An Extension to Study MA21573, Evaluating Tocilizumab in Patients With Active Rheumatoid Arthritis and an Inadequate Response to Current Non-Biological DMARDs and/or Anti-tumor Necrosis Factor (TNF) Therapy

An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. The percentage of participants with AEs and SAEs that occurred in the Extension Study grouped according to the number of disease-modifying anti-rheumatic drugs (DMARD) a participant was taking at Core Baseline is presented.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The serum concentration of CRP was measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at Baseline and the given time-point.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeters/hour (mm/hr). A reduction in the level is considered an improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at Baseline and the given time-point.

FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient'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 patient'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). A higher score reflects an improvement in the patient's health status. A positive change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available for both Baseline and at the given time-point.

The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as no pain and the right-hand extreme equals 100 mm as unbearable pain. A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

The patients global assessment of disease activity was assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as maximum disease activity (maximum arthritis disease activity). A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available for both Baseline and at the given time-point.

The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

66 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

Blood samples were collected for liver function test: Alanine aminotransferase (serum glutamic-pyruvic transaminase) \[ALT(SGPT)\] every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The Upper Limit of Normal (ULN) for ALT=55 Units/Liter. The number of participants categorized by the highest value for ALT/GPT during the study is reported: Normal (ALT result within the central lab reference range), Greater than the ULN to 1.5 times the ULN (\>ULN to 1.5\*ULN), 1.5 times the ULN to 3 times the ULN (1.5\*ULN to 3\*ULN) and 3 times the ULN to 5 times the ULN (3\*ULN to 5\*ULN).

Time frame: 108 Weeks

Population: Participants from the LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE) with data available for analysis.

Blood samples were collected for liver function test: Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) \[AST (SGOT)\] every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The Upper Limit of Normal (ULN) for AST=40 Units/Liter. The number of participants categorized by worst value for AST(SGOT) during the study is reported: Normal (AST result is within the central lab reference range), Greater than the ULN to 1.5 times the ULN (\>ULN to 1.5\*ULN), 1.5 times the ULN to 3 times the ULN (1.5\*ULN to 3\*ULN) and 3 times the ULN to 5 times the ULN (3\*ULN to 5\*ULN).

Time frame: 108 Weeks

Population: Participants from the LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE) with data available for analysis.

Blood samples were collected for LDL Cholesterol every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by the worst value for LDL Cholesterol during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.

Time frame: 108 Weeks

Population: Participants from the LTE Safety population (all participants who received study drug and had at least one assessment of safety in the long term extension) with data available for analysis.

Blood samples were collected for a Neutrophil Count every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by the worst value for Neutrophil Count during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.

Time frame: 108 Weeks

Population: Participants from the LTE Safety population (all participants who received study drug and had at least one assessment of safety in the long term extension) with data available for analysis.

Blood samples were collected for Total Cholesterol every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. The number of participants categorized by worst value for Total Cholesterol during the study is reported: Low is below central lab reference range, Normal is within the central lab reference range and High is above central lab reference range.

Time frame: 108 Weeks

Population: Participants from the LTE Safety population (all participants who received study drug and had at least one assessment of safety in the long term extension) with data available for analysis.

The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). Clinically meaningful improvement is defined as a reduction from Baseline in the HAQ-DI score ≥ 0.2.

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at the given time-point.

The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). Clinical Remission is defined as a HAQ-DI score \< 0.5.

Time frame: Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at the given time-point.

An Adverse Event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Adverse Events of special interest for this study were: Infections (preferred term in the infection adverse event group term), Serious Infections (an infection that qualified as Serious Adverse Event), Infusion Reactions (occurred during infusion or within 24 hours of infusion), Major Cardiac AE (Myocardial Infarction/ Acute Coronary Syndrome), Stroke or Death.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

An Adverse Event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

Blood samples were collected for the Liver Function Test: Alanine aminotransferase (ALT) every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. Percentage of participants with any values greater than 3 times the Upper Limit of Normal (3\*ULN) is reported. ULN= 55 Units/Liter.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

ACR20 response was defined as a ≥ 20 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

ACR50 response is defined as a ≥ 50 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

ACR70 response is defined as a ≥ 70 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

ACR90 response is defined as a ≥ 90 % improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant \[either C-reactive protein or Erythrocyte Sedimentation Rate\].

Time frame: Core Baseline, Extension Weeks 12, 24, 36 ,48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at both Baseline and the given time-point.

Blood was collected for the Liver Function Test: Aspartate aminotransferase (AST) every 12 weeks and at the follow-up visit in the Extension study and were sent to a central laboratory for analysis. Percentage of participants with any values greater than 3 times the Upper Limit of Normal (3\*ULN) is reported. ULN= 40 Units/Liter.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. Clinical meaningful improvement was defined as a ≥ 1.2 unit reduction in DAS28.

Time frame: Core Baseline, Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: Long Term Extension Intent-to-treat (LTE ITT) population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available for both Baseline and the given time-point.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. Low Disease Activity was defined as a score of \< 3.2.

Time frame: Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at the given time-point.

The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission was defined as a DAS28 score \< 2.6.

Time frame: Extension Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108

Population: LTE ITT population included all participants from the Core Study who received at least one dose of study drug in the Extension Study. n in each of the categories is the number of participants with data available at the given time-point.

Percentage of participants who discontinued treatment with tocilizumab for any reason.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

Fasting blood samples were collected for Lipids: Cholesterol, Triglyceride, High-density lipoprotein (HDL) Cholesterol, Low-density lipoprotein (LDL) Cholesterol every 12 weeks and at follow-up in the Extension study and were sent to a central laboratory for analysis. Lipid abnormalities were defined as a High Cholesterol, High Triglyceride, Low HDL Cholesterol and a High LDL Cholesterol that occurred at any time in the extension study.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE).

Time in days from start of the Core Study Day 1 to discontinuation of tocilizumab for any reason.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension (LTE). Participants who did not experience discontinuation of tocilizumab treatment were censored.

Time to withdrawal was defined as the number of days from Core Study Day 1 to the first date of onset of the AE leading to discontinuation of tocilizumab.

Time frame: 108 Weeks

Population: LTE Safety population included all participants who received study drug and had at least one assessment of safety in the long term extension(LTE). Participants who did not experience an AE-related treatment discontinuation of tocilizumab were censored.