Efficacy, Safety and Tolerability of AIN457 in Patients With Rheumatoid Arthritis (RA) Taking Methotrexate (MTX)

A participant was considered to have achieved the incidence of response (ACR20 criteria) if he/she had at least a 20% improvement in both the tender and swollen 28-joint counts and had at least 20% improvement in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's self-assesseddisability (Health Assessment Questionnaire \[HAQ©\] score)and acute phase rectant (C-reactive protein \[hsCRP\]/ESR).

Time frame: 16cweeks

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

Only values that were above normal range (20 units) were included.

Time frame: Baseline, Week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

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, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

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, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

Blood for ESR, which is helpful to diagnose inflammatory diseases and to monitor disease activity and response to therapy, was obtained at the visits.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

HAQ© was used to assess physical ability and functional status of patients as well as quality of life at the visits in these 8 categories assessed by the Disability Index: dressing & grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Patients report amount of difficulty they have in performing 2 or 3 specific activities. There are 4 possible responses (0, 1, 2, 3) for these questions which include types of assistance, if any; the participant uses for his/her usual activities: 0: without any difficulty- No assistance is needed; 1: with some difficulty - A special device is used by the patient in his/her usual activities; 2: with much difficulty - The patient usually needs help from another person. 3: Unable to do - the patient usually needs both a special device and help from another person. Scores of 0 - 1 are generally considered to represent mild to moderate difficulty, 1-2 moderate to severe disability, and 2 -3 severe to very severe disability.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

Blood for this assessment was obtained at the visits in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment.Since the results of this test may have unblinded study personnel, results from the central lab were provided for screening and baseline only. The hsCRP results from samples collected during the treatment period were revealed only after final database lock.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The patient's assessment of pain was performed at all visits using 100 mm visual analog scale (VAS) ranging from no pain to unbearable pain after the question Please indicate with a vertical mark ( \| ) through the horizontal line the most pain you had from your rheumatoid arthritis over the last 24 hours.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The patient's global assessment of disease activity was performed at the visits on a 100 mm non-anchored visual analog scale, from no arthritis (0) activity to maximal arthritis (100) activity, after the question, Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The physician's global assessment of disease activity was performed at the visits usingon a 100 mm non-anchored visual analog scale, from no arthritis (0) activity to maximal arthritis (100) activity, after the question, Considering all the ways your arthritis affects you, draw a line on the scale for how well you are doing.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The DAS28 is a measure of disease activity in Rheumatoid Arthritis (RA). The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR) or hsCRP, and the patient's 'global assessment of global health (indicated by marking a 100 mm line between very good and very bad). A DAS28 score greater than 5.1 implies active disease, less than 3.2 well controlled disease, and less than 2.6 remission. The DAS28-CRP was derived from swollen joint count, tender joint count, hsCRP and patient's global assessment of disease activity.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The DAS28 is a measure of disease activity in Rheumatoid Arthritis (RA). The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR) or hsCRP, and the patient's 'global assessment of global health (indicated by marking a 100 mm line between very good and very bad). A DAS28 score greater than 5.1 implies active disease, less than 3.2 well controlled disease, and less than 2.6 remission.The DAS28 was also derived using erythrocyte sedimentation rate (ESR) (referred to as DAS28-ESR).

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue©) is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants responded 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 weeThe scale score was computed by summing the item scores, after reversing those items that were worded in the negative direction. When there were missing item scores, the subscale score was computed by summing the non-missing item scores, multiplying by 13 (the total number of items in the scale) and dividing by the number of non-missing items. The latter rule applied only when at least half of the items (seven or more) were non-missing. FACIT-Fatigue subscale scores range from 0 to 52, where higher scores represent less fatigue.

Time frame: Baseline, Week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The SF-36 Scale is a 36-item, patient-reported survey which measures overall quality of life. It consists of 8 subscales (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) which can be aggregated to derive a physical-component summary score and a mental-component score. Scores are normally determined with the use of norm-based methods which standardize scores based on an assessment of the general U.S. population free of chronic conditions. The scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with the higher scores indicative of better health.

Time frame: Baseline, week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

Only values that were above normal range (12 U/mL) were were included.

Time frame: Baseline, Week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

A participant was considered as improved according to the ACR20, ACR50 or ACR70 criteria if he/she had as least a 20%, 50% or 70% improvement, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's self-assessed disability and acute phase rectant or Erythrocyte sedimentation rate (ESR).

Time frame: at Weeks2, 4, 8, 12, 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

A participant was considered as improved according to the ACR50 or ACR70 criteria if he/she had at least a 50% or 70% improvement, respectively, in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures: patient's assessment of rheumatoid athritis (RA) pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient self-assessed disability (Health Assessment Questionnaire \[HAQ©\] score) and Acute phase reactant (C-reactive protein \[hsCRP\]/ESR). Participants were defined as ACR50/70 responders at a given post-randomization visit if they satisfied the ACR50/70 criteria, respectively. Participants were considered ACR50/70 nonresponders if they failed the ACR50/70 criteria respectively. Participants who prematurely discontinued from study due to insufficient therapeutic effect were also considered nonresponders.

Time frame: Week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.

The distribution of EULAR response criteria was according to DAS28-CRP at Week 16. EULAR response criteria are based on DAS28-CRP status in combination with DAS28-CRP improvements. The EULAR response criteria are as follows: Week 16 DAS28-CRP \<3.2 with DAS28-CRP improvement \>1.2 corresponds to 'good response'; Week 16 DAS28-CRP \<3.2 with DAS28-CRP improvement between 0.6 to 1.2, or Week 16 DAS28-CRP between 3.2 to 5.1 with DAS28-CRP improvement \>1.2 or from 0.6 to 1.2, or WeeK 16 DAS28-CRP \>5.1 with DAS28-CRP improvement \>1.2 correspond to 'moderate response; Week 16 DAS28-CRP \<3.2 with DAS28-CRP improvement \<0.6, or Week 16 DAS28-CRP between 3.2 to 5.1 with DAS28-CRP improvement \<0.6, or Week 16 DAS28-CRP \>5.1 with DAS28-CRP improvement between 0.6 to 1.2 or \<0.6 correspond to 'no response'.

Time frame: Week 16

Population: Full analysis set (FAS) all subjects to whom study drug was assigned. Following the intent-to-treat principle, subjects were analyzed according to the treatment they were assigned to at randomization. FAS did not include subjects who have missing values for all post-baseline (visit \>=3) assessments on all of the specified efficacy variables.