A Study of Ixekizumab (LY2439821) in TNF Inhibitor Experienced Participants With Radiographic Axial Spondyloarthritis

ASAS40 is defined as improvement from baseline of greater than or equal to (>=) 40 % and absolute improvement from baseline of at least 2 units (range of 0 to 10) in at least 3 of the following 4 domains without any worsening in the remaining domain.

• Patient Global: How active was your spondylitis on average during the last week? score ranges 0 (not active) to 10 (very active).
• Spinal Pain: How much Pain of your spine due to Ankylosing spondylitis? score ranges 0 (no pain) to 10 (severe pain).
• Bath Ankylosing Spondylitis Functional Index (BASFI): Participant asked to rate the difficulty associated with 10 individual basic functional activities. Participant response was captured using Numeric Rating Scale (NRS) (range 0 to 10) with a higher score indicating worse function.
• 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 (range 0 to 10) in ≥3 of 4 domains, and no worsening of ≥20% and ≥1 unit (range 0 to 10) in the remaining domain.

• Patient Global: How active was your spondylitis on average during the last week? score ranges 0 (not active) to 10 (very active).
• Spinal Pain: How much Pain of your spine due to Ankylosing spondylitis? score ranges 0 (no pain) to 10 (severe pain).
• Bath Ankylosing Spondylitis Functional Index (BASFI): Participant asked to rate the difficulty associated with 10 individual basic functional activities. Participant response was captured using Numeric Rating Scale (NRS) (range 0 to 10) with a higher score indicating worse function.
• 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

• Total back pain
• Patient global
• Peripheral pain/swelling
• Duration of morning stiffness and
• 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(normal) to 10(very severe); Ln represents the natural logarithm). Data from five variables combined to yield a score (0.6361 to no defined upper limit), where higher scores indicated higher disease activity. Least Square (LS) mean was determined by mixed-model repeated measures (MMRM) with treatment, geographic region, baseline CRP status, number of prior tumor necrosis factor inhibitor (TNFi), 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 (rad-axSpA): 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), with a higher score indicating more severe AS symptom. BASDAI50 represents an improvement of ≥50% of the BASDAI score from baseline.

The BASDAI is a participant-reported assessment consisting of 6 questions that relate to 5 major symptoms relevant to radiographic axial spondyloarthritis (rad-axSpA): 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), with a higher score indicating more severe AS symptom. LSmean was determined by MMRM with factors for treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The BASFI is a participant-reported assessment that establishes a participant's functional baseline and subsequent response to treatment. The BASFI is composed with 10 questions to assess the disease severity, including the first 8 questions regarding to functional anatomy related activities and the remaining 2 questions related to daily activities of AS participants. Participants respond to each question using an NRS scale (range 0 to 10). The BASFI score is the average of the 10 responses and has a possible minimum value of 0 and a possible maximum value of 10, with a higher score indicating worse function. LS mean was determined by MMRM with factors for treatment, geographic region, baseline CRP status, number of prior TNFi, 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. ASDAS Inactive Disease is defined as a score of <1.3.

The parameters used for the ASDAS (with CRP as acute phase reactant) are

• Total back pain
• Patient global
• Peripheral pain/swelling
• Duration of morning stiffness and
• 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(normal) to 10(very severe); Ln represents the natural logarithm). Data from five variables combined to yield a score (0.6361 to no defined upper limit), where higher the score worse the disease activity.

ASDAS is a composite index to assess disease activity in AS. ASDAS <2.1 defines moderate disease activity.

The parameters used for the ASDAS (with CRP as acute phase reactant) are

• Total back pain
• Patient global
• Peripheral pain/swelling
• Duration of morning stiffness and
• 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(normal) to 10(very severe); Ln represents the natural logarithm). Data from five variables combined to yield a score (0.6361 to no defined upper limit), where higher the score worse the disease activity.

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 determined by MMRM with factors for treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The ASAS Health Index (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 1 question that the patient needs to respond to with either "I agree" (score 1) or "I do not agree (score 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. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The study used MRI with fat-saturating techniques such as short tau inversion recovery (STIR) to look for the presence of bone marrow edema. The Berlin modification of Ankylosing Spondylitis spine MRI score for activity (ASspiMRI) scoring technique assesses inflammation in each of the 23 disco-vertebral units (DVU) of the spine (from C2 to S1), capturing 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.LS mean was determined by analysis of covariance (ANCOVA) with treatment, geographic region, baseline CRP status, number of prior TNF inhibitors used and baseline value as fixed factors.

