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A Study of Tocilizumab in Combination With Disease-Modifying Anti-Rheumatic Drugs (DMARDs) in Participants With Moderate to Severe Active Rheumatoid Arthritis With an Inadequate Response to DMARDs

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00996606
First received: October 15, 2009
Last updated: September 20, 2016
Last verified: September 2016
Results First Received: September 20, 2016  
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Rheumatoid Arthritis
Interventions: Drug: DMARDs
Drug: Tocilizumab

  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
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Reporting Groups
  Description
Tocilizumab in Active Rheumatoid Arthritis (RA) Participants with active RA received tocilizumab as 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks. A total of 12 infusions were given from Baseline to Week 44, and participants were assessed through Week 48.

Participant Flow:   Overall Study
    Tocilizumab in Active Rheumatoid Arthritis (RA)
STARTED   58 
COMPLETED   50 
NOT COMPLETED   8 
Adverse Event or Intercurrent Illness                2 
Insufficient Therapeutic Response                2 
Protocol Violation                1 
Withdrawal by Subject                3 



  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.
Intent-to-Treat (ITT) Population: All participants who received at least one dose of study medication.

Reporting Groups
  Description
Tocilizumab in Active RA Participants with active RA received tocilizumab as 8 mg/kg via IV infusion every 4 weeks. A total of 12 infusions were given from Baseline to Week 44, and participants were assessed through Week 48.

Baseline Measures
   Tocilizumab in Active RA 
Overall Participants Analyzed 
[Units: Participants]
 58 
Age 
[Units: Years]
Mean (Standard Deviation)
 51.5  (13.0) 
Gender 
[Units: Participants]
 
Female   45 
Male   13 


  Outcome Measures
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1.  Primary:   Change From Baseline to Week 4 in Synovitis of the Wrist According to Rheumatoid Arthritis Magnetic Resonance Imaging (RAMRIS) Score   [ Time Frame: Baseline and Week 4 ]

2.  Primary:   Change From Baseline to Week 4 in Synovitis of the Wrist According to Relative Enhancement (RE) Before and After Contrast Injection   [ Time Frame: Baseline and Week 4 ]

3.  Primary:   Change From Baseline to Week 4 in Synovitis of the Wrist According to Rate of Early Enhancement (REE) Per Second Before and After Contrast Injection   [ Time Frame: Baseline and Week 4 ]

4.  Secondary:   Change From Baseline to Weeks 2, 12, 24, and 48 in Synovitis of the Wrist According to RAMRIS Score   [ Time Frame: Baseline and Weeks 2, 12, 24, 48 ]

5.  Secondary:   Change From Baseline to Weeks 2, 12, 24, and 48 in Synovitis of the Wrist According to RE Before and After Contrast Injection   [ Time Frame: Baseline and Weeks 2, 12, 24, 48 ]

6.  Secondary:   Change From Baseline to Weeks 2, 12, 24, and 48 in Synovitis of the Wrist According to REE Per Second Before and After Contrast Injection   [ Time Frame: Baseline and Weeks 2, 12, 24, 48 ]

7.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Synovitis of the Wrist and Metacarpo-Phalangeal (MCP) Joints According to Modified RAMRIS Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

8.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Number of Bones With Erosion in the Wrist and MCP Joints   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

9.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Erosion of the Wrist and MCP Joints According to RAMRIS Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

10.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Number of Bones With Bone Marrow Edema in the Wrist and MCP Joints   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

11.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Bone Marrow Edema of the Wrist and MCP Joints According to RAMRIS Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

12.  Secondary:   Change From Baseline to Weeks 24 and 48 in Total Modified Sharp Score (TMSS), Erosion Score (ES), and Joint Space Narrowing Score (JSNS)   [ Time Frame: Baseline and Weeks 24, 48 ]

13.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Ritchie Articular Index Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

14.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Perceived Pain According to Visual Analog Scale (VAS) Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

15.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Perceived General Health According to VAS Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

16.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Health Assessment Questionnaire Disability Index (HAQ-DI) Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

17.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Disease Activity Score of 28 Joints (DAS28) Score   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

18.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Vascular Endothelial Growth Factor (VEGF) Concentration   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

19.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Erythrocyte Sedimentation Rate (ESR)   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

20.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in High-Sensitivity C-Reactive Protein (hsCRP) Concentration   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

