Safety and Efficacy of ACZ885 in Adult Patients With Established Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study was intended to assess the safety, efficacy, and response to treatment using the American College of Rheumatology (ACR) criteria of 20% improvement in symptoms (ACR20) and to investigate a potential biomarker profile in adult patients with established rheumatoid arthritis

Official Title
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A 12-week, Phase II, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Assess the Response to Treatment (ACR20) and to Determine a Biomarker Profile in Adult Patients With Established Rheumatoid Arthritis Responding to ACZ885 (Anti-interleukin-1beta Monoclonal Antibody) as Compared to Healthy Subjects Exposed to ACZ885

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: ACZ885 (investigational)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RA patients: Male and female patients aged 18 - 75 years (inclusive). Body weight between 50 and 100 kg (inclusive). Post menopausal or surgically sterile female patients are allowed. Female patients of child-bearing potential may participate if they are already on a stable dose of methotrexate. Additional birth control details to be provided at screening. Male patients must use an effective contraception method during the study and at least for 2 months following the completion/discontinuation of the study. Diagnosis of RA, classified by American Rheumatism Association 1987 revised criteria. Disease duration of at least 6 months is essential. Functional status class I, II or III classified according to the American College of Rheumatology 1991 revised criteria. Active disease evaluation (≥ 6 tender and ≥ 6 swollen joints) Prior treatment with 1-3 disease-modifying anti-rheumatic drugs (DMARDs) - Patients should have failed at least 1 DMARD but should not be deemed refractory to all therapies. It is expected that patients are on a current treatment with methotrexate ≤ 25 mg/week and with the current dose stable for at least 3 months, however patients who did not tolerate MTX may also be considered. All patients will take folic acid 1 mg daily, or 5 mg weekly post MTX dose, to minimize toxicity, according to local guidelines. In addition to methotrexate, patients may be on either a stable dose of non-steroidal anti-inflammatory drugs (NSAIDs) and/or a stable dose of oral corticosteroids (prednisone or equivalent ≤ 10 mg daily) for at least 4 weeks prior to randomization. Patients who failed any DMARDs will be allowed. Negative purified protein derivative (PPD) tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice). Exclusion Criteria: RA patients: Previous treatment with anti-Tumor Necrosis Factor (TNF)-α or anti IL-1 therapy (or other biological therapy), immunosuppressive agents such as cyclosporine, mycophenolate or tacrolimus. The following washout period will be required for such patients to be eligible to participate in the trial. 2 months washout prior to screening for etanercept or adalimumab 3 months washout prior to screening for infliximab 3 months washout prior to screening for rituximab 1 month washout prior to screening for cyclosporine, mycophenolate and tacrolimus. If patient has been discontinued from other DMARDs (disease modifying antirheumatic drugs) for lack of efficacy or toxicity, the patient should be at least 1 month off the agent. Patients with congestive heart failure, QT prolongation syndrome or poorly controlled diabetes mellitus. Patients with a history of QTc prolongation will be excluded. Patients who have received intra-articular or systemic corticosteroid injections having been required for treatment of acute RA flare (not being part of a regular therapeutic regimen) within 4 weeks prior to randomization. Exclusion criteria 2-6 of the Health Volunteer section also applies here. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACZ885<br>Healthy Volunteers: Single administration of 600 mg of ACZ885 (Canakinumab) Intravenous (IV) on Day 1. Rheumatoid Arthritis (RA) Patients: Dose of 600 mg of ACZ885 (Canakinumab) Intravenous (IV) on Day 1, Day 15, and Day 43. | Drug: ACZ885 (investigational)<br>* The ACZ885 was supplied in 6 mL colorless glass vials each containing nominally 150 mg ACZ885 (with 20% overfill). The vials were kept at 2-8°C. At the investigator's site, solutions for infusion were prepared depending on the volume and dose administered.<br>* Other names: Canakinumab;|
| Placebo Comparator: Placebo<br>Healthy Volunteers: Single administration of 600 mg of Placebo Intravenous (IV) on Day 1. Rheumatoid Arthritis (RA) Patients: Dose of 600 mg of Placebo Intravenous (IV) on Day 1, Day 15, and Day 43. | Drug: Placebo<br>* Matching placebo of ACZ885 was supplied in the form of a lyophilized cake (Powder for Solution for Infusion). At the investigator's site, solutions for infusion were prepared depending on the volume and dose administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | At each post-dose visit, an ACR20 responder was defined as someone who achieved at least 20% improvement in the tender and the swollen 28-joint count, and 20% improvement in at least 3 of the following 5 measures:: Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) 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)) | 6 weeks and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | SDAI is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). SDAI measures the high sensitivity C-reactive protein (hsCRP) level, patient's global disease activity (PGDA) and evaluator's global disease activity (EGDA). PGDA and EGDA are measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. SDAI = tender28 + swollen28 + CRP + (PGDA/10) + (EGDA/10). Lower scores indicate less disease activity. | 6 weeks and 12 weeks | 
| Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | DAS28 is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). DAS28 measures the C-reactive protein (CRP) (in mg/L) and the patient's general health (GH). GH is measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. DAS28 = 0.56*√(tender28) + 0.28*√(swollen28) + 0.36*log_e(CRP+1) + 0.014*PGDA + 0.96. Lower scores indicate less disease activity. | 6 weeks and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis