Substudy - Low Dose of Abatacept in Subjects With Rheumatoid Arthritis

An event of disease relapse was defined as additional Disease-modifying antirheumatic drug (DMARD) therapy given, or 2 or more courses of high steroids given, or return to abatacept 10 mg/kg (rescue medication given), or DAS28 C-reactive protein (CRP) score \>=3.2 at 2 consecutive visits. Time to disease relapse was evaluated using life tables (Kaplan-Meier Cumulative Percentage of Events of Disease Relapse).

Time frame: Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

Population: Number of participants analyzed=number of participants randomized. n=number of participants at risk at the end of a specified month.

Mean baseline DAS28 CRP values for the cohort of participants with serum samples available at that timepoint. DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a VAS of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (\>5.1=high disease activity; \<3.2=low disease activity; \<2.6=remission).

Time frame: Baseline, Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365

Population: Number of participants analyzed=number of participants randomized; n=the number of participants with available DAS28 CRP scores at that time point.

Clinical significance was determined by investigator. Parameters include blood pressure, heart rate, respiration rate, and temperature.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: This analysis was not done because clinically significant changes in vital signs and physical findings were reported as adverse events.

Mean baseline DAS28 CRP values for the cohort of participants with serum samples available at that timepoint. DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (\>5.1=high disease activity; \<3.2=low disease activity; \<2.6=remission).

Time frame: Baseline

Population: Number of participants analyzed=number of participants randomized; n=All treated participants with available DAS28 CRP scores at that time point. Mean time-matched baseline values reflect changing n-values over time.

Disease relapse is defined as additional DMARD therapy given, or 2 or more courses of high steroids given, or return to abatacept 10 mg/kg (rescue medication given), or DAS28 CRP score \>= 3.2 at 2 consecutive visits.

Time frame: After 12 Months of treatment

Population: Number of participants analyzed=number randomized.

A positive antibody response to Abatacept (measured by the ECL assay) is further classified as a positive response for either Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Possibly immunoglobulin (Ig)' or 'Ig and/or Junction Region'

Time frame: After 12 months of treatment

Population: Number of participants analyzed= Number of participants with available immunogenicity measurements

Additional DMARD therapy is defined as a re-introduction of methotrexate (MTX), an increase of at least 2.5 mg of MTX, or the addition of at least 1 DMARD.

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

All subjects in the sub-study randomized to receive double-blind abatacept 5 mg/kg or 10 mg/kg. Subjects rescued to open-label treatment received abatacept 10 mg/kg.

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

A course of high dose steroids is defined as a course of intramuscular, intravenous, or high dose oral corticosteroids (use of \> 10 mg/day equivalent of prednisone for a minimum of 3 consecutive days or for those subjects who had continued use for long durations of time, each course was determined by 28 day intervals).

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

Loss of remission is defined as DAS 28 CRP \>=2.6.

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

Modified therapy=additional DMARD therapy, 2 or more courses of high dose steroids or rescue medication. Additional DMARD therapy=re-introduction of methotrexate (MTX), an increase of at least 2.5 mg of MTX, or the addition of at least 1 DMARD. A course of high dose steroids=a course of intramuscular, intravenous, or high dose oral corticosteroids (use of \> 10 mg/day equivalent of prednisone for a minimum of 3 consecutive days or for those subjects who had continued use for long durations of time, each course was determined by 28 day intervals). Rescue medication=abatacept 10 mg/kg.

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a VAS of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (\>5.1=high disease activity; \<3.2=low disease activity; \<2.6=remission).

Time frame: After 12 months of treatment

Population: Number of participants analyzed= number of participants randomized.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Related AE/SAE=Certain, Probable, Possible, or Missing. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Infection and Infestation AEs = any AE within the System Organ Class Infection and Infestation.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

Not evaluated: high hemoglobin,high hematocrit,high erythrocytes,high neutrophils+bands(N+B),low monocytes,low basophils,low eosinophils,low alkaline phosphatase(ALP),low aspartate aminotransferase(AST),low alanine aminotransferase(ALT),low G-Glutamyl transferase(GGT),low total bilirubin,low blood urea nitrogen,low creatinine,high albumin,low uric acid,low urine protein,low urine glucose,low urine blood,low urine leukocyte esterase,low urine white blood cells,low red blood cells.Pre Rx=pretreatment,(\*)Lymphocytes(c/uL):Low\<.750x10\^3,High\>7.50x10\^3.(\*)Eosinophils:\>.750x10\^3 c/uL.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period; n=number of participants with specific measure

All neoplasms were assessed by medical review as to whether or not the event was malignant.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Acute Infusional AE= a subset of the peri-infusional AEs with onset during the first hour after the start of the study drug infusion. A total of 105 infusional events were prespecified in the protocol.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

A total of 127 autoimmune disorders were prespecified in the protocol. MCTD=Musculoskeletal and Connective Tissue Disorders

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Peri-infusional AE=a pre-specified infusional AE occuring during the first 24 hours after the start of study drug infusion.A total of 105 infusional events were prespecified in the protocol. GDASC=General Disorders and Administration Site Conditions, RTMD=Respiratory, Thoracic and Mediastinal Disorders.

Time frame: From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks)

Population: Number of participants analyzed = All treated participants during the double-blind period.

Time frame: Day 701 of the main study; sub-study Days 1, 85, 169, 253

Population: Number of participants analyzed= number of participants randomized; n =randomized participants with measurement at given time point. For the Day 701 measure, one apparent outlier sample was deleted..