Methotrexate-Inadequate Response Study

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.

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.

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.

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.

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

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.

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

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.

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.

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

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

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.

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).

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.

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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

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

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.

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.

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.