Rheumatoid Arthritis
Conditions
Keywords
abatacept, methotrexate, erosive RA
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.
Interventions
DRUGAbatacept
abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months
DRUGplacebo
placebo IV, monthly, methotrexate weekly for 12 months followed by abatacept 10 mg/kg IV monthly, methotrexate weekly for 12 months
DRUGmethotrexate
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
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 \[ie, CRP\]. |
| 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 |
| 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. |
| 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 \[ie, CRP\]). |
| 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. |
| 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. |
| 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. |
| 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 |
| 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). |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
Australia, Belgium, Brazil, Canada, Czechia, France, Germany, Italy, Mexico, Netherlands, Poland, Puerto Rico, Russia, South Africa, South Korea, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| ABA + MTX (Double-Blind) 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. | 256 |
| PLA + MTX (Double-Blind) 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. | 253 |
| Total | 509 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Study | Adverse Event | 9 | 11 | 0 |
| Double-Blind Study | Death | 2 | 2 | 0 |
| Double-Blind Study | Lack of Efficacy | 0 | 8 | 0 |
| Double-Blind Study | Lost to Follow-up | 2 | 1 | 0 |
| Double-Blind Study | Methotrexate Discontinued | 0 | 1 | 0 |
| Double-Blind Study | Pregnancy | 2 | 0 | 0 |
| Double-Blind Study | Protocol Violation | 1 | 0 | 0 |
| Double-Blind Study | Randomized but not treated | 0 | 2 | 0 |
| Double-Blind Study | Subject No Longer Meets Study Criteria | 1 | 0 | 0 |
| Double-Blind Study | Withdrawal of Consent | 7 | 3 | 0 |
| Open-Label Study | Adverse Event | 0 | 0 | 11 |
| Open-Label Study | Death | 0 | 0 | 2 |
| Open-Label Study | Lack of Efficacy | 0 | 0 | 3 |
| Open-Label Study | Lost to Follow-up | 0 | 0 | 3 |
| Open-Label Study | Poor/Non-Compliance | 0 | 0 | 1 |
| Open-Label Study | Pregnancy | 0 | 0 | 2 |
| Open-Label Study | Withdrawal of Consent | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | ABA + MTX (Double-Blind) | PLA + MTX (Double-Blind) | Total |
|---|---|---|---|
| Age Continuous | 50.1 years STANDARD_DEVIATION 12.4 | 49.7 years STANDARD_DEVIATION 13 | 49.9 years STANDARD_DEVIATION 12.7 |
| Anti-Cyclic Citrullinated Peptide 2 (CCP2) Status negative | 18 participants | 36 participants | 54 participants |
| Anti-Cyclic Citrullinated Peptide 2 (CCP2) Status positive | 236 participants | 217 participants | 453 participants |
| Anti-Cyclic Citrullinated Peptide 2 (CCP2) Status unknown | 2 participants | 0 participants | 2 participants |
| Disease Activity Scale 28 (DAS 28) C-reactive Protein (CRP) | 6.3 units on a scale STANDARD_DEVIATION 1 | 6.2 units on a scale STANDARD_DEVIATION 1 | 6.3 units on a scale STANDARD_DEVIATION 1 |
| Duration of RA | 6.2 months STANDARD_DEVIATION 7.5 | 6.7 months STANDARD_DEVIATION 7.1 | 6.5 months STANDARD_DEVIATION 7.3 |
| Duration of Rheumatoid Arthritis (RA) Disease > 12 months | 53 participants | 62 participants | 115 participants |
| Duration of Rheumatoid Arthritis (RA) Disease </= 6 months | 167 participants | 157 participants | 324 participants |
| Duration of Rheumatoid Arthritis (RA) Disease > 6 months - 12 months | 36 participants | 34 participants | 70 participants |
| Erosion Score | 5.4 units on a scale STANDARD_DEVIATION 6.1 | 4.8 units on a scale STANDARD_DEVIATION 5.4 | 5.1 units on a scale STANDARD_DEVIATION 5.8 |
| Health Assessment Questionnaire - Disability Index (HAQ-DI) | 1.7 units on a scale STANDARD_DEVIATION 0.7 | 1.7 units on a scale STANDARD_DEVIATION 0.7 | 1.7 units on a scale STANDARD_DEVIATION 0.7 |
| Joint Space Narrowing (JSN) Score | 2.1 units on a scale STANDARD_DEVIATION 4.2 | 1.9 units on a scale STANDARD_DEVIATION 4 | 2.0 units on a scale STANDARD_DEVIATION 4.1 |
| Physician Global Assessment per Visual Analogue Scale (VAS) | 67.1 mm STANDARD_DEVIATION 18.2 | 65.7 mm STANDARD_DEVIATION 18.9 | 66.4 mm STANDARD_DEVIATION 18.5 |
| Rheumatoid Factor (RF) Status negative | 9 participants | 7 participants | 16 participants |
