A Study to Assess the Effect of Tocilizumab + Methotrexate on Prevention of Structural Joint Damage in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00106535
First received: March 25, 2005
Last updated: December 18, 2013
Last verified: December 2013
Results First Received: February 9, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Rheumatoid Arthritis
Interventions: Drug: tocilizumab [RoActemra/Actemra]
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
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This study was divided into two phases: a 2-year core placebo controlled treatment phase and an optional 3-year extension phase.

Reporting Groups
  Description
Placebo + Methotrexate Placebo intravenously (IV) every 4 weeks plus methotrexate (MTX) 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with < 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a >70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Tocilizumab 4 mg/kg + Methotrexate Tocilizumab (TCZ) 4 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with < 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a >70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension (LTE) period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with < 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a >70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
All Tocilizumab Exposure + MTX All tocilizumab (TCZ) exposure + methotrexate (MTX) group included all participants who received at least one dose of tocilizumab during the placebo controlled core study or the long term extension period plus MTX 10-25 mg (oral or parenteral) weekly. Participants received either Placebo, Tocilizumab 4 mg/kg or Tocilizumab 8 mg/kg in the 2 year placebo controlled core treatment phase. In the extension 3 to 5 year period, all participants received 8 mg/kg IV every 4 weeks.

Participant Flow for 2 periods

Period 1:   2-year Placebo Controlled Period
    Placebo + Methotrexate     Tocilizumab 4 mg/kg + Methotrexate     Tocilizumab 8 mg/kg + Methotrexate     All Tocilizumab Exposure + MTX  
STARTED     394     401     401     0  
Intent-to-treat: Received Study Drug     393     399     398     0  
Safety: Actual Treatment Received     392     399     399     0  
Completed Week 24     356     373     366     0  
Completed Week 52     326     342     338     0  
COMPLETED     287 [1]   309 [2]   310 [3]   0  
NOT COMPLETED     107     92     91     0  
[1] Completed Week 104 (Year 2). 284 participants randomized to the Placebo arm entered the LTE period.
[2] Completed Week 104. 304 participants randomized to the TCZ 4 mg/kg arm entered the LTE period.
[3] Completed Week 104. 306 participants randomized to the TCZ 8 mg/kg arm entered the LTE period.

Period 2:   Long-term Extension Period (Year 3 to 5)
    Placebo + Methotrexate     Tocilizumab 4 mg/kg + Methotrexate     Tocilizumab 8 mg/kg + Methotrexate     All Tocilizumab Exposure + MTX  
STARTED     0     0     0     894 [1]
COMPLETED     0     0     0     704 [2]
NOT COMPLETED     0     0     0     190  
[1] Entered the Long-term Extension.
[2] Completed the study.



  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.
Baseline measures are based on the Intent-to-treat population that included all randomized participants who received study drug.

Reporting Groups
  Description
Placebo + Methotrexate Placebo intravenously (IV) every 4 weeks plus methotrexate (MTX) 10-25 mg (oral or parenteral) weekly.
Tocilizumab 4 mg/kg + Methotrexate Tocilizumab 4 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly.
Tocilizumab 8 mg/kg + Methotrexate Tocilizumab 8 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly.
Total Total of all reporting groups

Baseline Measures
    Placebo + Methotrexate     Tocilizumab 4 mg/kg + Methotrexate     Tocilizumab 8 mg/kg + Methotrexate     Total  
Number of Participants  
[units: participants]
  393     399     398     1190  
Age  
[units: years]
Mean ± Standard Deviation
  51.3  ± 12.41     51.4  ± 12.59     53.4  ± 11.72     52.0  ± 12.24  
Gender  
[units: participants]
       
Female     328     336     325     989  
Male     65     63     73     201  



  Outcome Measures
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1.  Primary:   Percentage of Participants With American College of Rheumatology-ACR20 Response   [ Time Frame: Baseline, Week 24 ]

2.  Primary:   Change From Baseline in Modified Total Sharp-Genant Score at Week 52   [ Time Frame: Baseline, Week 52 ]

3.  Primary:   Change in Physical Function as Measured by the Area Under the Curve (AUC) for the Change From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 52   [ Time Frame: Baseline to Week 52 ]

4.  Primary:   Change From Baseline in the Modified Total Sharp-Genant Score at Week 104   [ Time Frame: Baseline, Week 104 ]

5.  Primary:   Change in Physical Function as Measured by the Area Under the Curve for the Change From Baseline in the Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 104   [ Time Frame: Baseline to Week 104 ]

