Trial Outcomes & Findings for Methotrexate-Inadequate Response Study (NCT NCT00559585)

Last Updated: 2015-11-09

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2492 participants

Primary outcome timeframe

Day 169

Results posted on

2015-11-09

Participant Flow

During the double blind short term (ST) period of the Main study, a sub-study in RA participants was initiated to evaluate anti-tumor necrosis factor (TNF) failure population. The sub-study was terminated early due to slow recruitment and participants from the sub-study were allowed to roll into the Main study during the LT Open Label Period.

2492 enrolled: 2472 in Main Study:1008 not randomized: 918 no longer met criteria, 61 withdrew consent, 7 lost to follow-up, 22 other reasons. Randomized, not treated: 4 no longer met criteria, 2 withdrew consent, and 1 randomization error; 20 enrolled in Anti-TNF sub-study; 2 not randomized as no longer met criteria; 18 randomized in substudy.

Participant milestones

Participant milestones
Measure	Subcutaneous (SC) Abatacept During the Main Study Double Blind ST Period, participants received 125 mg weekly SC abatacept injections for 6 months (with an IV abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. During the Open Label Long Term (LT) Period, participants in both the Main Study and the Anti-TNF Failure Sub-study switched to open-label SC abatacept. The study continued until SC formulation became commercially available on a country basis or the Sponsor terminated the study.	Intravenous (IV) Abatacept During the Main study Double Blind ST Period, participants received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, participants also received SC injections of placebo (SC Placebo). During the Open Label LT Period, participants in both the Main Study and the Anti-TNF Failure Sub-study switched to open-label SC abatacept. The study continued until SC formulation became commercially available on a country basis or the Sponsor terminated the study.
Double Blind ST Period Main Study STARTED	736	721
Double Blind ST Period Main Study COMPLETED	693	676
Double Blind ST Period Main Study NOT COMPLETED	43	45
Anti-TNF Sub-Study in ST Period STARTED	8	10
Anti-TNF Sub-Study in ST Period COMPLETED	7	9
Anti-TNF Sub-Study in ST Period NOT COMPLETED	1	1
Open Label LT Period Main + Sub-Study STARTED	1373	0
Open Label LT Period Main + Sub-Study COMPLETED	945	0
Open Label LT Period Main + Sub-Study NOT COMPLETED	428	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Subcutaneous (SC) Abatacept During the Main Study Double Blind ST Period, participants received 125 mg weekly SC abatacept injections for 6 months (with an IV abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. During the Open Label Long Term (LT) Period, participants in both the Main Study and the Anti-TNF Failure Sub-study switched to open-label SC abatacept. The study continued until SC formulation became commercially available on a country basis or the Sponsor terminated the study.	Intravenous (IV) Abatacept During the Main study Double Blind ST Period, participants received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, participants also received SC injections of placebo (SC Placebo). During the Open Label LT Period, participants in both the Main Study and the Anti-TNF Failure Sub-study switched to open-label SC abatacept. The study continued until SC formulation became commercially available on a country basis or the Sponsor terminated the study.
Double Blind ST Period Main Study Adverse Event	17	25
Double Blind ST Period Main Study Withdrawal by Subject	11	5
Double Blind ST Period Main Study Lost to Follow-up	0	6
Double Blind ST Period Main Study Administrative Reason By Sponsor	1	0
Double Blind ST Period Main Study Death	1	1
Double Blind ST Period Main Study No Longer Meets Study Criteria	2	1
Double Blind ST Period Main Study Lack of Efficacy	6	1
Double Blind ST Period Main Study Poor/Non-Compliance	3	0
Double Blind ST Period Main Study Missed Doses	0	1
Double Blind ST Period Main Study Incomplete Breast Exam	0	1
Double Blind ST Period Main Study Suspended Drug Due To Surgery	0	1
Double Blind ST Period Main Study Early Discontinuation	0	1
Double Blind ST Period Main Study Participant Weight Gain	1	0
Double Blind ST Period Main Study Participant Withdrew-Recurrent Infection	0	1
Double Blind ST Period Main Study Investigator Decision	0	1
Double Blind ST Period Main Study Ongoing Infection Risk	1	0
Anti-TNF Sub-Study in ST Period Lack of Efficacy	1	1
Open Label LT Period Main + Sub-Study Adverse Event	100	0
Open Label LT Period Main + Sub-Study Withdrawal by Subject	81	0
Open Label LT Period Main + Sub-Study Pregnancy	16	0
Open Label LT Period Main + Sub-Study Lost to Follow-up	32	0
Open Label LT Period Main + Sub-Study Administrative reason by Sponsor	9	0
Open Label LT Period Main + Sub-Study Death	20	0
Open Label LT Period Main + Sub-Study No longer met criteria	1	0
Open Label LT Period Main + Sub-Study Lack of Efficacy	89	0
Open Label LT Period Main + Sub-Study Poor/non-compliance	8	0
Open Label LT Period Main + Sub-Study non-specified	71	0
Open Label LT Period Main + Sub-Study no end of study status page	1	0