| Rheumatoid Factor (RF) Status positive | 246 participants | 245 participants | 491 participants |
| Rheumatoid Factor (RF) Status unknown | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 196 Participants | 199 Participants | 395 Participants |
| Sex: Female, Male Male | 60 Participants | 54 Participants | 114 Participants |
| Subject Global Assessment per VAS | 65.8 mm STANDARD_DEVIATION 21.8 | 63.7 mm STANDARD_DEVIATION 24 | 64.8 mm STANDARD_DEVIATION 22.9 |
| Subject Pain Assessment per VAS | 66.6 mm STANDARD_DEVIATION 22.5 | 67.1 mm STANDARD_DEVIATION 22.6 | 66.8 mm STANDARD_DEVIATION 22.5 |
| Swollen Joints | 22.9 number of swollen joints STANDARD_DEVIATION 11.3 | 21.9 number of swollen joints STANDARD_DEVIATION 10.1 | 22.4 number of swollen joints STANDARD_DEVIATION 10.8 |
| Tender Joints | 31.3 number of tender joints STANDARD_DEVIATION 14.8 | 30.8 number of tender joints STANDARD_DEVIATION 14 | 31.0 number of tender joints STANDARD_DEVIATION 14.4 |
| Total Genant-modified Sharp score | 7.5 units on a scale STANDARD_DEVIATION 9.7 | 6.7 units on a scale STANDARD_DEVIATION 8.8 | 7.1 units on a scale STANDARD_DEVIATION 9.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 150 / 256 | 155 / 253 |
| serious Total, serious adverse events | 20 / 256 | 20 / 253 |
Outcome results
Primary
Incidence Rates of Autoimmune Disorders in ABA-Treated Participants
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).
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Incidence Rates of Autoimmune Disorders in ABA-Treated Participants | 2.47 Number of participants/100 patient-years |
| PLA + MTX (Double-Blind) | Incidence Rates of Autoimmune Disorders in ABA-Treated Participants | 1.30 Number of participants/100 patient-years |
Primary
Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants
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).
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants | 78.37 Number of patients/100 patient-years |
| PLA + MTX (Double-Blind) | Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants | 66.68 Number of patients/100 patient-years |
Primary
Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants
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).
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants | 0.81 number of patients/100 patient-years |
| PLA + MTX (Double-Blind) | Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants | 0 number of patients/100 patient-years |
Primary
Mean Change From Baseline in Radiographic Total Score to 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.
Time frame: Baseline, Month 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total Score to Month 12 | Baseline Mean | 7.50 units on a scale | Standard Deviation 9.52 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total Score to Month 12 | Mean Change from Baseline | 0.63 units on a scale | Standard Deviation 1.74 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total Score to Month 12 | Baseline Mean | 6.67 units on a scale | Standard Deviation 8.71 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total Score to Month 12 | Mean Change from Baseline | 1.06 units on a scale | Standard Deviation 2.45 |
p-value: <0.04non-parametric ANCOVA
Primary
Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at 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.
Time frame: Month 12
Population: Intent to treat = all randomized and treated subjects. Those with missing data post-discontinuation were considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at Month 12 | 106 participants |
| PLA + MTX (Double-Blind) | Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at Month 12 | 59 participants |
Comparison: Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving DAS28-CRP remission.p-value: <0.00195% CI: [9.6, 26.6]Chi-squared, Continuity-Corrected
Primary
Number of Participants With a Serious Acute-Infusional AE of Anaphylactic Shock During Open-Label Period
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)
Population: All participants treated during the Open-Label period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With a Serious Acute-Infusional AE of Anaphylactic Shock During Open-Label Period | 1 Participants |
Primary
Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period
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.