21.  Secondary:   Change From Baseline to Weeks 2 and 4 in Soluble Interleukin-6 Receptor (sIL6R) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

22.  Secondary:   Change From Baseline to Weeks 2 and 4 in Messenger Ribonucleic Acid (mRNA) for Interleukin (IL)-17 (2^Delta Cycle Threshold [ΔCt]) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

23.  Secondary:   Change From Baseline to Weeks 2 and 4 in mRNA for IL-23 Receptor (2^ΔCt) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

24.  Secondary:   Change From Baseline to Weeks 2 and 4 in mRNA for RAR-Related Orphan Receptor (ROR)-γT (2^ΔCt) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

25.  Secondary:   Change From Baseline to Weeks 2 and 4 in mRNA for Forkhead Box Protein (FOXP) 3 (2^ΔCt) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

26.  Secondary:   Change From Baseline to Weeks 2 and 4 in Cluster of Differentiation (CD) 4-Positive Cells as a Percentage of Peripheral Blood Mononuclear Cells (PBMCs)   [ Time Frame: Baseline and Weeks 2, 4 ]

27.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD4 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

28.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD25-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

29.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD25 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

30.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD45 "RO" Isoform (RO)-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

31.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD45RO Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

32.  Secondary:   Change From Baseline to Weeks 2 and 4 in Cysteine-Cysteine Chemokine Receptor (CCR) 6-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

33.  Secondary:   Change From Baseline to Weeks 2 and 4 in CCR6 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

34.  Secondary:   Change From Baseline to Weeks 2 and 4 in CCR4-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

35.  Secondary:   Change From Baseline to Weeks 2 and 4 in CCR4 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

36.  Secondary:   Change From Baseline to Weeks 2 and 4 in IL-23 Receptor p19 Subunit (IL-23Rp19)-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

37.  Secondary:   Change From Baseline to Weeks 2 and 4 in IL-23Rp19 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

38.  Secondary:   Change From Baseline to Weeks 2 and 4 in Regulatory T (Treg) Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

39.  Secondary:   Change From Baseline to Weeks 2 and 4 in Treg Cells as a Percentage of T Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

40.  Secondary:   Change From Baseline to Weeks 2 and 4 in Treg Cell Level   [ Time Frame: Baseline and Weeks 2, 4 ]

41.  Secondary:   Change From Baseline to Weeks 2 and 4 in Helper T (Th) 17 Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

42.  Secondary:   Change From Baseline to Weeks 2 and 4 in Th17 Cells as a Percentage of T Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

43.  Secondary:   Change From Baseline to Weeks 2 and 4 in Th17 Cell Level   [ Time Frame: Baseline and Weeks 2, 4 ]

44.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD19-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

45.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD19 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

46.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD24-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

47.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD24 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

48.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD27-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

49.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD27 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

50.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD38-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

51.  Secondary:   Change From Baseline to Weeks 2 and 4 in CD38 Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

52.  Secondary:   Change From Baseline to Weeks 2 and 4 in Immunoglobulin (Ig) M-Positive Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

53.  Secondary:   Change From Baseline to Weeks 2 and 4 in IgM Mean Intensity of Fluorescence   [ Time Frame: Baseline and Weeks 2, 4 ]

54.  Secondary:   Change From Baseline to Weeks 2 and 4 in Mature B Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

55.  Secondary:   Change From Baseline to Weeks 2 and 4 in Mature B Cells as a Percentage of B Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

56.  Secondary:   Change From Baseline to Week 4 in Mature B Cell Level   [ Time Frame: Baseline and Week 4 ]

57.  Secondary:   Change From Baseline to Weeks 2 and 4 in Memory B Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

58.  Secondary:   Change From Baseline to Weeks 2 and 4 in Memory B Cells as a Percentage of B Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

59.  Secondary:   Change From Baseline to Week 4 in Memory B Cell Level   [ Time Frame: Baseline and Week 4 ]

60.  Secondary:   Change From Baseline to Weeks 2 and 4 in Transitional B Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

61.  Secondary:   Change From Baseline to Weeks 2 and 4 in Transitional B Cells as a Percentage of B Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

62.  Secondary:   Change From Baseline to Week 4 in Transitional B Cell Level   [ Time Frame: Baseline and Week 4 ]

63.  Secondary:   Change From Baseline to Weeks 2 and 4 in Plasma B Cells as a Percentage of PBMCs   [ Time Frame: Baseline and Weeks 2, 4 ]