Baseline Characteristics

Methotrexate-Inadequate Response Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Subcutaneous (SC) Abatacept n=696 Participants Participants received 125 mg weekly SC abatacept injections (with an intravenous \[IV\] abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. The Per Protocol (PP) Analysis Population (instead of the Intent-To-Treat Population) was used to perform primary and key secondary efficacy analyses as per regulatory guidelines for non-inferiority studies.	Intravenous (IV) Abatacept n=683 Participants Participants received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter. A double-dummy design was used to protect the blind, thus, participants also received SC injections of placebo (SC Placebo). The Per Protocol (PP) Analysis Population (instead of the Intent-To-Treat Population) was used to perform primary and key secondary efficacy analyses as per regulatory guidelines for non-inferiority studies.	Total n=1379 Participants Total of all reporting groups
Age, Continuous	49.9 years STANDARD_DEVIATION 13.0 • n=93 Participants	49.9 years STANDARD_DEVIATION 12.7 • n=4 Participants	49.9 years STANDARD_DEVIATION 12.8 • n=27 Participants
Sex: Female, Male Female	586 Participants n=93 Participants	549 Participants n=4 Participants	1135 Participants n=27 Participants
Sex: Female, Male Male	110 Participants n=93 Participants	134 Participants n=4 Participants	244 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	5 Participants n=93 Participants	1 Participants n=4 Participants	6 Participants n=27 Participants
Race (NIH/OMB) Asian	63 Participants n=93 Participants	72 Participants n=4 Participants	135 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	26 Participants n=93 Participants	24 Participants n=4 Participants	50 Participants n=27 Participants
Race (NIH/OMB) White	516 Participants n=93 Participants	505 Participants n=4 Participants	1021 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	86 Participants n=93 Participants	81 Participants n=4 Participants	167 Participants n=27 Participants
Region Of Enrollment North America	129 participants n=93 Participants	111 participants n=4 Participants	240 participants n=27 Participants
Region Of Enrollment South America	338 participants n=93 Participants	340 participants n=4 Participants	678 participants n=27 Participants
Region Of Enrollment Europe	123 participants n=93 Participants	123 participants n=4 Participants	246 participants n=27 Participants
Region Of Enrollment Rest of the World	106 participants n=93 Participants	109 participants n=4 Participants	215 participants n=27 Participants
Baseline Weight Category <60 kg	175 participants n=93 Participants	171 participants n=4 Participants	346 participants n=27 Participants
Baseline Weight Category 60 to 100 kg	464 participants n=93 Participants	465 participants n=4 Participants	929 participants n=27 Participants
Baseline Weight Category >100 kg	57 participants n=93 Participants	47 participants n=4 Participants	104 participants n=27 Participants
Duration of RA Disease	7.6 years STANDARD_DEVIATION 8.0 • n=93 Participants	7.7 years STANDARD_DEVIATION 7.9 • n=4 Participants	7.7 years STANDARD_DEVIATION 7.9 • n=27 Participants
Duration of Disease Category ≤2 Years	229 participants n=93 Participants	206 participants n=4 Participants	435 participants n=27 Participants
Duration of Disease Category 2 - ≤5 yrs	144 participants n=93 Participants	145 participants n=4 Participants	289 participants n=27 Participants
Duration of Disease Category 5 - ≤10 yrs	134 participants n=93 Participants	155 participants n=4 Participants	289 participants n=27 Participants
Duration of Disease Category > 10 yrs	189 participants n=93 Participants	177 participants n=4 Participants	366 participants n=27 Participants
Number of Tender Joints	30 tender joints STANDARD_DEVIATION 14.1 • n=93 Participants	29.2 tender joints STANDARD_DEVIATION 13.1 • n=4 Participants	29.6 tender joints STANDARD_DEVIATION 13.6 • n=27 Participants
Number of Swollen Joints	20.5 swollen joints STANDARD_DEVIATION 9.4 • n=93 Participants	19.6 swollen joints STANDARD_DEVIATION 8.5 • n=4 Participants	20.0 swollen joints STANDARD_DEVIATION 9.0 • n=27 Participants
Participant Pain Assessment	68.0 units on a scale STANDARD_DEVIATION 20.0 • n=93 Participants	66.9 units on a scale STANDARD_DEVIATION 20.5 • n=4 Participants	67.5 units on a scale STANDARD_DEVIATION 20.3 • n=27 Participants
Physical Function (Health Assessment Questionnaire Disability Index [HAQ-DI])	1.73 units on a scale STANDARD_DEVIATION 0.68 • n=93 Participants	1.69 units on a scale STANDARD_DEVIATION 0.67 • n=4 Participants	1.71 units on a scale STANDARD_DEVIATION 0.67 • n=27 Participants
Participant Global Assessment	67.2 units on a scale STANDARD_DEVIATION 20.1 • n=93 Participants	65.2 units on a scale STANDARD_DEVIATION 19.9 • n=4 Participants	66.2 units on a scale STANDARD_DEVIATION 20.0 • n=27 Participants
Physician Global Assessment	64.3 units on a scale STANDARD_DEVIATION 16.5 • n=93 Participants	63.4 units on a scale STANDARD_DEVIATION 16.3 • n=4 Participants	63.9 units on a scale STANDARD_DEVIATION 16.4 • n=27 Participants
High Sensitivity C-Reactive Protein (hsCRP) Level	2.65 mg/dL STANDARD_DEVIATION 2.91 • n=93 Participants	2.72 mg/dL STANDARD_DEVIATION 2.91 • n=4 Participants	2.69 mg/dL STANDARD_DEVIATION 2.91 • n=27 Participants
Disease Activity Score (CRP)	6.25 units on a scale STANDARD_DEVIATION 0.84 • n=93 Participants	6.22 units on a scale STANDARD_DEVIATION 0.83 • n=4 Participants	6.24 units on a scale STANDARD_DEVIATION 0.83 • n=27 Participants
Rheumatoid Factor Status Negative	102 participants n=93 Participants	91 participants n=4 Participants	193 participants n=27 Participants
Rheumatoid Factor Status Positive	582 participants n=93 Participants	583 participants n=4 Participants	1165 participants n=27 Participants
Rheumatoid Factor Status Unknown	12 participants n=93 Participants	9 participants n=4 Participants	21 participants n=27 Participants
Baseline Methotrexate (MTX) Dose	16.3 mg/wk STANDARD_DEVIATION 3.6 • n=93 Participants	16.5 mg/wk STANDARD_DEVIATION 3.7 • n=4 Participants	16.4 mg/wk STANDARD_DEVIATION 3.6 • n=27 Participants
Weight	72.1 kg STANDARD_DEVIATION 18.1 • n=93 Participants	71.5 kg STANDARD_DEVIATION 17.5 • n=4 Participants	71.8 kg STANDARD_DEVIATION 17.8 • n=27 Participants

PRIMARY outcome

Timeframe: Day 169

Population: Per protocol (PP) population, defined as participants who are compliant with the study criteria.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=693 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=678 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants Achieving American College of Rheumatology (ACR) 20 Response at Day 169	527 participants	514 participants

PRIMARY outcome

Timeframe: Days 85, and 169 and postvisits on Days 28, 56, and 85

Population: All randomized participants in the Anti-TNF Failure Sub-study who received at least 1 dose of study medication. n=Number of participants with at least 1 assessment available.

