Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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
  Purpose
This open-label, single-arm study will evaluate the efficacy and safety of tocilizumab in combination with DMARDs in participants with moderate to severe active rheumatoid arthritis who have an inadequate response to DMARDs. Participants will receive tocilizumab as 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks in addition to their current DMARD therapy.

Condition Intervention Phase
Rheumatoid Arthritis
Drug: DMARDs
Drug: Tocilizumab
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open Label, Multicentric Phase IIIb Study to Evaluate the Effect of Tocilizumab in Combination With DMARDs in the Inhibition of Progression of Synovitis, Bone Marrow Edema, and Erosions Evaluated by Dedicated Magnetic Resonance Imaging (MRI) in the Hand of Patients With Rheumatoid Arthritis (RA)

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Synovitis of the wrist was assessed at three sites including the radioulnar joint (RUJ), the radiocarpal joint (RCJ), and the intercarpal-carpometacarpal joints (IC-CMCJ). Global RAMRIS scores were assigned on a scale of 0 to 3 at each site, where 0 represented normal appearance with no synovial enhancement and each 1-point increase reflected one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. The scores for all three sites were added to give an aggregated score of 0 to 9. Baseline absolute value (AV) and change from Baseline to Week 4 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    RE was calculated as [S0 minus (-) S55] divided by (÷) S0, multiplied by (×) 100 percent (%), where S0 was defined as the signal noise ratio before contrast injection, and S55 was defined as the signal noise ratio 55 seconds after injection. Signal noise ratios were measured as the ratio between the signal in the region of interest and the standard deviation of background noise. Baseline AV and change from Baseline to Week 4 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    REE per second was calculated as [S55 - S0] ÷ [S0 × 55 seconds] × 100%, where S0 was defined as the signal noise ratio before contrast injection, and S55 was defined as the signal noise ratio 55 seconds after injection. Signal noise ratios were measured as the ratio between the signal in the region of interest and the standard deviation of background noise. Baseline AV and change from Baseline to Week 4 were averaged among all participants, where negative changes indicated improvement in synovitis.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Synovitis of the wrist was assessed at three sites including the RUJ, the RCJ, and the IC-CMCJ. Global RAMRIS scores were assigned on a scale of 0 to 3 at each site, where 0 represented normal appearance with no synovial enhancement and each 1-point increase reflected one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. The scores for all three sites were added to give an aggregated score of 0 to 9. The changes from Baseline to Weeks 2, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    RE was calculated as [S0 - S55] ÷ S0 × 100%, where S0 was defined as the signal noise ratio before contrast injection, and S55 was defined as the signal noise ratio 55 seconds after injection. Signal noise ratios were measured as the ratio between the signal in the region of interest and the standard deviation of background noise. The changes from Baseline to Weeks 2, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    REE per second was calculated as [S55 - S0] ÷ [S0 × 55 seconds] × 100%, where S0 was defined as the signal noise ratio before contrast injection, and S55 was defined as the signal noise ratio 55 seconds after injection. Signal noise ratios were measured as the ratio between the signal in the region of interest and the standard deviation of background noise. The changes from Baseline to Weeks 2, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    Synovitis of the wrist was assessed at three sites including the RUJ, the RCJ, and the IC-CMCJ. Global RAMRIS scores were assigned on a scale of 0 to 3 at each site, where 0 represented normal appearance with no synovial enhancement and each 1-point increase reflected one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. The scores for all three sites were added to give an aggregated score of 0 to 9. Synovitis of MCP joints was determined on the basis of Short Inversion Time Inversion Recovery (STIR) sequence evaluation with modification of the RAMRIS score. Four MCP joint compartments were each assessed 0 to 3, so the aggregated MCP joint score ranged from 0 to 12. Combined synovitis in wrist and MCP joints was determined on the basis of STIR sequences to produce overall score from 0 to 21. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, 48 were averaged among all participants, where negative changes indicated improvement in synovitis.

  • 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 ] [ Designated as safety issue: No ]
    Erosion was evaluated at 15 sites in the wrist and 8 sites in the MCP joints. Bone erosion was scored on a scale of 0 to 10, where 0 represented no bone erosion and each 1-point increase reflected up to a 10% increase in extent of erosion. The number of bones with erosion was taken as the count of joints with a bone erosion score greater than or equal to (≥) 1. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in erosion.

