Remission and Joint Damage Progression in Early Rheumatoid Arthritis

Study Overview
=================
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.

Official Title
-----------------
A Phase IIIB Multi-center, Randomized, Double-Blind Study to Evaluate Remission and Joint Damage Progression in Methotrexate Naive Early Erosive RA Subjects Treated With Abatacept Plus Methotrexate Compared With Methotrexate

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Abatacept
* Drug: placebo
* Drug: methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ABA + MTX<br>abatacept 10 mg/kg intravenous (IV) + methotrexate | Drug: Abatacept<br>* abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months<br>Drug: methotrexate<br>* 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<br>|
| Active Comparator: Placebo (PLA) + MTX<br>placebo IV + methotrexate | Drug: Abatacept<br>* abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months<br>Drug: placebo<br>* placebo IV, monthly, methotrexate weekly for 12 months followed by abatacept 10 mg/kg IV monthly, methotrexate weekly for 12 months<br>Drug: methotrexate<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 12 | 
| 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. | Baseline, Month 12 | 
| 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. | 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 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. | 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 Participants With SAEs With an Outcome of Death During the Open-label Period | Any untoward medical occurrence (SAE) that resulted in death | 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. | 
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 
| 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. | Open-Label Period (Month 12 to Month 24) | 
| 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. | 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 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 | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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]. | Month 12 | 
| 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]). | Month 12 | 
| 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. | Baseline, Month 12 | 
| 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. | Month 12 | 
| 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. | Baseline, Month 12 | 
| 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 | Baseline, Month 12 | 
| 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). | 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. | 
| 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). | 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. | 
| 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. | Baseline, Month 24 | 
| 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. | Baseline, Month 24 | 
| 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. | Baseline, Month 24 | 
| 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. | 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) | 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. | Baseline, Month 12, Month 24 | 
| 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. | 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 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 | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
abatacept, methotrexate, erosive RA