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

실험적: Canakinumab 600 mg IV + 300 mg q2wk

Participants received canakinumab 600 mg intravenous (IV) loading dose on Day 1 and 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg every 4 weeks.

의약품: 카나키누맙

다른 이름들:

• ACZ885

실험적: Canakinumab 300 mg q2wk

Participants received canakinumab 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.

의약품: 카나키누맙

다른 이름들:

• ACZ885

실험적: Canakinumab 150 mg q4wk

Participants received canakinumab 150 mg subcutaneous injections every 4 weeks (q4wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.

의약품: 카나키누맙

다른 이름들:

• ACZ885

위약 비교기: Placebo

Participants received placebo subcutaneous injections every 2 weeks for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.

의약품: 위약

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

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:

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]).

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:

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]).

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.