Remission and Joint Damage Progression in Early Rheumatoid Arthritis

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00122382
• Collaborator: (none)
• Enrollment: 1,052
• Locations: 89
• Arms: 2
• Duration (Months): 43.1
• Patients Per Site: 11.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a world wide study to evaluate the remission and joint damage in subjects treated with abatacept in addition to methotrexate versus subjects who receive methotrexate along with a placebo.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Abatacept; Drug: placebo; Drug: methotrexate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1052 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase IIIB Multi-center, Randomized, Double-Blind Study to Evaluate Remission and Joint Damage Progression in Methotrexate Naive Early Erosive RA Subjects Treated With Abatacept Plus Methotrexate Compared With Methotrexate
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ABA + MTX abatacept 10 mg/kg intravenous (IV) + methotrexate	Drug: Abatacept; abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months; Drug: methotrexate; Oral, titrated to at least 15 mg per week not to exceed 20 mg per week administered every 28 days from Month 12 to Month 24
Active Comparator: Placebo (PLA) + MTX placebo IV + methotrexate	Drug: Abatacept; abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months; Drug: placebo; placebo IV, monthly, methotrexate weekly for 12 months followed by abatacept 10 mg/kg IV monthly, methotrexate weekly for 12 months; Drug: methotrexate; Oral, titrated to at least 15 mg per week not to exceed 20 mg per week administered every 28 days from Month 12 to Month 24

Outcome Measures

Primary Outcome Measures

1. Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at Month 12 [Month 12]

   Number of participants who achieved remission at Month 12 of treatment, as defined by a Disease Activity Score (DAS) 28-CRP score of <2.6. DAS 28-CRP is a continuous measure, a composite of 4 variables: number of tender joints out of 28 joints, 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 millimeters (mm). The DAS28 scale=0 (best) to 10 (worst), indicating the current activity of the rheumatoid arthritis. A DAS28 >5.1 = high disease activity; <=3.2 = low disease activity; <2.6 = remission.

2. Mean Change From Baseline in Radiographic Total Score to Month 12 [Baseline, Month 12]

   To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and joint space narrowing (JSN). The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.

3. Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period [Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

   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.

4. Number of Participants With Serious Adverse Events Reported During the Open-Label Period [Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

   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.

5. Number of Participants With SAEs With an Outcome of Death During the Open-label Period [Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

   Any untoward medical occurrence (SAE) that resulted in death

6. Incidence Rates of Autoimmune Disorders in ABA-Treated Participants [Double Blind Period (+56 days post last dose in double-blind period or start of open-label period, whichever came first). Open-label period (56 days post last dose in the open-label period or start of maintenance sub-study, whichever came first).]

   The incidence rates of autoimmune disorders are defined as the (number of patients experiencing the event/exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.

7. Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants [Double Blind Period (+56 days post last dose in double-blind period or start of the open-label period, whichever came first). Open-label period (56 days post last dose in open-label period or start of maintenance sub-study, whichever came first).]

   The incidence rates of infections and infestations are defined as the (number of patients experiencing the event /exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.

8. Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants [Double Blind Period (+56 days post last dose in double-blind period or start of the open-label period, whichever came first). Open-label period (56 days post last dose in open-label period or start of maintenance sub-study, whichever came first).]

   The incidence rates of malignant neoplasms are defined as the (number of patients experiencing the event /exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.

9. Number of Participants With a Serious Acute-Infusional AE of Anaphylactic Shock During Open-Label Period [Open-Label Period (Month 12 to Month 24)]

   There were 107 Prespecified, acute-infusional SAEs (occurring within 1 hour after the start of study drug infusion) pre-specified in the protocol; anaphylactic shock was the only one occuring in this study.

10. Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period [Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

    Number of subjects with high liver function and kinedy tests: alkaline phosphatase (ALP) >2x upper limit of normal (ULN) or if pretreatment (PRE-RX) >ULN then >3x PRE-RX; aspartate aminotransferase (AST) >3x ULN or if PRE-RX >ULN then >4x PRE-RX; alanine aminotransferase (ALT) >3x ULN or if PRE-RX >ULN then >4x PRE-RX; g-glutamyl transferase (GGT)>2x ULN or if PRE-RX >ULN then >3x PRE-RX; total bilirubin >2x ULN or if PRE-RX >ULN then >4x PRE-RX; blood urea nitrogen >2x PRE-RX; creatinine >1.5x PRE-RX.

11. Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period [Continuously from start of open-label period up to 56 days post the last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

    Marked abnormalities in hemoglobin >3 g/dL decrease from PRE-RX; hematocrit <0.75x PRE-RX; erythrocytes <0.75x PRE-RX; platelet count <0.67x lower limit of normal (LLN) or >1.5x ULN or if PRE-RX <LLN then <0.5x PRE-RX and <100,000/mm3; leukocytes <0.75x LLN or >1.25x ULN or if PRE-RX <LLN then <0.8x PRE-RX or >ULN if PRE-RX >ULN then >1.2x PRE-RX or <LLN; neutrophils if value <1.00 x10^3 c/uL; lymphocytes if value <.750 x10^3 c/uL or if value >7.50 x10^3 c/uL; monocytes if value >2000/MM3; basophils if value >400/mm3; eosinophils if value >.750 x10^3 c/uL

Secondary Outcome Measures

1. Number of Participants With American College of Rheumatology (ACR) 50 Response at Month 12 [Month 12]

   ACR 50 response was defined as a 50% improvement from baseline to Month 12 in tender and swollen joint counts and 50% improvement in 3 of the remaining 5 core set measures (subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function), and 1 acute phase reactant value [ie, CRP].

2. Number of Participants With Major Clinical Response (MCR) at Month 12 [Month 12]

   MCR was defined as 6 months of consecutive ACR 70 response at Month 12. ACR 70, the American College of Rheumatology (ACR) definition of 70% improvement was based on a 70% improvement (compared to baseline values) in tender and swollen joint counts and 70% improvement in 3 of the remaining 5 core set measures (subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function, and 1 acute phase reactant value [ie, CRP]).

3. Adjusted Mean Change From Baseline in DAS-28-CRP Score to Month 12 [Baseline, Month 12]

   DAS 28-CRP is a continuous variable that is a composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, CRP in milligrams/Liter (mg/L), and subject assessment of disease activity measure on a Visual Analogue Scale (VAS) of 100 millimeters (mm). The DAS28 scale=0 to 10, indicating the current activity of the rheumatoid arthritis. A DAS28 >5.1=high disease activity; <3.2=low disease activity; <2.6=remission. Change from Baseline=Post-baseline - Baseline value; Adjusted for baseline value.

4. Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 12 [Month 12]

   Physical function was evaluated using the HAQ-disability index (HAQ-DI), a questionnaire with 20 questions assessing function 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; 3 = unable to do. The 8 category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 3 (completely disabled). Higher scores indicate greater dysfunction. HAQ response=improvement of at least 0.3 units from baseline.

5. Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12 [Baseline, Month 12]

   The SF-36 covers 8 health dimensions: 4 physical subscales (physical function, role-physical, bodily pain, and general health) and 4 mental subscales (vitality, social function, role-emotional, and mental health). The scores range from 0 to 100, with a higher score indicating better quality of life. Two summary scores (physical and mental component summaries) were produced taking a weighted linear combination of the 8 individual subscales. Change from Baseline=Post-baseline - Baseline value; adjusted for baseline value.

6. Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 [Baseline, Month 12]

   To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The erosion score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). The joint space narrowing score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). Higher scores indicated more damage. Change from baseline = Post-baseline - Baseline value

7. Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses in the Double-blind Period as Analyzed by Enzyme-linked-immunosorbent Serologic Assay (ELISA) [includes data up to approximately 85 days past the last dose of the double-blind period or start of the open-label period, whichever occurred first.]

   Serum samples were analyzed by ELISA to detect antibodies against the whole molecule (both CTLA4 and Ig [anti-abatacept antibody]) or solely to CTLA4 (anti-CTLA4-T antibody). Reported as titer, the reciprocal of the sample dilution which yielded a signal equivalent to the statistically set cut point for the assay. For the anti-abatacept assay, minimum required dilution is 400-fold, therefore seronegative samples are those < lowest reportable titer (<400). For the anti-CTLA4-T assay, minimum required dilution is 25-fold, therefore seronegative samples are those < lowest reportable titer (<25).

8. Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses During the Open-Label Period (From Month 12 to Month 24) as Analyzed by ELISA [Includes open-label data up to approximately 85 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.]

   Serum samples were analyzed by ELISA to detect antibodies against the whole molecule (both CTLA4 and Ig [anti-abatacept antibody]) or solely to CTLA4 (anti-CTLA4-T antibody). Reported as titer, the reciprocal of the sample dilution which yielded a signal equivalent to the statistically set cut point for the assay. For the anti-abatacept assay, minimum required dilution is 400-fold, therefore seronegative samples are those < lowest reportable titer (<400). For the anti-CTLA4-T assay, minimum required dilution is 25-fold, therefore seronegative samples are those < lowest reportable titer (<25).

9. Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 24 [Baseline, Month 24]

   Physical function was evaluated using the HAQ-disability index (HAQ-DI), a questionnaire with 20 questions assessing function 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; 3 = unable to do. The 8 category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 3 (completely disabled). Higher scores indicate greater dysfunction. HAQ response=improvement of at least 0.3 units from baseline.

10. Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 [Baseline, Month 24]

    To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage. Change from baseline = Postbaseline - baseline value.

11. Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 [Baseline, Month 24]

    Participants with no radiographic progression (defined as change in score <=0 or <=0.5), from baseline to Month 24. To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.

12. Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) at Month 24 in Participants Without Progression at Month 12 [Month 12, Month 24]

    Participants with no radiographic progression ((defined as change in score <=0 or <=0.5), sustained from Month 12 and Month 24. To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.

13. Mean Difference Observed in Change From Baseline to Month 12 and Between Month 12 and Month 24 in Radiographic Scores (Total Score) [Baseline, Month 12, Month 24]

    Mean difference observed in change from baseline to Month 12 and between Month 12 and Month 24 in radiographic scores (Total Score). To assess joint damage, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.

14. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period [Includes data up to 56 days post the last dose in the double-blind period or start of the open-label period, whichever occurred first.]

    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.

15. Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period [Includes data up to 56 days post the last dose in the double-blind period or start of the open-label period, whichever occurred first.]

    Number of participants with laboratory values (hematology, liver and kidney functions, electrolytes, glucose tests, protein tests, metabolite tests, and urine chemistry tests) considered markedly abnormal according to prespecified protocol criteria

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of rheumatoid arthritis (RA) <=2 years; MTX naive or <=10 mg/wk for <=3 weeks. No dose within 3 months prior to informed consent.

• C-Reactive Protein (CRP) >= 4.5 mg/L (after amendment)

• Rheumatoid factor or anti-cyclic citrullinated peptide antibody (anti-CCP) positive

• Tender joints >=12 and swollen joints >=10

Exclusion Criteria:

