A Study of Tocilizumab (RoActemra) in Tocilizumab-Naive Participants With Rheumatoid Arthritis and Inadequate Response to Non-Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) and/or Biologic Therapy

The DAS28-ESR was derived from assessments of ESR, TJC, SJC, and PGA according to 100-mm VAS. DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. ESR was measured in mm/h. DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

The DAS28-ESR was derived from assessments of ESR, TJC, SJC, and PGA according to 100-mm VAS. DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. ESR was measured in mm/h. DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. DAS28-ESR score less than or equal to (</=) 3.2 indicates LDA, DAS28-ESR score greater than (>) 3.2 indicates moderate to high disease activity, and DAS28-ESR less than (<) 2.6 indicates remission. Percentage of participants with DAS28-ESR LDA and remission at Week 24 is reported. 95 percent (%) confidence interval (CI) was determined using Clopper-Pearson method.

The DAS28-ESR was derived from assessments of ESR, TJC, SJC, and PGA according to 100-millimeter (mm) VAS. DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. ESR was measured in mm/h. DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

The DAS28-ESR was derived from assessments of ESR, TJC, SJC, and PGA according to 100-mm VAS. DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. ESR was measured in mm/h. DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. DAS28-ESR score </=3.2 indicates LDA, DAS28-ESR score >3.2 indicates moderate to high disease activity, and DAS28-ESR <2.6 indicates remission. Percentage of participants with DAS28-ESR LDA and remission at Week 24 and at last assessment is reported.

The ACR 20, 50, and 70 responses at any time was defined as greater than or equal to (>/=) 20%, 50%, and 70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20%, 50%, 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) PGA according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein [CRP] in milligrams per liter [mg/L]). Percentage of participants with ACR 20, 50, and 70 responses at Week 24 is reported. 95% CI was determined using Clopper-Pearson method.

The ACR 20, 50, and 70 responses at any time is defined as >/=20%, 50%, and 70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20%, 50%, 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) PGA according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/L). Percentage of participants with ACR 20, 50, and 70 responses at Week 24 and at last assessment is reported.

The DAS28-ESR-based EULAR response criteria were used to measure individual response as 'Good', 'Moderate', and 'No Response', depending upon DAS28-ESR absolute scores at Week 24 and the DAS28-ESR reduction from Baseline to Week 24. Good Response: change from baseline >1.2 with DAS28-ESR score </=3.2; Moderate Response: change from baseline >1.2 with DAS28-ESR score >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28-ESR score </=5.1; No Response: change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28-ESR score >5.1. Percentage of participants with EULAR responses at Week 24 is reported. 95% CI was determined using Clopper-Pearson method.

The DAS28-ESR-based EULAR response criteria were used to measure individual response as 'Good', 'Moderate', and 'No Response', depending upon DAS28-ESR absolute scores at Week 24 and the DAS28-ESR reduction from Baseline to Week 24. Good Response: change from baseline >1.2 with DAS28-ESR score </=3.2; Moderate Response: change from baseline >1.2 with DAS28-ESR score >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28-ESR score </=5.1; No Response: change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28-ESR score >5.1. Percentage of participants with EULAR responses at Week 24 and at last assessment is reported.

SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS and CRP in mg per deciliter (dL). Higher scores indicate greater affection due to disease activity. SDAI total score = 0-86. SDAI </=3.3 indicates disease remission, </=11 indicates LDA, </=26 indicates moderate disease activity, and >26 indicates high disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS and CRP in mg/dL. Higher scores indicate greater affection due to disease activity. SDAI total score = 0-86. SDAI </=3.3 indicates disease remission, </=11 indicates LDA, </=26 indicates moderate disease activity, and >26 indicates high disease activity. Percentage of participants with SDAI LDA and remission at Week 24 is reported. 95% CI was determined using Clopper-Pearson method.

SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS and CRP in mg/dL. Higher scores indicate greater affection due to disease activity. SDAI total score = 0-86. SDAI </=3.3 indicates disease remission, </=11 indicates LDA, </=26 indicates moderate disease activity, and >26 indicates high disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS and CRP in mg/dL. Higher scores indicate greater affection due to disease activity. SDAI total score = 0-86. SDAI </=3.3 indicates disease remission, </=11 indicates LDA, </=26 indicates moderate disease activity, and >26 indicates high disease activity. Percentage of participants with SDAI LDA and remission at Week 24 and at last assessment is reported.

CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS. Higher scores represent greater affection due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, </=10 indicates LDA, </=22 indicates moderate disease activity, and >22 indicates high disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS. Higher scores represent greater affection due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, </=10 indicates LDA, </=22 indicates moderate disease activity, and >22 indicates high disease activity. Percentage of participants with CDAI LDA and remission at Week 24 is reported. 95% CI was determined using Clopper-Pearson method.

CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS. Higher scores represent greater affection due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, </=10 indicates LDA, </=22 indicates moderate disease activity, and >22 indicates high disease activity. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PGA and Physician's global assessment of disease activity according to 100-mm VAS. Higher scores represent greater affection due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, </=10 indicates LDA, </=22 indicates moderate disease activity, and >22 indicates high disease activity. Percentage of participants with CDAI LDA and remission at Week 24 and at last assessment is reported.

A total of 28 joints were assessed for swelling. The number of swollen joints at could range from 0 to 28, where higher values represented more swollen joints. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

A total of 28 joints were assessed for swelling. The number of swollen joints at could range from 0 to 28, where higher values represented more swollen joints. The change from Baseline to any time point was averaged among all participants, where negative changes indicated an improvement in disease activity.

A total of 28 joints were assessed for tenderness. The number of tender joints at could range from 0 to 28, where higher values represented more tender joints. The change from Baseline to any time points was averaged among all participants, where negative changes indicated an improvement in disease activity.

A total of 28 joints were assessed for tenderness. The number of tender joints at could range from 0 to 28, where higher values represented more tender joints. The change from Baseline to any time points was averaged among all participants, where negative changes indicated an improvement in disease activity.

Physician-assessed disease activity was scored on a 100-mm VAS, where the distance from 0 mm represented the physician's evaluation of disease activity (0 mm=none; 100 mm=very severe). The change from Baseline to any time point was averaged among all participants, where negative change indicated a decrease in physician-assessed disease activity.

Participant-assessed disease activity was scored on a 100-mm VAS, where the distance from 0 mm represented the participant's self evaluation of disease activity (0 mm=none; 100 mm=very severe). The change from Baseline to any time point was averaged among all participants, where negative change indicated a decrease in participant-assessed disease activity.

Participant-assessed pain was scored on a 100-mm VAS, where the distance from 0 mm represented the participant's self evaluation of pain (0 mm=none; 100 mm=very severe). The change from Baseline to any time point was averaged among all participants, where negative change indicated a decrease in participant-assessed pain.

FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated questions), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). The changes from Baseline to any time point were averaged among all participants, where negative changes indicated an increase in fatigue.

HAQ-DI assessed 20 items in 8 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 (range = 0-3) was calculated as an average of all item scores. Percentage of participants with HAQ-DI remission (HAQ-DI score <0.5) at each time point is reported.

HAQ-DI assessed 20 items in 8 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 (range = 0-3) was calculated as an average of all item scores. Percentage of participants with HAQ-DI clinically meaningful improvement (reduction in HAQ-DI score from baseline >/=0.22) at each time point is reported.

Treatment compliance from Baseline up to Week 24 was assessed using following formula: (number of actual injection received / number of theoretical injection which should be received at week 24) * 100.

RAID assessed the impact of rheumatoid arthritis on participant's quality of life. It comprised 7 domains: pain, function, fatigue, physical and psychological well-being, sleep disturbance and coping. Each domain was a single question scored from 0 (best) to 10 (worst) on a continuous numerical rating scale (NRS). Each domain also had a specific weight assigned by a participant survey and RAID total score ranged from 0 (best) to 10 (worst). If only 1 domain was missing it was replaced by the mean of the others; otherwise, RAID score was not calculated. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better quality of life.

RAPID-3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain VAS, and PGA VAS. The total RAPID-3 score ranges from 0 to 10 where higher scores represent worse outcomes. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better outcome.

Participants were asked: "If you were to remain in the same condition for the next few months as you have been over the last 8 days, would this be 1) acceptable, 2) Inacceptable?" The number of participants who responded "acceptable" or "Inacceptable" at each time point is presented.

BRAF-MDQ assessed the overall experience and impact of disease related fatigue, using four dimensions (physical fatigue [4 items], living with fatigue [7 items], cognitive fatigue [5 items], and emotional fatigue [4 items]). A total fatigue score (range 0 to 70) was obtained by summing the 20 item scores ranging from 0 to 3, except for item 1 (0-10), item 2 (0-7) and item 3 (0-2). Higher scores reflect greater fatigue. If only 1 domain was missing it was replaced by the mean of the others; otherwise, the total score was not calculated. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better quality of life.

BRAF-NRS are 3 standardized NRS (range = 0-10) for disease related fatigue domains (severity of fatigue, fatigue effect, and coping with fatigue). Higher values reflect greater problems for severity/level fatigue and effect fatigue NRS, but lower scores reflect greater problems for copped fatigue NRS.

MOS sleep scale comprised of 6-item with each item score ranged from 0 to 100. The total score was the average of scores sum (range 0-100), with highest values reflecting biggest participant's sleeping problems. If more than 3 items were missing the index was not calculated. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better outcome.

FLARE is a 13-item questionnaire assessed disease flares between two medical consultations. Each item score ranged from 0 (completely untrue) to 10 (absolutely true) on a 6-step scale. The FLARE questionnaire global score (range = 0-10) is a mean score of 11 of the 13 items [items 6 ('doses of pain killers or anti-inflammatory medication') and 13 ('need for help') not taken into account], with the highest score corresponding to the highest disease activity. The global score was computed if at least the scores of 6 items were available. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better outcome.