Serum samples from all treated adult participants with active rheumatoid arthritis who were from the Anti-TNF failure population were screened for the presence of drug-specific antibodies using Enzyme Linked Immunoabsorbant Assay (ELISA). The number of participants who had the presence of anti-abatacept antibodies or anti-CTLA-4 antibodies present in their serum are summarized.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=8 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=10 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Overall Treatment Anti-abatacept (n=8,10)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Day 169 Anti-CTLA4-T(n=6,9)	1 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Day 85 Anti-abatacept (n=8,10)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Day 85 Anti-CTLA4-T (n=8,10)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Day 169 Anti-abatacept (n=6,9)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population Overall on Treatment Anti-CTLA4-T(n=8,10)	1 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 28 days post Anti-abatacept (n=1,1)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 28 days post Anti-CTLA4-T (n=1,1)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 56 days post Anti-abatacept (n=0,1)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 56 days post Anti-CTLA4-T (n=0,1)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 85 days post Anti-abatacept (n=0,1)	0 participants	0 participants
Anti-TNF Failure Sub-Study Double Blind Period : Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population 85 days post Anti-CTLA4-T (n=0,1)	0 participants	0 participants

SECONDARY outcome

Timeframe: Day 169

Population: PP population, defined as participants who are compliant with the study criteria.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=693 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=678 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants Achieving ACR 50 and ACR 70 Responses at Day 169 ACR 50	357 participants	341 participants
Double-blind Period: Number of Participants Achieving ACR 50 and ACR 70 Responses at Day 169 ACR 70	183 participants	170 participants

SECONDARY outcome

Timeframe: Day 169

Population: All participants who received at least 1 dose of study medication at any time and had HAD-QI scores available.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=729 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=711 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Participants With Assessments at Day 169	1.72 units on a scale Standard Deviation 0.68	1.67 units on a scale Standard Deviation 0.67

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: All participants who received at least 1 dose of study medication at any time and had HAD-QI scores available.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=729 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=711 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI	-0.69 units on a scale Standard Error 0.02	-0.70 units on a scale Standard Error 0.02

SECONDARY outcome

Timeframe: Day 169

Population: All participants who received at least 1 dose of study medication at any time and had HAD-QI scores available

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=729 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=711 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants Achieving Clinically Meaningful HAQ-DI Response at Day 169	483 participants	442 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication.

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

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
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 Deaths	2 participants	5 participants
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 SAEs	31 participants	35 participants
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 Treatment-related SAEs	5 participants	12 participants
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 SAEs Leading to Discontinuation	8 participants	14 participants
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 AEs	493 participants	470 participants
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 Treatment-related AEs	204 participants	210 participants
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 AEs Leading to Discontinuation	15 participants	25 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=8 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=10 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Anti-TNF Failure Sub-study Double-blind Period: Number of Participants With SAEs, AEs Leading to Discontinuation or Who Died Deaths	0 participants	0 participants
Anti-TNF Failure Sub-study Double-blind Period: Number of Participants With SAEs, AEs Leading to Discontinuation or Who Died SAEs	0 participants	0 participants
Anti-TNF Failure Sub-study Double-blind Period: Number of Participants With SAEs, AEs Leading to Discontinuation or Who Died AEs Leading to Discontinuation	0 participants	0 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication.

