Remission and Joint Damage Progression in Early Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00122382
First received: July 19, 2005
Last updated: November 3, 2010
Last verified: November 2010
Results First Received: May 3, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Rheumatoid Arthritis
Interventions: Drug: Abatacept
Drug: placebo
Drug: methotrexate

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
Abatacept (ABA) + Methotrexate (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 (end of double blind period).
Placebo (PLA) + Methotrexate (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 (end of double blind period).
ABA + MTX (Open-Label) Participants who received ABA + MTX in the 12-month, open-label period of the study (including 232 subjects who previously received ABA + MTX and 227 subjects who previously received PLA + MTX in the 12-month, double-blind period of the study). ABA 10 mg/kg (weight-tiered dose) intravenous (IV) infusions in combination with weekly oral MTX were administered every 28 days from Month 12 to Month 24 (open-label period).

Participant Flow for 2 periods

Period 1:   Double-Blind Study
    Abatacept (ABA) + Methotrexate (MTX) (Double-Blind)     Placebo (PLA) + Methotrexate (MTX) (Double-Blind)     ABA + MTX (Open-Label)  
STARTED     256 [1]   255 [1]   0  
Treated     256     253     0  
COMPLETED     232     227     0  
NOT COMPLETED     24     28     0  
Adverse Event                 9                 11                 0  
Death                 2                 2                 0  
Lack of Efficacy                 0                 8                 0  
Lost to Follow-up                 2                 1                 0  
Pregnancy                 2                 0                 0  
Subject No Longer Meets Study Criteria                 1                 0                 0  
Withdrawal of Consent                 7                 3                 0  
Protocol Violation                 1                 0                 0  
Methotrexate Discontinued                 0                 1                 0  
Randomized but not treated                 0                 2                 0  
[1] participants randomized

Period 2:   Open-Label Study
    Abatacept (ABA) + Methotrexate (MTX) (Double-Blind)     Placebo (PLA) + Methotrexate (MTX) (Double-Blind)     ABA + MTX (Open-Label)  
STARTED     0     0     459  
COMPLETED     0     0     433  
NOT COMPLETED     0     0     26  
Adverse Event                 0                 0                 11  
Death                 0                 0                 2  
Lack of Efficacy                 0                 0                 3  
Lost to Follow-up                 0                 0                 3  
Pregnancy                 0                 0                 2  
Poor/Non-Compliance                 0                 0                 1  
Withdrawal of Consent                 0                 0                 4  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.
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.
Total Total of all reporting groups

Baseline Measures
    ABA + MTX (Double-Blind)     PLA + MTX (Double-Blind)     Total  
Number of Participants  
[units: participants]
  256     253     509  
Age  
[units: years]
Mean ± Standard Deviation
  50.1  ± 12.4     49.7  ± 13.0     49.9  ± 12.7  
Gender  
[units: participants]
     
Female     196     199     395  
Male     60     54     114  
Anti-Cyclic Citrullinated Peptide 2 (CCP2) Status [1]
[units: participants]
     
unknown     2     0     2  
positive     236     217     453  
negative     18     36     54  
Duration of Rheumatoid Arthritis (RA) Disease  
[units: participants]
     
</= 6 months     167     157     324  
> 6 months - 12 months     36     34     70  
> 12 months     53     62     115  
Rheumatoid Factor (RF) Status [2]
[units: participants]
     
