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

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Canakinumab
Placebo
Sponsored by
Novartis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Active Rheumatoid Arthritis, anti-interleukin-1beta monoclonal antibody, methotrexate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Pinnacle Research Group
  • University of Alabama at Birmingham
  • Sun Valley Arthritis Center, Ltd
  • Catalina Pointe Arthritis & Rheumatology Specialists
  • Arthritis Center
  • Arthritis Research of Florida, Inc.
  • The Arthritis Center
  • St. Louis Cener for Clinical Research
  • The Center for Rheumatology
  • AAIR Research Center
  • Oregon Health Sciences University
  • Tacoma Center for Arthritis Research
  • Novartis
  • Novartis
  • Novartis
  • Novartis
  • Novartis

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Canakinumab 600 mg IV + 300 mg q2wk

Canakinumab 300 mg q2wk

Canakinumab 150 mg q4wk

Placebo

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at 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
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
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.
Percentage of American College of Rheumatology [ACR] 70 Criteria Responders During the Extension Phase
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.
Change From Baseline in Disease Activity Score (DAS) 28 During the Extension Phase
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

Secondary Outcome Measures

Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Weeks 2, 4 and 8
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.
Percentage of American College of Rheumatology [ACR] 20 Criteria Responders
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 ACR20 non-responders if they failed the ACR20 criteria. Patients who prematurely discontinued the study due to insufficient therapeutic effect were also considered non responders.
Percentage of American College of Rheumatology [ACR] 70 Criteria Responders
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 ACR70 non-responders if they failed the ACR70 criteria. Patients who prematurely discontinued the study due to insufficient therapeutic effect were also considered non responders.
Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at Week 12
To assess differences between the level of clinical response attained and not just whether the patient did or did not achieve a particular level of response, participants were categorized as follows: Did not attain an ACR20 response; Attained a 20% but not a 50% response; Attained a 50% but not a 70% response; Attained a 70% or greater response. A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if they had at least a 20, 50 or 70% improvement from Baseline, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: Patient's pain assessment (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]).
Change From Baseline in Swollen 28-joint Count
The following 28 joints were assessed by the physician for swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Tender 28-joint Count
The following 28 joints were assessed by the physician for tenderness: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Patient's Pain Intensity
The patient's assessment of pain was performed using a 100 mm visual analog scale (VAS) ranging from no pain (0) to unbearable pain (100). The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in pain intensity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Patient's Global Assessment of Disease Activity
The patient's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100), after the question "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing". The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Physician's Global Assessment of Disease Activity
The physician's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100). To enhance objectivity, the physician was not aware of the specific patient's global assessment of disease activity when performing their own assessment on that patient. The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Health Assessment Questionnaire (HAQ) Score
The patient health assessment questionnaire (HAQ) was used to assess the physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from Baseline score indicates improvement in disability status. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels
HsCRP is a marker for inflammation and was measured from blood samples to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Change From Baseline in Disease Activity Score (DAS) 28
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. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline DAS28 value as a covariate.
Change From Baseline in Erythrocyte Sedimentation Rate
Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. A negative change from Baseline score indicates improvement.
Change From Baseline in Rheumatoid Factor Concentration
Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) that is an indicator of inflammation and rheumatoid arthritis.
Change From Baseline in Short Form 36 Health Survey (SF-36)
The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores for each subscale range from 0 to 10, and the composite scores range from 0 to 100, with higher scores indicating better health. A positive change from Baseline score indicates improvement in quality of life.
Change From Baseline in Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F)
The fatigue subscale of the FACIT is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants respond to each item on a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much) based on their experience of fatigue during the past 2 weeks. The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. FACIT Fatigue subscale scores range from 0 to 52, where higher scores represent less fatigue. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline FACIT-F value as a covariate.
Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at the End of the Extension Study
To assess differences between the level of clinical response attained and not just whether the patient did or did not achieve a particular level of response, patients were categorized as follows: Did not attain an ACR20 response; Attained a 20% but not a 50% response; Attained a 50% but not a 70% response; Attained a 70% or greater response. A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if they had at least a 20, 50 or 70% improvement from Baseline, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: Patient's pain assessment (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]).
Change From Baseline in Swollen 28-joint Count During the Extension Study
The following 28 joints were assessed by the physician for swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2).
Change From Baseline in Tender 28-joint Count During the Extension Study
The following 28 joints were assessed by the physician for tenderness: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2).
Change From Baseline in Patient's Pain Intensity During the Extension Study
The patient's assessment of pain was performed using a 100 mm visual analog scale (VAS) ranging from no pain (0) to unbearable pain (100). The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in pain intensity.
Change From Baseline in Patient's Global Assessment of Disease Activity During the Extension Study
The patient's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100), after the question "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing". The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity.
Change From Baseline in Physician's Global Assessment of Disease Activity During the Extension Study
The physician's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100). To enhance objectivity, the physician was not aware of the specific patient's global assessment of disease activity when performing their own assessment on that patient. The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity.
Change From Baseline in Health Assessment Questionnaire (HAQ) Score During the Extension Study
The patient health assessment questionnaire (HAQ) was used to assess the physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from Baseline score indicates improvement in disability status.
Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels During the Extension Study
HsCRP is a marker for inflammation and was measured from blood samples to identify the presence of inflammation, to determine its severity, and to monitor response to treatment.
Change From Baseline in Erythrocyte Sedimentation Rate During the Extension Study
Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. A negative change from Baseline score indicates improvement.