• Women and men who are not willing to use birth control

• Diagnosed with other rheumatic disease

• History of cancer within 5 years

• Active tuberculosis

• Treatment with another investigation drug within 28 days

• Active bacterial or viral infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rheumatology Associates Of North Alabama	Huntsville	Alabama	United States	35801
2	Talbert Medical Group	Huntington Beach	California	United States	92646
3	Arthritis Assoc And Osteo Ctr Of Col Sprgs	Colorado Springs	Colorado	United States	80910
4	New England Research Associates, Llc	Trumbull	Connecticut	United States	06611
5	Diagnostic Rheumatology And Research	Indianapolis	Indiana	United States	46227
6	Osteoporosis And Clinical Trials Center	Cumberland	Maryland	United States	21502
7	Malamet & Klein, Md, Pa	Hagerstown	Maryland	United States	21740
8	Arthritis Center Of Nebraska	Lincoln	Nebraska	United States	68516
9	Regional Rheumatology Associates	Binghamton	New York	United States	13905
10	Carolina Bone & Joint	Charlotte	North Carolina	United States	28210
11	Physicians East, Pa	Greenville	North Carolina	United States	27834
12	Carolina Pharmaceutical Research	Statesville	North Carolina	United States	28625
13	Lion Research	Norman	Oklahoma	United States	73071
14	Health Research Of Oklahoma	Oklahoma City	Oklahoma	United States	73103
15	Lynn Health Sciences Institute	Oklahoma City	Oklahoma	United States	73112
16	Altoona Center For Clinical Research	Duncansville	Pennsylvania	United States	16635
17	Low Country Research Center	Charleston	South Carolina	United States	29406
18	Walter F Chase Md Pa	Austin	Texas	United States	78705
19	Arthritis Clinic Of Northern Virginia, P.C.	Arlington	Virginia	United States	22205
20	Local Institution	Malvern	Victoria	Australia	3144
21	Local Institution	Shenton Park	Western Australia	Australia	6008
22	Local Institution	Antwerpen		Belgium	2020
23	Local Institution	Bruxelles		Belgium	1070
24	Local Institution	Bruxelles		Belgium	1200
25	Local Institution	Hasselt		Belgium	3500
26	Local Institution	Leuven		Belgium	3000
27	Local Institution	Goiania	Goias	Brazil	74043
28	Local Institution	Curitiba	Parana	Brazil	80060
29	Local Institution	Rio De Janeiro - Rj	Rio De Janeiro	Brazil	20551
30	Local Institution	Porto Alegre	Rio Grande Do Sul	Brazil	91610
31	Local Institution	Sao Paulo		Brazil	04039
32	Local Institution	Sao Paulo		Brazil	04230
33	Local Institution	St. John'S	Newfoundland and Labrador	Canada	A1B 3E1
34	Local Institution	Kitchener	Ontario	Canada	N2M 5N6
35	Local Institution	Toronto	Ontario	Canada	M5G 1X5
36	Local Institution	Montreal	Quebec	Canada	H2L 1S6
37	Local Institution	Sherbrooke	Quebec	Canada	J1H 5N4
38	Local Institution	Saskatoon	Saskatchewan	Canada	S7N 0W8
39	Local Institution	Quebec		Canada	G1V 3M7
40	Local Institution	Prague 2		Czech Republic	128 50
41	Local Institution	Dijon		France	21000
42	Local Institution	Montpellier Cedex 5		France	34295
43	Local Institution	Nice Cedex 03		France	06202
44	Local Institution	Strasbourg Cedex		France	67098
45	Local Institution	Berlin		Germany	14059
46	Local Institution	Hamburg		Germany	22081
47	Local Institution	Leipzig		Germany	04103
48	Local Institution	Leipzig		Germany	04229
49	Local Institution	Jesi(Ancona)		Italy	60055
50	Local Institution	Milano		Italy	20157
51	Local Institution	Anyang		Korea, Republic of	431-070
52	Local Institution	Daegu		Korea, Republic of	705-718
53	Local Institution	Daejeon		Korea, Republic of	302-799
54	Local Institution	Seoul		Korea, Republic of	110-744
55	Local Institution	Seoul		Korea, Republic of	133-792
56	Local Institution	Seoul		Korea, Republic of	137-040
57	Local Institution	Seoul		Korea, Republic of	138-736
58	Local Institution	D.f.	Distrito Federal	Mexico	06700
59	Local Institution	Metepec	Estado De Mexico	Mexico	52140
60	Local Institution	Leon	Guanajuato	Mexico	37000
61	Local Institution	Guadalajara	Jalisco	Mexico	42650
62	Local Institution	Guadalajara	Jalisco	Mexico	44340
63	Local Institution	Guadalajara	Jalisco	Mexico	44690
64	Local Institution	Morelia	Michioacan	Mexico	58000
65	Local Institution	Cuernavaca	Morelos	Mexico	62270
66	Local Institution	Monterrey	Nuevo Leon	Mexico	64020
67	Local Institution	Chihuahua		Mexico	31000
68	Local Institution	San Luis Potosi		Mexico	78240
69	Local Institution	Amsterdam		Netherlands	1081 HV
70	Local Institution	Leiden		Netherlands	2300 RC
71	Local Institution	Nijmegen		Netherlands	6500 HB
72	Local Institution	Poznan		Poland	60773
73	Local Institution	Poznan		Poland	61-545
74	Local Institution	Warszawa		Poland	02-637
75	Local Institution	Ponce		Puerto Rico	00716
76	Local Institution	Moscow		Russian Federation	115522
77	Local Institution	Moscow		Russian Federation	119049
78	Local Institution	Bloemfontein	Free State	South Africa	9317
79	Local Institution	Muckleneuk	Gauteng	South Africa	0002
80	Local Institution	Pretoria	Gauteng	South Africa	0084
81	Local Institution	Berea	Kwa Zulu Natal	South Africa	4001
82	Local Institution	Panorama	Western Cape	South Africa	7506
83	Local Institution	A Coruna		Spain	15706
84	Local Institution	Santander		Spain	39008
85	Local Institution	Sevilla		Spain	41071
86	Local Institution	Manchester	Greater Manchester	United Kingdom	M13 9WL
87	Local Institution	Glasgow	Lanarkshire	United Kingdom	G12 0YN
88	Local Institution	Leeds	North Yorkshire	United Kingdom	LS7 4SA
89	Local Institution	Newcastle	Northumberland	United Kingdom	NE1 4LP

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00122382
• Other Study ID Numbers: IM101-023
• First Posted: Jul 22, 2005
• Last Update Posted: Nov 16, 2010
• Last Verified: Nov 1, 2010

• Keywords provided by , ,: abatacept, methotrexate, erosive RA
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Methotrexate; Abatacept

Study Results

Participant Flow

Pre-assignment Detail	1052 participants were enrolled, 541 were not randomized (2 for adverse events, 32 subjects withdrew consent, 1 pregnancy, 6 lost to follow-up, 470 no longer met study criteria, 30 for other reasons).

Arm/Group Title	Abatacept (ABA) + Methotrexate (MTX) (Double-Blind)	Placebo (PLA) + Methotrexate (MTX) (Double-Blind)	ABA + MTX (Open-Label)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12 (end of double blind period).	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX) titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12 (end of double blind period).	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with weekly oral MTX were administered every 28 days from Month 12 to Month 24 (open-label period).
Period Title: Double-Blind Study
STARTED	256	255	0
Treated	256	253	0
COMPLETED	232	227	0
NOT COMPLETED	24	28	0
Period Title: Double-Blind Study
STARTED	0	0	459
COMPLETED	0	0	433
NOT COMPLETED	0	0	26

Baseline Characteristics

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)	Total
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.	Total of all reporting groups
Overall Participants	256	253	509
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.1 (12.4)	49.7 (13.0)	49.9 (12.7)
Sex: Female, Male (Count of Participants)
Female	196 76.6%	199 78.7%	395 77.6%
Male	60 23.4%	54 21.3%	114 22.4%
Anti-Cyclic Citrullinated Peptide 2 (CCP2) Status (participants) [Number]
unknown	2 0.8%	0 0%	2 0.4%
positive	236 92.2%	217 85.8%	453 89%
negative	18 7%	36 14.2%	54 10.6%
Duration of Rheumatoid Arthritis (RA) Disease (participants) [Number]
</= 6 months	167 65.2%	157 62.1%	324 63.7%
> 6 months - 12 months	36 14.1%	34 13.4%	70 13.8%
> 12 months	53 20.7%	62 24.5%	115 22.6%
Rheumatoid Factor (RF) Status (participants) [Number]
unknown	1 0.4%	1 0.4%	2 0.4%
positive	246 96.1%	245 96.8%	491 96.5%
negative	9 3.5%	7 2.8%	16 3.1%
Disease Activity Scale 28 (DAS 28) C-reactive Protein (CRP) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.3 (1.0)	6.2 (1.0)	6.3 (1.0)
Duration of RA (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	6.2 (7.5)	6.7 (7.1)	6.5 (7.3)
Erosion Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.4 (6.1)	4.8 (5.4)	5.1 (5.8)
Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.7 (0.7)	1.7 (0.7)	1.7 (0.7)
Joint Space Narrowing (JSN) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.1 (4.2)	1.9 (4.0)	2.0 (4.1)
Physician Global Assessment per Visual Analogue Scale (VAS) (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	67.1 (18.2)	65.7 (18.9)	66.4 (18.5)
Subject Global Assessment per VAS (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	65.8 (21.8)	63.7 (24.0)	64.8 (22.9)
Subject Pain Assessment per VAS (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	66.6 (22.5)	67.1 (22.6)	66.8 (22.5)
Swollen Joints (number of swollen joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [number of swollen joints]	22.9 (11.3)	21.9 (10.1)	22.4 (10.8)
Tender Joints (number of tender joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [number of tender joints]	31.3 (14.8)	30.8 (14.0)	31.0 (14.4)
Total Genant-modified Sharp score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.5 (9.7)	6.7 (8.8)	7.1 (9.2)

