A Study of Ixekizumab (LY2439821) in bDMARD-Naive Participants With Radiographic Axial Spondyloarthritis (COAST-V)

Okres podwójnie ślepej próby: Dawka początkowa 80 lub 160 miligramów (mg) iksekizumabu podawana podskórnie (SC) na początku badania, a następnie 80 mg iksekizumabu podawane podskórnie co dwa tygodnie (Q2W) do tygodnia 14.

Przedłużony okres leczenia: 80 mg iksekizumabu podawane podskórnie co 2 tygodnie od tygodnia 16 do tygodnia 52.

• LY2439821

Okres podwójnie ślepej próby: Dawka początkowa 80 lub 160 mg iksekizumabu podawana podskórnie na początku badania, a następnie 80 mg iksekizumabu podawane podskórnie co cztery tygodnie (Q4W) do tygodnia 14.

Przedłużony okres leczenia: 80 mg iksekizumabu podawane podskórnie co 4 tygodnie od 16 do 52 tygodnia.

• LY2439821

Double Blind Period: Placebo given SC Q2W to week 14.

Extended Treatment Period: 80 mg ixekizumab given SC Q2W or Q4W from week 16 to week 52.

• LY2439821

Double Blind Period: 40 mg Adalimumab given SC Q2W to week 14.

Extended Treatment Period: 80 mg ixekizumab given SC Q2W or Q4W from week 20 to week 52.

• LY2439821

ASAS40 is defined as improvement from baseline of greater than or equal to (>=) 40% and absolute improvement from baseline of at least 2 units in at least 3 of the following 4 domains without any worsening in the remaining domains.

1. Patient Global: How active was your spondylitis on average during the last week? score range 0 (not active) to 10 (very active).
2. Spinal Pain: How much Pain of your spine due to Ankylosing spondylitis? score ranges 0 (no pain) to 10 (severe pain).
3. Bath Ankylosing Spondylitis Functional Index: Participant is asked to rate the difficulty associated with 10 individual basic functional activities. Participants response is captured using numeric rating scale (NRS) scale (range 0 to 10) with a higher score indicating worse function.
4. Inflammation based on Q5 & Q6 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).

ASAS20 response is defined as a ≥20% improvement and an absolute improvement from baseline of ≥1 units in ≥3 of 4 following domains and no worsening of ≥20% and ≥1 unit (range 0 to 10) in the remaining domain.

1. Patient Global: How active was your spondylitis on average during the last week? score range 0 (not active) to 10 (very active).
2. Spinal Pain: How much Pain of your spine due to Ankylosing spondylitis? score ranges 0 (no pain) to 10 (severe pain).
3. Bath Ankylosing Spondylitis Functional Index: Participant is asked to rate the difficulty associated with 10 individual basic functional activities. Participants response is captured using NRS scale (range 0 to 10) with a higher score indicating worse function.
4. Inflammation based on Q5 & Q6 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).

ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with CRP as acute phase reactant) are the following:

1. Total back pain
2. Patient global
3. Peripheral pain/swelling
4. Duration of morning stiffness
5. CRP in mg/L The ASDAScrp is calculated with the following equation: 0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral pain/swelling + 0.058 × duration of morning stiffness + 0.579 × Ln(CRP+1). CRP is in mg/liter, the range of other variables is from 0 to 10.Data from five variables combined to yield a score (0.6361 to no defined upper limit), where higher scores indicated higher disease activity. Ln represents the natural logarithm.

Least Square (LS) Mean was calculated using mixed model repeated measures (MMRM) model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The BASDAI is a participant-reported assessment consisting of 6 questions that relate to 5 major symptoms relevant to radiographic axial spondyloarthritis measuring discomfort, pain, and fatigue. 1) Fatigue, 2) Spinal pain, 3) Peripheral arthritis, 4) Enthesitis, 5) Intensity, and 6) Duration of morning stiffness. participants need to score each item with a score from 0 to 10 (NRS). total score is obtained from the average of symptom scores ranging 0 (no problem) to 10 (worst problem).

BASDAI50 represents an improvement of ≥50% of the BASDAI score from baseline.

The BASFI is a participant-reported assessment that establishes a participants functional baseline and subsequent response to treatment. To complete the BASFI, a participant is asked to rate the difficulty associated with 10 individual basic functional activities. Participants respond to each question using an NRS scale (range 0 to 10) with a higher score indicating worse function. The participants final BASFI score is the mean of the 10 item scores has a possible minimum value of 0 and a possible maximum value of 10, with a higher score indicating worse function.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with CRP as acute phase reactant) are the following:

1. Total back pain
2. Patient global
3. Peripheral pain/swelling
4. Duration of morning stiffness
5. CRP in mg/L The ASDAScrp is calculated with the following equation: 0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral pain/swelling + 0.058 × duration of morning stiffness + 0.579 × Ln(CRP+1). CRP is in mg/liter, the range of other variables is from 0 to 10.Data from five variables combined to yield a score (0.6361 to no defined upper limit), where higher scores indicated higher disease activity. Ln represents the natural logarithm. ASDAS Inactive Disease is defined as a score of <1.3.

The Berlin modification of Ankylosing Spondylitis spine MRI score for activity (ASspiMRI) scoring technique assesses inflammation in each of 23 disco-vertebral units (DVU). All 23 disco-vertebral units (DVU) of the spine (from C2 to S1) are scored for bone marrow edema. Scores for each DVU range from 0-3 (0=normal; 1=minor bone marrow edema [less than or equal to 25% of DVU; 3=severe bone marrow edema (more that 50% of DVU)]. The composite score ranges from 0 to 69, with higher scores reflecting worse disease.

Least Squares (LS) Mean was calculated using ANCOVA model with treatment, geographic region, baseline CRP status and baseline value as fixed factors.

The SF-36 is a 36-item participant administered measure designed to be a short, multipurpose assessment of health in the areas of physical functioning, role - physical, role - emotional, bodily pain, vitality, social functioning, mental health, and general health. The 2 overarching domains of mental well- being and physical well-being are captured by the Mental Component Summary and Physical Component Summary scores. T-scores are used for analysis. The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

ASAS HI is a disease-specific health-index instrument designed to assess the impact of interventions for SpA, including axSpA. The 17-item instrument has scores ranging from 0 (good health) to 17 (poor health). Each item consists of one question that the participant needs to respond to with either "I agree" (score of 1) or "I do not agree" (score of 0). A score of "1" is given where the item is affirmed, indicating adverse health. All item scores are summed to give a total score or index.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors

High sensitivity CRP is the measure of acute phase reactant. It will be measured with a high sensitivity assay at the central laboratory to help assess the effect of Ixekizumab on disease activity.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, visit and treatment-by-visit interaction as fixed factors.

The BASMI is a combined index comprising the following 5 clinical measurements of spinal mobility in participants with rad-axSpA.

1. Lateral spinal flexion
2. Tragus-to-wall distance
3. Lumbar flexion (modified Schrober)
4. Maximal intermalleolar distance
5. Cervical rotation. The BASMI includes these 5 measurements that are each scaled to a score of 0 to 10 depending on the result of the assessment (BASMI linear function). The average score of the 5 assessments gives the BASMI linear result. The higher the BASMI score the more severe the participants limitation of movement due to their AS.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

While participants have their hands resting on or behind the head, the assessor has measured the chest's encircled length by centimeter at the fourth intercostal level anteriorly. The difference between maximal inspiration and expiration in centimeters was recorded. Two tries were recorded. The better measurement (larger difference) of 2 tries (in centimeters) was used for analyses.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The participant is to make a maximum effort to touch the head against the wall when standing with heels and back against the wall (occiput). Then the distance from occiput to wall is measured. Two tries will be recorded. The better (smaller) measurement of 2 tries (in centimeters) will be used for analyses.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Both left and right SIJ are scored for bone marrow edema.Each side has 6 slices and each slice has 6 scoring units, and each scoring unit has a score of 0 or 1. Total SIJ SPARCC scores can range from 0 to 72 with higher scores reflecting worse disease.

