Remission and Joint Damage Progression in Early Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00122382
• Other study ID #: IM101-023
• Status: Completed
• Phase: Phase 3
• First received: July 19, 2005
• Last updated: November 3, 2010
• Start date: July 2005
• Est. completion date: February 2009

Study information

• Verified date: November 2010
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1052
• Est. completion date: February 2009
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Abatacept
abatacept 10 mg/kg IV monthly, methotrexate weekly, for 24 months
• placebo
placebo IV, monthly, methotrexate weekly for 12 months followed by abatacept 10 mg/kg IV monthly, methotrexate weekly for 12 months
• methotrexate
Oral, titrated to at least 15 mg per week not to exceed 20 mg per week administered every 28 days from Month 12 to Month 24

Locations

Country	Name	City	State
Australia	Local Institution	Malvern	Victoria
Australia	Local Institution	Shenton Park	Western Australia
Belgium	Local Institution	Antwerpen
Belgium	Local Institution	Bruxelles
Belgium	Local Institution	Bruxelles
Belgium	Local Institution	Hasselt
Belgium	Local Institution	Leuven
Brazil	Local Institution	Curitiba	Parana
Brazil	Local Institution	Goiania	Goias
Brazil	Local Institution	Porto Alegre	Rio Grande Do Sul
Brazil	Local Institution	Rio De Janeiro - Rj	Rio De Janeiro
Brazil	Local Institution	Sao Paulo
Brazil	Local Institution	Sao Paulo
Canada	Local Institution	Kitchener	Ontario
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Quebec
Canada	Local Institution	Saskatoon	Saskatchewan
Canada	Local Institution	Sherbrooke	Quebec
Canada	Local Institution	St. John'S	Newfoundland and Labrador
Canada	Local Institution	Toronto	Ontario
Czech Republic	Local Institution	Prague 2
France	Local Institution	Dijon
France	Local Institution	Montpellier Cedex 5
France	Local Institution	Nice Cedex 03
France	Local Institution	Strasbourg Cedex
Germany	Local Institution	Berlin
Germany	Local Institution	Hamburg
Germany	Local Institution	Leipzig
Germany	Local Institution	Leipzig
Italy	Local Institution	Jesi(Ancona)
Italy	Local Institution	Milano
Korea, Republic of	Local Institution	Anyang
Korea, Republic of	Local Institution	Daegu
Korea, Republic of	Local Institution	Daejeon
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Mexico	Local Institution	Chihuahua
Mexico	Local Institution	Cuernavaca	Morelos
Mexico	Local Institution	D.f.	Distrito Federal
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Leon	Guanajuato
Mexico	Local Institution	Metepec	Estado De Mexico
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Morelia	Michioacan
Mexico	Local Institution	San Luis Potosi
Netherlands	Local Institution	Amsterdam
Netherlands	Local Institution	Leiden
Netherlands	Local Institution	Nijmegen
Poland	Local Institution	Poznan
Poland	Local Institution	Poznan
Poland	Local Institution	Warszawa
Puerto Rico	Local Institution	Ponce
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
South Africa	Local Institution	Berea	Kwa Zulu Natal
South Africa	Local Institution	Bloemfontein	Free State
South Africa	Local Institution	Muckleneuk	Gauteng
South Africa	Local Institution	Panorama	Western Cape
South Africa	Local Institution	Pretoria	Gauteng
Spain	Local Institution	A Coruna
Spain	Local Institution	Santander
Spain	Local Institution	Sevilla
United Kingdom	Local Institution	Glasgow	Lanarkshire
United Kingdom	Local Institution	Leeds	North Yorkshire
United Kingdom	Local Institution	Manchester	Greater Manchester
United Kingdom	Local Institution	Newcastle	Northumberland
United States	Arthritis Clinic Of Northern Virginia, P.C.	Arlington	Virginia
United States	Walter F Chase Md Pa	Austin	Texas
United States	Regional Rheumatology Associates	Binghamton	New York
United States	Low Country Research Center	Charleston	South Carolina
United States	Carolina Bone & Joint	Charlotte	North Carolina
United States	Arthritis Assoc And Osteo Ctr Of Col Sprgs	Colorado Springs	Colorado
United States	Osteoporosis And Clinical Trials Center	Cumberland	Maryland
United States	Altoona Center For Clinical Research	Duncansville	Pennsylvania
United States	Physicians East, Pa	Greenville	North Carolina
United States	Malamet & Klein, Md, Pa	Hagerstown	Maryland
United States	Talbert Medical Group	Huntington Beach	California
United States	Rheumatology Associates Of North Alabama	Huntsville	Alabama
United States	Diagnostic Rheumatology And Research	Indianapolis	Indiana
United States	Arthritis Center Of Nebraska	Lincoln	Nebraska
United States	Lion Research	Norman	Oklahoma
United States	Health Research Of Oklahoma	Oklahoma City	Oklahoma
United States	Lynn Health Sciences Institute	Oklahoma City	Oklahoma
United States	Carolina Pharmaceutical Research	Statesville	North Carolina
United States	New England Research Associates, Llc	Trumbull	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czech Republic,  France,  Germany,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Puerto Rico,  Russian Federation,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Month 12	No
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.	Baseline, Month 12	No
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.	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.	Yes
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.	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.	Yes
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	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.	Yes
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.	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).	Yes
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.	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).	Yes
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.	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).	Yes
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.	Open-Label Period (Month 12 to Month 24)	Yes
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.	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.	Yes
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	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.	Yes
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].	Month 12	No
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]).	Month 12	No
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.	Baseline, Month 12	No
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.	Month 12	No
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.	Baseline, Month 12	No
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	Baseline, Month 12	No
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).	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.	No
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).	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.	No
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.	Baseline, Month 24	No
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.	Baseline, Month 24	No
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.	Baseline, Month 24	No
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.	Month 12, Month 24	No
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.	Baseline, Month 12, Month 24	No
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.	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.	Yes
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	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.	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm