Abatacept and Infliximab in Combination With Methotrexate in Subjects With Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00095147
First received: November 1, 2004
Last updated: December 21, 2010
Last verified: December 2010
Results First Received: October 26, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Rheumatoid Arthritis
Interventions: Drug: Abatacept (ABA) + Methotrexate (MTX), double-blind (DB)
Drug: Infliximab (INF) + MTX, DB
Drug: Placebo (PLA) + MTX, DB
Drug: PLA + MTX switched to ABA+ MTX, DB
Drug: ABA, open-label (OL)

  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
748 participants enrolled in this study; 317 participants were not randomized or treated. 384 participants completed the double-blind period; 12 participants did not enter the open-label period.

Reporting Groups
  Description
Abatacept (ABA) + Methotrexate (MTX) [Double-blind (DB)] Abatacept was administered intravenously (IV) on Days 1, 15, 29 and every 28 days thereafter for a total of 14 doses. Administration was as follows: 500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1 gram for participants > 100 kg. All participants received a stable dose of MTX (minimum 15 mg weekly).
Infliximab (INF) + MTX [DB] Infliximab was given 3 mg/kg IV (approved labeled dose) on Days 1, 15, 43, 85 and every 56 days thereafter for a total of 8 doses. All participants received a stable dose of MTX (minimum 15 mg weekly)
Placebo (PLA) + MTX [DB] Normal saline was administered as placebo. All participants received a stable dose of MTX (minimum 15 mg weekly)
PLA Switched to ABA + MTX [DB] Normal saline was administered as placebo. All participants received a stable dose of MTX (minimum 15 mg weekly). After placebo treatment from Day 1-197, participants were reallocated to receive abatacept (weight based) plus a stable dose of MTX (minimum 15 mg weekly).
ABA + MTX [Open-label (OL)] All participants received ABA at a weight-tiered dose of 10 mg/kg plus a stable dose of MTX (minimum 15 mg weekly).

Participant Flow for 3 periods

Period 1:   Double-blind Period 1 (Days 1-197)
    Abatacept (ABA) + Methotrexate (MTX) [Double-blind (DB)]     Infliximab (INF) + MTX [DB]     Placebo (PLA) + MTX [DB]     PLA Switched to ABA + MTX [DB]     ABA + MTX [Open-label (OL)]  
STARTED     156     165     110     0     0  
COMPLETED     147     152     107     0     0  
NOT COMPLETED     9     13     3     0     0  
Death                 1                 0                 0                 0                 0  
Adverse Event                 2                 8                 1                 0                 0  
Lack of Efficacy                 2                 2                 1                 0                 0  
Lost to Follow-up                 2                 2                 0                 0                 0  
Withdrawal of consent                 1                 0                 1                 0                 0  
Pregnancy                 1                 1                 0                 0                 0  

Period 2:   Double-blind Period 2 (Days 198-365)
    Abatacept (ABA) + Methotrexate (MTX) [Double-blind (DB)]     Infliximab (INF) + MTX [DB]     Placebo (PLA) + MTX [DB]     PLA Switched to ABA + MTX [DB]     ABA + MTX [Open-label (OL)]  
STARTED     147     152     0     107     0  
COMPLETED     139     141     0     104     0  
NOT COMPLETED     8     11     0     3     0  
Death                 0                 1                 0                 1                 0  
Adverse Event                 2                 4                 0                 0                 0  
Lack of Efficacy                 2                 4                 0                 1                 0  
Withdrawal of consent                 3                 2                 0                 0                 0  
Participant relocation                 1                 0                 0                 1                 0  

Period 3:   Long-term Extension Period
    Abatacept (ABA) + Methotrexate (MTX) [Double-blind (DB)]     Infliximab (INF) + MTX [DB]     Placebo (PLA) + MTX [DB]     PLA Switched to ABA + MTX [DB]     ABA + MTX [Open-label (OL)]  
STARTED     0     0     0     0     372  
COMPLETED     0     0     0     0     327  
NOT COMPLETED     0     0     0     0     45  
Death                 0                 0                 0                 0                 3  
Adverse Event                 0                 0                 0                 0                 11  
Lack of Efficacy                 0                 0                 0                 0                 9  
Lost to Follow-up                 0                 0                 0                 0                 6  
Withdrawal of consent                 0                 0                 0                 0                 12  
Pregnancy                 0                 0                 0                 0                 1  
No longer meets study criteria                 0                 0                 0                 0                 1  
Participant chose to use Revellex                 0                 0                 0                 0                 1  
Leaving country                 0                 0                 0                 0                 1  



