This Phase IIIb, multicenter, open label, single arm study will evaluate the safety and efficacy of subcutaneous (SC) tocilizumab as monotherapy or in combination with methotrexate or other non-biologic DMARDs in participants with active rheumatoid arthritis who are either naïve to or have an inadequate response to prior non-biologic or/and biologic DMARDs. The anticipated time on study treatment is 52 weeks. Those participants who will complete the 60-week study period and have achieved Disease Activity Score 28 (DAS28) remission or a good European League Against Rheumatism (EULAR) response at 52 weeks will be eligible to enter the extension phase until tocilizumab is commercially available and reimbursed in Greece.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
100
Participants may receive azathioprine as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants may receive chloroquine as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants may receive hydroxychloroquine as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants may receive leflunomide as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants may receive methotrexate as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants may receive sulfasalazine as a concomitant therapy with tocilizumab as per physician's judgment at a stable dose that was initiated at least 4 weeks prior to baseline.
Participants will receive tocilizumab at a fixed dose of 162 mg SC QW either as monotherapy or in combination with non-biologic DMARDs.
District Gen. Hosp. of Athens Laiko; A Propedeutic Internal Medicine Clinic & Research Center
Athens, Greece
Laiko General Hospital; Dept. of Pathophysiology-Uni of Athens
Athens, Greece
Hippokratio Hospital; 2Nd Internal Medicine
Athens, Greece
ATTIKO Hospital_4th University Internal Medicine Clinic
Haidari, Greece
Uni General Hospital of Heraklion; Medicine and Rheumatology Clinical Immunology and Allergy Dept
Heraklion, Greece
Uni Hospital of Ioannina; Rheumatology
Ioannina, Greece
University General Hospital of Larissa; Rheumatology Unit
Larissa, Greece
University Hospital of Patras; Rheumatology
Pátrai, Greece
EUROMEDICA Geniki Kliniki Thessalonikis; Rheumatology Department
Thessaloniki, Greece
General Hospital of Thessaloniki HIPPOKRATIO; Clinical Immunology Unit,2nd Dept of Internal Medicine
Thessaloniki, Greece
Percentage of Participants Who Achieved Disease Activity Score Based on 28 Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR) Remission at Week 24
DAS28-ESR score is a measure of participant's disease activity calculated using tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), patient global assessment of disease activity (PGA) (general health \[GH\]) using visual analog scale (VAS): 0 millimeter (mm)=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (ESR in millimeters per hour \[mm/hr\]). The score is calculated using the following formula: DAS28-ESR = \[0.56 multiplied by (\*) square root (√) of TJC28\] plus (+) \[0.28\*√SJC28\]+\[0.70\*the natural logarithm (ln) ESR\]+\[0.014\*GH\]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity. DAS28-ESR score of less than (\<) 2.6 represents DAS28-ESR remission.
Time frame: Week 24
Percentage of Participants Who Maintained DAS28-ESR Remission From Week 24 up to Week 52 Among Participants on Tocilizumab Monotherapy Since Week 24
DAS28-ESR score is a measure of participant's disease activity calculated using TJC28, SJC28, PGA using VAS 0 mm=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (ESR in mm/hr) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28-ESR = \[0.56 \* √TJC28 + \[0.28\*√SJC28\]+\[0.70\*ln ESR\]+\[0.014\*GH\]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity. DAS28-ESR score \<2.6 represents DAS28-ESR remission. The percentage reported for Week 24 is based on confirmation on switching to SC tocilizumab monotherapy.
Time frame: Weeks 24, 28, 32, 36, 40, 44, 48, 52
Percentage of Participants Who Achieved DAS28-ESR Remission/Low Disease Activity (LDA) From Week 28 up to Week 52 Among Participants With Intensification of Methotrexate/Other Non-Biologic DMARDs in Combination With Tocilizumab Since Week 24
DAS28-ESR score is a measure of participant's disease activity calculated using TJC28, SJC28, PGA using VAS 0 mm=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (ESR in mm/hr) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28-ESR = \[0.56 \* √TJC28 + \[0.28\*√SJC28\]+\[0.70\*ln ESR\]+\[0.014\*GH\]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity. DAS28-ESR score \<2.6 represents DAS28-ESR remission. DAS28-ESR score greater than or equal to (\>/=) 2.6 and \<3.2 represents LDA.
Time frame: Weeks 28, 32, 36, 40, 44, 48, 52
Change From Baseline in DAS28-ESR up to Week 52
DAS28-ESR score is a measure of participant's disease activity calculated using TJC28, SJC28, PGA using VAS 0 mm=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (ESR in mm/hr) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28-ESR = \[0.56 \* √TJC28 + \[0.28\*√SJC28\]+\[0.70\*ln ESR\]+\[0.014\*GH\]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity. A negative change from baseline indicates an improvement.
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Number of Participants With American College of Rheumatology 20 (ACR20) Response
ACR20 response was defined as \>/=20% improvement from baseline in both TJC28 and SJC28 as well as in 3 out of 5 additional parameters: Separate patient and physician's global assessment of disease activity on VAS (0 mm=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS), patient's assessment of pain on VAS (0 mm=no pain to 100 mm=unbearable pain, displayed on the 100 mm horizontal VAS), Health Assessment Questionnaire - Disability Index (HAQ-DI) (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without any difficulty to 3=unable to do), and acute phase response (ESR in mm/hr, for a total possible score of 0 to 10).