MRI score of spine was assessed using SPARCC method. All 23 disco-vertebral units (DVU) of the spine (from C2 to S1) were scored for bone marrow edema. A single DVU has 18 scoring units, and each has score of 0 or 1, bringing the maximum total score to 414, the sum ranges from 0 to 414 with higher scores reflecting worse disease. Scoring was performed by central readers. LS mean was determined by ANCOVA with factors for treatment, geographic region, baseline CRP status, number of prior TNF inhibitors used and baseline value.

High sensitivity CRP is the measure of acute phase reactant. It was measured with a high sensitivity assay at the central laboratory to help assess the effect of ixekizumab on disease activity. High sensitivity CRP is a sensitive laboratory assay for serum levels of C-Reactive Protein, which is a biomarker of inflammation. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, visit, and treatment-by-visit interaction as fixed factors.

BASMI is a combined index comprising of 5 clinical measurements of spinal mobility in patients with radiographic axial spondyloarthritis (rad-axSpA).

• Lateral Spinal Flexion
• Tragus-to-wall distance
• Lumbar Flexion (modified Schober)
• Maximal intermalleolar distance and
• Cervical rotation. The BASMI linear result is the average of the 5 assessments and ranges from 0 to 10. The higher the BASMI score the more severe the patient's limitation of movement due to their AS. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit and treatment-by-visit interaction as fixed factors.

Chest expansion is the difference, in centimeter (cm), between the circumference of the chest in maximal inspiration and maximal expiration. While patients have their hands resting on or behind the head, the assessor will measure the chest encircled length by centimeter (cm) at the fourth intercostal level anteriorly. Two tries were recorded. The better measurement (larger difference) of 2 tries (in centimeters) was used for analyses. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, 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. LS mean was determined by MMRM with factors for treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit and treatment-by-visit interaction 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. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, 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. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, 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 body). The 46 joints were assessed and classified as tender or not tender. Sum of all joints checked to be tender/painful divided by number of evaluable joints which was multiplied by 46 to obtain TJC score. The scores ranges from 0 (no tender/painful joints) to 46 (all joints tender/painful). LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction.

The number of swollen joints was determined by examination of 44 joints (22 joints on each side of the body). The 44 joints were assessed and classified as swollen or not swollen. Sum of all joints checked to be swollen divided by number of evaluable joints which was multiplied by 44 to obtain SJC score. The SJC score ranges from 0 (no swollen joints) to 44 (all joints swollen). LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction.

Anterior uveitis is an inflammation of the middle layer of the eye. which includes the iris (colored part of the eye) and the adjacent tissue, known as the ciliary body.

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 1 number that describes their worst level of fatigue during the previous 24 hours. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

The Jenkins Sleep Evaluation Questionnaire (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. Patients report the numbers 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. LS mean was determined by MMRM with treatment, geographic region, baseline CRP status, number of prior TNFi, 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, with higher scores indicating greater impairment and less productivity. LS mean was determined by ANCOVA with treatment, geographic region, baseline CRP status, number of prior TNFi and baseline value as fixed factors.

ASAS-NSAID score is used to present the NSAID intake by considering the type of NSAID, the total dose, & the number of days taking NSAID during a period of interest (PI). For NSAID equivalent scoring system, range is from 0 to 100, higher the score greated the NSAID intake. ASAS-NSAID score= (equivalent NSAID score) x (days of intake during PI) x (days per week)/(PI in days).

A treatment emergent - antidrug antibody (TE-ADA) positive patient is defined as: a) a patient with a >= 4-fold increase over a positive baseline antibody titer; or b) for a negative baseline titer, a patient with an increase from the baseline to a level of >= 1:10. Percentage was calculated based on the number of evaluable participants and was calculated by number of participants with treatment-emergent positive anti-ixekizumab antibodies / number of evaluable participants * 100%.

Pharmacokinetics (PK): Steady-state trough serum concentration of Ixekizumab at week 16.