A Study of RoActemra/Actemra (Tocilizumab) Given Subcutaneously in Combination With Traditional DMARDs in Patients With Moderate to Severe Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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This randomized, parallel-group, placebo-controlled, multicenter study will evaluate the reduction in disease activity and the safety of tocilizumab (RoActemra/Actemra) in combination with traditional disease-modifying anti-rheumatic drugs (DMARDs) in patients with active, moderate to severe rheumatoid arthritis. In the double-blind part of the study, patients will be randomized to receive either 162 mg tocilizumab or placebo subcutaneously every 2 weeks for 24 weeks using a pre-filled syringe. In the open-label part of the study, patients will be randomized to receive 162 mg tocilizumab subcutaneously every 2 weeks from Week 24 to Week 96 using a pre-filled syringe or an auto-injector.

Official Title
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A Randomized, Double-blind, Parallel Group Study of Safety and the Effect on Clinical Outcome of Tocilizumab Subcutaneous (sc) Versus Placebo sc in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab 162 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, ≥ years of age. Moderate to severe rheumatoid arthritis of ≥ 6 months duration. Receiving treatment on an outpatient basis. Swollen joint count (SJC) ≥ 6 (66 joint count) and tender joint count (TJC)≥ 8 (68 joint count) at screening and study start. On a stable dose of disease-modifying anti-rheumatic drugs for at least 8 weeks prior to study start. Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization. Rheumatic autoimmune disease other than rheumatoid arthritis, Secondary Sjögren's Syndrome with rheumatoid arthritis is allowed. Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis. Diagnosis of juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis before the age of 16 years. Prior history of or current inflammatory joint disease other than rheumatoid arthritis. History of malignancy, active or recurrent infections, positive to hepatitis B surface antigen or hepatitis C antibody, active tuberculosis, serious allergy to biologics, or a history of diverticular disease or other symptomatic GI conditions that might predispose to perforations. Other inclusion and exclusion criteria applied to the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab 162 mg sc<br>Patients will receive tocilizumab 162 mg subcutaneously (sc) every 2 weeks for 24 weeks. | Drug: Tocilizumab 162 mg<br>* Tocilizumab will be supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers will be trained to administer the injection.<br>* Other names: Actemra;|
| Placebo Comparator: Placebo sc<br>Patients will receive placebo subcutaneously (sc) every 2 weeks for 24 weeks. | Drug: Placebo<br>* Placebo will be supplied in a ready-to-use, single-use, pre-filled syringe. Patients and/or caregivers will be trained to administer the injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With an American College of Rheumatology 20 (ACR20) Response at Week 24 | A patient had an ACR20 response if there was at least a 20% improvement, ie, reduction from baseline, in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, left end=no disease activity [symptom-free and no arthritis symptoms], right end=maximum disease activity; patient assessment of pain in previous 24 hours on a VAS (left end=no pain and right end=unbearable pain); Health Assessment Questionnaire-Disability Index (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). | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With ACR50 and ACR70 Responses at Week 24 | A patient had an ACR50 response if there was at least a 50% improvement in the ACR scores. A patient had an ACR70 response if there was at least a 70% improvement in the ACR scores. | Baseline to Week 24 | 
| Time to Onset of ACR20, ACR50, and ACR70 Responses | Time to first ACR response was calculated as the number of days between the date of the first ACR response minus the date of the first dose of study drug. Median days are reported. | Baseline to Week 24 | 
| Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 24 | Joints (28 joints) will be assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation on physical examination. | Baseline to Week 24 | 
| Change From Baseline in C-reactive Protein at Week 24 |  | Baseline to Week 24 | 
| Change From Baseline in Erythrocyte Sedimentation Rate at Week 24 |  | Baseline to Week 24 | 
| Change From Baseline in the Patient's and the Physician's Global Assessment of Disease Activity Visual Analog (VAS) Score | Patients and physicians assessed the patient's disease activity in the previous 24 hours on a 100 mm visual analog scale, where the extreme left end of the line represented no disease activity (symptom-free and no arthritis symptoms) and the extreme right end represented maximum disease activity. Scores ranged from 0 to 100 with a higher score indicating more disease activity. A negative change score indicated less disease activity. | Baseline to Week 24 | 
| Change From Baseline in the Patient's Pain Visual Analog Score | Patients assessed their pain in the previous 24 hours on a visual analog scale, where the extreme left end of the line represented no pain and the extreme right end represented unbearable pain. Scores ranged from 0 to 100 with a higher score indicating more pain. A negative change score indicated less pain. | Baseline to Week 24 | 
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 | The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to Week 24 | 
| Percentage of Patients With an Improvement of ≥ 0.3 Units From Baseline in the HAQ-DI Score at Week 24 | The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Patients completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in Disease Activity Score 28 (DAS28) at Week 24 | The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement. | Baseline to Week 24 | 
| Percentage of Patients With a DAS28 Score ≤ 3.2 (DAS28 Low Disease Activity) at Week 24 | The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement. | Baseline to Week 24 | 
| Percentage of Patients With a DAS28 Score < 2.6 (DAS28 Remission) at Week 24 | The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A negative change score indicates improvement. | Week 24 | 
| Percentage of Patients With Good, Moderate, or no European League Against Rheumatism (EULAR) Responses at Week 24 | Change of the Disease Activity Score 28 score from baseline was used to determine EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2. | Baseline to Week 24 | 
| Change From Baseline in the Van Der Heijde Modified Sharp Radiographic Score at Week 24 | The degree of joint damage was assessed using the van der Heijde modified total Sharp score (mTSS). The methodology quantifies the extent of bone erosions for 44 joints and joint space narrowing (JSN) for 42 joints, with higher scores representing greater damage. The independent read of X-ray images was performed by 2 primary readers. In case of discrepancy between the 2 primary readers, an adjudicator was involved. The mTSS can range from 0 to 448 with a higher score indicating more joint damage. A negative change score indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in the Physical and Mental Component Scores of the Short Form 36 (SF-36) Health Survey at Week 24 | The SF-36 Health Survey uses patient-reported symptoms on 8 subscales to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100 with a higher score indicating better HRQoL. A positive change score indicates an improvement in HRQoL. | Baseline to Week 24 | 
| Change From Baseline in Hemoglobin at Week 24 |  | Baseline to Week 24 |