A Study of Tocilizumab Plus Non-biological DMARD in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Non-biological DMARDs

Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Three wrist regions (distal radioulnar joint, radiocarpal joint, the intercarpal and intermetacarpal joint) and the 2nd to 5th metacarpophalangeal (MCP) were assessed for synovitis via magnetic resonance imaging (MRI) and scored using a scale ranging from 0-3 where 0 is normal and scores 1-3 (mild, moderate, severe) are by thirds of the presumed volume of enhancing tissue in the synovial compartment. These values were then summed yielding scores of 0-9 in the wrist region, 0-12 for MCP joints, and 0-22 on the aggregate. A negative value in synovitis change from Baseline score indicates an improvement.

Time frame: Week 12

Population: ITT population; n (number) equals (=) number of participants assessed for the specified parameter

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the MCP ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the wrist ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from all the assessed ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for edema via MRI and scored separately based on the proportion of bone with edema. Scoring ranged from 0 to 3 as follows: 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Summing these values yielded a scale from 0-45 for the wrist region, 0-24 for the MCP joints, and 0-69 on aggregate.

Time frame: Week 12

Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranges from 0 (no erosion) to 10 (91-100%). For long bones, the 'assessed bone volume' is from the articular surface to a depth of 1 centimeter (cm) (if the articular surface is absent its best estimated position is used), and in carpal bones it is the whole bone. Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value in change from Baseline score indicates an improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

RAMRIS score is the sum of its core components: Synovitis Score, Edema Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Edema scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score plus (+) Edema Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Edema Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Three wrist regions (distal radioulnar joint, radiocarpal joint, the intercarpal and intermetacarpal joint) and the 2nd to 5th MCP were assessed for synovitis via MRI and scored using a scale ranging from 0-3 where 0 is normal and scores 1-3 (mild, moderate, severe) are by thirds of the presumed volume of enhancing tissue in the synovial compartment. These values were then summed yielding scores of 0-9 in the wrist region, 0-12 for MCP joints, and 0-22 on the aggregate. A negative value in synovitis change from Baseline score indicates an improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from all the assessed ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population;

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the MCP ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population;

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the wrist ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for edema via MRI and scored separately based on the proportion of bone with edema. Scoring ranged from 0 to 3 as follows: 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Summing these values yielded a scale from 0-45 for the wrist region, 0-24 for the MCP joints, and 0-69 on aggregate.

Time frame: Week 24

Population: ITT population; participants from the placebo group who did not show an improvement of ≥ 20% in TJC and SJC were offered recovery therapy with tocilizumab 8mg/kg and were placed in Placebo-Tocilizumab 8mg/kg group.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranges from 0 (no erosion) to 10 (91-100%). For long bones, the 'assessed bone volume' is from the articular surface to a depth of 1 cm (if the articular surface is absent its best estimated position is used), and in carpal bones it is the whole bone. Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value in change from Baseline score indicates an improvement.

Time frame: Week 24

Population: ITT population; participants from the placebo group who did not show an improvement of ≥ 20% in TJC and SJC were offered recovery therapy with tocilizumab 8mg/kg and were placed in Placebo-Tocilizumab 8mg/kg group.

RAMRIS score is the sum of its core components: Synovitis Score, Edema Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Edema scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score + Edema Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Edema Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.

Time frame: Week 24

Population: ITT population; participants from the placebo group who did not show an improvement of ≥20% in TJC and SJC were offered recovery therapy with tocilizumab 8 mg/kg and were placed in Placebo-Tocilizumab 8 mg/kg group.

Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Three wrist regions (distal radioulnar joint, radiocarpal joint, the intercarpal and intermetacarpal joint) and the 2nd to 5th MCP were assessed for synovitis via MRI and scored using a scale ranging from 0-3 where 0 is normal and scores 1-3 (mild, moderate, severe) are by thirds of the presumed volume of enhancing tissue in the synovial compartment. These values were then summed yielding scores of 0-9 in the wrist region, 0-12 for MCP joints, and 0-22 on the aggregate. A negative value in synovitis change from Baseline score indicates an improvement.

Time frame: Week 24

Population: ITT population.

Change in 17OHP was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. CRP was measured in milligrams per deciliter (mg/dL).

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

DAS28 was calculated from the number of swollen joints and tender joints (SJC and TJC) using the 28-joint count, the ESR (mm/hr) and global health assessment (participant rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. Change in DAS28 global score was determined as the difference in the scores at baseline and Week 12. A negative number indicated improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

ESR is an inflammatory marker and is used to assess disease activity in rheumatoid arthritis (RA). A reduction in ESR indicates improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Change in Neuropeptide Y was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

General health was assessed using the Patient Global Assessment of Disease Activity, a 0 to 10 mm VAS, where 0 mm = very well and 10 mm = extremely bad. Participants were asked to answer the following question: In general how would you rate your health over the last 2-3 weeks?. Participants responded by marking the line and the distance from the left edge was recorded.

Time frame: Week 12

Population: ITT population

Patient's Global Assessment of Pain was assessed using a 10-mm horizontal VAS (0 to 10 mm) where 0=pain absent and 10=intolerable pain. Participants responded by placing a mark on the line to indicate their current level of pain; the distance from the left edge to the mark was recorded. Change in Patient Global Assessment of Pain was determined as the difference in the scores at baseline and Week 12. A negative number indicated improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Change in Plasma ACTH was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

Change in serum androstenedione was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

Change in serum cortisol was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

Change in DHEA was determined as the difference in the scores at Baseline and Week 12.

Time frame: Week 12

Population: ITT population

Change in SJC was determined as the difference in the number of swollen joints at baseline and the number at Week 12. A negative number indicated improvement.

Time frame: Week 12

Population: ITT population

Change in TJC was determined as the difference in the number of tender joints at baseline and the number at Week 12. A negative number indicated improvement.

Time frame: Week 12

Population: ITT population

Change in 17OHP was determined as the difference in the scores at Baseline and Week 24.

Time frame: Week 24

Population: ITT population

The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.

Time frame: Week 24

Population: ITT population

DAS28 was calculated from the number of swollen joints and tender joints (SJC and TJC) using the 28-joint count, the ESR (mm/hr) and global health assessment (participant rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. Change in DAS28 global score was determined as the difference in the scores at baseline and Week 24. A negative number indicated improvement.

Time frame: Week 24

Population: ITT population

ESR is an inflammatory marker and is used to assess disease activity in RA. A reduction in ESR indicates improvement.

Time frame: Week 24

Population: ITT population

Change in Neuropeptide Y was determined as the difference in the scores at Baseline and Week 24.

Time frame: Week 24

Population: ITT population

General health was assessed using the Patient Global Assessment of Disease Activity, a 0 to 10 mm VAS, where 0 mm = very well and 10 mm = extremely bad. Participants were asked to answer the following question: In general how would you rate your health over the last 2-3 weeks?. Participants responded by marking the line and the distance from the left edge was recorded.

Time frame: Week 24

Population: ITT population

Patient's Global Assessment of Pain was assessed using a 10-mm horizontal VAS (0 to 10 mm) where 0=pain absent and 10=intolerable pain. Participants responded by placing a mark on the line to indicate their current level of pain; the distance from the left edge to the mark was recorded. Change in Patient Global Assessment of Pain was determined as the difference in the scores at baseline and Week 24. A negative number indicated improvement.

Time frame: Week 24

Population: ITT population

Change in plasma ACTH was determined as the difference in the scores at baseline and Week 24.

Time frame: Week 24

Population: ITT population

Change in serum androstenedione was determined as the difference in the scores at Baseline and Week 24.

Time frame: Week 24

Population: ITT population

Change in serum cortisol was determined as the difference in the scores at Baseline and Week 24.

Time frame: Week 24

Population: ITT population;

Change in DHEA was determined as the difference in the scores at Baseline and Week 24.

Time frame: Week 24

Population: ITT population

Change in SJC was determined as the difference in the number of swollen joints at baseline and the number at Week 24. A negative number indicated improvement.

Time frame: Week 24

Population: ITT population

Change in TJC was determined as the difference in the number of tender joints at baseline and the number at Week 24. A negative number indicated improvement.

Time frame: Week 24

Population: ITT population

DAS28 was calculated from the number of swollen joints and tender joints (SJC and TJC) using the 28-joint count, the erythrocyte sedimentation rate (ESR) (millimeters per hour \[mm/hr\]) and global health assessment (participant rated global assessment of disease activity using 10-mm visual analog scale \[VAS\]); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity.

Time frame: Baseline, Weeks 12 and 24

Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.

The HAQ-DI includes 20 questions concerning participant's activities of daily life, grouped in 8 scales of 2 to 3 questions for each activity. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0=without difficulties; 1=with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3.