Outcome Measures

1. Secondary Outcome

Title	Number of Participants With American College of Rheumatology (ACR) 50 Response at Month 12
Description	ACR 50 response was defined as a 50% improvement from baseline to Month 12 in tender and swollen joint counts and 50% improvement in 3 of the remaining 5 core set measures (subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function), and 1 acute phase reactant value [ie, CRP].
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Number [participants]	147 57.4%	107 42.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving an ACR 50 response.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	Chi-squared, Continuity-Corrected
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference between ABA and PLA
	Estimated Value	15.1
	Confidence Interval	(2-Sided) 95%; 6.0 to 24.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Major Clinical Response (MCR) at Month 12
Description	MCR was defined as 6 months of consecutive ACR 70 response at Month 12. ACR 70, the American College of Rheumatology (ACR) definition of 70% improvement was based on a 70% improvement (compared to baseline values) in tender and swollen joint counts and 70% improvement in 3 of the remaining 5 core set measures (subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function, and 1 acute phase reactant value [ie, CRP]).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Number [participants]	70 27.3%	30 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving MCR.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	Chi-squared, Continuity-Corrected
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference between ABA and PLA
	Estimated Value	15.5
	Confidence Interval	(2-Sided) 95%; 8.2 to 22.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change From Baseline in DAS-28-CRP Score to Month 12
Description	DAS 28-CRP is a continuous variable that is a composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, CRP in milligrams/Liter (mg/L), and subject assessment of disease activity measure on a Visual Analogue Scale (VAS) of 100 millimeters (mm). The DAS28 scale=0 to 10, indicating the current activity of the rheumatoid arthritis. A DAS28 >5.1=high disease activity; <3.2=low disease activity; <2.6=remission. Change from Baseline=Post-baseline - Baseline value; Adjusted for baseline value.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward (LOCF) Intent to Treat population = all randomized and treated. As change from baseline analysis, only those with baseline and post-baseline included.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	253	251
Mean (Standard Error) [units in a scale]	-3.22 (0.09)	-2.49 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	ANCOVA
	Comments	Adjustment based on ANCOVA model with treatment as factor and baseline value as covariate.
Method of Estimation	Estimation Parameter	Estimate of/Adjusted Difference
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -0.98 to -0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 12
Description	Physical function was evaluated using the HAQ-disability index (HAQ-DI), a questionnaire with 20 questions assessing function 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; 3 = unable to do. The 8 category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 3 (completely disabled). Higher scores indicate greater dysfunction. HAQ response=improvement of at least 0.3 units from baseline.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Number [participants]	184 71.9%	157 62.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving HAQ response.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	Chi-squared, Continuity-Corrected
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference between ABA and PLA
	Estimated Value	9.8
	Confidence Interval	(2-Sided) 95%; 1.3 to 18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12
Description	The SF-36 covers 8 health dimensions: 4 physical subscales (physical function, role-physical, bodily pain, and general health) and 4 mental subscales (vitality, social function, role-emotional, and mental health). The scores range from 0 to 100, with a higher score indicating better quality of life. Two summary scores (physical and mental component summaries) were produced taking a weighted linear combination of the 8 individual subscales. Change from Baseline=Post-baseline - Baseline value; adjusted for baseline value.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward (LOCF) Intent to Treat population = all randomized and treated. As change from baseline analysis, only those with baseline and post-baseline included.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	254	249
Physical Component Summary (PCS) Score	11.68 (0.62)	9.18 (0.63)
Mental Component Summary (MCS) Score	8.15 (0.64)	6.34 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	PCS Adjusted Mean Change from Baseline to Month 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	ANCOVA
	Comments	Adjustment based on ANCOVA model with treatment as factor and baseline value as covariate.
Method of Estimation	Estimation Parameter	Estimate of/Adjusted Difference
	Estimated Value	2.50
	Confidence Interval	(2-Sided) 95%; 0.77 to 4.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	MCS Adjusted Mean Change from Baseline to Month 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments	p-value of <0.05: probability for testing the difference between ABA and PLA.
	Method	ANCOVA
	Comments	Adjustment based on ANCOVA model with treatment as factor and baseline value as covariate.
Method of Estimation	Estimation Parameter	Estimate of/Adjusted Difference
	Estimated Value	1.81
	Confidence Interval	(2-Sided) 95%; 0.03 to 3.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12
Description	To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The erosion score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). The joint space narrowing score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). Higher scores indicated more damage. Change from baseline = Post-baseline - Baseline value
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

Intention-to-Treat - linear extrapolation imputation. Analysis of change from baseline restricts subjects included in to the analysis to those with baseline and post-baseline.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	242	242
Baseline Mean Erosion Score	5.48 (6.15)	4.81 (5.46)
Mean Change from Baseline in Erosion Score	0.50 (1.39)	0.89 (2.24)
Baseline Mean JSN Score	2.03 (3.99)	1.86 (3.95)
Mean Change from Baseline in JSN Score	0.13 (0.53)	0.17 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	comparison of change in erosion scores between abatacept and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments	P-value of <0.05: probability for comparison of change in radiographic scores between abatacept and placebo.
	Method	Nonparametric ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	comparison of change in JSN scores between abatacept and placebo
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.353
	Comments	P-value of <0.05: probability for comparison of change in radiographic scores between abatacept and placebo.
	Method	Nonparametric ANCOVA
	Comments

7. Secondary Outcome

Title	Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses in the Double-blind Period as Analyzed by Enzyme-linked-immunosorbent Serologic Assay (ELISA)
Description	Serum samples were analyzed by ELISA to detect antibodies against the whole molecule (both CTLA4 and Ig [anti-abatacept antibody]) or solely to CTLA4 (anti-CTLA4-T antibody). Reported as titer, the reciprocal of the sample dilution which yielded a signal equivalent to the statistically set cut point for the assay. For the anti-abatacept assay, minimum required dilution is 400-fold, therefore seronegative samples are those < lowest reportable titer (<400). For the anti-CTLA4-T assay, minimum required dilution is 25-fold, therefore seronegative samples are those < lowest reportable titer (<25).
Time Frame	includes data up to approximately 85 days past the last dose of the double-blind period or start of the open-label period, whichever occurred first.