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

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With AEs of Special Interest Infections	234 participants	221 participants
Double-blind Period: Number of Participants With AEs of Special Interest Malignancies	3 participants	5 participants
Double-blind Period: Number of Participants With AEs of Special Interest Autoimmune Disorders	7 participants	6 participants
Double-blind Period: Number of Participants With AEs of Special Interest Acute Infusional AEs	20 participants	16 participants
Double-blind Period: Number of Participants With AEs of Special Interest Peri-infusional AEs	59 participants	59 participants
Double-blind Period: Number of Participants With AEs of Special Interest Local Injection Site Reactions	19 participants	18 participants
Double-blind Period: Number of Participants With AEs of Special Interest Systemic Injection Reactions	56 participants	56 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements	0 participants	0 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication. n=Number of participants with assessments available.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low hemoglobin (LLN=11.5 g/dL); n=729, 713	2 participants	5 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low hematocrit (LLN=34%); n=726, 713	2 participants	4 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low erythrocytes(LLN=3.8 x10*6c/uL);n=729, 713	2 participants	3 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low platelets (LLN=140*10^9 c/L); n=725, 709	1 participants	0 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High platelets (ULN=450*10^9 c/L); n=725, 709	0 participants	0 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low leukocytes (LLN= 3.8*10^3 c/uL); n=729, 713	6 participants	2 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High leukocytes (ULN = 10.6*10^3 c/uL);n=729, 713	25 participants	18 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low neutrophils+bands(LLN=1.8*10^3 c/uL);n=730,713	0 participants	0 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High eosinophils (ULN= 7*10^3 c/uL); n=730, 712	22 participants	16 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High basophils (ULN= 0.2*10^3 c/uL); n=730, 712	0 participants	0 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High monocytes (ULN=1*10^3 c/uL); n=730, 712	0 participants	1 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality Low lymphocytes (LLN= 0.7*10^3 c/uL);n=730,712	40 participants	42 participants
Double-blind Period: Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality High lymphocytes(ULN=4.5*10^3 c/uL);n=730,712	40 participants	42 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication. n=Number of participants with assessments available.

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

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High ALP (ULN=400 U/L); n=730, 713	1 participants	3 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High AST (ULN=44 U/L); n=729, 713	5 participants	5 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High ALT (ULN=55 U/L);n=729, 713	12 participants	16 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High GGT (ULN=65 U/L); n=730, 713	8 participants	14 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High bilirubin (ULN=1.2 mg/dL); n=730, 713	1 participants	0 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High blood urea nitrogen (26 mg/dL); n=730, 713	21 participants	27 participants
Double-blind Period: Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality High creatinine (ULN=1.5 mg/dL); n=730, 713	19 participants	30 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication. N=number of participants with assessments available.

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

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality Low potassium (LLN=3.5 mEq/L)	9 participants	9 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality High potassium (ULN=5.5 mEq/L)	1 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality Low chlorine (LLN= 96 mEq/L)	0 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality High chlorine (ULN=109 mEq/L)	0 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality Low calcium (LLN=8.4 mg/dL)	1 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality High calcium (ULN=10.6 mg/dL)	1 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality Low phosphorous (LLN=0.8 mg/dL)	1 participants	2 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality High phosphorous (ULN=5.6 mg/dL)	0 participants	1 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality Low sodium (LLN=135 mEq/L)	2 participants	0 participants
Double-blind Period: Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality High sodium (ULN=148 mEq/L)	0 participants	0 participants

SECONDARY outcome

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

Population: Participants who received at least 1 dose of study medication and from whom at least 1 pharmacokinetic (PK) sample was collected and reported (N). Only participants with adequate PK profiles were included in the summary statistics and statistical analysis (n).

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=630 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=649 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 57 (n=25, n=16)	31.60 µg/mL Standard Deviation 21.483	23.14 µg/mL Standard Deviation 14.008
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 85 (n=630, n=649)	28.30 µg/mL Standard Deviation 21.692	20.00 µg/mL Standard Deviation 13.441
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 113 (n=44, n=29)	26.49 µg/mL Standard Deviation 16.569	18.76 µg/mL Standard Deviation 16.322
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 120 (n=27)	25.10 µg/mL Standard Deviation 14.933	NA µg/mL Standard Deviation NA PK values were not sampled for IV abatacept group on Day 120
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 127 (n=28)	29.16 µg/mL Standard Deviation 14.780	NA µg/mL Standard Deviation NA PK values were not sampled for IV abatacept group on Day 127
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 134 (n=27)	25.10 µg/mL Standard Deviation 15.753	NA µg/mL Standard Deviation NA PK values were not sampled for IV abatacept group on Day 134
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 141 (n=26, n=26)	25.79 µg/mL Standard Deviation 14.264	18.10 µg/mL Standard Deviation 17.717
Double-blind Period: Minimum Observed Serum Concentration of Abatacept Day 169 (n=530, n=521)	24.91 µg/mL Standard Deviation 14.989	18.10 µg/mL Standard Deviation 17.94