unknown     1     1     2  
positive     246     245     491  
negative     9     7     16  
Disease Activity Scale 28 (DAS 28) C-reactive Protein (CRP) [3]
[units: units on a scale]
Mean ± Standard Deviation
  6.3  ± 1.0     6.2  ± 1.0     6.3  ± 1.0  
Duration of RA  
[units: months]
Mean ± Standard Deviation
  6.2  ± 7.5     6.7  ± 7.1     6.5  ± 7.3  
Erosion Score [4]
[units: units on a scale]
Mean ± Standard Deviation
  5.4  ± 6.1     4.8  ± 5.4     5.1  ± 5.8  
Health Assessment Questionnaire - Disability Index (HAQ-DI) [5]
[units: units on a scale]
Mean ± Standard Deviation
  1.7  ± 0.7     1.7  ± 0.7     1.7  ± 0.7  
Joint Space Narrowing (JSN) Score [6]
[units: units on a scale]
Mean ± Standard Deviation
  2.1  ± 4.2     1.9  ± 4.0     2.0  ± 4.1  
Physician Global Assessment per Visual Analogue Scale (VAS) [7]
[units: mm]
Mean ± Standard Deviation
  67.1  ± 18.2     65.7  ± 18.9     66.4  ± 18.5  
Subject Global Assessment per VAS [8]
[units: mm]
Mean ± Standard Deviation
  65.8  ± 21.8     63.7  ± 24.0     64.8  ± 22.9  
Subject Pain Assessment per VAS [9]
[units: mm]
Mean ± Standard Deviation
  66.6  ± 22.5     67.1  ± 22.6     66.8  ± 22.5  
Swollen Joints [10]
[units: number of swollen joints]
Mean ± Standard Deviation
  22.9  ± 11.3     21.9  ± 10.1     22.4  ± 10.8  
Tender Joints [11]
[units: number of tender joints]
Mean ± Standard Deviation
  31.3  ± 14.8     30.8  ± 14.0     31.0  ± 14.4  
Total Genant-modified Sharp score [12]
[units: units on a scale]
Mean ± Standard Deviation
  7.5  ± 9.7     6.7  ± 8.8     7.1  ± 9.2  
[1] Anti-CCP2 antibodies are autoantibodies that react with citrullinated proteins, are frequent in Rheumatoid Arthritis and are associated with erosive disease. > 5 units/mL is a positive result.
[2] Rheumatoid Factor is an autoantibody that is usually present in the serum of people with rheumatoid arthritis. The cut-point value for seroconversion was 15 IU/mL (>/= 15 IU/mL resulted in a positive result).
[3] DAS 28-CRP=continuous composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28, CRP in milligrams/Liter (mg/L), and subject assessment of disease activity measured on a Visual Analogue Scale (VAS) of 100 millimeters (mm). Current disease activity is presented on a scale of 0 to 10, with a score above 5.1=high disease activity and below 3.2=low disease activity. VAS=a measurement instrument for characteristics that range across a continuum of values. Range is 1 to 100; a lower value signifies improvement. 1 participant in Placebo group was not evaluated.
[4] 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). Higher scores indicated more damage. 3 participants in the abatacept group were not included in the measure.
[5] HAQ-DI=self-reported measure of physical function calculated as a mean of 8 category scores: Dressing/Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, Activities. Each category score is calculated as the maximum of the scores for the questions within the category. HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute HAQ score. Changes to lower scores=improvement in physical function. 2 participants in the abatacept and placebo groups were not evaluated.
[6] 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 joint space narrowing score range is 0 (no radiographic damage) to 145 (worst possible radiographic damage). Higher scores indicated more damage. 3 participants in the abatacept group were not included in the measure.
[7] Physician Global Assessment is measured by VAS (100 mm). A Visual Analogue Scale (VAS) is a measurement instrument for characteristics that range across a continuum of values. Range is 1-100; a lower score indicates a better Physician Assessment of Global Health. 1 participant in the abatacept group was not evaluated for this measure.
[8] Subject Global Assessment is measured by VAS (100 mm). A Visual Analogue Scale (VAS) is a measurement instrument for characteristics that range across a continuum of values. Range is 1-100; a lower score indicates a better Subject Assessment of Global Health. 1 participant in the Placebo group was not evaluated for this measure.
[9] Subject Pain Assessment measured by VAS (100 mm). A Visual Analogue Scale (VAS) is a measurement instrument for characteristics that range across a continuum of values. Range is 1-100; a lower value signifies a better subject pain assessment. 1 participant in the Placebo group was not evaluated for this measure.
[10] Total number of joints analyzed=66
[11] Total number of joints analyzed=68
[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 total Genant-modified Sharp score ranges from 0 (no radiographic damage) to 290 (worst possible radiographic damage) and is the sum of the erosion score (range 0-145) and the joint space narrowing score (range 0-145). Higher scores indicated more damage. 3 participants in the abatacept group were not included in the measure.



  Outcome Measures
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1.  Primary:   Number of Participants in DAS 28 C-reactive Protein (CRP) Remission at Month 12   [ Time Frame: Month 12 ]

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

3.  Primary:   Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs During the Open-Label Period   [ 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. ]

4.  Primary:   Number of Participants With Serious Adverse Events Reported During the Open-Label Period   [ 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. ]

5.  Primary:   Number of Participants With SAEs With an Outcome of Death During the Open-label Period   [ 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. ]

6.  Primary:   Incidence Rates of Autoimmune Disorders in ABA-Treated Participants   [ 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). ]

7.  Primary:   Incidence Rates of Infections and Infestations of Adverse Events in ABA-Treated Participants   [ 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). ]

8.  Primary:   Incidence Rates of Malignant Neoplasm Adverse Events in ABA-Treated Participants   [ 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). ]

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

10.  Primary:   Number of Participants With Select Blood Chemistry Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period   [ 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. ]

11.  Primary:   Number of Participants With Hematology Laboratory Values Meeting the Marked Abnormality Criteria During the Open-Label Period   [ 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. ]

12.  Secondary:   Number of Participants With American College of Rheumatology (ACR) 50 Response at Month 12   [ Time Frame: Month 12 ]

13.  Secondary:   Number of Participants With Major Clinical Response (MCR) at Month 12   [ Time Frame: Month 12 ]

14.  Secondary:   Adjusted Mean Change From Baseline in DAS-28-CRP Score to Month 12   [ Time Frame: Baseline, Month 12 ]

15.  Secondary:   Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 12   [ Time Frame: Month 12 ]

16.  Secondary:   Adjusted Mean Change in Short Form 36 (SF-36) From Baseline to Month 12   [ Time Frame: Baseline, Month 12 ]

17.  Secondary:   Mean Change From Baseline in Radiographic Erosion and Joint Space Narrowing (JSN) Scores to Month 12   [ Time Frame: Baseline, Month 12 ]

18.  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)   [ 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. ]

19.  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   [ 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. ]

20.  Secondary:   Number of Participants With Health Assessment Questionnaire (HAQ) Response at Month 24   [ Time Frame: Baseline, Month 24 ]

21.  Secondary:   Mean Change From Baseline in Radiographic Total, Erosion and JSN Scores to Month 24   [ Time Frame: Baseline, Month 24 ]

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

23.  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   [ Time Frame: Month 12, Month 24 ]

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

25.  Secondary:   Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Reported During the Double-blind Period   [ 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. ]

26.  Secondary:   Number of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During the Double-blind Period   [ 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. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


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Publications automatically indexed to this study:

Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00122382     History of Changes
Other Study ID Numbers: IM101-023
Study First Received: July 19, 2005
Results First Received: May 3, 2010
Last Updated: November 3, 2010
Health Authority: United States: Food and Drug Administration