A 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose-finding Study to Evaluate the Efficacy, Safety and Tolerability of ACZ885 (Anti-interleukin-1beta Monoclonal Antibody) With Three Different Dose Regimens in Patients With Active Rheumatoid Arthritis Despite Stable Treatment With Methotrexate Including 76-week and 96-week Extensions
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Novartis
- Enrollment
- 274
- Locations
- 13
- Primary Endpoint
- Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Week 12
Study Overview
Brief Summary
The 12-week core study was designed to evaluate risk-benefit of three subcutaneous dose regimens of ACZ885, added on to stable methotrexate (MTX) therapy (greater than or equal to 7.5 mg/week), compared to placebo in patients with active rheumatoid arthritis (RA). The study investigated the magnitude of effect as well as onset of effect for the different dose regimens.
The primary objective of the extension studies was to assess long-term safety and tolerability of canakinumab (ACZ885) in patients with active RA. CACZ885A2201E1 evaluated this objective in patients who had participated in the core study (CACZ885A2201) and CACZ885A2201E2 did the same in patients who completed the first extension study.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients who completed the core CACZ885A2201 study may enter the first extension study upon signing informed consent. A patient is defined as completing the study if he/she completed the core CACZ885A2201 study up to and including Visit
- •Patients who completed the first extension study, may enter the second.
- •Extension Studies Exclusion Criteria
- •Patients for whom continued treatment in the extension is not considered appropriate by the treating physician.
- •Patients who were non-compliant or who demonstrated a major protocol violation in the core CACZ885A2201 study.
- •Patients who discontinued from the core CACZ885A2201 study before Visit 12.
Exclusion Criteria
- Not provided
Arms & Interventions
Canakinumab 600 mg IV + 300 mg q2wk
Participants received canakinumab 600 mg intravenous (IV) loading dose on Day 1 and 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg every 4 weeks.
Intervention: Canakinumab (Drug)
Canakinumab 300 mg q2wk
Participants received canakinumab 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.
Intervention: Canakinumab (Drug)
Canakinumab 150 mg q4wk
Participants received canakinumab 150 mg subcutaneous injections every 4 weeks (q4wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.
Intervention: Canakinumab (Drug)
Placebo
Participants received placebo subcutaneous injections every 2 weeks for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Week 12
Time Frame: Baseline and Week 12
Participants were defined as ACR50 responders if they had at least a 50% improvement from Baseline in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: * Patient's pain assessment (assessed using a 100 mm Visual Analog Scale \[VAS\]); * Patient's global assessment of disease activity (VAS 100 mm); * Physician's global assessment of disease activity (VAS 100 mm); * Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score); * Acute phase reactant (high sensitivity C-reactive Protein \[hsCRP\]). Details on each of these components are provided in Outcome Measures 10-16. Participants were considered as non-responders if they failed the ACR50 criteria. Participants who prematurely discontinued due to insufficient therapeutic effect were also considered non-responders.
Percentage of American College of Rheumatology [ACR] 20 Criteria Responders During the Extension Phase
Time Frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Participants were defined as ACR20 responders if they had at least a 20% improvement from Baseline in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: * Patient's pain assessment (assessed using a 100 mm Visual Analog Scale \[VAS\]) * Patient's global assessment of disease activity (VAS 100 mm) * Physician's global assessment of disease activity (VAS 100 mm) * Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) * Acute phase reactant (high sensitivity C-reactive Protein \[hsCRP\]). Participants were considered as non-responders if they failed the ACR20 criteria. Participants who prematurely discontinued due to insufficient therapeutic effect were also considered non-responders.
Percentage of American College of Rheumatology [ACR] 50 Criteria Responders During the Extension Phase
Time Frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Participants were defined as ACR50 responders if they had at least a 50% improvement from Baseline in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: * Patient's pain assessment (assessed using a 100 mm Visual Analog Scale \[VAS\]) * Patient's global assessment of disease activity (VAS 100 mm) * Physician's global assessment of disease activity (VAS 100 mm) * Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) * Acute phase reactant (high sensitivity C-reactive Protein \[hsCRP\]). Participants were considered as non-responders if they failed the ACR50 criteria. Participants who prematurely discontinued due to insufficient therapeutic effect were also considered non-responders.
Change From Baseline in Disease Activity Score (DAS) 28 During the Extension Phase
Time Frame: Baseline and Weeks 24, 72 and 112
The Disease Activity Score (DAS) 28 is a combined index to measure the disease activity in patients with rheumatoid arthritis, and includes the following variables: * The number of swollen and tender joints assessed using the 28-joint count; * C-reactive protein (CRP) in mg/L; * Patient's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6
Percentage of American College of Rheumatology [ACR] 70 Criteria Responders During the Extension Phase
Time Frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Participants were defined as ACR70 responders if they had at least a 70% improvement from Baseline in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: * Patient's pain assessment (assessed using a 100 mm Visual Analog Scale \[VAS\]) * Patient's global assessment of disease activity (VAS 100 mm) * Physician's global assessment of disease activity (VAS 100 mm) * Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) * Acute phase reactant (high sensitivity C-reactive Protein \[hsCRP\]). Participants were considered as non-responders if they failed the ACR70 criteria. Participants who prematurely discontinued due to insufficient therapeutic effect were also considered non-responders.
Secondary Outcomes
- Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Weeks 2, 4 and 8(Baseline and Weeks 2, 4 and 8)
- Percentage of American College of Rheumatology [ACR] 20 Criteria Responders(Baseline and Weeks 2, 4, 8 and 12)
- Percentage of American College of Rheumatology [ACR] 70 Criteria Responders(Baseline and Weeks 2, 4, 8 and 12)
- Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at Week 12(Baseline and Week 12)
- Change From Baseline in Swollen 28-joint Count(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Tender 28-joint Count(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Patient's Pain Intensity(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Patient's Global Assessment of Disease Activity(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Physician's Global Assessment of Disease Activity(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Health Assessment Questionnaire (HAQ) Score(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Disease Activity Score (DAS) 28(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Erythrocyte Sedimentation Rate(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Rheumatoid Factor Concentration(Baseline and Weeks 4, 8 and 12)
- Change From Baseline in Short Form 36 Health Survey (SF-36)(Baseline and Weeks 2, 4, 8 and 12)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F)(Baseline and Weeks 2, 4, 8 and 12)
- Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at the End of the Extension Study(Baseline and End of Study (up to 124 weeks))
- Change From Baseline in Swollen 28-joint Count During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Tender 28-joint Count During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Patient's Pain Intensity During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Patient's Global Assessment of Disease Activity During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Physician's Global Assessment of Disease Activity During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Health Assessment Questionnaire (HAQ) Score During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.)
- Change From Baseline in Erythrocyte Sedimentation Rate During the Extension Study(Baseline and Weeks 24, 36, 48, 60, 72 and 88.)