A Multi-Center Open-Label Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous Tocilizumab in Tocilizumab-Naive Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Current Non-Biologic DMARD and/or Biologic Therapy
Overview
- Phase
- Phase 3
- Intervention
- Tocilizumab
- Conditions
- Rheumatoid Arthritis
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 139
- Primary Endpoint
- Change From Baseline in Disease Activity Score Based on 28-joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
This two part, multi-center, open-label, single-arm study will evaluate the efficacy and safety of tocilizumab as a monotherapy or in combination with methotrexate or other conventional synthetic disease modifying antirheumatic drugs (csDMARDs) in participants with moderate to severe active rheumatoid arthritis who have an inadequate response or are intolerant to non-biologic csDMARDs and/or biologic therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants with a diagnosis of active rheumatoid arthritis according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria and receiving outpatient treatment
- •Oral corticosteroids (\</= 10 mg/day prednisone or equivalent), nonsteroidal anti-inflammatory drugs (NSAIDs), and permitted csDMARDs are allowed at a stable dose for at least 4 weeks prior to Baseline
- •At Screening either CRP \>/=10 mg/L or ESR \>/=20 mm/h and SJC \>/=3 (based on 44 joints)
- •Inadequate response (IR) to tumor necrosis factor, abatacept and/or non-biological DMARDs
Exclusion Criteria
- •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 rheumatoid arthritis; Secondary Sjögren's syndrome with rheumatoid arthritis is permitted
- •Functional Class IV as defined by the 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
- •Prior history of or current inflammatory joint disease other than rheumatoid arthritis
- •Exposure to tocilizumab at any time prior to Baseline
- •Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever was longer) of Screening
- •Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies or any alkylating agents such as chlorambucil, or with total lymphoid irradiation
- •Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline
- •Intraarticular or parenteral corticosteroids within 4 weeks prior to Baseline
Arms & Interventions
Tocilizumab
Participants will receive tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection once a week administered as monotherapy or in combination with methotrexate or other csDMARDs (at investigator's discretion) for 24 weeks. Participants who complete the core study period will be allowed to enter a long-term-extension (LTE) period to continue study treatment for up to a maximum of another 52 weeks or until the commercial availability of SC tocilizumab, whichever occurs first.
Intervention: Tocilizumab
Tocilizumab
Participants will receive tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection once a week administered as monotherapy or in combination with methotrexate or other csDMARDs (at investigator's discretion) for 24 weeks. Participants who complete the core study period will be allowed to enter a long-term-extension (LTE) period to continue study treatment for up to a maximum of another 52 weeks or until the commercial availability of SC tocilizumab, whichever occurs first.
Intervention: Methotrexate
Tocilizumab
Participants will receive tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection once a week administered as monotherapy or in combination with methotrexate or other csDMARDs (at investigator's discretion) for 24 weeks. Participants who complete the core study period will be allowed to enter a long-term-extension (LTE) period to continue study treatment for up to a maximum of another 52 weeks or until the commercial availability of SC tocilizumab, whichever occurs first.
Intervention: csDMARDs
Outcomes
Primary Outcomes
Change From Baseline in Disease Activity Score Based on 28-joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24
Time Frame: Baseline, Week 24
The DAS28-ESR was derived from assessments of erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), and Patient Global Assessment of disease activity (PGA) according to 100-millimeter (mm) Visual Analog Scale (VAS). DAS28-ESR scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. TJC was defined as the number of painful joints and SJC was defined as the number of swollen joints, each assessed on 28 joints. ESR was measured in millimeters per hour (mm/h). DAS28-ESR scores could range from 0 to 10, where higher scores represented higher disease activity. The change from Baseline to Week 24 was averaged among all participants, where negative changes indicated an improvement in disease activity.