Full Information

First Posted
January 17, 2007
Last Updated
January 14, 2014
Sponsor
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT00424346
Brief Title
Efficacy, Safety and Tolerability of ACZ885 in Patients With Active Rheumatoid Arthritis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
November 2006 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
October 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Active Rheumatoid Arthritis, anti-interleukin-1beta monoclonal antibody, methotrexate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
274 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Canakinumab 600 mg IV + 300 mg q2wk
Arm Type
Experimental
Arm Description
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.
Arm Title
Canakinumab 300 mg q2wk
Arm Type
Experimental
Arm Description
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.
Arm Title
Canakinumab 150 mg q4wk
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
Canakinumab
Other Intervention Name(s)
ACZ885
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Week 12
Description
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.
Time Frame
Baseline and Week 12
Title
Percentage of American College of Rheumatology [ACR] 20 Criteria Responders During the Extension Phase
Description
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.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Title
Percentage of American College of Rheumatology [ACR] 50 Criteria Responders During the Extension Phase
Description
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.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Title
Percentage of American College of Rheumatology [ACR] 70 Criteria Responders During the Extension Phase
Description
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.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124
Title
Change From Baseline in Disease Activity Score (DAS) 28 During the Extension Phase
Description
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
Time Frame
Baseline and Weeks 24, 72 and 112
Secondary Outcome Measure Information:
Title
Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at Weeks 2, 4 and 8
Description
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.
Time Frame
Baseline and Weeks 2, 4 and 8
Title
Percentage of American College of Rheumatology [ACR] 20 Criteria Responders
Description
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 ACR20 non-responders if they failed the ACR20 criteria. Patients who prematurely discontinued the study due to insufficient therapeutic effect were also considered non responders.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Percentage of American College of Rheumatology [ACR] 70 Criteria Responders
Description
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 ACR70 non-responders if they failed the ACR70 criteria. Patients who prematurely discontinued the study due to insufficient therapeutic effect were also considered non responders.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at Week 12
Description
To assess differences between the level of clinical response attained and not just whether the patient did or did not achieve a particular level of response, participants were categorized as follows: Did not attain an ACR20 response; Attained a 20% but not a 50% response; Attained a 50% but not a 70% response; Attained a 70% or greater response. A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if they had at least a 20, 50 or 70% improvement from Baseline, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: Patient's pain assessment (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]).
Time Frame
Baseline and Week 12
Title
Change From Baseline in Swollen 28-joint Count
Description
The following 28 joints were assessed by the physician for swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Tender 28-joint Count
Description
The following 28 joints were assessed by the physician for tenderness: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Patient's Pain Intensity
Description
The patient's assessment of pain was performed using a 100 mm visual analog scale (VAS) ranging from no pain (0) to unbearable pain (100). The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in pain intensity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Patient's Global Assessment of Disease Activity
Description
The patient's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100), after the question "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing". The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Physician's Global Assessment of Disease Activity
Description
The physician's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100). To enhance objectivity, the physician was not aware of the specific patient's global assessment of disease activity when performing their own assessment on that patient. The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Health Assessment Questionnaire (HAQ) Score
Description
The patient health assessment questionnaire (HAQ) was used to assess the physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from Baseline score indicates improvement in disability status. Least squares means (LSM) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels
Description
HsCRP is a marker for inflammation and was measured from blood samples to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Disease Activity Score (DAS) 28
Description
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. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline DAS28 value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Erythrocyte Sedimentation Rate
Description
Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. A negative change from Baseline score indicates improvement.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Rheumatoid Factor Concentration
Description
Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) that is an indicator of inflammation and rheumatoid arthritis.
Time Frame
Baseline and Weeks 4, 8 and 12
Title
Change From Baseline in Short Form 36 Health Survey (SF-36)
Description
The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores for each subscale range from 0 to 10, and the composite scores range from 0 to 100, with higher scores indicating better health. A positive change from Baseline score indicates improvement in quality of life.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Change From Baseline in Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F)
Description
The fatigue subscale of the FACIT is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants respond to each item on a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much) based on their experience of fatigue during the past 2 weeks. The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. FACIT Fatigue subscale scores range from 0 to 52, where higher scores represent less fatigue. Least squares means (LSMs) were derived from an Analysis of Covariance (ANCOVA) model adjusting for treatment and center with baseline FACIT-F value as a covariate.
Time Frame
Baseline and Weeks 2, 4, 8 and 12
Title
Number of Distinct Responders According to ACR20, ACR50 and ACR70 Criteria at the End of the Extension Study
Description