SECONDARY outcome

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

Population: Participants who received at least 1 dose of study medication and who had adequate PK profiles were analyzed. n= number of participants available at each specific time point.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=6 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=9 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 57 (n=3,4)	25.53 μg/mL Geometric Coefficient of Variation 16	15.51 μg/mL Geometric Coefficient of Variation 25
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 85 (n=6,9)	21.51 μg/mL Geometric Coefficient of Variation 26	12.50 μg/mL Geometric Coefficient of Variation 48
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 113 (n=6,6)	23.14 μg/mL Geometric Coefficient of Variation 27	11.10 μg/mL Geometric Coefficient of Variation 31
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 120 (n=4)	25.75 μg/mL Geometric Coefficient of Variation 17	NA μg/mL Geometric Coefficient of Variation NA PK values were not sampled for IV abatacept group on Day 120.
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 127 (n=3)	25.42 μg/mL Geometric Coefficient of Variation 9	NA μg/mL Geometric Coefficient of Variation NA PK values were not sampled for IV abatacept group on Day 127.
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 134 (n=3)	25.55 μg/mL Geometric Coefficient of Variation 13	NA μg/mL Geometric Coefficient of Variation NA PK values were not sampled for IV abatacept group on Day 134.
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 141 (n=4,6)	20.85 μg/mL Geometric Coefficient of Variation 24	8.34 μg/mL Geometric Coefficient of Variation 44
Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept Day 169 (n=5,7)	19.66 μg/mL Geometric Coefficient of Variation 25	9.00 μg/mL Geometric Coefficient of Variation 53

SECONDARY outcome

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

Population: Participants who received at least 1 dose of study medication and who had adequate PK profiles for analysis

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=39 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=39 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Maximum Observed Serum Concentration of Abatacept	40.39 µg/mL Standard Deviation 30.148	222.35 µg/mL Standard Deviation 71.920

SECONDARY outcome

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

Population: Participants in the Sub-study who received at least 1 dose of study medication and who had adequate PK profiles were analyzed

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).

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=5 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=5 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept	35.84 μg/mL Geometric Coefficient of Variation 24	229.88 μg/mL Geometric Coefficient of Variation 26

SECONDARY outcome

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

Population: Participants who received at least 1 dose of study medication and who had adequate PK profiles for analysis

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=39 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=39 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept	5182.37 µg*h/mL Standard Deviation 2854.136	39587.08 µg*h/mL Standard Deviation 15444.743

SECONDARY outcome

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

Population: Participants in the sub-study who received at least 1 dose of study medication and who had adequate PK profiles for analysis

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=5 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=6 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept	4384.80 μg*h/mL Geometric Coefficient of Variation 17	34260.55 μg*h/mL Geometric Coefficient of Variation 35

SECONDARY outcome

Timeframe: Days 85, and 169 and postvisits on Days 28, 56, and 85

Population: All randomized participants who received at least 1 dose of study medication. n=Number of participants with at least 1 assessment available.

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).

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
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) Day 85 anti-ABA (n=700, n=682)	0 participants	2 participants
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) Day 85 anti-CTLA4 (n=705, n=689	0 participants	0 participants
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) Day 85 total (n=706, n=689)	0 participants	2 participants
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) Day 169 anti-ABA (n=671, n=648)	3 participants	4 participants
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) Day 169 anti-CTLA4 (n=681, n=658)	2 participants	4 participants
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) Day 169 total (n=681, n=658)	5 participants	8 participants
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) Overall on-treatment visits anti-ABA (n=707, 691)	3 participants	5 participants
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) Overall on-treatment visits anti-CTLA4 (n=716,702)	2 participants	4 participants
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) Overall on-treatment visits total (n=716, 702)	5 participants	9 participants
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) 28 days post last dose anti-ABA (n=18, n=25)	0 participants	0 participants
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) 28 days post last dose anti-CTLA4 (n=20, n=27)	0 participants	2 participants
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) 28 days post last dose total (n=20, n=27)	0 participants	2 participants
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) 56 days post last dose anti-ABA (n=19, n=22)	0 participants	0 participants
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) 56 days post last dose anti-CTLA4 (n=19, n=23)	1 participants	1 participants
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) 56 days post last dose total (n=19, n=23)	1 participants	1 participants
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) 85 days post last dose anti-ABA (n=12, n=15)	0 participants	0 participants
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) 85 days post last dose anti-CTLA4 (n=13, n=15)	2 participants	5 participants
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) 85 days post last dose total (n=13, n=15)	2 participants	5 participants
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) Overall post visits anti-ABA (n=26, n=29)	0 participants	0 participants
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) Overall post visits anti-CTLA4 (n=28, n=31)	3 participants	7 participants
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) Overall post visits total (n=28, n=31)	3 participants	7 participants
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) Overall anti-ABA (n=714, n=698)	3 participants	5 participants
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) Overall anti-CTLA4 (n=725, n=710)	5 participants	11 participants
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) Overall total (n=725, n=710)	8 participants	16 participants

