A Study on Safety and Efficacy of Tocilizumab (RoActemra/Actemra) Alone or in Combination With Non-Biologic Antirheumatics in Participants With Rheumatoid Arthritis

Study Overview
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Brief Summary
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This multi-center, open-label single arm Phase IIIb study will evaluate the safety and efficacy of subcutaneous (SC) tocilizumab administered as monotherapy and/or in combination with methotrexate or other non-biologic disease modifying antirheumatic drugs (DMARDs) in participants with rheumatoid arthritis (RA) with an inadequate response to non-biologic DMARDs.

Official Title
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Multi-Center, Open Label, Single Arm Phase IIIB Study on Safety and Efficacy of Subcutaneous Tocilizumab in Monotherapy or in Combination With Methotrexate or Other Non-Biologic Disease Modifying Antirheumatic Drugs in Rheumatoid Arthritis Patients With an Inadequate Response to Non-Biologic DMARDs - OSCAR

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Non-Biologic DMARDs
* Drug: Tocilizumab
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria. Oral corticosteroids (≤10 mg/day prednisone or equivalent), nonsteroidal anti-inflammatory drugs (NSAIDs) and non-biologic DMARDs are permitted if on a stable dose regimen for greater than or equal to (≥]) 4 weeks prior to Baseline. Use of effective contraception throughout the study as defined by protocol; female participants of childbearing potential cannot be pregnant. Exclusion Criteria: Presence of clinically significant medical conditions. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower gastrointestinal disease that might predispose to perforation. Current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections. Any infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening. Clinically significant findings on laboratory tests. Positive hepatitis B surface antigen or hepatitis C antibody. Active tuberculosis requiring treatment within the previous 3 years. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years, or breast cancer diagnosed within the previous 20 years. History of alcohol, drug, or chemical abuse within 1 year prior to Screening. Neuropathies or other conditions that might interfere with pain evaluation. Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following Baseline. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjögren's syndrome with RA is permitted. Functional Class IV as defined by the ACR Classification of Functional Status in RA. Diagnosis of juvenile idiopathic arthritis or juvenile RA, and/or RA before the age of 16 years. Prior history of or current inflammatory joint disease other than RA. Exposure to tocilizumab (either intravenous or SC) at any time prior to Baseline. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, with alkylating agents such as chlorambucil, or with total lymphoid irradiation. Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline. Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab Alone or in Combination with Methotrexate or DMARD<br>Participants will receive a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy or in combination with methotrexate or other non-biologic DMARDs for 24 weeks. | Drug: Non-Biologic DMARDs<br>* Treatment with non-biologic DMARDs, at a stable dose that was initiated at least 4 weeks prior to baseline, is permitted during the study and is at the investigator's discretion.<br>Drug: Tocilizumab<br>* Tocilizumab 162 mg will be administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 24 weeks.<br>* Other names: RoActemra, Actemra;Drug: Methotrexate<br>* Methotrexate will be administered per investigator's discretion.<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 | An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Adverse events included serious as well as non-serious adverse events. | Baseline up to Week 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal | DAS28 was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, erythrocyte sedimentation rate (ESR; millimeters per hour [mm/hour]), and patient's global assessment of disease activity (measured on a 0 to 100 mm Visual Analog Scale [VAS] where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR less than or equal to (≤) 3.2 implied low disease activity and greater than (>) 3.2 to 5.1 implied moderate to high disease activity, and DAS28-ESR less than (<) 2.6 implied clinical remission. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response | A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) 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 5) an acute-phase reactant (either C-reactive protein [CRP] or ESR). | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants Achieving an ACR50 Response | A participant had an ACR50 response if there was at least a 50% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) 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 5) an acute-phase reactant (either CRP or ESR). | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants Achieving an ACR70 Response | A participant had an ACR70 response if there was at least a 70% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) 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 5) an acute-phase reactant (either CRP or ESR). | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants Achieving an ACR90 Response | A participant had an ACR90 response if there was at least a 90% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) 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 5) an acute-phase reactant (either CRP or ESR). | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR | DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (VAS: 0 mm=no disease activity to 100 mm=maximum disease activity). DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. The DAS28-ESR based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders had a change from baseline >1.2 with a DAS28 score ≤3.2; moderate responders had a change from baseline >1.2 with a DAS28 score >3.2 or a change from baseline >0.6 to ≤1.2 with a DAS28 score ≤5.1. Participants with change from baseline >0.6 to ≤1.2 with a DAS28 score >5.1, or any score with change from baseline ≤0.6, were assessed as non-responders. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal | The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician global assessment of disease activity assessed on 0-10 centimeter (cm) VAS (0 cm= no disease activity and 10 cm= worst disease activity), and CRP in milligrams per liter (mg/L). SDAI total score = 0-86. SDAI <=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 . | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 16, 20, 24, and Early Withdrawal | The CDAI is the numerical sum of four outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician's global assessment of disease activity assessed on 0-10 cm VAS (0 cm= no disease activity and 10 cm= worst disease activity). CDAI total score = 0-76. CDAI <= 2.8 indicates clinical remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high (or severe) disease activity. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Change From Baseline in Total TJC at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal | Number of tender joints was determined by examining 28 joints for TJC28 and 68 joints for TJC68, and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28 for a TJC28 and 68 for a TJC68. A reduction in number of tender joints compared to baseline indicates improvement. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Change From Baseline in Total SJC at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal | Number of swollen joints was determined by examination of 28 joints for SJC28 and 66 joints for SJC66 and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28 for a SJC28 and 66 for a SJC66. A reduction in number of swollen joints compared to baseline indicates improvement. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) | 
| Percentage of Participants With Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Dose Reductions or Discontinuation Categorized by Reasons | Results are reported for percentage of participants who had NSAIDs dose reductions or discontinuation by reasons for dose reductions or discontinuation (unknown reasons, safety reasons, other reasons, lack of efficacy, and discomfort). | From Week 16 and before Week 20; From Week 20 and before Week 24 | 
| Percentage of Participants With Corticosteroid Dose Reductions or Discontinuation Categorized by Reasons | Results are reported for percentage of participants who had corticosteroid dose reductions or discontinuation by reasons for dose reductions or discontinuation (unknown reasons, safety reasons, other reasons, lack of efficacy, and discomfort). | From Week 16 and before Week 20; From Week 20 and before Week 24 | 
| Time to Discontinuation or First Dose Reduction of Corticosteroids or NSAIDs | Time to discontinuation or first dose reduction of corticosteroids or NSAIDs (weeks) = (Date of the first dose reduction or end date of corticosteroids or NSAIDs treatment - date of first drug intake of this study) + 1. Time to discontinuation or first dose reduction was based on the first occurring event (corticosteroid discontinuation or corticosteroid first dose reduction or NSAIDs discontinuation or NSAIDs first dose reduction, whichever occurred first). | Baseline up to Week 32 | 
| Percentage of Participants With Anti-Tocilizumab Antibodies |  | Baseline, Weeks 12 and 24, early withdrawal (up to Week 24), follow-up visit (8 weeks after last dose of tocilizumab, up to 32 weeks) | 
| Serum Levels of Tocilizumab |  | Baseline, Weeks 12 and 24, Early Withdrawal (up to Week 24), Follow-up Visit (8 weeks after last dose of tocilizumab, up to 32 weeks) | 
| Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs) |  | Baseline, Weeks 12 and 24, Early Withdrawal (up to Week 24), Follow-up Visit (8 weeks after last dose of tocilizumab, up to 32 weeks) | 
| Patient Global Assessment of Disease Activity VAS Scores | Patient global assessment of disease activity was measured on a 0 to 100 mm horizontal VAS where 0 mm=no disease activity and 100 mm=maximum disease activity. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and Early withdrawal (up to Week 24) | 
| Patient Pain VAS Scores | This assessment represents the participant's assessment of his/her current level of pain on a 100 mm horizontal VAS where 0 mm= no pain to 100 mm= unbearable pain. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and Early withdrawal (up to Week 24) | 
| Health Assessment Questionnaire-Disability Index (HAQ-DI) Score | The HAQ-DI questionnaire measures functional status (disability) and health-related quality of life. It measures the participant's ability to perform everyday tasks. The index consists of 20 questions regarding the function of the upper and lower extremities. These questions are summarized in 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common activities over past week. Each question is evaluated according to the degree of severity on a 4-point scale. Total score for HAQ-DI was the average of all questions and ranges from 0 = without any difficulty to 3 = unable to do. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) | 
| Percentage of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records | A diary card was provided to participants to record home injections. Participants were asked to return all empty drug supply boxes, unused pre-filled syringe, and diary cards to the clinic at each visit as a measure of drug accountability and participant compliance. A participant was considered compliant if the participant correctly administered all scheduled doses of SC tocilizumab during the assessment period. | Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) | 
| Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score | The FACIT-F score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants 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 participant'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). | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) |