Time frame: Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Percentage of Participants With Good, Moderate, or No Response According to European League Against Rheumatism (EULAR) Response Criteria
Response to treatment was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from the baseline visit. Participants with a score lesser than or equal to (\</=) 3.2 and reduction of greater than (\>) 1.2 points were assessed as having a 'good' response. Participants with a score \>3.2 with reduction of \>1.2 points, or a score \</=5.1 with reduction of \>0.6 to \</=1.2 points, were assessed as having a 'moderate' response. Participants with a score \>5.1 with reduction of \>0.6 to \</=1.2 points, or any score with reduction \</=0.6 points, were assessed as having 'no response'.
Time frame: Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Change From Baseline in Simplified Disease Activity Index (SDAI) Score up to Week 52
SDAI is an index for measuring disease activity. SDAI is the numerical sum of five outcome parameters: TJC28 and SJC28, PGA and physician global assessment of disease activity assessed on VAS (0 centimeter \[cm\]-10 cm); 0 cm= no disease activity and 10 cm= worst disease activity, and CRP (in milligrams per deciliter \[mg/dL\]). SDAI total score ranges from 0 to 86, with higher scores indicating increased (or severe) disease activity. SDAI score \</=3.3 indicates clinical remission, \>3.4 to 11 = low disease activity, \>11 to 26 = moderate disease activity, and \>26 = high (or severe) disease activity.
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Change From Baseline in TJC28 up to Week 52
28 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 28. A negative change from baseline indicated improvement.
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Change From Baseline in SJC28 up to Week 52
28 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 28. A negative change from baseline indicated improvement.
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Percentage of Participants With Corticosteroid Dose Reduction or Discontinuation
Time frame: From Baseline up to Week 52
Number of Participants by Reasons (Categories) for Corticosteroid Dose Reduction or Discontinuation
Reasons for corticosteroid dose reduction included: Safety Reasons (including elevated liver function test results, respiratory infections, infections and infestations, gastrointestinal disorders etc.); Other Reasons (disease remission, improvement etc.); and Unknown Reasons (including no reason). Number of participants by reasons (Safety, Other, Unknown) for corticosteroid dose reduction or discontinuation were reported.
Time frame: From Baseline up to Week 52
Number of Participants With Anti-Tocilizumab Antibodies (ATA)
All samples were tested using a screening assay and, if positive, by a confirmation assay to determine specificity and a neutralizing assay to test for the ability to inhibit the activity of tocilizumab. Number of participants with a positive assay result for screening assay (ATA - Screen), confirmatory assay (ATA - Confirmatory), and neutralizing assay (ATA - Neutralizing) was reported separately.
Time frame: Baseline (Week 1), Weeks 12, 24, 36, 52, and 8 weeks after Week 52 dose (Week 60)
Soluble Interleukin-6 Receptor (sIL-6R) Levels
Time frame: Baseline (Week 1), Weeks 12, 24, 36, 52, and 8 weeks after Week 52 dose (Week 60)
Tocilizumab Serum Levels
Time frame: Baseline (Week 1), Weeks 12, 24, 36, 52, and 8 weeks after Week 52 dose (Week 60)
PGA, Using VAS Score
PGA was assessed on a 0 to 100 mm horizontal VAS. The extreme left end of the line = 0 mm, and was described as "no disease activity" (symptom-free and no arthritis symptoms) and the extreme right end = 100 mm, and was described as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Patient Assessment of Pain, Using VAS Score
The participant's level of pain was assessed on a 0 to 100 mm horizontal VAS. The extreme left end of the line = 0 mm, and was described as "no pain" and the extreme right end = 100 mm, and was described as "unbearable pain". Higher values correspond to worst state of participant (higher level of pain).
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
HAQ-DI Score
The Stanford HAQ-DI is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Responses in each component set were scored from 0 (without any difficulty) to 3 (unable to do). The highest score recorded for any question in a category determines the score for the category, unless aids, devices, or help from another person was required. The HAQ-DI score was calculated as the sum of the category scores divided by the number of categories scored, giving a possible range of scores from 0 to 3. Scores of 0 to 1 are generally considered to represent "mild to moderate difficulty", 1 to 2 as "moderate to severe disability", and 2 to 3 as "severe to very severe disability".
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Percentage of Participants Who Received All Planned Study Medication (Compliance)
Compliance (in terms of percentage of participants who received all planned study medication) was assessed on the basis of participant diary cards and return records.
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score
FACIT-Fatigue total score is sum of FACIT-General subscale score and FACIT-Fatigue (additional concerns) subscale score. FACT-General consists of 27 questions grouped in 4 domains of general health-related quality of life: physical well-being, social/family well-being, emotional well-being, and functional well-being; each item ranges from 0 (not at all) to 4 (very much). FACT-General score ranges between 0-108. FACIT-Fatigue subscale is a 13-item questionnaire that evaluates self-reported fatigue and its impact upon daily activities. Each item ranges from 0 (Not at all) to 4 (Very much). For all items, 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 subscale score for a total possible score of 0 (worse score) to 52 (better score). FACIT-Fatigue total score (FACT-G plus FACT-F subscale scores) ranges from 0 (better score) to 160 (worse score).
Time frame: Baseline (Week 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
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