6.  Secondary:   Percentage of Participants With ACR50 Response   [ Time Frame: Baseline, Week 24 ]

7.  Secondary:   Percentage of Participants With ACR70 Response   [ Time Frame: Baseline,Week 24 ]

8.  Secondary:   Swollen Joint Count (66 Joint Count): Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

9.  Secondary:   Tender Joint Count (68 Joint Count): Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

10.  Secondary:   Patient's Global Visual Analog Scale (VAS): Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

11.  Secondary:   Physician's Global VAS: Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

12.  Secondary:   Patient's Pain VAS: Mean Change From Baseline at Week 24   [ Time Frame: Baseline and Week 24 ]

13.  Secondary:   C-Reactive Protein (CRP): Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

14.  Secondary:   Erythrocyte Sedimentation Rate: Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

15.  Secondary:   Health Assessment Questionnaire Disability Index (HAQ-DI): Mean Change From Baseline at Week 24   [ Time Frame: Baseline, Week 24 ]

16.  Secondary:   Percentage of Participants With American College of Rheumatology (ACR20) Response at Week 52   [ Time Frame: Baseline, Week 52 ]

17.  Secondary:   Percentage of Participants With ACR20 Response at Week 104   [ Time Frame: Baseline, Week 104 ]

18.  Secondary:   Percentage of Participants With ACR50 Response at Week 52   [ Time Frame: Baseline, Week 52 ]

19.  Secondary:   Percentage of Participants With ACR50 Response at Week 104   [ Time Frame: Baseline, Week 104 ]

20.  Secondary:   Percentage of Participants With ACR70 Response at Week 52   [ Time Frame: Baseline, Week 52 ]

21.  Secondary:   Percentage of Participants With ACR70 Response at Week 104   [ Time Frame: Baseline, Week 104 ]

22.  Secondary:   Percentage of Participants With ACR70 Response Maintained for 6 Consecutive Months   [ Time Frame: 104 Weeks ]

23.  Secondary:   Change From Baseline in Swollen Joint Count at Week 52   [ Time Frame: Baseline, Week 52 ]

24.  Secondary:   Change From Baseline in Tender Joint Count at Week 52   [ Time Frame: Baseline, Week 52 ]

25.  Secondary:   Change From Baseline in Patient's Global Assessment of Disease Activity at Week 52   [ Time Frame: Baseline, Week 52 ]

26.  Secondary:   Change From Baseline in Physicians Global Assessment of Disease Activity at Week 52   [ Time Frame: Baseline, Week 52 ]

27.  Secondary:   Change From Baseline in the Patient's Pain VAS at Week 52   [ Time Frame: Baseline, Week 52 ]

28.  Secondary:   Change From Baseline in C-Reactive Protein (CRP) at Week 52   [ Time Frame: Baseline, Week 52 ]

29.  Secondary:   Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 52   [ Time Frame: Baseline, Week 52 ]

30.  Secondary:   Change From Baseline in Swollen Joint Count at Week 104   [ Time Frame: Baseline, Week 104 ]

31.  Secondary:   Change From Baseline in Tender Joint Count at Week 104   [ Time Frame: Baseline, Week 104 ]

32.  Secondary:   Change From Baseline in Patient's Global Assessment of Disease Activity at Week 104   [ Time Frame: Baseline, Week 104 ]

33.  Secondary:   Change From Baseline in Physicians Global Assessment of Disease Activity at Week 104   [ Time Frame: Baseline, Week 104 ]

34.  Secondary:   Change From Baseline in the Patient's Pain VAS at Week 104   [ Time Frame: Baseline, Week 104 ]

35.  Secondary:   Change From Baseline in C-Reactive Protein (CRP) at Week 104   [ Time Frame: Baseline, Week 104 ]

36.  Secondary:   Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 104   [ Time Frame: Baseline, Week 104 ]

37.  Secondary:   Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 52   [ Time Frame: Baseline, Week 52 ]

38.  Secondary:   Percentage of Participants Who Achieve an Improvement of at Least 0.3 Units From Baseline in the HAQ Disability Index at Week 104   [ Time Frame: Baseline, Week 104 ]

39.  Secondary:   Area Under Curve (AUC) of the ACRn to Week 24   [ Time Frame: 24 Weeks ]

40.  Secondary:   Area Under Curve (AUC) of the ACRn to Week 52   [ Time Frame: 52 Weeks ]

41.  Secondary:   Area Under Curve (AUC) of the ACRn Score at Week 104   [ Time Frame: 104 Weeks ]

42.  Secondary:   Change From Baseline in Disease Activity Score (DAS28) at Week 24   [ Time Frame: Baseline, Week 24 ]

43.  Secondary:   Change From Baseline in Disease Activity Score (DAS28) at Week 52   [ Time Frame: Baseline, Week 52 ]

44.  Secondary:   Change From Baseline in Disease Activity Score (DAS28) at Week 104   [ Time Frame: Baseline, Week 104 ]

