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

Novartis274 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

274

Conditions

Rheumatoid Arthritis

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (17)

Pinnacle Research Group

Anniston, Alabama, United States

University of Alabama at Birmingham

Birmingham, Alabama, United States

Sun Valley Arthritis Center, Ltd

Peoria, Arizona, United States

Catalina Pointe Arthritis & Rheumatology Specialists

Tucson, Arizona, United States

Arthritis Center

Palm Harbor, Florida, United States

Arthritis Research of Florida, Inc.

Palm Harbor, Florida, United States

The Arthritis Center

Springfield, Illinois, United States

St. Louis Cener for Clinical Research

St Louis, Missouri, United States

The Center for Rheumatology

Albany, New York, United States

AAIR Research Center

Rochester, New York, United States

...and 7 more locations

Outcomes

Primary Outcomes

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.

Time frame: Baseline and Week 12

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.

Time frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124

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.

Time frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124

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.

Time frame: Baseline and Weeks 24, 36, 48, 60, 72, 88, 100, 112 and 124

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

Time frame: Baseline and Weeks 24, 72 and 112

Secondary Outcomes

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.

Time frame: Baseline and Weeks 2, 4 and 8

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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: 1. Did not attain an ACR20 response; 2. Attained a 20% but not a 50% response; 3. Attained a 50% but not a 70% response; 4. 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

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

Change From Baseline in Disease Activity Score (DAS) 28

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: Baseline and Weeks 4, 8 and 12

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.

Time frame: Baseline and Weeks 2, 4, 8 and 12

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.

Time frame: 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

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: 1. Did not attain an ACR20 response; 2. Attained a 20% but not a 50% response; 3. Attained a 50% but not a 70% response; 4. 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)

Change From Baseline in Swollen 28-joint Count During the Extension Study

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

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.

Change From Baseline in Erythrocyte Sedimentation Rate During the Extension Study

Time frame: Baseline and Weeks 24, 36, 48, 60, 72 and 88.