A Study of RoActemra/Actemra (Tocilizumab) in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to DMARDs (REMISSION)

Study Overview
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Brief Summary
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This open label, single arm study will assess the safety and efficacy of RoActemra/Actemra (tocilizumab) in patients with moderate to severe active rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARDs). Patients will receive RoActemra/Actemra at a dose of 8 mg/kg intravenously every 4 weeks for 24 weeks (6 infusions).

Official Title
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A Single Arm, Open Label Study to Assess the Safety, Tolerability and Efficacy of Tocilizumab in Active Rheumatoid Arthritis Patients With Inadequate Response to the DMARDs (REMISSION Study)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: tocilizumab [RoActemra/Actemra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Moderate to severe active rheumatoid arthritis (DAS28 > 3.2 at screening) Inadequate response to DMARDs Body weight < 150 kg Exclusion Criteria: Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months of enrollment Rheumatic autoimmune disease other than RA American College of Rheumatology (ACR) functional class IV Prior history of or current inflammatory joint disease other than RA Previous treatment with any biologic drug that is used in the treatment of RA Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline Pregnant or lactating women Active current or history of recurrent infection, active TB within the previous 3 years, HIV infection

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br> | Drug: tocilizumab [RoActemra/Actemra]<br>* 8 mg/kg iv every 4 weeks, total of 6 infusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events | Percentage of participants with adverse events (AEs), serious adverse events (SAEs), severe AEs, AEs leading to withdrawal, AEs leading to death, and treatment-related AEs. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With All-Cause Discontinuation of Tocilizumab by Study Visit | Percentage of participants discontinuing study treatment for any reason at every visit; causes of discontinuation in the summary included AEs, deaths, lost to follo-wup, AE and investigator decision and 'not determined'. | Weeks 4, 8, 12, 16, 20, and 24 | 
| Change From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Highest Value | The difference between baseline and highest values until Week 24 of ALT and AST. The values are measures as international units per liter (UI/L). The change was calculated as the value (highest) at a later timepoint up to Week 24, minus the value at Baseline. | Baseline through Week 24 | 
| Change From Baseline Low-Density Lipoprotein (LDL) and Total Cholesterol (TC) to Highest Values | Levels of LDL and TC were measured in milligrams/deciliter (mg/dL). Change in LDL and TC were calculated as the value (highest) through Week 24, minus the value at Baseline. | Baseline through Week 24 | 
| Percentage of Participants With Lipid Elevations by Study Visit | Lipid panel assessed included TC, triglycerides, high-density lipoprotein (HDL), and LDL. Elevations were categorized as follows: LDL cholesterol: Optimal equals (=) less than (<)100 mg/dL, Near optimal=100-129 mg/dL, Borderline high 130-159 mg/dL, High 160-189 mg/dL, Very High ≥190 mg/dL; Total cholesterol: Desirable <200 mg/dL, Borderline high 200-239 mg/dL, High ≥240 mg/dL; HDL cholesterol: Low <40 mg/dL, High ≥60 mg/dL; Triglycerides: Normal <150 mg/dL, Borderline high 150-199 mg/dL, High 200-499 mg/dL, and Very high ≥500 mg/dL. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Disease Activity Score Based on 28-Joint Count (DAS28) | DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the erythrocyte sedimentation rate (ESR; in millimeters per hour [mm/hour]) and global health assessment (participant-rated global assessment of disease activity using 10-mm visual analog assessment [VAS]); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 less than or equal to (≤3.2) = low disease activity, DAS28 greater than (>)3.2 to less than or equal to (≤) 5.1=moderate to high disease activity; DAS28 >5.1=high disease activity. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants by DAS28 Response Category | DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hour) and global health assessment (participant-rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 ≤3.2 =low disease activity, DAS28 >3.2 to ≤5.1=moderate to high disease activity; DAS28 >5.1=high disease activity. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With a Clinically Meaningful Improvement in Disease Activity | DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hour) and global health assessment (participant-rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. A reduction in DAS28 of at least 1.2 units was considered a clinically meaningful improvement. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Time to Achieve Clinically Meaningful Reduction in DAS28 | A clinically meaningful improvement in DAS28 was defined as a reduction of at least 1.2 units. Time to achieving clinically meanigful improvement was calculated as the number of days from the first infusion to the first achievement of reduction of 1.2 units in DAS28. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants Achieving Remission (DAS28 <2.6) | DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hour) and global health assessment (participant-rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. Participants with a DAS28 score <2.6 were considered to have achieved remission. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Percentage of Participants With a Response Assessed Using American College of Rheumatology (ACR) Criteria | The ACR response rates ACR20, ACR50, ACR70 are defined as ≥20%, ≥50%, ≥70% improvement, respectively, in: swollen joint count (SJC) (66 joints) and tender joint count (TJC) (68 joints) and 3 of the following 5 assessments: Patient assessment of pain (VAS); Patient global assessment of disease activity (VAS); Investigator global assessment of disease activity (VAS); and acute phase response (ESR or CRP) | Weeks 4, 8, 12, 16, 20, and 24 | 
| Swollen and Tender Joint Counts | The following 28 joints were assessed by the physician for swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). The following 28 joints were assessed by the physician for tenderness : metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). The change in SJC and TJC was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Health Assessment Questionnaire (HAQ) | HAQ was used to assess the physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple-choice items concerning difficulty in performing 8 common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from 4 response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The change in HAQ was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Patient Global Assessment of Disease Activity (VAS) | The participant's overall assessment of their current disease activity was displayed on a 100-mm horizontal VAS. The left-hand extreme (0 mm) of the line was described as no disease activity (symptom free and no arthritis symptoms) and the right-hand extreme (100 mm) was described as maximum disease activity (maximum arthritis disease activity). The change in Patient Global Assessment of Disease Activity was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Physician's Global Assessment of Disease Activity (VAS) | The physician's assessment of the participant's current disease activity was displayed on a 100-mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as no disease activity (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) was described as maximum disease activity. The Physician's Global Assessment of Disease Activity was completed by the Efficacy Assessor who could or could not be a physician. The change in Physician's Global Assessment of Disease Activity was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Patient Assessment of of Pain (VAS) | The participant's assessment of their current level of pain was displayed on a 100-mm horizontal VAS. The left-hand extreme (0 mm) of the line was described as no pain and the right-hand extreme of the line (100 mm) was described as unbearable pain. The change in participant's perception of pain was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| C-Reactive Protein (CRP) | CRP is an acute phase inflammatory marker. Levels of CRP increase with inflammation. The change in CRP was determined as the difference in values from baseline and at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 | 
| Erythrocyte Sedimentation Rate (ESR) | ESR indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. The change in ESR was determined as the difference in values from baseline at each visit. | Baseline, Weeks 4, 8, 12, 16, 20, and 24 |