To assess differences between the level of clinical response attained and not just whether the patient did or did not achieve a particular level of response, patients were categorized as follows: Did not attain an ACR20 response; Attained a 20% but not a 50% response; Attained a 50% but not a 70% response; Attained a 70% or greater response. A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if they had at least a 20, 50 or 70% improvement from Baseline, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: Patient's pain assessment (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]).
Time Frame
Baseline and End of Study (up to 124 weeks)
Title
Change From Baseline in Swollen 28-joint Count During the Extension Study
Description
The following 28 joints were assessed by the physician for swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2).
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Tender 28-joint Count During the Extension Study
Description
The following 28 joints were assessed by the physician for tenderness: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2).
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Patient's Pain Intensity During the Extension Study
Description
The patient's assessment of pain was performed using a 100 mm visual analog scale (VAS) ranging from no pain (0) to unbearable pain (100). The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in pain intensity.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Patient's Global Assessment of Disease Activity During the Extension Study
Description
The patient's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100), after the question "Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing". The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Physician's Global Assessment of Disease Activity During the Extension Study
Description
The physician's global assessment of disease activity was performed using a 100 mm visual analog scale (VAS) ranging from no arthritis activity (0) to maximal arthritis activity (100). To enhance objectivity, the physician was not aware of the specific patient's global assessment of disease activity when performing their own assessment on that patient. The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in assessment of disease activity.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Health Assessment Questionnaire (HAQ) Score During the Extension Study
Description
The patient health assessment questionnaire (HAQ) was used to assess the physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from Baseline score indicates improvement in disability status.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in High-sensitive C-Reactive Protein (hsCRP) Levels During the Extension Study
Description
HsCRP is a marker for inflammation and was measured from blood samples to identify the presence of inflammation, to determine its severity, and to monitor response to treatment.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124.
Title
Change From Baseline in Erythrocyte Sedimentation Rate During the Extension Study
Description
Erythrocyte sedimentation rate (ESR) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. A negative change from Baseline score indicates improvement.
Time Frame
Baseline and Weeks 24, 36, 48, 60, 72 and 88.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Other protocol-defined inclusion/exclusion criteria may apply CORE STUDY Inclusion Criteria Core Study Inclusion Criteria At Screening 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. 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. Functional status class I, II or III classified according to the ACR 1991 revised criteria. 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. Patients who had failed any disease-modifying antirheumatic drugs (DMARDs) (including biologic agents and any DMARD used in combination with MTX) were allowed. 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. 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. 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. 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. Weight ≥45 kg and body mass index (BMI) <34.0 Women of non-child-bearing potential, defined as all women physiologically not capable of becoming pregnant. Core Study Inclusion criteria At Baseline (Visit 3) Disease activity criteria of ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints. One of the following also had to be present: High-sensitive C-Reactive Protein (hsCRP) concentration ≥10 mg/L Erythrocyte Sedimentation Rate (ESR) ≥28 mm/1st hr a. + b. based on screening values. EXCLUSION History of hypersensitivity to study drug or to molecules with similar structures. Any therapy by intra-articular injections (e.g. corticosteroid) required for treatment of acute RA flare within 4 weeks before randomization. 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. 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. Patients with evidence of active pulmonary disease (e.g. tuberculosis, fungal diseases). Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing. 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. 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. 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. 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). 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. 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. 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). 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: 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. 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.
Facility Information:
Facility Name
Pinnacle Research Group
City
Anniston
State/Province
Alabama
ZIP/Postal Code
36207
Country
United States
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Sun Valley Arthritis Center, Ltd
City
Peoria
State/Province
Arizona
ZIP/Postal Code
85381
Country
United States
Facility Name
Catalina Pointe Arthritis & Rheumatology Specialists
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85704
Country
United States
Facility Name
Arthritis Center
City
Palm Harbor
State/Province
Florida
ZIP/Postal Code
34684
Country
United States
Facility Name
Arthritis Research of Florida, Inc.
City
Palm Harbor
State/Province
Florida
ZIP/Postal Code
34684
Country
United States
Facility Name
The Arthritis Center
City
Springfield
State/Province
Illinois
ZIP/Postal Code
62704
Country
United States
Facility Name
St. Louis Cener for Clinical Research
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63128
Country
United States
Facility Name
The Center for Rheumatology
City
Albany
State/Province
New York
ZIP/Postal Code
12206
Country
United States
Facility Name
AAIR Research Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14618
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Tacoma Center for Arthritis Research
City
Tacoma
State/Province
Washington
ZIP/Postal Code
98405
Country
United States
Facility Name
Novartis
City
Vienna
Country
Austria
Facility Name
Novartis
City
Vilvoorde
Country
Belgium
Facility Name
Novartis
City
Dorval
State/Province
Quebec
Country
Canada
Facility Name
Novartis
City
Nuernberg
Country
Germany
Facility Name
Novartis
City
Barcelona
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
21736751
Citation
Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, Preiss R, Arulmani U, Widmer A, Gitton X, Kellner H. Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. 2011 Jul 7;12:153. doi: 10.1186/1471-2474-12-153.
Results Reference
derived

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

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