This study was an extension to study MA21573 \[NCT00750880\], which was an open label single arm study to investigate the safety, tolerability and efficacy of tocilizumab monotherapy, or combination therapy with non-biological disease-modifying antirheumatic drugs (DMARDS), in patients with moderate to severe active rheumatoid arthritis. Patients who completed the 24 week core study, and had at least a moderate European League Against Rheumatism (EULAR) response, were eligible to enter this long-term extension study, and received tocilizumab 8 mg/kg intravenous (iv) every 4 weeks. The anticipated time on study treatment was 1-2 years, and the target sample size was \> 500 individuals.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
934
8 mg/kg IV (maximum dose not exceeding 800 mg in a single infusion) every 4 weeks.
Unnamed facility
Canberra, Australian Capital Territory, Australia
Unnamed facility
Coffs Harbour, New South Wales, Australia
Unnamed facility
Kogarah, New South Wales, Australia
Unnamed facility
Cairns, Queensland, Australia
Unnamed facility
Adelaide, South Australia, Australia
Unnamed facility
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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
Percentage of Participants With Adverse Events Leading to Withdraw
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
Time to Withdrawal Due to an Adverse Event (AE)
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
Percentage of Participants With Discontinuation of Treatment Due to Any Cause
Percentage of participants who discontinued treatment with tocilizumab for any reason.
Time frame: 108 Weeks
Time to Discontinuation of Tocilizumab Treatment for Any Cause
Time in days from start of the Core Study Day 1 to discontinuation of tocilizumab for any reason.
Time frame: 108 Weeks
Percentage of Participants With Marked Lipid Abnormalities
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
Percentage of Participants With Adverse Events (AEs) of Special Interest
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
Percentage of Participants With ALT Elevations > 3*ULN
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
Percentage of Participants With AST Elevations > 3*ULN
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
Number of Participants Categorized by Highest Value for ALT (SGPT) During the Study
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
Number of Participants Categorized by Worst Value for AST (SGOT) During the Study
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
Number of Participants Categorized by Worst Value for LDL Cholesterol During the Study
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
Number of Participants Categorized by Worst Value for Total Cholesterol During the Study
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
Number of Participants Categorized by Worst Value for Neutrophil Count During the Study
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
Percentage of Participants With Clinically Meaningful Improvement in Disease Activity Score-28 (DAS28)
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
Percentage of Participants With DAS28 Low Disease Activity
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
Percentage of Participants With DAS28 Remission
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
Change From Baseline in DAS28
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
Change From Baseline in Tender Joint Count
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
Change From Baseline in Swollen Joint Count
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
Change From Baseline in Patient Assessment of Pain Visual Analog Scale (VAS)
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
Change From Baseline in Patient Global Assessment of Disease Activity VAS
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
Change From Baseline in Physician Global Assessment of Disease Activity VAS
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
Change From Baseline in Erythrocyte Sedimentation Rate (ESR)
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
Change From Baseline in C-Reactive Protein (CRP)
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
Percentage of Participants With American College of Rheumatology 20 (ACR20) Response
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
Percentage of Participants With American College of Rheumatology 50 (ACR50) Response
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
Percentage of Participants With American College of Rheumatology 70 (ACR70) Response
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
Percentage of Participants With American College of Rheumatology 90 (ACR90) Response
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
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Response
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
Percentage of Participants Achieving Clinical Meaningful Health Assessment Questionnaire Disability Index (HAQ-DI) Response
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
Percentage of Participants Achieving Health Assessment Questionnaire Disability Index (HAQ-DI) Clinical Remission
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
Change From Baseline in Quality of Life Short Form (SF-36): Physical Component Score
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
Change From Baseline in Quality of Life Short Form (SF-36):Mental Component Score
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
Change From Baseline in FACIT-Fatigue Score
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
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