  • 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 ] [ Designated as safety issue: No ]
    Erosion was evaluated at 15 sites in the wrist and 8 sites in the MCP joints. Bone erosion was scored on a scale of 0 to 10, where 0 represented no bone erosion and each 1-point increase reflected up to 10% increase in extent of erosion. Global RAMRIS scores were calculated as the sum of all joint sites for the wrist (range, 0 to 150) and MCP joints (range, 0 to 80). Aggregate wrist and MCP joint scores could range from 0 to 230 points. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in erosion.

  • 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 ] [ Designated as safety issue: No ]
    Edema was evaluated at 15 sites in the wrist and 8 sites in the MCP joints. Bone edema was scored on a scale of 0 to 3, where 0 represented no bone edema and each 1-point increase reflected one-third increase in extent of edema. The number of bones with edema was taken as the count of joints with a bone edema score greater than or equal to (≥) 1. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in edema.

  • 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 ] [ Designated as safety issue: No ]
    Edema was evaluated at 15 sites in the wrist and 8 sites in the MCP joints. Bone edema was scored on a scale of 0 to 3, where 0 represented no bone edema and each 1-point increase reflected one-third increase in extent of edema. Global RAMRIS scores were calculated as the sum of all joint sites for the wrist (range, 0 to 45) and MCP joints (range, 0 to 24). Aggregate wrist and MCP joint scores could range from 0 to 69 points. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in edema.

  • 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 ] [ Designated as safety issue: No ]
    The TMSS was calculated as the sum of ES and JSNS and ranged from 0 to 202. The ES was taken as the sum of joint scores collected for 14 joints in each hand (individually scored from 0 to 7) and ranged from 0 to 98 for both hands. The JSNS was the sum of joint scores collected for 13 joints in each hand (individually scored from 0 to 8) and ranged from 0 to 104 for both hands. Scores of 0 reflected no change, while higher scores reflected increased disease activity. Baseline AV and changes from Baseline to Weeks 24 and 48 were averaged among all participants, where negative changes indicated improvement in disease activity.

  • 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 ] [ Designated as safety issue: No ]
    The Ritchie Articular Index was scored on a scale of 0 to 3, according to the grades of tenderness in each of 26 assessed joints. The total score was taken as the sum of joint scores and ranged from 0 to 78. Scores of 0 reflected no tenderness, while higher scores reflected increased tenderness. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in joint tenderness.

  • 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 ] [ Designated as safety issue: No ]
    Perceived pain was assessed on a 0- to 100-millimeter (mm) VAS, where the distance from 0 mm represented the participant's self evaluation of pain (0 mm = no pain, 100 mm = maximum pain). Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated a decrease in perceived pain.

  • 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 ] [ Designated as safety issue: No ]
    Global assessment of disease activity was performed using a 0- to 100-mm VAS, where the distance from 0 mm represented the investigator's evaluation or the participant's self evaluation of disease activity (0 mm = no pain, 100 mm = maximum pain). Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated improvement in disease activity.

  • 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 ] [ Designated as safety issue: No ]
    The HAQ-DI assessed 20 items in eight functional activity domains including dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. Each item was scored on a scale of 0 to 3, where 0 represented activities performed without difficulty and 3 represented inability to perform activities alone. The total score was calculated as an average of all item scores, and thus also ranged from 0 to 3. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated an increase in ability to perform activities independently.

  • 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 ] [ Designated as safety issue: No ]
    The DAS28 was derived from assessments of C-reactive protein (CRP), tender joint count (TJC), swollen joint count (SJC), and general health according to 100-mm VAS. DAS28 scores were calculated as [0.56 × square root of TJC] plus (+) [0.28 × square root of SJC] + [0.36 × natural log (CRP + 1)] + [0.014 × VAS] + 0.96. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. CRP was measured in milligrams per deciliter (mg/dL). DAS28 scores could range from 0 to 10, where higher scores represented higher disease activity. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants, where negative changes indicated an improvement in disease activity.