The BioSecure questionnaire comprised of 54-item aimed at evaluating the safety competences of participants (for example, participants' self-care safety skills and socio-demographic characteristics, type of information received, quality of life, and coping style data) treated by biologics for inflammatory arthritis and to determine the factors associated with a lower level of competences.

Percentage of participants with a discontinuation in corticosteroid dosage during core study period is reported. The discontinuations were categorized as either permanent or temporary. Participants with temporary discontinuation first followed by permanent discontinuation were counted in both categories. Participants who were receiving corticosteroids at Baseline were only included in the analysis.

Time to permanent discontinuation in corticosteroid dosage during core study period is reported. Participants who permanently discontinued corticosteroids at any time during core study period were only included in the analysis.

Time to first temporary discontinuation in corticosteroid dosage during core study period is reported. Participants who temporarily discontinued corticosteroids at any time during core study period were only included in the analysis.

Percentage of participants with a change in corticosteroid dosage during core study period compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage.

Time to first change in corticosteroid dosage during core study period compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage. Participants with a change in corticosteroid dosage during core study period were only included in the analysis.

Number of participants according to reasons for a change in corticosteroid dosage during core study period compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage. Participants with a change in corticosteroid dosage during core study period were only included in the analysis.

Percentage of participants with a discontinuation in corticosteroid dosage during study is reported. The discontinuations were categorized as either permanent or temporary. Participants with temporary discontinuation first followed by permanent discontinuation were counted in both categories. Participants who were receiving corticosteroids at Baseline were only included in the analysis.

Time to permanent discontinuation in corticosteroid dosage during study is reported. Participants who permanently discontinued corticosteroids at any time during entire study were only included in the analysis.

Time to first temporary discontinuation in corticosteroid dosage during study is reported. Participants who temporarily discontinued corticosteroids at any time during entire study were only included in the analysis.

Percentage of participants with a change in corticosteroid dosage during study compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage.

Time to first change in corticosteroid dosage during study compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage. Participants with a change in corticosteroid dosage during entire study were only included in the analysis.

Number of participants according to reasons for a change in corticosteroid dosage during study compared to Baseline is reported. The change included either an initiation/ increase (>+5mg/day prednisone or equivalent) of corticosteroid dosage or a decrease (</=-5mg/day prednisone or equivalent) of corticosteroid dosage. Participants with a change in corticosteroid dosage during entire study were only included in the analysis.

Number of participants according to reasons for changes in csDMARDs treatment during core study period is reported. The changes included Increase of dose (the dose increase had to be greater than the highest dose received within the 4 weeks on or before baseline); Addition of another csDMARD (without suppression of the first one); Switch (add and suppression) of a csDMARD for another reason than intolerance to the csDMARD suppressed; Modification of the administration route of MTX (with increase or maintenance of the dose): per oral route to intravenous (IV)/ intramuscular (IM)/ SC. Participants with a change in csDMARDs treatment during core study period were only included in the analysis.

Number of participants according to reasons for changes in csDMARDs treatment during study is reported. The changes included Increase of dose (the dose increase had to be greater than the highest dose received within the 4 weeks on or before baseline); Addition of another csDMARD (without suppression of the first one); Switch (add and suppression) of a csDMARD for another reason than intolerance to the csDMARD suppressed; Modification of the administration route of MTX (with increase or maintenance of the dose): per oral route to IV/IM/SC. Participants with a change in csDMARDs treatment during entire study were only included in the analysis.

Synovitis was assessed by ultrasonographic evaluation (B-mode ultrasound) and scored from "0" to "3" for each 7 paired joints (wrists on both sides, 2nd and 3rd metacarpo-phalangeal [MCP 2/3] on both sides, 2nd and 3rd proximal inter-phalangeal [PIP 2/3] on both sides, 2nd and 5th metatarsophalangeal [MTP 2/5] on both sides). Synovitis total score was calculated by adding the sum of scores for each joint for a total score ranging from 0 to 42. A score of 0 indicated no damage and a score of 42 indicated most severe damage. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better outcome.

Synovitis was assessed by ultrasonographic evaluation (Power-Doppler-mode ultrasound) and scored from "0" to "3" for each 7 paired joints (wrists on both sides, 2nd and 3rd metacarpo-phalangeal [MCP 2/3] on both sides, 2nd and 3rd proximal inter-phalangeal [PIP 2/3] on both sides, 2nd and 5th metatarsophalangeal [MTP 2/5] on both sides). Synovitis total score was calculated by adding the sum of scores for each joint for a total score ranging from 0 to 42. A score of 0 indicated no damage and a score of 42 indicated most severe damage. The changes from Baseline to any time point were averaged among all participants, where negative changes indicated better outcome.

Percentage of participants with a positive response to anti-therapeutic antibodies against tocilizumab by confirmatory assays at any time during the study is reported.