  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 [DB] Abatacept was administered intravenously (IV) on Days 1, 15, 29 and every 28 days thereafter for a total of 14 doses. Administration was as follows: 500 mg for participants < 60 kg, 750 mg for participants 60 to 100 kg and 1 gram for participants > 100 kg. All participants received a stable dose of MTX (minimum 15 mg weekly).
INF + MTX [DB] Infliximab was given 3 mg/kg IV (approved labeled dose) on Days 1, 15, 43, 85 and every 56 days thereafter for a total of 8 doses. All participants received a stable dose of MTX (minimum 15 mg weekly)
PLA + MTX [DB] Normal saline was administered as placebo. All participants received a stable dose of MTX (minimum 15 mg weekly)
Total Total of all reporting groups

Baseline Measures
    ABA + MTX [DB]     INF + MTX [DB]     PLA + MTX [DB]     Total  
Number of Participants  
[units: participants]
  156     165     110     431  
Age  
[units: years]
Mean ± Standard Deviation
  49.0  ± 12.5     49.1  ± 12.0     49.4  ± 11.5     49.1  ± 12.0  
Gender  
[units: participants]
       
Female     130     136     96     362  
Male     26     29     14     69  
Baseline Disease Activity Score (DAS) 28 (Erythrocyte Sedimentation Rate [ESR]) [1]
[units: units on a scale]
Mean ± Standard Deviation
  6.9  ± 1.0     6.8  ± 0.9     6.8  ± 1.0     6.8  ± 1.0  
[1] The DAS28 is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, ESR or C-reactive protein (CRP), and participant assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (> 5.1), low disease activity (< 3.2) and remission (< 2.6). A clinically significant response= decrease in DAS28 score of >1.2 from baseline.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   DB; Adjusted Mean Change From Baseline to Day 197 in Disease Activity Score (DAS) 28 Score (Erythrocyte Sedimentation Rate [ESR]) For ABA Versus PLA (Last Observation Carried Forward [LOCF] Analysis)   [ Time Frame: Baseline (Day 1), 6 months (Day 197) ]

2.  Primary:   OL; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, and AEs Leading to Discontinuation   [ Time Frame: From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months) ]

3.  Primary:   OL; Number of Participants With AEs of Special Interest   [ Time Frame: From beginning of OL (Day 366) through end of OL (range from 1.9 months to 42.3 months) ]

4.  Primary:   OL; Number of Participants With Select Hematologic Laboratory Abnormalities   [ Time Frame: From Day 366 through end of OL (range from 1.9 months to 42.3 months) ]

5.  Primary:   OL; Number of Participants With Select Blood Chemistry Laboratory Abnormalities   [ Time Frame: From Day 366 through end of OL (range from 1.9 months to 42.3 months) ]

6.  Primary:   OL; Mean Change From Baseline to Day 365 in Hemoglobin, Total Protein, and Albumin   [ Time Frame: Baseline (Day 1), Day 365 ]

7.  Primary:   OL; Mean Change From Baseline to Day 365 in Platelets   [ Time Frame: Baseline (Day 1), Day 365 ]

8.  Primary:   OL; Mean Change From Baseline to Day 365 in Hematocrit   [ Time Frame: Baseline (Day 1), Day 365 ]

9.  Primary:   OL; Mean Change From Baseline to Day 365 in White Blood Cells   [ Time Frame: Baseline (Day 1), Day 365 ]

10.  Primary:   OL; Mean Change From Baseline to Day 365 in Erythrocytes   [ Time Frame: Baseline (Day 1), Day 365 ]

11.  Primary:   OL; Mean Change From Baseline to Day 365 in Electrolytes   [ Time Frame: Baseline (Day 1), Day 365 ]

12.  Primary:   OL; Mean Change From Baseline to Day 365 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid   [ Time Frame: Baseline (Day 1), Day 365 ]

13.  Primary:   OL; Mean Change From Baseline to Day 365 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase   [ Time Frame: Baseline (Day 1), Day 365 ]

14.  Primary:   OL; Mean Change From Baseline to Day 729 in Hemoglobin, Total Protein, and Albumin   [ Time Frame: Baseline (Day 1), Day 729 ]

15.  Primary:   OL; Mean Change From Baseline to Day 729 in Platelets   [ Time Frame: Baseline (Day 1), Day 729 ]

16.  Primary:   OL; Mean Change From Baseline to Day 729 in Hematocrit   [ Time Frame: Baseline (Day 1), Day 729 ]

17.  Primary:   OL; Mean Change From Baseline to Day 729 in White Blood Cells   [ Time Frame: Baseline (Day 1), Day 729 ]

