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)

Hoffmann-La Roche0 sites58 target enrollmentOctober 2009

ConditionsRheumatoid Arthritis

InterventionsDMARDs Tocilizumab

DrugsDMARDs Tocilizumab

Overview

Phase: Phase 3
Intervention: DMARDs
Conditions: Rheumatoid Arthritis
Sponsor: Hoffmann-La Roche
Enrollment: 58
Primary Endpoint: 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
Status: Completed
Last Updated: 8 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Similar Trials

Overview

Brief Summary

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.

Registry

clinicaltrials.gov

Start Date

October 2009

End Date

April 2012

Last Updated

8 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Hoffmann-La Roche

Responsible Party

Sponsor

Eligibility 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

Arms & Interventions

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.

Intervention: DMARDs

Tocilizumab in Active RA

Intervention: Tocilizumab

Outcomes

Primary Outcomes

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

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.

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

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

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.

Secondary Outcomes

Change From Baseline to Weeks 2, 12, 24, and 48 in Synovitis of the Wrist According to RE Before and After Contrast Injection(Baseline and Weeks 2, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Erosion of the Wrist and MCP Joints According to RAMRIS Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Disease Activity Score of 28 Joints (DAS28) Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2 and 4 in CCR6 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CCR4-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 24 and 48 in Total Modified Sharp Score (TMSS), Erosion Score (ES), and Joint Space Narrowing Score (JSNS)(Baseline and Weeks 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Ritchie Articular Index Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Vascular Endothelial Growth Factor (VEGF) Concentration(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in High-Sensitivity C-Reactive Protein (hsCRP) Concentration(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2 and 4 in Regulatory T (Treg) Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Helper T (Th) 17 Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Plasma B Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Week 4 in Plasma B Cell Level(Baseline and Week 4)
Change From Baseline to Weeks 2 and 4 in A Proliferation-Inducing Ligand (APRIL) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Osteocalcin Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2, 12, 24, and 48 in Synovitis of the Wrist According to RAMRIS Score(Baseline and Weeks 2, 12, 24, 48)
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(Baseline and Weeks 2, 4, 12, 24, 48)
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(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Perceived General Health According to VAS Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2 and 4 in Messenger Ribonucleic Acid (mRNA) for Interleukin (IL)-17 (2^Delta Cycle Threshold [ΔCt]) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD25 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Cysteine-Cysteine Chemokine Receptor (CCR) 6-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
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(Baseline and Weeks 2, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Number of Bones With Erosion in the Wrist and MCP Joints(Baseline and Weeks 2, 4, 12, 24, 48)
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(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Erythrocyte Sedimentation Rate (ESR)(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2 and 4 in Soluble Interleukin-6 Receptor (sIL6R) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in mRNA for IL-23 Receptor (2^ΔCt) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in mRNA for RAR-Related Orphan Receptor (ROR)-γT (2^ΔCt) Level(Baseline and Weeks 2, 4)
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)(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Perceived Pain According to Visual Analog Scale (VAS) Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Health Assessment Questionnaire Disability Index (HAQ-DI) Score(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Weeks 2 and 4 in mRNA for Forkhead Box Protein (FOXP) 3 (2^ΔCt) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD4 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD25-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD45 "RO" Isoform (RO)-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD45RO Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in IL-23Rp19 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Th17 Cell Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Mature B Cells as a Percentage of B Cells(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in IL-1β Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Treg Cells as a Percentage of T Cells(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in IgM Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Week 4 in Mature B Cell Level(Baseline and Week 4)
Change From Baseline to Weeks 2 and 4 in Transitional B Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Tumor Necrosis Factor (TNF)-α Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in IL-17 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CCR4 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Treg Cell Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD19-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD19 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD24 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD27-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD38-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Immunoglobulin (Ig) M-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Mature B Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Memory B Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in IL-23 Receptor p19 Subunit (IL-23Rp19)-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Th17 Cells as a Percentage of T Cells(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD24-Positive Cells as a Percentage of PBMCs(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD27 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in CD38 Mean Intensity of Fluorescence(Baseline and Weeks 2, 4)
Change From Baseline to Week 4 in Memory B Cell Level(Baseline and Week 4)
Change From Baseline to Weeks 2 and 4 in Transitional B Cells as a Percentage of B Cells(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in B Cell-Activating Factor (BAFF) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Memory B Cells as a Percentage of B Cells(Baseline and Weeks 2, 4)
Change From Baseline to Week 4 in Transitional B Cell Level(Baseline and Week 4)
Change From Baseline to Weeks 2 and 4 in Plasma B Cells as a Percentage of B Cells(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Th17 Cysteine-Cysteine Chemokine Ligand (CCL) 20 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Th17CCL17 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in B Cell-Attracting Chemokine (BCA) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Stromal Cell-Derived Factor (SDF) 1 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Monocyte Chemoattractant Protein (MCaP)-1 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Type I Collagen N-Propeptide Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Type II Collagen N-Propeptide (PIIANP) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in C-Terminal Telopeptide (CTX)-1 Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2, 4, 12, 24, and 48 in Hemoglobin (Hb) Concentration(Baseline and Weeks 2, 4, 12, 24, 48)
Change From Baseline to Week 48 in Number of Enhancing Voxels (Ntotal) by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Weeks 2 and 4 in Type I Collagen C-Terminal Telopeptide (ICTP) Level(Baseline and Weeks 2, 4)
Change From Baseline to Weeks 2 and 4 in Type II Collagen Helical Peptide (HELIX-II) Level(Baseline and Weeks 2, 4)
Change From Baseline to Week 48 in Maximum Enhancement (ME) by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Week 48 in Number of Washout Enhancing Voxels (Nwashout) by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Week 48 in Ntotal×IRE by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Week 48 in Ntotal×ME by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Day 2 and Weeks 2 and 4 in Soluble Transferrin Receptor (STR) Concentration(Baseline; Day 2; and Weeks 2, 4)
Change From Baseline to Week 48 in Initial Rate of Enhancement (IRE) by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Week 48 in Number of Persistent Enhancing Voxels (Npersistent) by DYNAMIKA Software Analysis(Baseline and Week 48)
Change From Baseline to Week 48 in Number of Plateau Enhancing Voxels (Nplateau) by DYNAMIKA Software Analysis(Baseline and Week 48)