Outcome Measure Data

Analysis Population Description

Treated participants in the double-blind period who were evaluated for anti-abatacept or anti-CTLA4-T responses

Arm/Group Title	ABA+ MTX On-treatment	ABA + MTX Post-discontinuation
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.
Measure Participants	249	13
Anti-abatacept Responses	3 1.2%	0 0%
Anti-CTLA4-T Responses	1 0.4%	1 0.4%

8. Primary Outcome

Title	Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at Month 12
Description	Number of participants who achieved remission at Month 12 of treatment, as defined by a Disease Activity Score (DAS) 28-CRP score of <2.6. DAS 28-CRP is a continuous measure, a composite of 4 variables: number of tender joints out of 28 joints, 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 millimeters (mm). The DAS28 scale=0 (best) to 10 (worst), indicating the current activity of the rheumatoid arthritis. A DAS28 >5.1 = high disease activity; <=3.2 = low disease activity; <2.6 = remission.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Intent to treat = all randomized and treated subjects. Those with missing data post-discontinuation were considered non-responders.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Number [participants]	106 41.4%	59 23.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments	Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving DAS28-CRP remission.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Total score was tested only if there was statistical significance in remission rate. For each test, the nominal type I error rate is set at 5%; this sequential testing procedure preserves the overall type I error rate at 5%.
	Method	Chi-squared, Continuity-Corrected
	Comments
Method of Estimation	Estimation Parameter	Estimated Difference between ABA and PLA
	Estimated Value	18.1
	Confidence Interval	(2-Sided) 95%; 9.6 to 26.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Mean Change From Baseline in Radiographic Total Score to Month 12
Description	To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and joint space narrowing (JSN). The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

The analysis was intent-to-treat. Because the analysis was change from baseline, only those with baseline and post-baseline were included. Linear extrapolation imputation was applied.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	242	242
Baseline Mean	7.50 (9.52)	6.67 (8.71)
Mean Change from Baseline	0.63 (1.74)	1.06 (2.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.040
	Comments	Total score was tested only if there was statistical significance in remission rate. For each test, the nominal type I error rate is set at 5%; this sequential testing procedure preserves the overall type I error rate at 5%.
	Method	non-parametric ANCOVA
	Comments

10. Primary Outcome

Title	Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period
Description	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	Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.

Arm/Group Title	ABA + MTX (Open-Label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
AEs	345 134.8%
Related AEs	128 50%
SAEs	29 11.3%
Related SAEs	10 3.9%
Discontinuations due to AEs	11 4.3%
Discontinuations due to SAEs	4 1.6%
Deaths	2 0.8%

11. Primary Outcome

Title	Number of Participants With Serious Adverse Events Reported During the Open-Label Period
Description	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	Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.

Arm/Group Title	ABA + MTX (Open Label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
Any SAE	29 11.3%
Infections and infestations	8 3.1%
Gastrointestinal disorders	4 1.6%
Nervous system disorders	4 1.6%
Cardiac disorders	3 1.2%
Hepatobiliary disorders	3 1.2%
Eye disorders	2 0.8%
Musculoskeletal and connective tissue disorders	2 0.8%
Vascular disorders	2 0.8%
Immune System Disorders	1 0.4%
Injury, Poisoning, and Procedural Complications	1 0.4%
Investigations	1 0.4%
Metabolism and Nutrition Disorders	1 0.4%
Renal and Urinary Disorders	1 0.4%
Respiratory, Thoracic, and Mediastinal Disorders	1 0.4%

12. Secondary Outcome

Title	Number of Participants With Anti-abatacept or Anti-CTLA4-T Responses During the Open-Label Period (From Month 12 to Month 24) as Analyzed by ELISA
Description	Serum samples were analyzed by ELISA to detect antibodies against the whole molecule (both CTLA4 and Ig [anti-abatacept antibody]) or solely to CTLA4 (anti-CTLA4-T antibody). Reported as titer, the reciprocal of the sample dilution which yielded a signal equivalent to the statistically set cut point for the assay. For the anti-abatacept assay, minimum required dilution is 400-fold, therefore seronegative samples are those < lowest reportable titer (<400). For the anti-CTLA4-T assay, minimum required dilution is 25-fold, therefore seronegative samples are those < lowest reportable titer (<25).
Time Frame	Includes open-label data up to approximately 85 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

Treated participants in the open-label period were evaluated for anti-abatacept or anti-CTLA4-T responses

Arm/Group Title	Anti-Abatacept Antibody Response	Anti-CTLA4-T Antibody Response
Arm/Group Description
Measure Participants	451	456
Number [participants]	13 5.1%	16 6.3%

13. Secondary Outcome

Title	Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 24
Description	Physical function was evaluated using the HAQ-disability index (HAQ-DI), a questionnaire with 20 questions assessing function 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; 3 = unable to do. The 8 category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 3 (completely disabled). Higher scores indicate greater dysfunction. HAQ response=improvement of at least 0.3 units from baseline.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

All treated participants in the Open-label period. Treatment groups represent treatment received in the Double Blind Period.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.
Measure Participants	232	227
Number [participants]	189 73.8%	178 70.4%

14. Secondary Outcome

Title	Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24
Description	To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage. Change from baseline = Postbaseline - baseline value.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

All treated participants in the open-label period. Because the analysis was change from baseline, only those with baseline and post-baseline were included. Linear extrapolation imputation was applied. Treatment groups represent treatment received in the double-blind period.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.
Measure Participants	213	192
Erosion Score Baseline Mean	5.91 (6.48)	5.49 (5.85)
Erosion Score Mean Change from Baseline	0.59 (2.31)	1.40 (3.08)
JSN Score Baseline Mean	1.83 (3.82)	1.75 (3.92)
JSN Score Mean Change from Baseline	0.25 (1.03)	0.34 (0.99)
Total Score Baseline Mean	7.73 (9.50)	7.24 (8.89)
Total Score Mean Change from Baseline	0.84 (3.22)	1.75 (3.59)

15. Primary Outcome

Title	Number of Participants With SAEs With an Outcome of Death During the Open-label Period
Description	Any untoward medical occurrence (SAE) that resulted in death
Time Frame	Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.