64.  Secondary:   Change From Baseline to Weeks 2 and 4 in Plasma B Cells as a Percentage of B Cells   [ Time Frame: Baseline and Weeks 2, 4 ]

65.  Secondary:   Change From Baseline to Week 4 in Plasma B Cell Level   [ Time Frame: Baseline and Week 4 ]

66.  Secondary:   Change From Baseline to Weeks 2 and 4 in Th17 Cysteine-Cysteine Chemokine Ligand (CCL) 20 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

67.  Secondary:   Change From Baseline to Weeks 2 and 4 in Th17CCL17 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

68.  Secondary:   Change From Baseline to Weeks 2 and 4 in B Cell-Attracting Chemokine (BCA) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

69.  Secondary:   Change From Baseline to Weeks 2 and 4 in Stromal Cell-Derived Factor (SDF) 1 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

70.  Secondary:   Change From Baseline to Weeks 2 and 4 in B Cell-Activating Factor (BAFF) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

71.  Secondary:   Change From Baseline to Weeks 2 and 4 in A Proliferation-Inducing Ligand (APRIL) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

72.  Secondary:   Change From Baseline to Weeks 2 and 4 in Tumor Necrosis Factor (TNF)-α Level   [ Time Frame: Baseline and Weeks 2, 4 ]

73.  Secondary:   Change From Baseline to Weeks 2 and 4 in IL-1β Level   [ Time Frame: Baseline and Weeks 2, 4 ]

74.  Secondary:   Change From Baseline to Weeks 2 and 4 in IL-17 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

75.  Secondary:   Change From Baseline to Weeks 2 and 4 in Monocyte Chemoattractant Protein (MCaP)-1 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

76.  Secondary:   Change From Baseline to Weeks 2 and 4 in Osteocalcin Level   [ Time Frame: Baseline and Weeks 2, 4 ]

77.  Secondary:   Change From Baseline to Weeks 2 and 4 in Type I Collagen N-Propeptide Level   [ Time Frame: Baseline and Weeks 2, 4 ]

78.  Secondary:   Change From Baseline to Weeks 2 and 4 in C-Terminal Telopeptide (CTX)-1 Level   [ Time Frame: Baseline and Weeks 2, 4 ]

79.  Secondary:   Change From Baseline to Weeks 2 and 4 in Type I Collagen C-Terminal Telopeptide (ICTP) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

80.  Secondary:   Change From Baseline to Weeks 2 and 4 in Type II Collagen N-Propeptide (PIIANP) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

81.  Secondary:   Change From Baseline to Weeks 2 and 4 in Type II Collagen Helical Peptide (HELIX-II) Level   [ Time Frame: Baseline and Weeks 2, 4 ]

82.  Secondary:   Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Hemoglobin (Hb) Concentration   [ Time Frame: Baseline and Weeks 2, 4, 12, 24, 48 ]

83.  Secondary:   Change From Baseline to Day 2 and Weeks 2 and 4 in Soluble Transferrin Receptor (STR) Concentration   [ Time Frame: Baseline; Day 2; and Weeks 2, 4 ]

84.  Secondary:   Change From Baseline to Week 48 in Initial Rate of Enhancement (IRE) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

85.  Secondary:   Change From Baseline to Week 48 in Maximum Enhancement (ME) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

86.  Secondary:   Change From Baseline to Week 48 in Number of Enhancing Voxels (Ntotal) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

87.  Secondary:   Change From Baseline to Week 48 in Number of Persistent Enhancing Voxels (Npersistent) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

88.  Secondary:   Change From Baseline to Week 48 in Number of Plateau Enhancing Voxels (Nplateau) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

89.  Secondary:   Change From Baseline to Week 48 in Number of Washout Enhancing Voxels (Nwashout) by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

90.  Secondary:   Change From Baseline to Week 48 in Ntotal×IRE by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]

91.  Secondary:   Change From Baseline to Week 48 in Ntotal×ME by DYNAMIKA Software Analysis   [ Time Frame: Baseline and Week 48 ]


  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
e-mail: genentech@druginfo.com



Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00996606     History of Changes
Other Study ID Numbers: ML22413
2009-012185-32
Study First Received: October 15, 2009
Results First Received: September 20, 2016
Last Updated: September 20, 2016
Health Authority: Italy: Italian Medicines Agency