45.  Secondary:   Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 24   [ Time Frame: Baseline, Week 24 ]

46.  Secondary:   Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 52   [ Time Frame: Baseline, Week 52 ]

47.  Secondary:   Percentage of Participants With DAS28 Good or Moderate EULAR Response at Week 104   [ Time Frame: Baseline, Week 104 ]

48.  Secondary:   Percentage of Participants With DAS28 Remission at Week 24   [ Time Frame: Week 24 ]

49.  Secondary:   Percentage of Participants With DAS28 Remission at Week 52   [ Time Frame: Week 52 ]

50.  Secondary:   Percentage of Participants With DAS28 Remission at Week 104   [ Time Frame: Week 104 ]

51.  Secondary:   Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 24   [ Time Frame: 24 Weeks ]

52.  Secondary:   Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 52   [ Time Frame: 52 Weeks ]

53.  Secondary:   Area Under Curve (AUC) of Disease Activity Score (DAS28) at Week 104   [ Time Frame: 104 Weeks ]

54.  Secondary:   Change From Baseline in Modified Total Sharp-Genant Score at Week 24   [ Time Frame: Baseline, Week 24 ]

55.  Secondary:   Change From Baseline in Modified Total Sharp-Genant Score at Week 80   [ Time Frame: Baseline, Week 80 ]

56.  Secondary:   Change From Baseline in Erosion Score at Week 24   [ Time Frame: Baseline, Week 24 ]

57.  Secondary:   Change From Baseline in Erosion Score at Week 52   [ Time Frame: Baseline, Week 52 ]

58.  Secondary:   Change From Baseline in Erosion Score at Week 80   [ Time Frame: Baseline, Week 80 ]

59.  Secondary:   Change From Baseline in Erosion Score at Week 104   [ Time Frame: Baseline, Week 104 ]

60.  Secondary:   Change From Baseline in Joint Space Narrowing Score at Week 24   [ Time Frame: Baseline, Week 24 ]

61.  Secondary:   Change From Baseline in Joint Space Narrowing Score at Week 52   [ Time Frame: Baseline, Week 52 ]

62.  Secondary:   Change From Baseline in Joint Space Narrowing Score at Week 80   [ Time Frame: Baseline, Week 80 ]

63.  Secondary:   Change From Baseline in Joint Space Narrowing Score at Week 104   [ Time Frame: Baseline, Week 104 ]

64.  Secondary:   Percentage of Participants With no Progression of Erosion at Week 24   [ Time Frame: Baseline, Week 24 ]

65.  Secondary:   Percentage of Participants With no Progression of Erosion at Week 52   [ Time Frame: Baseline, Week 52 ]

66.  Secondary:   Percentage of Participants With no Progression of Erosion at Week 104   [ Time Frame: Baseline, Week 104 ]

67.  Secondary:   Percentage of Participants With no Progression of Joint Space Narrowing at Week 24   [ Time Frame: Baseline, Week 24 ]

68.  Secondary:   Percentage of Participants With no Progression of Joint Space Narrowing at Week 52   [ Time Frame: Baseline, Week 52 ]

69.  Secondary:   Percentage of Participants With no Progression of Joint Space Narrowing at Week 104   [ Time Frame: Baseline, Week 104 ]

70.  Secondary:   Change From Baseline in HAQ Disability Index (HAQ-DI) at Week 52   [ Time Frame: Baseline, Week 52 ]

71.  Secondary:   Change From Baseline in HAQ Disability Index at Week 104   [ Time Frame: Baseline, Week 104 ]

72.  Secondary:   Change From Baseline in Quality Life Short Form-36 (SF-36) Score at Week 24   [ Time Frame: Baseline, Week 24 ]

73.  Secondary:   Change From Baseline in SF-36 Score at Week 52   [ Time Frame: Baseline, Week 52 ]

74.  Secondary:   Change From Baseline in SF-36 Score at Week 104   [ Time Frame: Baseline, Week 104 ]

75.  Secondary:   Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score at Week 24   [ Time Frame: Baseline, Week 24 ]