Arm/Group Title	ABA + MTX (Open-Label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
Pneumonia	1 0.4%
Pneumonia/septic shock	1 0.4%

16. Primary Outcome

Title	Incidence Rates of Autoimmune Disorders in ABA-Treated Participants
Description	The incidence rates of autoimmune disorders are defined as the (number of patients experiencing the event/exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.
Time Frame	Double Blind Period (+56 days post last dose in double-blind period or start of open-label period, whichever came first). Open-label period (56 days post last dose in the open-label period or start of maintenance sub-study, whichever came first).

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of abatacept. Double-blind (DB) period: all treated in DB period; Open-label (OL) Period: all treated in OL period.

Arm/Group Title	ABA + MTX (Double-Blind)	ABA + MTX (Open-Label)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	256	459
Number [Number of participants/100 patient-years]	2.47 1%	1.30 0.5%

17. Primary Outcome

Title	Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants
Description	The incidence rates of infections and infestations are defined as the (number of patients experiencing the event /exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.
Time Frame	Double Blind Period (+56 days post last dose in double-blind period or start of the open-label period, whichever came first). Open-label period (56 days post last dose in open-label period or start of maintenance sub-study, whichever came first).

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of abatacept. Double-blind (DB) period: all treated in DB period; Open-label (OL) Period: all treated in OL period.

Arm/Group Title	ABA + MTX (Double-Blind)	ABA + MTX (Open-Label)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	256	459
Number [Number of patients/100 patient-years]	78.37	66.68

18. Primary Outcome

Title	Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants
Description	The incidence rates of malignant neoplasms are defined as the (number of patients experiencing the event /exposure within the period)*100 and are expressed in 100 person-years. Subjects experiencing the event had their exposure censored at the time of the 1st event.
Time Frame	Double Blind Period (+56 days post last dose in double-blind period or start of the open-label period, whichever came first). Open-label period (56 days post last dose in open-label period or start of maintenance sub-study, whichever came first).

Outcome Measure Data

Analysis Population Description

All subjects who received at least 1 dose of abatacept. Double-blind (DB) period: all treated in DB period; Open-label (OL) Period: all treated in OL period.

Arm/Group Title	ABA + MTX (Double-Blind)	ABA + MTX (Open-Label)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	256	459
Number [number of patients/100 patient-years]	0.81	0

19. Primary Outcome

Title	Number of Participants With a Serious Acute-Infusional AE of Anaphylactic Shock During Open-Label Period
Description	There were 107 Prespecified, acute-infusional SAEs (occurring within 1 hour after the start of study drug infusion) pre-specified in the protocol; anaphylactic shock was the only one occuring in this study.
Time Frame	Open-Label Period (Month 12 to Month 24)

Outcome Measure Data

Analysis Population Description

All participants treated during the Open-Label period.

Arm/Group Title	ABA + MTX (Open-label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
Number [Participants]	1 0.4%

20. Primary Outcome

Title	Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period
Description	Number of subjects with high liver function and kinedy tests: alkaline phosphatase (ALP) >2x upper limit of normal (ULN) or if pretreatment (PRE-RX) >ULN then >3x PRE-RX; aspartate aminotransferase (AST) >3x ULN or if PRE-RX >ULN then >4x PRE-RX; alanine aminotransferase (ALT) >3x ULN or if PRE-RX >ULN then >4x PRE-RX; g-glutamyl transferase (GGT)>2x ULN or if PRE-RX >ULN then >3x PRE-RX; total bilirubin >2x ULN or if PRE-RX >ULN then >4x PRE-RX; blood urea nitrogen >2x PRE-RX; creatinine >1.5x PRE-RX.
Time Frame	Continuously through open-label period (from Month 12 to Month 24). Includes data up to 56 days post last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All Treated participants in the Open-label Period; n=number of participants evaluated for this measure.

Arm/Group Title	ABA + MTX (Open-Label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
ALP (n=459)	2 0.8%
AST (n=459)	10 3.9%
ALT (n=459)	24 9.4%
GGT (n=459)	15 5.9%
Total Bilirubin (n=459)	0 0%
Blood Urea Nitrogen (n=459)	13 5.1%
Creatinine (n=457)	81 31.6%

21. Primary Outcome

Title	Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period
Description	Marked abnormalities in hemoglobin >3 g/dL decrease from PRE-RX; hematocrit <0.75x PRE-RX; erythrocytes <0.75x PRE-RX; platelet count <0.67x lower limit of normal (LLN) or >1.5x ULN or if PRE-RX <LLN then <0.5x PRE-RX and <100,000/mm3; leukocytes <0.75x LLN or >1.25x ULN or if PRE-RX <LLN then <0.8x PRE-RX or >ULN if PRE-RX >ULN then >1.2x PRE-RX or <LLN; neutrophils if value <1.00 x10^3 c/uL; lymphocytes if value <.750 x10^3 c/uL or if value >7.50 x10^3 c/uL; monocytes if value >2000/MM3; basophils if value >400/mm3; eosinophils if value >.750 x10^3 c/uL
Time Frame	Continuously from start of open-label period up to 56 days post the last dose in the open-label period or start of the maintenance sub-study, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All participants treated during the open-label period; n= number of participants evaluated for this measure.

Arm/Group Title	ABA + MTX (Open-Label)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period).
Measure Participants	459
Low Hemoglobin (n=458)	9 3.5%
Low Hematocrit (n=458)	5 2%
Low Erythrocyte (n=458)	8 3.1%
Low Platelet Count (n=455)	1 0.4%
High Platelet Count (n=455)	1 0.4%
Low Leukocytes (n=458)	14 5.5%
High Leukocytes (n=458)	12 4.7%
Low Neutrophils + Bands (absolute) (n=459)	6 2.3%
Low Lymphocytes (absolute) (n=459)	39 15.2%
High Lymphocytes (absolute) (n=459)	1 0.4%
High Monocytes (absolute) (n=459)	0 0%
High Basophils (absolute) (n=459)	2 0.8%
High Eosinophils (absolute) (n=459)	19 7.4%

22. Secondary Outcome

Title	Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24
Description	Participants with no radiographic progression (defined as change in score <=0 or <=0.5), from baseline to Month 24. To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

All treated participants in the open-label period. Treatment groups represent treatment received in the double-blind period.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.	Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week was administered every 28 days from Month 12 to Month 24 (open-label period). The groups are determined by treatment status in the double blind period to observe efficacy differences.
Measure Participants	213	192
Change from Baseline <= 0 in Erosion Score	125 48.8%	92 36.4%
Change from Baseline <= 0.5 in Erosion Score	144 56.3%	114 45.1%
Change from Baseline <= 0 in JSN Score	175 68.4%	150 59.3%
Change from Baseline <= 0.5 in JSN Score	190 74.2%	166 65.6%
Change from Baseline <= 0 in Total Score	121 47.3%	84 33.2%
Change from Baseline <= 0.5 in Total Score	139 54.3%	107 42.3%

23. Secondary Outcome

Title	Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) at Month 24 in Participants Without Progression at Month 12
Description	Participants with no radiographic progression ((defined as change in score <=0 or <=0.5), sustained from Month 12 and Month 24. To assess joint damage progression, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.
Time Frame	Month 12, Month 24

Outcome Measure Data

Analysis Population Description

Number of Participants Analyzed=All treated participants in the open-label period. (Treatment groups represent treatment received in the double-blind period.) n=the number of subjects with observed data included in the analysis.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	232	227
Erosion Score Sustained <=0 (n=125; n=100)	116 45.3%	87 34.4%
Erosion Score Sustained <=0.5 (n=145; n=114)	135 52.7%	107 42.3%
JSN Score Sustained <=0 (n=180; n=165)	169 66%	150 59.3%
JSN Score Sustained <=0.5 (n=192; n=177)	185 72.3%	163 64.4%
Total Score sustained <=0 (n=123; n=97)	112 43.8%	81 32%
Total Score sustained <=0.5 (n=144; n=112)	131 51.2%	101 39.9%

24. Secondary Outcome

Title	Mean Difference Observed in Change From Baseline to Month 12 and Between Month 12 and Month 24 in Radiographic Scores (Total Score)
Description	Mean difference observed in change from baseline to Month 12 and between Month 12 and Month 24 in radiographic scores (Total Score). To assess joint damage, the Genant-modified Sharp scoring method was used to evaluate radiographs of hands/wrists and feet for erosions and JSN. The total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage.
Time Frame	Baseline, Month 12, Month 24

Outcome Measure Data

Analysis Population Description

Analysis includes all treated participants in the open-label period originally randomized to abatacept. Analysis includes all participants with observed assessments collected at Baseline (Day 1), Day 365 (Month 12), and Day 729 (Month 24)

Arm/Group Title	Year 1 Change	Year 2 Change
Arm/Group Description	Year 1 Change = Day 365 - Day 1	Year 2 Change = Day 729 (Month 24) - Day 365 (Month 12)
Measure Participants	207	207
Mean (Standard Error) [units on a scale]	0.66 (0.13)	0.18 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABA + MTX (Double-Blind), PLA + MTX (Double-Blind)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	signed rank test
	Comments

25. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period
Description	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	Includes data up to 56 days post the last dose in the double-blind period or start of the open-label period, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All treated participants in the Double-Blind period

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Deaths	2 0.8%	4 1.6%
SAEs	20 7.8%	20 7.9%
Related SAEs	5 2%	6 2.4%
Discontinued due to SAEs	3 1.2%	3 1.2%
AEs	217 84.8%	211 83.4%
Related AEs	98 38.3%	114 45.1%
Discontinued due to AEs	8 3.1%	11 4.3%

26. Secondary Outcome

Title	Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period
Description	Number of participants with laboratory values (hematology, liver and kidney functions, electrolytes, glucose tests, protein tests, metabolite tests, and urine chemistry tests) considered markedly abnormal according to prespecified protocol criteria
Time Frame	Includes data up to 56 days post the last dose in the double-blind period or start of the open-label period, whichever occurred first.

Outcome Measure Data

Analysis Population Description

All treated in the DB period. n=Number of participants evaluated for this measure.

Arm/Group Title	ABA + MTX (Double-Blind)	PLA + MTX (Double-Blind)
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.	Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
Measure Participants	256	253
Low Hemoglobin (n=254; n=251)	3 1.2%	3 1.2%
Low Hematocrit (n=254; n=250)	1 0.4%	2 0.8%
Low Erythrocytes (n=254; n=250)	1 0.4%	4 1.6%
Low Platelet Count (n=252; n=250)	0 0%	1 0.4%
High Platelet Count (n=252; n=250)	1 0.4%	3 1.2%
Low Leukocytes (n=254; n=251)	5 2%	11 4.3%
High Leukocytes (n=254; n=251)	5 2%	14 5.5%
Low Neutrophils + Bands (absolute) (n=254; n=252)	2 0.8%	5 2%
Low Lymphocytes (absolute) (n=254; n=252)	13 5.1%	29 11.5%
High Lymphocytes (absolute) (n=254; n=252)	0 0%	0 0%
High Monocytes (absolute) (n=254; n=252)	1 0.4%	1 0.4%
High Basophils (absolute) (n=254; n=252)	0 0%	0 0%
High Eosinophils (absolute) (n=254; n=252)	7 2.7%	13 5.1%
High Alkaline Phosphatase (n=254; n=253)	1 0.4%	0 0%
High Aspartate Aminotransferase (n=254; n=253)	7 2.7%	14 5.5%
High Alanine Aminotransferase (n=254; n=253)	15 5.9%	21 8.3%
G-Glutamyl Transferase (n=254; n=253)	11 4.3%	9 3.6%
High Bilirubin, Total (n=254; n=253)	0 0%	2 0.8%
High Blood Urea Nitrogen (n=254; n=253)	9 3.5%	10 4%
High Creatinine (n=254; n=251)	33 12.9%	32 12.6%
Low Sodium, Serum (n=254; n=253)	0 0%	1 0.4%
High Sodium, Serum (n=254; n=253)	2 0.8%	0 0%
Low Potassium, Serum (n=254; n=251)	6 2.3%	3 1.2%
High Potassium, Serum (n=254; n=251)	3 1.2%	2 0.8%
Low Chloride, Serum (n=254; n=253)	0 0%	0 0%
High Chloride, Serum (n=254; n=253)	1 0.4%	0 0%
Low Calcium, Total (n=254; n=253)	0 0%	0 0%
High Calcium, Total (n=254; n=253)	0 0%	0 0%
Low Phosphorus, Inorganic (n=254; n=251)	1 0.4%	2 0.8%
High Phosphorus, Inorganic (n=254; n=251)	3 1.2%	3 1.2%
Low Glucose, Serum (n=254; n=253)	22 8.6%	24 9.5%
High Glucose, Serum (n=254; n=253)	10 3.9%	13 5.1%
Low Protein, Total (n=254; n=253)	2 0.8%	0 0%
High Protein, Total (n=254; n=253)	0 0%	1 0.4%
Low Albumin (n=254; n=253)	2 0.8%	5 2%
High Protein, Urine (n=252; n=250)	6 2.3%	3 1.2%
High Glucose, Urine (n=252; n=250)	4 1.6%	6 2.4%
High Blood, Urine (n=252; n=250)	30 11.7%	22 8.7%
High Leukocyte Esterase (n=87; n=88)	13 5.1%	13 5.1%
High Red Blood Cells, Urine (n=92; n=103)	30 11.7%	25 9.9%
High White Blood Cells, Urine (n=94; n=105)	38 14.8%	42 16.6%
High Uric Acid (n=254; n=253)	1 0.4%	1 0.4%