Time frame: Baseline, Weeks 12 and 24

Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Patient's Global Assessment of Pain was assessed using a 10-mm horizontal VAS (0 to 10 mm) where 0=pain absent and 10=intolerable pain. Participants responded by placing a mark on the line to indicate their current level of pain; the distance from the left edge to the mark was recorded.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, and 24

Population: ITT population; n=number of participants assessed for the specific parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the MCP ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the wrist ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of initial rate of enhancement (IRE) and number of voxels (Nvox), which are extracted by examining individual signal intensity vs time curves derived from defined regions of interest (ROIs). A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. Maximum enhancement (ME)=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of signal intensity (SI) until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from all the assessed ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for edema via MRI and scored separately based on the proportion of bone with edema. Scoring ranged from 0 to 3 as follows: 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Summing these values yielded a scale from 0-45 for the wrist region, 0-24 for the MCP joints, and 0-69 on aggregate.

Time frame: Week 12

Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranges from 0 (no erosion) to 10 (91-100%). For long bones, the 'assessed bone volume' is from the articular surface to a depth of 1 centimeter (cm) (if the articular surface is absent its best estimated position is used), and in carpal bones it is the whole bone. Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value in change from Baseline score indicates an improvement.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

RAMRIS score is the sum of its core components: Synovitis Score, Edema Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Edema scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score plus (+) Edema Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Edema Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.

Time frame: Week 12

Population: ITT population. After Week 12, participants receiving placebo could have been switched to tocilizumab.

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from all the assessed ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the MCP ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population;

Contrast enhancement was quantified in terms of IRE and Nvox, which are extracted by examining individual signal intensity vs time curves derived from defined ROIs. A volume ROI was manually drawn around wrist and MCP 2-5 joints at each visit representative of size/volume of enhancement and underlying inflammation. ME=mean of ME and Nplateau+Nwashout (Nvoxels) are number of voxels that have a plateau and washout, used to assess volume of enhancing voxels within drawn ROIs. IRE=percentage increase of SI until l ME is reached calculated as maximum increase in post-contrast SI divided by baseline SI; IRE=increase in SI in %/s from time of onset of enhancement to ME. EER reflects the IRE parameter and the output is the mean from the wrist ROIs (range=between 0 and 1; 0=no change/enhancement, 1=maximum change/enhancement. Negative change from Baseline score=improvement.

Time frame: Week 24

Population: ITT population

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for edema via MRI and scored separately based on the proportion of bone with edema. Scoring ranged from 0 to 3 as follows: 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Summing these values yielded a scale from 0-45 for the wrist region, 0-24 for the MCP joints, and 0-69 on aggregate.

Time frame: Week 24

Population: ITT population; participants from the placebo group who did not show an improvement of ≥ 20% in TJC and SJC were offered recovery therapy with tocilizumab 8mg/kg and were placed in Placebo-Tocilizumab 8mg/kg group.

Bones from the wrist regions (carpal bones, distal radius, distal ulna and metacarpal bases) and the MCP joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranges from 0 (no erosion) to 10 (91-100%). For long bones, the 'assessed bone volume' is from the articular surface to a depth of 1 cm (if the articular surface is absent its best estimated position is used), and in carpal bones it is the whole bone. Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value in change from Baseline score indicates an improvement.

Time frame: Week 24

Population: ITT population

RAMRIS score is the sum of its core components: Synovitis Score, Edema Score, and Erosion Score. Synovitis scored from 0 (normal) to 9 (maximum distension of synovial cavity). Edema scored 0 (normal) to 69 (maximum articular bone involvement). Erosion scored from 0 (normal) to 230 (maximum erosion of articular bone). RAMRIS=Synovial Score + Edema Score + Erosion Score. Minimum RAMRIS score=0 (normal), maximum RAMRIS score=308 (severe structural damage). For Synovial Score, Edema Score, Erosion Score, and RAMRIS score, increasing number=increasing severity.

Time frame: Week 24

Population: ITT population; participants from the placebo group who did not show an improvement of ≥20% in TJC and SJC were offered recovery therapy with tocilizumab 8 mg/kg and were placed in Placebo-Tocilizumab 8 mg/kg group.

TJC and SJC were determined using the 28 joint counts. Joints were classified as tender/not tender and swollen/not swollen and counted. The scores ranged from 0 to 28. Higher scores indicated higher disease activity.

Time frame: Weeks 12 and 24

Population: ITT population; n=number of participants assessed for the specified parameter at a given visit. After Week 12, participants receiving placebo could have been switched to tocilizumab.