Population: All participants treated during the open-label period; n= number of participants evaluated for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Hematocrit (n=458) | 5 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Leukocytes (n=458) | 12 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Hemoglobin (n=458) | 9 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Erythrocyte (n=458) | 8 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Platelet Count (n=455) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Platelet Count (n=455) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Leukocytes (n=458) | 14 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Neutrophils + Bands (absolute) (n=459) | 6 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Low Lymphocytes (absolute) (n=459) | 39 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Lymphocytes (absolute) (n=459) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Monocytes (absolute) (n=459) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Basophils (absolute) (n=459) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | High Eosinophils (absolute) (n=459) | 19 participants |
Primary
Number of Participants With SAEs With an Outcome of Death During the Open-label Period
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.
Population: All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With SAEs With an Outcome of Death During the Open-label Period | Pneumonia | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With SAEs With an Outcome of Death During the Open-label Period | Pneumonia/septic shock | 1 participants |
Primary
Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period
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.
Population: All Treated participants in the Open-label Period; n=number of participants evaluated for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | ALP (n=459) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | AST (n=459) | 10 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | ALT (n=459) | 24 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | GGT (n=459) | 15 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Total Bilirubin (n=459) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Blood Urea Nitrogen (n=459) | 13 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period | Creatinine (n=457) | 81 participants |
Primary
Number of Participants With Serious Adverse Events Reported During the Open-Label Period
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.
Population: All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Any SAE | 29 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Infections and infestations | 8 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Gastrointestinal disorders | 4 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Nervous system disorders | 4 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Cardiac disorders | 3 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Hepatobiliary disorders | 3 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Eye disorders | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Musculoskeletal and connective tissue disorders | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Vascular disorders | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Immune System Disorders | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Injury, Poisoning, and Procedural Complications | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Investigations | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Metabolism and Nutrition Disorders | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Renal and Urinary Disorders | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Serious Adverse Events Reported During the Open-Label Period | Respiratory, Thoracic, and Mediastinal Disorders | 1 participants |
Primary
Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. 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.
Population: All subjects who received at least 1 dose of ABA in the open-label period were included in the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | Discontinuations due to SAEs | 4 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | AEs | 345 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | Related AEs | 128 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | SAEs | 29 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | Related SAEs | 10 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | Discontinuations due to AEs | 11 participants |
| ABA + MTX (Double-Blind) | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period | Deaths | 2 participants |
Secondary
Adjusted Mean Change From Baseline in DAS-28-CRP Score to 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.
Time frame: Baseline, Month 12
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Adjusted Mean Change From Baseline in DAS-28-CRP Score to Month 12 | -3.22 units in a scale | Standard Error 0.09 |
| PLA + MTX (Double-Blind) | Adjusted Mean Change From Baseline in DAS-28-CRP Score to Month 12 | -2.49 units in a scale | Standard Error 0.09 |
p-value: <0.00195% CI: [-0.98, -0.48]ANCOVA
Secondary
Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to 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.
Time frame: Baseline, Month 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ABA + MTX (Double-Blind) | Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12 | Physical Component Summary (PCS) Score | 11.68 units on a scale | Standard Error 0.62 |
| ABA + MTX (Double-Blind) | Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12 | Mental Component Summary (MCS) Score | 8.15 units on a scale | Standard Error 0.64 |
| PLA + MTX (Double-Blind) | Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12 | Physical Component Summary (PCS) Score | 9.18 units on a scale | Standard Error 0.63 |
| PLA + MTX (Double-Blind) | Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12 | Mental Component Summary (MCS) Score | 6.34 units on a scale | Standard Error 0.64 |
Comparison: PCS Adjusted Mean Change from Baseline to Month 12p-value: 0.00595% CI: [0.77, 4.23]ANCOVA
Comparison: MCS Adjusted Mean Change from Baseline to Month 12p-value: 0.04695% CI: [0.03, 3.6]ANCOVA
Secondary
Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to 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
Time frame: Baseline, Month 12
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Baseline Mean Erosion Score | 5.48 units on a scale | Standard Deviation 6.15 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Mean Change from Baseline in Erosion Score | 0.50 units on a scale | Standard Deviation 1.39 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Baseline Mean JSN Score | 2.03 units on a scale | Standard Deviation 3.99 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Mean Change from Baseline in JSN Score | 0.13 units on a scale | Standard Deviation 0.53 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Mean Change from Baseline in JSN Score | 0.17 units on a scale | Standard Deviation 0.54 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Baseline Mean Erosion Score | 4.81 units on a scale | Standard Deviation 5.46 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Baseline Mean JSN Score | 1.86 units on a scale | Standard Deviation 3.95 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12 | Mean Change from Baseline in Erosion Score | 0.89 units on a scale | Standard Deviation 2.24 |
Comparison: comparison of change in erosion scores between abatacept and placebop-value: 0.033Nonparametric ANCOVA
Comparison: comparison of change in JSN scores between abatacept and placebop-value: 0.353Nonparametric ANCOVA
Secondary
Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores 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. Change from baseline = Postbaseline - baseline value.
