Efficacy, Safety and Tolerability of ACZ885 in Patients With Active Rheumatoid Arthritis

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

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.

Other protocol-defined inclusion/exclusion criteria may apply

CORE STUDY

Inclusion Criteria

Core Study Inclusion Criteria At Screening

1. Cooperative male or non-pregnant, non-lactating female patients at least 18 years of age who signed an informed consent before the initiation of any study procedure.

2. Diagnosis of rheumatoid arthritis (RA) classified by American College of Rheumatology (ACR) 1987 revised criteria and with symptoms for at least 3 months before randomization.

3. Functional status class I, II or III classified according to the ACR 1991 revised criteria.

4. Patients treated with methotrexate (MTX) at the maximum tolerated (≤25 mg/week) and stable dose of ≥7.5 mg/week for at least 12 weeks before randomization.

5. Patients who had failed any disease-modifying antirheumatic drugs (DMARDs) (including biologic agents and any DMARD used in combination with MTX) were allowed.

6. For patients with previous treatment of biological therapy, the following wash-out periods were required before randomization:

   • 3 days for Kineret™ (anakinra) - with a terminal half-life of 4 to 6 hours (s.c. route).
   • 4 weeks for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours (s.c.

   route).

   • 8 weeks for Remicade® (infliximab) - with a terminal half-life of 8.0-9. 5 days (intravenous (i.v.) infusion).
   • 12 weeks for Humira® (adalimumab) - with a terminal half-life of 10-20 days (average 2 weeks) (subcutaneous (s.c.) route).
   • 12 weeks for Orencia® (abatacept) - with a terminal half-life of 13.1 (8-25) days (i.v. infusion).
   • 26 weeks for any other biologic - or 10 half-lives, whichever was longer.

7. Patients who took systemic corticosteroids had to be on a stable dose of ≤10 mg/d prednisone or equivalent for at least 4 weeks before randomization.

8. Patients who were regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors or paracetamol/ acetaminophen as part of their RA therapy must have been on a stable dose for at least 4 weeks before randomization. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen as needed within 2 weeks before randomization had to stop their medication at least 24 hours before an ACR visit (i.e. Visits 3, 7, 8, 10 and 12 [End of Study]). Patients taking folic acid supplementation had to be on stable dose for at least 4 weeks before randomization.

9. Patients with a history of immunization for Influenza (within past 12 months) and Pneumococcal vaccination (within 4 years) were included. If not already immunized, vaccination was completed when medically indicated (only during flu season for influenza) and such patients were included after approximately a 3 week window post-immunization to allow immunity to develop for vaccine.

10. Weight ≥45 kg and body mass index (BMI) <34.0

11. Women of non-child-bearing potential, defined as all women physiologically not capable of becoming pregnant.

Core Study Inclusion criteria At Baseline (Visit 3)

1. Disease activity criteria of ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints.

2. One of the following also had to be present:

   1. High-sensitive C-Reactive Protein (hsCRP) concentration ≥10 mg/L
   2. Erythrocyte Sedimentation Rate (ESR) ≥28 mm/1st hr
   3. a. + b. based on screening values.

EXCLUSION

1. History of hypersensitivity to study drug or to molecules with similar structures.

2. Any therapy by intra-articular injections (e.g. corticosteroid) required for treatment of acute RA flare within 4 weeks before randomization.

3. Current use of DMARDs other than MTX. DMARDs included but were not limited to: biologic agents, thiolates (D-penicillamine, thiopronine), sulfasalazine, gold compounds, antimalarials, cyclosporine A, azathioprine, leflunomide, and alkylating agents such as cyclophosphamide.

4. If a patient had been discontinued from DMARDs, the patient should have been off the agent for at least 4 weeks, except leflunomide which was 8 weeks.

5. Patients with evidence of active pulmonary disease (e.g. tuberculosis, fungal diseases).

6. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.

7. Who had a live vaccination within 12 weeks before randomization, or were planning to have one during the study and were not willing/able to postpone until study completion.

8. a) With bacterial, fungal or viral infections at the time of enrollment, including patients with evidence of human immunodeficiency virus (HIV) infection, hepatitis B and hepatitis C infection.

   b) History of a positive purified protein derivative (PPD) of tuberculin skin test without a follow-up of a negative chest X-ray.

   c) Patients requiring administration of antibiotics against latent tuberculosis, e.g. isoniazide.

9. Underlying metabolic, hematologic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromised the patient and/or placed the patient at unacceptable risk for participation in an immunomodulatory therapy. In particular, clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty's syndrome.

10. With significant medical problems, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure, type-I-diabetes(well controlled type-II-diabetes was allowed even when requiring insulin), thyroid disease (unless the patient was taking a stable dose of thyroid hormone for at least 12 weeks before randomization).

11. Other rheumatic diseases that could confound the evaluation of efficacy, including but not limited to primary fibromyalgia, ankylosing spondylitis, Lyme disease, adult juvenile RA, systemic lupus erythematosus, gout and pseudo gout, vasculitis, psoriatic arthritis, reactive arthritis, primary Sjoegren's Syndrome, and Behcet's Syndrome.

12. Any medical or psychiatric condition which, in the Investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol.

13. History of malignancy of any organ system, treated or untreated, within the past 5 years (with the exception of adequately treated basal cell carcinoma or squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, colon polyps with non-invasive malignancy that have been removed).

14. Use of any investigational drug other than RA therapy and/or devices at the time of randomization, or within 30 days or 5 half- lives of randomization, whichever was longer.

STUDY EXTENSIONS

Extension Studies Inclusion Criteria:

1. 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 12.
2. Patients who completed the first extension study, may enter the second.

Extension Studies Exclusion Criteria

1. Patients for whom continued treatment in the extension is not considered appropriate by the treating physician.
2. Patients who were non-compliant or who demonstrated a major protocol violation in the core CACZ885A2201 study.
3. Patients who discontinued from the core CACZ885A2201 study before Visit 12.