*BL; blood urea nitrogen: \>2\* BL; creatinine: \>1.5\*BL

Time frame: Day 1 through end of short-term period (Day 169)

Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality

Marked abnormality criteria: Sodium: \<0.95\*LLN/\>1.05\*ULN, or if BL\<LLN, use \<0.95\* BL or \>ULN, or if BL\>ULN, use\>1.05\* BL or \<LLN; potassium: \<0.9\* LLN/\>1.1\*ULN, or if BL\<LLN then use \<0.9\* BL or \>ULN, or if BL\>ULN, use\>1.1\* BL or \<LLN; chlorine: \<0.9\*LLN/\>1.1\* ULN, or if BL\<LLN, use \<0.9\*BL or \>ULN, or if BL\>ULN, use\>1.1\*BL or \<LLN; calcium: \<0.8\* LLN/\>1.2\* ULN, or if BL\<LLN, use \<0.75\*BL or \>ULN, or if BL\>ULN, use\>1.25\* BL or \<LLN; phosphorous: \<0.75\* LLN/\>1.25\*ULN, or if BL\<LLN, use 0.67\*BL or \>ULN, or if BL\>ULN, use\>1.33\* BL or \<LLN

Time frame: Day 1 through end of short-term period (Day 169)

Double-blind Period: Minimum Observed Serum Concentration of Abatacept

Time frame: Days 57, 85, 113, 120, 127, 134, 141, and 169

Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept

Serum concentrations of abatacept were analyzed using a validated ELISA. Steady-state trough observed concentration in serum (Cminss) was measured in μg/mL. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169.

Time frame: Days 57, 85, 113, 120, 127, 134, 141, and 169 (ST Period)

Double-blind Period: Maximum Observed Serum Concentration of Abatacept

Time frame: End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous

Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept

Serum concentrations of abatacept were analyzed using a validated enzyme-linked immunosorbent assay (ELISA). Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Cmax was measured in micrograms per milliliter (μg/mL).

Time frame: End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous

Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Time frame: Dosing interval between Days 113 and 141 (TAU=28 days)

Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Serum concentrations of abatacept were analyzed using a validated ELISA. AUC(TAU) was measured as μg\*h/mL. Samples for AUC (TAU) were obtained on Days 113, 120, 127, 134, and 141.

Time frame: Dosing Interval between Days 113 and 141 (TAU=28 days)

Double-blind Period: Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)

Serum samples from all treated adult participants with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept (anti-ABA) or anti-CTLA4 antibody (anti-CTLA4).

Time frame: Days 85, and 169 and postvisits on Days 28, 56, and 85

Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period

C-reactive protein is an acute phase reactant protein that is a clinical marker for rheumatoid arthritis. Time-matched median percent change from baseline= (time-matched baseline value - Post-baseline value)/time-matched baseline value\*100, where the time-matched baseline value represents the median baseline value for only that cohort of participants with measurements available at that visit.

Time frame: Baseline to Days 15, 29, 57, 85, 113, 141, and 169

Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized

An electrochemiluminescence immunoassay screened sera for drug-specific antibodies, immunocompetition was used to identify specific anti-abatacept reactivity. CTLA4 and Possibly Ig category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; abatacept molecule). Ig and/or Junction (JNCT) category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a postbaseline titer higher than Baseline, or any postbaseline positivity if Baseline value was missing. Trt=treatment.

Time frame: Days 85, and 169 and postvisits on Days 28, 56, and 85

Double-blind Period: Number of Participants Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline

Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process.

Time frame: Baseline to Day 169

Open-Label LT Period: Number of Participants Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, 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).

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Number of Participants Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% 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). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures.

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is \> 5.1, low disease activity is \< 3.2 and remission is \< 2.6. A clinically significant response= decrease in DAS28 score of \>1.2 from baseline.

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Number of Participants Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is \> 5.1, low disease activity is \< 3.2 and remission is \< 2.6.

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Number of Participants Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and participant assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is \> 5.1, low disease activity is \< 3.2 and remission is \< 2.6.

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Number of Participants With HAQ-DI Response at Days 169, 729, 1261, 1821

The disability section of the full HAQ includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0. HAQ response was defined as an improvement (reduction) from baseline (Day 1) of at least 0.3 units in the HAQ score.

Time frame: Days 169, 729, 1261, 1821

Open-Label LT Period: Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

AE=any new untoward medical event or worsening of a preexisting medical condition that 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. Treatment-related SAE=possibly, probably, or certainly related to study drug

Time frame: End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)

Open-Label LT Period: Number of Participants With AEs of Special Interest

AE=any new untoward medical occurrence or worsening of a preexisting medical condition that 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: all infections, serious infections, and opportunistic infections; autoimmune disorders; malignancies; system injection reactions, and local injection site reactions.

Time frame: End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)

Open-Label LT Period: Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements

Vital sign assessments were performed in the LT period at 12-week intervals and at a yearly visit (at 16-week intervals) and, for participants who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Vital signs included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator.

Time frame: End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)

Open-Label LT Period: Number of Participants With Clinically Significant Laboratory Abnormalities

Laboratory assessments were performed in the LT period at 12-week intervals and at a yearly visit and, for participants who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Abnormalities were determined to be clinically significant by the investigator.

Time frame: End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)