LSMean was calculated using ANCOVA model with treatment, geographic region, baseline CRP status and baseline value as fixed factors.

The MASES is an index used to measure the severity of enthesitis .The MASES assesses 13 sites for enthesitis using a score of "0" for no activity or "1" for activity. Sites assessed include costochondral 1 (right/left), costochondral 7 (right/left), spinal iliaca anterior superior (right/left), crista iliaca (right/left), spina iliaca posterior (right/left), processus spinosus L5, and Achilles tendon proximal insertion (right/left). The MASES is the sum of all site scores (range 0 to 13); higher scores indicate more severe enthesitis.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The SPARCC enthesitis is an index used to measure the severity of enthesitis. The SPARCC assesses 16 sites for enthesitis using a score of "0" for no activity or "1" for activity. Sites assessed include Medial epicondyle (left/right [L/R]), Lateral epicondyle (L/R), Supraspinatus insertion into greater tuberosity of humerus (L/R), Greater trochanter (L/R), Quadriceps insertion into superior border of patella (L/R), Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R), Achilles tendon insertion into calcaneum (L/R), and Plantar fascia insertion into calcaneum (L/R). The SPARCC is the sum of all site scores (range 0 to 16). Higher scores indicate more severe enthesitis.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The number of tender and painful joints was determined by examination of 46 joints (23 joints on each side of the participants body. The 46 joints are assessed and classified as tender or not tender. sum of all joints checked to be tender/painful divided by number of evaluable joints which is multiplied by 46 to obtain TJC score. The scores ranges from 0 (no tender/painful joints) to 46 (all joints tender/painful).

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The Fatigue Severity NRS is a participant-administered, single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing "no fatigue" and 10 representing "as bad as you can imagine". Participants rate their fatigue (feeling tired or worn out) by circling the one number that describes their worst level of fatigue during the previous 24 hours.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The JSEQ is a 4-item scale designed to estimate sleep problems in clinical research. The JSEQ assesses the frequency of sleep disturbance in 4 categories: 1) trouble falling asleep, 2) waking up several times during the night, 3) having trouble staying asleep (including waking up far too early), and 4) waking up after the usual amount of sleep feeling tired and worn out. Participants report the number of days they experience each of these problems in the past month on a 6-point Likert scale ranging from 0 = "no days" to 5 = "22-30 days." The total JSEQ score ranges from 0 to 20, with higher scores indicating greater sleep disturbance.

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The WPAI-SpA consists of 6 questions to determine employment status, hours missed from work because of SpA, hours missed from work for other reasons, hours actually worked, the degree to which SpA affected work productivity while at work, and the degree to which SpA affected activities outside of work. The WPAI-SpA has been validated in the rad-axSpA patient population. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combines absenteeism and presenteeism, and percentage of impairment in activities performed outside of work. The computed percentage range for each sub-scale was from 0-100. Greater scores indicate greater impairment and less productivity.

LSMean was calculated using ANCOVA model with treatment, geographic region, baseline CRP status and baseline value as fixed factors.

The number of swollen joints was determined by examination of 44 joints (22 joints on each side of the participants body. The 44 joints are assessed and classified as swollen or not swollen. "sum of all joints checked to be swollen" divided by "number of evaluable joints" and then multiplied by 44 to obtain SJC score. The SJC score ranges from 0 (no swollen joints) to 44 (all joints swollen).

LSMean was calculated using MMRM model with treatment, geographic region, baseline CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

MRI score of spine was assessed using SPARCC method. All 23 disco-vertebral units (DVUs) of the spine (from C2 to S1) are scored for bone marrow edema. A single DVU has a scoring range of 0 to 18, bringing the maximum total score to 414, with higher scores reflecting worse disease. Scoring was performed by central readers.

LSMean was calculated using ANCOVA model with treatment, geographic region, baseline CRP status and baseline value as fixed factors