  • 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 ] [ Designated as safety issue: No ]
    Level of VEGF was measured in picograms per milliliter (pg/mL). Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    ESR was measured in millimeters per hour (mm/h). Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of hsCRP was measured in mg/dL. Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Soluble Interleukin-6 Receptor (sIL6R) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of sIL6R was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of mRNA for IL-17 (2^ΔCt) was quantified by polymerase chain reaction (PCR). Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in mRNA for IL-23 Receptor (2^ΔCt) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of mRNA for IL-23 receptor (2^ΔCt) was quantified by PCR. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of ROR-γT (2^ΔCt) was quantified by PCR. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of mRNA for FOXP3 (2^ΔCt) was quantified by PCR. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of CD4-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD4 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD4-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD25-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CD25-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD25 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD25-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of CD45RO-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD45RO Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD45RO-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of CCR6-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CCR6 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CCR6-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CCR4-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CCR4-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CCR4 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CCR4-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of IL-23Rp19-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in IL-23Rp19 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of IL-23Rp19-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of Treg cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Treg Cells as a Percentage of T Cells [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of Treg cell infiltration was expressed as the percentage of T cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Treg Cell Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The absolute number of Treg cells was expressed as cells per microliter (cells/mcL). Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of Th17 cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Th17 Cells as a Percentage of T Cells [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of Th17 cell infiltration was expressed as the percentage of T cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Th17 Cell Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The absolute number of Th17 cells was expressed as cells/mcL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD19-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CD19-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD19 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD19-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD24-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CD24-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD24 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD24-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD27-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CD27-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD27 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD27-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD38-Positive Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of CD38-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in CD38 Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of CD38-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of IgM-positive cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in IgM Mean Intensity of Fluorescence [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The mean fluorescence intensity of IgM-positive cells was measured by flow cytometry. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Mature B Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of mature B cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of mature B cell infiltration was expressed as the percentage of B cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Week 4 in Mature B Cell Level [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The absolute number of mature B cells was expressed as cells/mcL. Baseline AV and change from Baseline to Week 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Memory B Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of memory B cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of memory B cell infiltration was expressed as the percentage of B cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Week 4 in Memory B Cell Level [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The absolute number of memory B cells was expressed as cells/mcL. Baseline AV and change from Baseline to Week 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Transitional B Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of transitional B cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of transitional B cell infiltration was expressed as the percentage of B cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Week 4 in Transitional B Cell Level [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The absolute number of transitional B cells was expressed as cells/mcL. Baseline AV and change from Baseline to Week 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Plasma B Cells as a Percentage of PBMCs [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    The intensity of plasma B cell infiltration was expressed as the percentage of PBMCs. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    The intensity of plasma B cell infiltration was expressed as the percentage of B cells. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Week 4 in Plasma B Cell Level [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The absolute number of plasma B cells was expressed as cells/mcL. Baseline AV and change from Baseline to Week 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Th17 Cysteine-Cysteine Chemokine Ligand (CCL) 20 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of Th17CCL20 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Th17CCL17 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of Th17CCL20 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in B Cell-Attracting Chemokine (BCA) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of BCA was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Stromal Cell-Derived Factor (SDF) 1 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of SDF1 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in B Cell-Activating Factor (BAFF) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of BAFF was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in A Proliferation-Inducing Ligand (APRIL) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of APRIL was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Tumor Necrosis Factor (TNF)-α Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of TNF-α was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in IL-1β Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of IL-1β was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in IL-17 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of IL-17 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Monocyte Chemoattractant Protein (MCaP)-1 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of MCaP-1 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Osteocalcin Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of osteocalcin was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Type I Collagen N-Propeptide Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of Type I collagen N-propeptide was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in C-Terminal Telopeptide (CTX)-1 Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of CTX-1 was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Type I Collagen C-Terminal Telopeptide (ICTP) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of ICTP was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Type II Collagen N-Propeptide (PIIANP) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of PIIANP was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Weeks 2 and 4 in Type II Collagen Helical Peptide (HELIX-II) Level [ Time Frame: Baseline and Weeks 2, 4 ] [ Designated as safety issue: No ]
    Level of HELIX-II was measured in pg/mL. Baseline AV and changes from Baseline to Weeks 2 and 4 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of Hb was measured in grams per liter (g/L). Baseline AV and changes from Baseline to Weeks 2, 4, 12, 24, and 48 were averaged among all participants.

  • 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 ] [ Designated as safety issue: No ]
    Level of STR was measured in pg/mL. Baseline AV and changes from Baseline to Day 2 and Weeks 2 and 4 were averaged among all participants.

  • Change From Baseline to Week 48 in Initial Rate of Enhancement (IRE) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    IRE was approximated by parametric mapping via DYNAMIKA software and expressed as change in relative signal intensity per second (ΔI/sec). The mean of three different slices was used in the determination of IRE. Each slice consisted of a two-dimensional (2D) sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Maximum Enhancement (ME) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    ME was approximated by parametric mapping via DYNAMIKA software and expressed as ratio of signal enhancement before and after contrast injection. The mean of three different slices was used in the determination of ME. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Number of Enhancing Voxels (Ntotal) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Ntotal was approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Ntotal. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Number of Persistent Enhancing Voxels (Npersistent) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Npersistent was approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Npersistent. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Number of Plateau Enhancing Voxels (Nplateau) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Nplateau was approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Nplateau. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Number of Washout Enhancing Voxels (Nwashout) by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Nwashout was approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Nwashout. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Ntotal×IRE by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Ntotal and IRE were approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Ntotal. The mean of three different slices was used in the determination of IRE. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Function of Ntotal×IRE was expressed as voxels times change in relative intensity per second (v*ΔI/sec). Baseline AV and change from Baseline to Week 48 were averaged among all participants.

  • Change From Baseline to Week 48 in Ntotal×ME by DYNAMIKA Software Analysis [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Ntotal and ME were approximated using DYNAMIKA software. The sum of three different slices was used in the determination of Ntotal. The mean of three different slices was used in the determination of ME. Each slice consisted of a 2D sequence of images acquired from the same physical location at different time instances. Function of NtotalME was expressed as voxels times ratio of signal intensity before and after contrast injection (v*ratio). Baseline AV and change from Baseline to Week 48 were averaged among all participants.


Enrollment: 58
Study Start Date: October 2009
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tocilizumab in Active RA
Participants with active RA will receive tocilizumab as 8 mg/kg via IV infusion every 4 weeks. A total of 12 infusions will be given from Baseline to Week 44, and participants will be assessed through Week 48.
Drug: DMARDs
Participants may continue on a stable dose of their current DMARD therapy as prescribed. The choice of DMARD is at the discretion of the treating physician and is not specified by the protocol.
Drug: Tocilizumab
Tocilizumab will be given as 8 mg/kg via IV infusion every 4 weeks for a total of 12 infusions. The maximum allowed dose is 800 mg.
Other Name: RoActemra, Actemra

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Moderate to severe active RA of ≥6 months duration
  • DAS28 >3.2
  • Inadequate response to a stable dose of non-biologic DMARD for ≥2 months
  • Those receiving oral corticosteroids must have been at stable dose for ≥25 days in the 28 days prior to first study treatment

Exclusion Criteria:

  • Rheumatic autoimmune disease other than RA
  • History of or current inflammatory joint disease other than RA
  • Previous treatment with alkylating agents or total lymphoid irradiation
  • Intra-articular or parenteral corticosteroids within 6 weeks prior to Baseline
  • Previous treatment with any cell-depleting therapies
  • American College of Rheumatology (ACR) Functional Class IV
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00996606

Locations
Italy
Coppito, Abruzzo, Italy, 67100
Napoli, Campania, Italy, 80131
Roma, Lazio, Italy, 00161
Genova, Liguria, Italy, 16132
Milano, Lombardia, Italy, 20122
Milano, Lombardia, Italy, 20157
Pavia, Lombardia, Italy, 27100
Palermo, Sicilia, Italy, 90127
Pisa, Toscana, Italy, 56100
Cona (Ferrara), Veneto, Italy, 44124
Padova, Veneto, Italy, 35128
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

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

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Antirheumatic Agents

ClinicalTrials.gov processed this record on December 07, 2016