Time frame: Baseline, Month 24
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Erosion Score Mean Change from Baseline | 0.59 units on a scale | Standard Deviation 2.31 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | JSN Score Mean Change from Baseline | 0.25 units on a scale | Standard Deviation 1.03 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Total Score Baseline Mean | 7.73 units on a scale | Standard Deviation 9.5 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Erosion Score Baseline Mean | 5.91 units on a scale | Standard Deviation 6.48 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Total Score Mean Change from Baseline | 0.84 units on a scale | Standard Deviation 3.22 |
| ABA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | JSN Score Baseline Mean | 1.83 units on a scale | Standard Deviation 3.82 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Total Score Mean Change from Baseline | 1.75 units on a scale | Standard Deviation 3.59 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Erosion Score Baseline Mean | 5.49 units on a scale | Standard Deviation 5.85 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Erosion Score Mean Change from Baseline | 1.40 units on a scale | Standard Deviation 3.08 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | JSN Score Baseline Mean | 1.75 units on a scale | Standard Deviation 3.92 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | Total Score Baseline Mean | 7.24 units on a scale | Standard Deviation 8.89 |
| PLA + MTX (Double-Blind) | Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24 | JSN Score Mean Change from Baseline | 0.34 units on a scale | Standard Deviation 0.99 |
Secondary
Mean Difference Observed in Change From Baseline to Month 12 and Between Month 12 and Month 24 in Radiographic Scores (Total Score)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Mean Difference Observed in Change From Baseline to Month 12 and Between Month 12 and Month 24 in Radiographic Scores (Total Score) | 0.66 units on a scale | Standard Error 0.13 |
| PLA + MTX (Double-Blind) | Mean Difference Observed in Change From Baseline to Month 12 and Between Month 12 and Month 24 in Radiographic Scores (Total Score) | 0.18 units on a scale | Standard Error 0.13 |
p-value: <0.001signed rank test
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. 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.
Population: All treated participants in the Double-Blind period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | SAEs | 20 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | AEs | 217 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Related SAEs | 5 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Related AEs | 98 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Deaths | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Discontinued due to AEs | 8 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Discontinued due to SAEs | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Discontinued due to AEs | 11 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | SAEs | 20 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Related SAEs | 6 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Discontinued due to SAEs | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | AEs | 211 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Related AEs | 114 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period | Deaths | 4 participants |
Secondary
Number of Participants With American College of Rheumatology (ACR) 50 Response at 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 \[ie, CRP\].
Time frame: Month 12
Population: Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With American College of Rheumatology (ACR) 50 Response at Month 12 | 147 participants |
| PLA + MTX (Double-Blind) | Number of Participants With American College of Rheumatology (ACR) 50 Response at Month 12 | 107 participants |
Comparison: Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving an ACR 50 response.p-value: <0.00195% CI: [6, 24.2]Chi-squared, Continuity-Corrected
Secondary
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
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.
Population: Treated participants in the open-label period were evaluated for anti-abatacept or anti-CTLA4-T responses
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | 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 | 13 participants |
| PLA + MTX (Double-Blind) | 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 | 16 participants |
Secondary
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)
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.