SECONDARY outcome

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

Population: All randomized participants who received at least 1 dose of study medication. n=Number of participants with at least 1 assessment available.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=736 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=721 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 15 (n=720, n=703)	34.16 percent change Interval -11.11 to 58.8	33.74 percent change Interval -6.24 to 58.41
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 29 (n=727, n=711)	39.74 percent change Interval 3.83 to 66.99	42.52 percent change Interval 0.42 to 68.66
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 57 (n=727, n=711)	47.88 percent change Interval 6.84 to 73.53	51.42 percent change Interval 7.53 to 74.95
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 85 (n=727, n=711)	52.90 percent change Interval 8.7 to 78.25	53.65 percent change Interval 11.05 to 79.42
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 113 (n=727, n=711)	53.33 percent change Interval 7.09 to 80.29	58.12 percent change Interval 11.21 to 81.26
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 141 (n=727, n=711)	56.12 percent change Interval 5.28 to 83.24	58.39 percent change Interval 16.14 to 81.52
Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period Day 169 (n=727, n=711)	57.18 percent change Interval 11.18 to 83.28	56.81 percent change Interval 17.92 to 82.7

SECONDARY outcome

Timeframe: Days 85, and 169 and postvisits on Days 28, 56, and 85

Population: All participants who received at least 1 dose of abatacept and had at least 1 immunogenicity result reported during the short-term period.

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.

Outcome measures

Outcome measures
Measure	Subcutaneous Abatacept n=82 Participants Participants received weekly injections of 125 mg subcutaneous abatacept (with a loading dose of intravenous (IV) abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, participants also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.	Intravenous Abatacept n=71 Participants Participants received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, participants also received subcutaneous injections of placebo (subcutaneous placebo).
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 85 CTLA4 + possibly Ig (n=78, n=67)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 85 Ig +/- JNCT (n=78, n=67)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 85 total (n=78, n=67)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 169 CTLA4 + possibly Ig (n=75, n=67)	0 participants	1 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 169 Ig +/- JNCT (n=75, n=67)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Day 169 total (n=75, n=67)	0 participants	1 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall on-TRT CTLA4 + possibly Ig (n=79, 70)	0 participants	1 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall on-TRT Ig +/- JNCT (n=79, 70)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall on-TRT total (n=79, 70)	0 participants	1 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 28 days post last dose CTLA4+possibly Ig (n=2,n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 28 days post last dose Ig +/- JNCT (n=2, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 28 days post last dose Total (n=2, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 56 days post last dose CTLA4+possibly Ig (n=2,n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 56 days post last dose Ig +/- JNCT (n=2, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 56 days post last dose total (n=2, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 85 days post last dose CTLA4+possibly Ig (n=1,n=1)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 85 days post last dose Ig +/- JNCT (n=1, n=1)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized 85 days post last dose total (n=1, n=1)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall post visits CTLA4+possibly Ig (n=3, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall post visits Ig +/- JNCT (n=3, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall post visits total (n=3, n=2)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall CTLA4+possibly Ig (n=82, n=71)	0 participants	1 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall Ig +/- JNCT (n=82, n=71)	0 participants	0 participants
Double-blind Period: Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized Overall total (n=82, n=71)	0 participants	1 participants

SECONDARY outcome

Timeframe: Baseline to Day 169

Population: All randomized participants who received at least 1 dose of study medication. n=Number of participants with at least 1 assessment available.

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.