Secondary Outcomes
- Change From Baseline in PGA at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64)
- Change From Baseline in Pain VAS Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64)
- Change From Baseline in Physician's Global Assessment of Disease Activity at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Change From Baseline in DAS28-ESR at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Percentage of Participants With DAS28-ESR Low Disease Activity (LDA) and Remission at Week 24(Week 24)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64)
- Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Score at Weeks 12, 24, 28, 40, 52, and 64(Baseline, Weeks 12, 24, 28, 40, 52, and 64)
- Change From Baseline in Routine Assessment of Patient Index Data 3 (RAPID-3) at Weeks 2, 4, 12, 24, 28, 40, 52, and 64(Baseline, Weeks 2, 4, 12, 24, 28, 40, 52, and 64)
- Percentage of Participants With Health Assessment Questionnaire-Disability Index (HAQ-DI) Remission at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64)
- Percentage of Participants With HAQ-DI Clinically Meaningful Improvement at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64)
- Number of Participants With Patient Acceptable Symptom State (PASS) Score(Baseline, Weeks 24, 52, and last assessment (up to Week 76))
- Change From Baseline in BioSecure Questionnaire Score at Week 24(Baseline, Week 24)
- Percentage of Participants With Change in Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Percentage of Participants With DAS28-ESR LDA and Remission at Week 24 and at Last Assessment(Week 24, last assessment (up to Week 76))
- Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response at Week 24(Baseline, Week 24)
- Percentage of Participants Achieving ACR20, ACR50, and ACR70 Response at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28-ESR at Week 24(Baseline, Week 24)
- Change From Baseline in Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ) Total Score at Weeks 24 and 52(Baseline, Weeks 24 and 52)
- Time to Change in Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Change From Baseline in Bristol Rheumatoid Arthritis Fatigue (BRAF)-NRS Score at Weeks 24 and 52(Baseline, Weeks 24 and 52)
- Change From Baseline in Medical Outcome Study (MOS) Sleep Questionnaire Score at Weeks 12, 24, 28, 40, 52, and 64(Baseline, Weeks 12, 24, 28, 40, 52, and 64)
- Change From Baseline in Fluctuations of Disease Activity in Rheumatoid Arthritis (FLARE) Questionnaire Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64)
- Change From Baseline in Synovitis Ultrasound Power-Doppler Mode Score at Week 24(Baseline, Weeks 24)
- Percentage of Participants With EULAR Response Based on DAS28-ESR at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Change From Baseline in CDAI at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Percentage of Participants With Discontinuations of Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Time to Permanent Discontinuation of Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Percentage of Participants With Discontinuations of Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Percentage of Participants With Change in Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Time to First Temporary Discontinuation of Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Number of Participants According to Reasons for Change in Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Time to Permanent Discontinuation of Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Time to First Temporary Discontinuation of Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Percentage of Participants With Anti-Therapeutic Antibodies to Tocilizumab(Baseline up to 8 weeks after last study drug administration (up to Week 84))
- Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Time to Change in Corticosteroid Dosage During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Number of Participants According to Reasons for Changes in csDMARDs Treatment During Core Study Period(Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks))
- Percentage of Participants With SDAI LDA and Remission at Week 24(Week 24)
- Change From Baseline in SDAI at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Change From Baseline in SJC at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Change From Baseline in TJC at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Percentage of Participants With SDAI LDA and Remission at Week 24 and at Last Assessment(Week 24, last assessment (up to Week 76))
- Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Percentage of Participants With CDAI LDA and Remission at Week 24(Week 24)
- Percentage of Participants With CDAI LDA and Remission at Week 24 and at Last Assessment(Week 24, last assessment (up to Week 76))
- Change From Baseline in DAS28-ESR at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Change From Baseline in SJC at Week 24 and at Last Assessment(Baseline, Week 24, last assessment (up to Week 76))
- Change From Baseline in TJC at Weeks 2, 4, 8, 12, 16, 20, and 24(Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24)
- Treatment Compliance From Baseline up to Week 24(Baseline up to Week 24)
- Number of Participants According to Reasons for Change in Corticosteroid Dosage During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Number of Participants According to Reasons for Changes in csDMARDs Treatment During Study(Screening up to 8 weeks after last dose (overall up to 88 weeks))
- Change From Baseline in Synovitis Ultrasound B-Mode Score at Week 24(Baseline, Weeks 24)