76.  Secondary:   Change From Baseline in FACIT-F Score at Week 52   [ Time Frame: Baseline, Week 52 ]

77.  Secondary:   Change From Baseline in FACIT-F Score at Week 104   [ Time Frame: Baseline, Week 104 ]

78.  Secondary:   Change From Baseline in Rheumatoid Factor (RF) at Week 24 in Those Patients With Positive RF   [ Time Frame: Baseline, Week 24 ]

79.  Secondary:   Change From Baseline in Rheumatoid Factor (RF) at Week 52 in Those Patients With Positive RF   [ Time Frame: Baseline, Week 52 ]

80.  Secondary:   Change From Baseline in Rheumatoid Factor (RF) at Week 104 in Those Patients With Positive RF   [ Time Frame: Baseline, Week 104 ]

81.  Secondary:   Time to Onset of ACR20 by Treatment Group   [ Time Frame: 6 months ]

82.  Secondary:   Time to Onset of ACR50 by Treatment Group   [ Time Frame: 6 months ]

83.  Secondary:   Time to Onset of ACR70 by Treatment Group   [ Time Frame: 6 months ]

84.  Secondary:   Percentage of Participants Who Withdraw Due to Lack of Sufficient Therapeutic Response   [ Time Frame: 104 Weeks ]

85.  Secondary:   Percentage of Participants in Each Treatment Group Who Receive Escape Therapy   [ Time Frame: 104 Weeks ]

86.  Secondary:   Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 24   [ Time Frame: 24 Weeks ]

87.  Secondary:   Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 52   [ Time Frame: 52 Weeks ]

88.  Secondary:   Percentage of Participants Who Achieved Remission According to the ACR Remission Criteria by Week 104   [ Time Frame: 104 Weeks ]

89.  Secondary:   Percentage of Participants Who Achieved Complete Clinical Response at Week 52   [ Time Frame: 52 Weeks ]

90.  Secondary:   Percentage of Participants Who Achieved Complete Clinical Response at Week 104   [ Time Frame: 104 Weeks ]

91.  Secondary:   End of Study: Percentage of Participants With ACR Response at Week 260   [ Time Frame: Baseline, Week 260 ]

92.  Secondary:   End of Study: Percentage of Participants With DAS28 Remission at Week 260   [ Time Frame: Week 260 ]

93.  Secondary:   End of Study: Percentage of Participants With DAS28 Low Disease Activity (LDA) at Week 260   [ Time Frame: Week 260 ]

94.  Secondary:   End of Study: Percentage of Participants With DAS28 European League Against Rheumatism (EULAR) Good or Moderate Response at Week 260   [ Time Frame: Baseline, Week 260 ]

95.  Secondary:   End of Study: Change From Baseline in Swollen Joint Count at Week 260   [ Time Frame: Baseline, Week 260 ]

96.  Secondary:   End of Study: Change From Baseline in Tender Joint Count at Week 260   [ Time Frame: Baseline, Week 260 ]

97.  Secondary:   End of Study: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 260   [ Time Frame: Baseline, Week 260 ]

98.  Secondary:   End of Study: Change From Baseline in the Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) at Week 260   [ Time Frame: Baseline, Week 260 ]

99.  Secondary:   End of Study: Change From Baseline in the Physician's Global Assessment of Disease Activity VAS at Week 260   [ Time Frame: Baseline, Week 260 ]

100.  Secondary:   End of Study: Change From Baseline in the Patient's Pain VAS at Week 260   [ Time Frame: Baseline, Week 260 ]

101.  Secondary:   End of Study: Percentage of Participants With Clinical Improvement in the FACIT-Fatigue Score at Week 260   [ Time Frame: Baseline, Week 260 ]

102.  Secondary:   End of Study: Percentage of Participants With Clinical Relevant Improvement in the SF-36 Score at Week 260   [ Time Frame: Baseline, Week 260 ]

103.  Secondary:   End of Study: Change From Baseline in Total Sharp-Genant Score at Week 260   [ Time Frame: Baseline, Week 260 ]

104.  Secondary:   End of Study: Change From Baseline in Erosion Score at Week 260   [ Time Frame: Baseline, Week 260 ]

105.  Secondary:   End of Study: Change From Baseline in Joint Space Narrowing Score at Week 260   [ Time Frame: Baseline, Week 260 ]


  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: Medical Communications
Organization: Hoffmann-La Roche
phone: 800-821-8590


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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00106535     History of Changes
Other Study ID Numbers: WA17823
Study First Received: March 25, 2005
Results First Received: February 9, 2010
Last Updated: December 18, 2013
Health Authority: United States: Food and Drug Administration