Population: Treated participants in the double-blind period who were evaluated for anti-abatacept or anti-CTLA4-T responses
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | 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) | Anti-abatacept Responses | 3 Participants |
| ABA + MTX (Double-Blind) | 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) | Anti-CTLA4-T Responses | 1 Participants |
| PLA + MTX (Double-Blind) | 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) | Anti-abatacept Responses | 0 Participants |
| PLA + MTX (Double-Blind) | 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) | Anti-CTLA4-T Responses | 1 Participants |
Secondary
Number of Participants With Health Assessment Questionnaire (HAQ) Response at 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.
Time frame: Month 12
Population: Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 12 | 184 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 12 | 157 participants |
Comparison: Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving HAQ response.p-value: 0.02495% CI: [1.3, 18.4]Chi-squared, Continuity-Corrected
Secondary
Number of Participants With Health Assessment Questionnaire (HAQ) Response at 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.
Time frame: Baseline, Month 24
Population: All treated participants in the Open-label period. Treatment groups represent treatment received in the Double Blind Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 24 | 189 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 24 | 178 participants |
Secondary
Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period
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.
Population: All treated in the DB period. n=Number of participants evaluated for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Hemoglobin (n=254; n=251) | 3 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Creatinine (n=254; n=251) | 33 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Lymphocytes (absolute) (n=254; n=252) | 13 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Sodium, Serum (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Platelet Count (n=252; n=250) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Sodium, Serum (n=254; n=253) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Lymphocytes (absolute) (n=254; n=252) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Potassium, Serum (n=254; n=251) | 6 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Protein, Urine (n=252; n=250) | 6 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Potassium, Serum (n=254; n=251) | 3 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Monocytes (absolute) (n=254; n=252) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Chloride, Serum (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Platelet Count (n=252; n=250) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Chloride, Serum (n=254; n=253) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Basophils (absolute) (n=254; n=252) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Calcium, Total (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Hematocrit (n=254; n=250) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Calcium, Total (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Eosinophils (absolute) (n=254; n=252) | 7 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Phosphorus, Inorganic (n=254; n=251) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Leukocytes (n=254; n=251) | 5 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Phosphorus, Inorganic (n=254; n=251) | 3 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Alkaline Phosphatase (n=254; n=253) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Glucose, Serum (n=254; n=253) | 22 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Glucose, Serum (n=254; n=253) | 10 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Bilirubin, Total (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Protein, Total (n=254; n=253) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Aspartate Aminotransferase (n=254; n=253) | 7 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Protein, Total (n=254; n=253) | 0 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Leukocytes (n=254; n=251) | 5 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Albumin (n=254; n=253) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Alanine Aminotransferase (n=254; n=253) | 15 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Blood, Urine (n=252; n=250) | 30 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Erythrocytes (n=254; n=250) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Leukocyte Esterase (n=87; n=88) | 13 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | G-Glutamyl Transferase (n=254; n=253) | 11 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Red Blood Cells, Urine (n=92; n=103) | 30 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Neutrophils + Bands (absolute) (n=254; n=252) | 2 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High White Blood Cells, Urine (n=94; n=105) | 38 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Blood Urea Nitrogen (n=254; n=253) | 9 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Uric Acid (n=254; n=253) | 1 participants |
| ABA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Glucose, Urine (n=252; n=250) | 4 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Uric Acid (n=254; n=253) | 1 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Bilirubin, Total (n=254; n=253) | 2 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Glucose, Serum (n=254; n=253) | 24 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Albumin (n=254; n=253) | 5 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Protein, Urine (n=252; n=250) | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Hemoglobin (n=254; n=251) | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Hematocrit (n=254; n=250) | 2 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Erythrocytes (n=254; n=250) | 4 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Platelet Count (n=252; n=250) | 1 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Platelet Count (n=252; n=250) | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Leukocytes (n=254; n=251) | 11 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Leukocytes (n=254; n=251) | 14 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Neutrophils + Bands (absolute) (n=254; n=252) | 5 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Lymphocytes (absolute) (n=254; n=252) | 29 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Lymphocytes (absolute) (n=254; n=252) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Monocytes (absolute) (n=254; n=252) | 1 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Basophils (absolute) (n=254; n=252) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Eosinophils (absolute) (n=254; n=252) | 13 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Alkaline Phosphatase (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Aspartate Aminotransferase (n=254; n=253) | 14 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Alanine Aminotransferase (n=254; n=253) | 21 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | G-Glutamyl Transferase (n=254; n=253) | 9 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Blood Urea Nitrogen (n=254; n=253) | 10 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Creatinine (n=254; n=251) | 32 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Sodium, Serum (n=254; n=253) | 1 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Sodium, Serum (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Potassium, Serum (n=254; n=251) | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Potassium, Serum (n=254; n=251) | 2 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Chloride, Serum (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Chloride, Serum (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Calcium, Total (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Calcium, Total (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Phosphorus, Inorganic (n=254; n=251) | 2 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Phosphorus, Inorganic (n=254; n=251) | 3 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Glucose, Serum (n=254; n=253) | 13 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | Low Protein, Total (n=254; n=253) | 0 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Protein, Total (n=254; n=253) | 1 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Glucose, Urine (n=252; n=250) | 6 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Blood, Urine (n=252; n=250) | 22 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Leukocyte Esterase (n=87; n=88) | 13 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High Red Blood Cells, Urine (n=92; n=103) | 25 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period | High White Blood Cells, Urine (n=94; n=105) | 42 participants |
Secondary
Number of Participants With Major Clinical Response (MCR) at 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 \[ie, CRP\]).
Time frame: Month 12
Population: Intention-to-Treat=All randomized and treated; all missing data subsequent to discontinuation are considered non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants With Major Clinical Response (MCR) at Month 12 | 70 participants |
| PLA + MTX (Double-Blind) | Number of Participants With Major Clinical Response (MCR) at Month 12 | 30 participants |
Comparison: Estimated Difference between ABA and PLA is the estimated difference between ABA and PLA in the proportion of subjects achieving MCR.p-value: <0.00195% CI: [8.2, 22.8]Chi-squared, Continuity-Corrected
Secondary
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
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | 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 | Erosion Score Sustained <=0.5 (n=145; n=114) | 135 Participants |
| ABA + MTX (Double-Blind) | 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 | JSN Score Sustained <=0.5 (n=192; n=177) | 185 Participants |
| ABA + MTX (Double-Blind) | 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 | Total Score sustained <=0 (n=123; n=97) | 112 Participants |
| ABA + MTX (Double-Blind) | 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 | Erosion Score Sustained <=0 (n=125; n=100) | 116 Participants |
| ABA + MTX (Double-Blind) | 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 | Total Score sustained <=0.5 (n=144; n=112) | 131 Participants |
| ABA + MTX (Double-Blind) | 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 | JSN Score Sustained <=0 (n=180; n=165) | 169 Participants |
| PLA + MTX (Double-Blind) | 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 | Total Score sustained <=0.5 (n=144; n=112) | 101 Participants |
| PLA + MTX (Double-Blind) | 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 | JSN Score Sustained <=0.5 (n=192; n=177) | 163 Participants |
| PLA + MTX (Double-Blind) | 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 | Erosion Score Sustained <=0 (n=125; n=100) | 87 Participants |
| PLA + MTX (Double-Blind) | 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 | Erosion Score Sustained <=0.5 (n=145; n=114) | 107 Participants |
| PLA + MTX (Double-Blind) | 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 | JSN Score Sustained <=0 (n=180; n=165) | 150 Participants |
| PLA + MTX (Double-Blind) | 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 | Total Score sustained <=0 (n=123; n=97) | 81 Participants |
Secondary
Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at 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.
Time frame: Baseline, Month 24
Population: All treated participants in the open-label period. Treatment groups represent treatment received in the double-blind period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in JSN Score | 190 Participants |
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in Erosion Score | 144 Participants |
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in Total Score | 121 Participants |
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in Erosion Score | 125 Participants |
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in Total Score | 139 Participants |
| ABA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in JSN Score | 175 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in Total Score | 107 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in Erosion Score | 92 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in Erosion Score | 114 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in JSN Score | 150 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0.5 in JSN Score | 166 Participants |
| PLA + MTX (Double-Blind) | Number of Participants Without Radiographic Progression (as Measured by in Erosion Scores, JSN Scores, and Total Scores) From Baseline at Month 24 | Change from Baseline <= 0 in Total Score | 84 Participants |