18.  Primary:   OL; Mean Change From Baseline to Day 729 in Erythrocytes   [ Time Frame: Baseline (Day 1), Day 729 ]

19.  Primary:   OL; Mean Change From Baseline to Day 729 in Electrolytes   [ Time Frame: Baseline (Day 1), Day 729 ]

20.  Primary:   OL; Mean Change From Baseline to Day 729 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid   [ Time Frame: Baseline (Day 1), Day 729 ]

21.  Primary:   OL; Mean Change From Baseline to Day 729 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase   [ Time Frame: Baseline (Day 1), Day 729 ]

22.  Primary:   OL; Mean Change From Baseline to Day 1121 in Hemoglobin, Total Protein, and Albumin   [ Time Frame: Baseline (Day 1), Day 1121 ]

23.  Primary:   OL; Mean Change From Baseline to Day 1121 in Platelets   [ Time Frame: Baseline (Day 1), Day 1121 ]

24.  Primary:   OL; Mean Change From Baseline to Day 1121 in Hematocrit   [ Time Frame: Baseline (Day 1), Day 1121 ]

25.  Primary:   OL; Mean Change From Baseline to Day 1121 in White Blood Cells   [ Time Frame: Baseline (Day 1), Day 1121 ]

26.  Primary:   OL; Mean Change From Baseline to Day 1121 in Erythrocytes   [ Time Frame: Baseline (Day 1), Day 1121 ]

27.  Primary:   OL; Mean Change From Baseline to Day 1121 in Electrolytes   [ Time Frame: Baseline (Day 1), Day 1121 ]

28.  Primary:   OL; Mean Change From Baseline to Day 1121 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid   [ Time Frame: Baseline (Day 1), Day 1121 ]

29.  Primary:   OL; Mean Change From Baseline to Day 1121 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase   [ Time Frame: Baseline (Day 1), Day 1121 ]

30.  Primary:   OL; Mean Change From Baseline to Day 1513 in Hemoglobin, Total Protein, and Albumin   [ Time Frame: Baseline (Day 1), Day 1513 ]

31.  Primary:   OL; Mean Change From Baseline to Day 1513 in Platelets   [ Time Frame: Baseline (Day 1), Day 1513 ]

32.  Primary:   OL; Mean Change From Baseline to Day 1513 in Hematocrit   [ Time Frame: Baseline (Day 1), Day 1513 ]

33.  Primary:   OL; Mean Change From Baseline to Day 1513 in White Blood Cells   [ Time Frame: Baseline (Day 1), Day 1513 ]

34.  Primary:   OL; Mean Change From Baseline to Day 1513 in Erythrocytes   [ Time Frame: Baseline (Day 1), Day 1513 ]

35.  Primary:   OL; Mean Change From Baseline to Day 1513 in Electrolytes   [ Time Frame: Baseline (Day 1), Day 1513 ]

36.  Primary:   OL; Mean Change From Baseline to Day 1513 in Bilirubin, Blood Urea Nitrogen, Creatinine, Calcium, Phosphorous, Serum Glucose, Fasting Serum Glucose, and Uric Acid   [ Time Frame: Baseline (Day 1), Day 1513 ]

37.  Primary:   OL; Mean Change From Baseline to Day 1513 in Alanine Aminotransferase, Aspartate Aminotransferase, G-Glutamyl Transferase, and Alkaline Phosphatase   [ Time Frame: Baseline (Day 1), Day 1513 ]

38.  Primary:   OL; Mean Systolic (SBP) and Diastolic (DBP) Blood Pressure During Open Label Period   [ Time Frame: Days 365, 729, 1121, and 1513 ]

39.  Primary:   OL; Mean Heart Rate (HR) During Open Label Period   [ Time Frame: Days 365, 729, 1121, and 1513 ]

40.  Primary:   OL; Mean Temperature (T) During Open Label Period   [ Time Frame: Days 365, 729, 1121, and 1513 ]

41.  Secondary:   DB; Adjusted Mean Change From Baseline to Day 197 in DAS 28 Score (ESR) For INF Versus PLA (LOCF Analysis)   [ Time Frame: Baseline (Day 1), 6 months (Day 197) ]

42.  Secondary:   DB; DAS 28 (ESR) Area Under The Curve (AUC) Over 12 Months For ABA Versus INF   [ Time Frame: From Day 1 through Day 365 (12 months) ]

43.  Secondary:   DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 197   [ Time Frame: DB Day 197 ]

44.  Secondary:   DB; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response at Day 365   [ Time Frame: DB Day 365 ]

45.  Secondary:   DB; Adjusted Mean Change From Baseline to Day 197 in HAQ-DI (LOCF Analysis)   [ Time Frame: Baseline (Day 1), 6 months (Day 197) ]

