Long-term Efficacy, Safety and Tolerability of ACZ885 in Patients With Rheumatoid Arthritis

Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.

Time frame: From start of the study up to End Of Study (Week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

Blood for this assessment was obtained in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. Assessment was performed by the central laboratory.

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR components included patient's assessment of pain using visual analog scale (VAS; 0-100 mm, 0=no pain and 100=worst possible pain).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR component included patient's global assessment (PtGA) of disease activity (arthritis, VAS; 0-100 mm, 0=excellent and 100= poor).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR component included physician's global assessment (PGA) of disease activity (VAS; 0-100 mm, 0=no arthritis activity and 100=extremely active arthritis).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive result for swollen joint count. Joint counts were performed according to the visit schedule by the physician or by well trained personnel. Whenever possible, the same evaluator performed these assessments at all visits. The following 28 joints were assessed for tenderness and swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). If the number of joints for which data were available (e.g., S) was less than 28, the number of swollen joints (e.g., s) was scaled up proportionately (i.e., 28\*(s/S)).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

The ACR tender joint count (28 joints) was done by scoring several different aspects of tenderness as assessed by pressure and joint manipulation on physical examination. Joint counts were performed according to the visit schedule by the physician or by well trained personnel. The following 28 joints were assessed for tenderness and swelling: metacarpophalangeal I-V (10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow (2), shoulders (2), and knees (2). If the number of joints for which data were available (e.g., T) was less than 28, the number of tender joints (e.g., t) was scaled up proportionately (i.e., 28\*(t/T)).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

Bone Mineral Density was measured by dual-energy X-ray absorptiometry (DXA) of the hand with the most swollen wrist (determined at baseline by the investigator site), lumbosacral (LS) spine and hip, in selected study sites. The reading of the DXA scans were performed centrally, by an experienced independent reader who was blinded to clinical details and MRI findings.

Time frame: Baseline, Week 18

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug. Number of participants analyzed signifies those who were evaluable for the assessment. Here, N (number of participants analyzed) included all participants who were evaluable for this outcome measure.

The MRI scan was scored according to OMERACT RAMRIS system. Erosions were scored on a scale of 0-10 per site, the scale is 0-10, based on the proportion of eroded bone compared to the assessed bone volume, judged on all available images-0: no erosion; 1: 1-10% of bone eroded; 2; 11-20%, etc. For long bones, the assessed bone volume is from the articular surface (or its best estimated position if absent) to a depth of 1 cm, and in carpal bones it is the whole bone. Edema were scored on a scale of 0-10 per site, the scale is 0-3 based on the proportion of bone with edema, as follows-0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%; and Synovitis on a scale of 0-3 per site, the scale is 0-3. Score 0 is normal, and 1-3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment.

Time frame: Baseline, Week 18

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug. Here, number of participants (N) analyzed included all participants who were evaluable for this outcome measure and number analyzed (n) included all participants who were evaluable for the specified categories.

Digital radiographic (X-ray) assessment of 16 joints and bones in the hand and wrist were assessed for and 15 joints in the hand and wrist were assessed for joint space narrowing. Scoring of the radiographic assessment was according to modified Sharp/van der Heijde score. The maximum number of erosions is 160 in the hands and 120 in the feet; and the maximum scores for joint space narrowing are 120 and 48, respectively. Erosions are scored 1 for a discrete interruption of the cortical surface, and scored 2-5 for a larger defect according to the surface area of the joint involved. Notably, the maximum erosion score in each joint in hands is 5, while it is 10 in the feet. For joint space narrowing, 0=normal; 1=focal or doubtful; 2=general, \<50% of the original joint space; 3=general, \>50% of the original joint space or subluxation; 4=ankylosis.

Time frame: Baseline, Week 18

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug. Here, number of participants analyzed (N) included all participants who were evaluable for this outcome measure.

Digital radiographic (X-ray) assessment of 16 joints and bones in the hand and wrist were assessed for and 15 joints in the hand and wrist were assessed for joint space narrowing. Scoring of the radiographic assessment was according to modified Sharp/van der Heijde score. The maximum number of erosions is 160 in the hands and 120 in the feet; and the maximum scores for joint space narrowing are 120 and 48, respectively. Erosions are scored 1 for a discrete interruption of the cortical surface, and scored 2-5 for a larger defect according to the surface area of the joint involved. Notably, the maximum erosion score in each joint in hands is 5, while it is 10 in the feet. For joint space narrowing, 0=normal; 1=focal or doubtful; 2=general, \<50% of the original joint space; 3=general, \>50% of the original joint space or subluxation; 4=ankylosis.

Time frame: Baseline, Week 18

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment. Here, N (number of participants analyzed) included all participants who were evaluable for this outcome measure.

HAQ assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities, and each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty (the best outcome), 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do (the worst outcome). Each category is given a score by taking the maximum score of each question.A decrease from baseline indicates improvement for HAQ-DI. The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. The HAQ-DI total score ranges from 0 to 3, with higher scores indicating greater disability.

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The safety population consisted of all randomized participants who received at least one dose of the study drug.

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.The scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with higher scores indicative of better health.

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The safety population consisted of all randomized participants who received at least one dose of the study drug.

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.The scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with higher scores indicative of better health.

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The safety population consisted of all randomized participants who received at least one dose of the study drug.

Anti-ACZ885 antibodies concentrations were assessed in serum. All blood samples were taken by direct venipuncture in a forearm vein. Immunogenicity was analyzed by BIAcore technology. immunogenicity was categorized as NO (no immunogenicity), BLQ (positive immunogenicity \< LLOQ (not quantifiable)), and ALQ (positive immunogenicity \> LLOQ (quantifiable).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

At each visit (including baseline) the DAS28 and SDAI variables were derived using the following formulas: DAS28 = 0.56\*√ (tender28) + 0.28 \* √ (swollen28) + 0.36 \* loge(CRP+1) + 0.014\*PGDA+ 0.96; SDAI = tender28 + swollen28 + CRP + (PGDA / 10) + (EGDA / 10) where tender28 is the tender 28-joint count, swollen28 is the swollen 28-joint count, CRP is C-reactive protein, PGDA is the patient's global assessment of disease activity and EGDA is the physician's global assessment of disease activity. The Number of Participants in clinical remission is defined as the DAS28 ≤ (less than or equal to) 2.6 or SDAI ≤ (less than or equal to) to3.3.

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR50 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR70 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 70% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all participants that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

ACR90 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 90% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR).

Time frame: Baseline Up to End Of Study (up to week 60)

Population: The Safety Analysis Set was defined as all subjects that received at least one dose of study drug (in this extension) with at least one post-baseline safety assessment.

The PK parameter were evaluated from serum concentration-time data using mixed effects modeling approach.

Time frame: Pre dose at Day 1, Pre dose at week 6, 12, 18, 24, 30, 36, 42, 48, follow up and at study completion (week 60)

Population: The PK set consisted of all participant who received at least one dose of study drug (in this extension) with at least one post-baseline pharmacokinetic assessment.

The PK parameter were evaluated from serum concentration-time data using mixed effects modeling approach.

Time frame: Pre dose at Day 1, Pre dose at week 6, 12, 18, 24, 30, 36, 42, 48, follow up and at study completion (week 60)

Population: The PK set consisted of all participants who received at least one dose of study drug (in this extension) with at least one post-baseline pharmacokinetic assessment.