Adverse Events

Arm/Group Title	Abatacept		Placebo
Arm/Group Description	ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Study drug administered on Days 1, 15, 29 and every 28 days thereafter up to Month 12.		Placebo (Dextrose 5% Water for Injection U.S.P. [D5W] or Normal Saline [NS] IV infusions in combination with oral MTX titrated to at least 15 mg per week not to exceed 20 mg per week. Administered on Days 1, 15, 29, and every 28 days thereafter up to Month 12.
All Cause Mortality
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/256 (7.8%)		20/253 (7.9%)
Cardiac disorders
PERICARDIAL EFFUSION	1/256 (0.4%)		0/253 (0%)
MYOCARDIAL INFARCTION	1/256 (0.4%)		1/253 (0.4%)
CARDIAC FAILURE CONGESTIVE	0/256 (0%)		1/253 (0.4%)
Gastrointestinal disorders
DIARRHOEA	1/256 (0.4%)		0/253 (0%)
ABDOMINAL PAIN	0/256 (0%)		1/253 (0.4%)
INGUINAL HERNIA	1/256 (0.4%)		0/253 (0%)
GASTROINTESTINAL HAEMORRHAGE	1/256 (0.4%)		0/253 (0%)
General disorders
SUDDEN DEATH	1/256 (0.4%)		0/253 (0%)
MULTI-ORGAN FAILURE	0/256 (0%)		1/253 (0.4%)
INFUSION RELATED REACTION	1/256 (0.4%)		0/253 (0%)
Hepatobiliary disorders
CHOLECYSTITIS	0/256 (0%)		1/253 (0.4%)
ACUTE HEPATIC FAILURE	0/256 (0%)		1/253 (0.4%)
Immune system disorders
ANAPHYLACTIC REACTION	0/256 (0%)		1/253 (0.4%)
Infections and infestations
PNEUMONIA	1/256 (0.4%)		3/253 (1.2%)
CELLULITIS	1/256 (0.4%)		0/253 (0%)
GASTROENTERITIS	1/256 (0.4%)		1/253 (0.4%)
BREAST CELLULITIS	0/256 (0%)		1/253 (0.4%)
STAPHYLOCOCCAL INFECTION	0/256 (0%)		1/253 (0.4%)
LUNG INFECTION PSEUDOMONAL	1/256 (0.4%)		0/253 (0%)
POSTOPERATIVE WOUND INFECTION	1/256 (0.4%)		0/253 (0%)
Injury, poisoning and procedural complications
FALL	1/256 (0.4%)		0/253 (0%)
TIBIA FRACTURE	1/256 (0.4%)		0/253 (0%)
ROAD TRAFFIC ACCIDENT	1/256 (0.4%)		0/253 (0%)
SPINAL COMPRESSION FRACTURE	1/256 (0.4%)		0/253 (0%)
Investigations
INTERNATIONAL NORMALISED RATIO INCREASED	1/256 (0.4%)		0/253 (0%)
Metabolism and nutrition disorders
DEHYDRATION	0/256 (0%)		1/253 (0.4%)
Musculoskeletal and connective tissue disorders
ARTHRITIS	0/256 (0%)		1/253 (0.4%)
OSTEOARTHRITIS	0/256 (0%)		1/253 (0.4%)
MUSCULOSKELETAL PAIN	0/256 (0%)		1/253 (0.4%)
RHEUMATOID ARTHRITIS	1/256 (0.4%)		1/253 (0.4%)
SPINAL OSTEOARTHRITIS	0/256 (0%)		1/253 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
LIPOMA	1/256 (0.4%)		0/253 (0%)
NEOPLASM SKIN	1/256 (0.4%)		0/253 (0%)
PANCREATIC CARCINOMA	1/256 (0.4%)		0/253 (0%)
Nervous system disorders
INTRACRANIAL PRESSURE INCREASED	0/256 (0%)		1/253 (0.4%)
Psychiatric disorders
DEPRESSION	2/256 (0.8%)		0/253 (0%)
Renal and urinary disorders
URETHRAL STENOSIS	0/256 (0%)		1/253 (0.4%)
Reproductive system and breast disorders
CERVICAL DYSPLASIA	0/256 (0%)		1/253 (0.4%)
Respiratory, thoracic and mediastinal disorders
PLEURISY	0/256 (0%)		1/253 (0.4%)
PLEURAL EFFUSION	1/256 (0.4%)		0/253 (0%)
PULMONARY EMBOLISM	0/256 (0%)		1/253 (0.4%)
RESPIRATORY FAILURE	0/256 (0%)		1/253 (0.4%)
INTERSTITIAL LUNG DISEASE	1/256 (0.4%)		0/253 (0%)
CRYPTOGENIC ORGANISING PNEUMONIA	1/256 (0.4%)		0/253 (0%)
Vascular disorders
HYPOTENSION	1/256 (0.4%)		0/253 (0%)
Other (Not Including Serious) Adverse Events
	Abatacept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	150/256 (58.6%)		155/253 (61.3%)
Gastrointestinal disorders
NAUSEA	26/256 (10.2%)		41/253 (16.2%)
DIARRHOEA	17/256 (6.6%)		24/253 (9.5%)
DYSPEPSIA	11/256 (4.3%)		14/253 (5.5%)
ABDOMINAL PAIN UPPER	9/256 (3.5%)		15/253 (5.9%)
Infections and infestations
INFLUENZA	19/256 (7.4%)		23/253 (9.1%)
BRONCHITIS	18/256 (7%)		12/253 (4.7%)
NASOPHARYNGITIS	21/256 (8.2%)		26/253 (10.3%)
URINARY TRACT INFECTION	17/256 (6.6%)		22/253 (8.7%)
UPPER RESPIRATORY TRACT INFECTION	26/256 (10.2%)		26/253 (10.3%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	16/256 (6.3%)		13/253 (5.1%)
Musculoskeletal and connective tissue disorders
BACK PAIN	13/256 (5.1%)		14/253 (5.5%)
Nervous system disorders
HEADACHE	30/256 (11.7%)		23/253 (9.1%)
DIZZINESS	19/256 (7.4%)		13/253 (5.1%)
Respiratory, thoracic and mediastinal disorders
COUGH	21/256 (8.2%)		16/253 (6.3%)
Vascular disorders
HYPERTENSION	17/256 (6.6%)		14/253 (5.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.