46.  Secondary:   DB; Adjusted Mean Change From Baseline to Day 365 in HAQ-DI (LOCF Analysis)   [ Time Frame: Baseline (Day 1), 12 months (Day 365) ]

47.  Secondary:   DB; Adjusted Mean Change From Baseline to Day 197 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)   [ Time Frame: Baseline (Day 1), 6 months (Day 197) ]

48.  Secondary:   DB; Adjusted Mean Change From Baseline to Day 365 in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS)   [ Time Frame: Baseline (Day 1), 12 months (Day 365) ]

49.  Secondary:   DB; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) at Day 365   [ Time Frame: DB Day 365 ]

50.  Secondary:   DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 197   [ Time Frame: DB Day 197 ]

51.  Secondary:   DB; Percentage of Participants With American College of Rheumatology (ACR) Responses at Day 365   [ Time Frame: DB Day 365 ]

52.  Secondary:   DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 197   [ Time Frame: From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study ]

53.  Secondary:   DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 197   [ Time Frame: From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study ]

54.  Secondary:   DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 1 Through Day 365   [ Time Frame: From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study ]

55.  Secondary:   DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, and AEs Leading to Discontinuation From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept   [ Time Frame: From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study ]

56.  Secondary:   DB; Number of Participants With AEs of Special Interest From Day 1 Through Day 365   [ Time Frame: From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study ]

57.  Secondary:   DB; Number of Participants With AEs of Special Interest From Day 198 Through Day 365 in Participants Receiving Placebo Switched to Abatacept   [ Time Frame: From Day 198 through Day 365, and up to 56 days after last dose if occurring on-study ]

58.  Secondary:   DB; Number of Participants With Significant Changes in Mean Systolic and Diastolic Blood Pressure During Days 1 Through 197 and Days 1 Through 365   [ Time Frame: From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study ]

59.  Secondary:   DB; Number of Participants With Significant Changes in Mean Heart Rate During Days 1 Through 197 and Days 1 Through 365   [ Time Frame: From Baseline (Day 1) through Day 197, or Day 1 through Day 365, and up to 56 days after last dose if occurring on-study ]

60.  Secondary:   DB; Number of Participants With Significant Changes in Mean Temperature During Days 1 Through 197 and Days 1 Through 365   [ Time Frame: From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study ]

61.  Secondary:   DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 197   [ Time Frame: From Baseline (Day 1) through Day 197, and up to 56 days after last dose if occurring on-study ]

62.  Secondary:   DB; Number of Participants With Select Hematologic and Blood Chemistry Laboratory Abnormalities on Days 1 Through 365   [ Time Frame: From Baseline (Day 1) through Day 365, and up to 56 days after last dose if occurring on-study ]

63.  Secondary:   DB; Number of Participants With Anti-Abatacept Antibodies From Day 1 Through Day 365 (Electrochemiluminescent [ECL] Immunoassay)   [ Time Frame: Day 1 through day 365 ]

64.  Secondary:   DB; Percentage of Participants With Antibodies Against Infliximab (Human Anti-chimeric Antibody [HACA]) From Day 1 Through Day 365   [ Time Frame: Day 1 through day 365 ]

65.  Secondary:   OL; Mean Change From Baseline Over Time in DAS 28 (ESR) Score   [ Time Frame: Baseline (Day 1), Day 365, Day 533, Day 729 ]

66.  Secondary:   OL; Percentage of Participants With DAS28 (ESR) Remission and Low Disease Activity (LDAS) Over Time   [ Time Frame: Baseline (Day 1), Day 365, Day 533, Day 729 ]

67.  Secondary:   OL; Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) Over Time   [ Time Frame: DB Days 365, 533, and 729 ]

68.  Secondary:   OL; Percentage of Participants With American College of Rheumatology (ACR) Responses Over Time   [ Time Frame: DB Day 197, Day 365, Day 533, Day 729 ]

69.  Secondary:   OL; Percentage of Participants Who Achieved Major Clinical Response   [ Time Frame: Defined from the date of achieving ACR 70 response to 6 months post response ]

70.  Secondary:   OL; Percentage of Participants With Clinically Meaningful Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Over Time   [ Time Frame: OL Days 197, 253, 281, 309, 337, 365, 449, 533, 617, and 729 ]

71.  Secondary:   OL; Adjusted Mean Change From Baseline to Day 729 in HAQ-DI   [ Time Frame: Day 1 (Baseline), Day 729 ]


  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: BMS 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: NCT00095147     History of Changes
Other Study ID Numbers: IM101-043
Study First Received: November 1, 2004
Results First Received: October 26, 2010
Last Updated: December 21, 2010
Health Authority: United States: Food and Drug Administration