A Study of Ixekizumab (LY2439821) in Participants With Nonradiographic Axial Spondyloarthritis

ASAS40 is defined as a greater than or equal to (≥)40% improvement and an absolute improvement from baseline of ≥2 units (ranges 0 to 10) in at least 3 of the 4 domains (Patient Global, Spinal Pain, Function, and Inflammation), without any worsening in the remaining domain. 1) Patient Global: How active was your spondylitis during the last week? score ranges 0 (not active) to 10 (very active). 2) Spinal Pain: How much spinal pain 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. Responses were captured using numeric rating scale (NRS) (ranges 0 to 10) with a higher score of worse function. 4) Inflammation based on mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question 5 and 6 (mean of intensity, duration of stiffness). Score ranges (0 (non) to 10 (very severe).

Time frame: Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data was imputed using the nonresponder imputation (NRI) method.

ASAS40 is defined as a greater than or equal to (≥)40% improvement and an absolute improvement from baseline of ≥2 units (ranges 0 to 10) in at least 3 of the 4 domains (Patient Global, Spinal Pain, Function, and Inflammation), without any worsening in the remaining domain. 1) Patient Global: How active was your spondylitis during the last week? score ranges 0 (not active) to 10 (very active). 2) Spinal Pain: How much spinal pain 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. Responses were captured using numeric rating scale (NRS) (ranges 0 to 10) with a higher score of worse function. 4) Inflammation based on mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question 5 and 6 (mean of intensity, duration of stiffness). Score ranges (0 (non) to 10 (very severe).

Time frame: Week 16

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data was imputed using the nonresponder imputation (NRI) method.

The medical outcomes study 36-item short-form health survey (SF-36) SF-36 PCS are summarized using the t-scores. The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

The SF-36 is a 36-item patient-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 Physical Component Summary score ranges from 0 to 100; higher scores indicate better levels of function and/or better health. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 16

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

ASDAS is a composite index to assess disease activity in axSpA. ASDAS parameters used (with CRP as acute phase reactant) are: 1 )Total back pain 2) Patient global 3) Peripheral pain/swelling 4) Duration of morning stiffness 5) CRP in mg/L: 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 milligram/liter (mg/L), 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. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

ASDAS is a composite index to assess disease activity in axial spondyloarthritis (axSpA). ASDAS parameters used with (C-reactive protein \[CRP\] as acute phase reactant) are: 1) Total back pain 2) Patient global 3) Peripheral pain/swelling, duration of morning stiffness 4) CRP in mg/L: ASDAScrp is calculated with the 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 milligram/liter (mg/L), 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 squares mean (LS Mean) was derived from mixed models repeated measure analysis (MMRM) with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 16

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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. LS Mean was derived MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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, the higher the score, the greater the NSAID intake. ASAS-NSAID score= (equivalent NSAID score) x (days of intake during PI) x (days per week)/(PI in days).

Time frame: Baseline, Week 52

Population: All randomized participants who had NSAID (including COX-2 Inhibitor) intake at Baseline. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

The BASDAI is a participant-reported assessment consisting of 6 questions that relate to 5 major symptoms relevant to axial spondyloarthritis (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. LS mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 16

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

The BASDAI is a participant-reported assessment consisting of 6 questions that relate to 5 major symptoms relevant to axial spondyloarthritis (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. LS mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

BASFI is a participant-reported assessment that establishes a participant's functional baseline and subsequent response to treatment. Participants were asked to rate the difficulty associated with 10 individual basic functional activities. Participant responded to each question using a NRS scale (range 0 to 10), with a higher score indicating worse functioning. The participant's final BASFI score is the mean of the 10 item scores with the minimum value of 0 and a possible maximum value of 10, with a higher score indicating worse function. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

Bath Ankylosing Spondylitis Metrology Index (BASMI) is a combined index comprising the following 5 clinical measurements of spinal mobility in participants with axSpA: 1) Lateral spinal flexion 2) Tragus-to-wall distance 3) Lumbar flexion (modified Schrober) 4) Maximal intermalleolar distance, and 5) Cervical rotation. The BASMI includes these 5 measurements that were 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. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

Maastricht Ankylosing Spondylitis Enthesitis Score (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 included costochondral 1 (right/left \[R/L\]), costochondral 7 (R/L), spinal iliaca anterior superior (R/L), crista iliaca (R/L), spina iliaca posterior (R/L), processus spinosus L5, and achilles tendon proximal insertion (R/L). The MASES is the sum of all site scores (range 0 to 13); higher scores indicate more severe enthesitis. LS mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants with baseline Mases score \> 0. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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. LS Mean was derived from ANCOVA model with treatment, geographic region, screening MRI/CRP status and baseline value as fixed factors.

Time frame: Baseline, Week 16

Population: All randomized participants with baseline and Week 16 SPARCC score. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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 derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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). Swollen joint count SJC was determined by examination of 44 joints (22 joints on each side of the participants body). The joints are classified as swollen or not swollen. Sum of all joints checked to be swollen divided by number of evaluable joints which is multiplied by 44 to obtain SJC score. Score ranges from 0 (not swollen) to 44 (all joints swollen). LS mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status and baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants with baseline TJC\>0 for the TJC analysis. All randomized participants with baseline SJC\>0 for the SJC analysis. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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 derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value visit, baseline value-by-visit and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants with a baseline SPARCC score \>0. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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 derived from using MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

High-sensitivity C-reactive protein (hs-CRP) was the measure of acute phase reactant and was measured with a high sensitivity assay at the central laboratory to help assess the effect of ixekizumab on disease activity. LS Mean was derived from MMRM with treatment, geographic region, screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction as fixed factors.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

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 derived from ANCOVA with treatment, geographic region, screening MRI/CRP status and baseline value.

Time frame: Baseline, Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data were imputed using the modified baseline observation carried forward (mBOCF).

Number of participants with anterior uveitis. 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.

Time frame: Baseline through Week 52

Population: All randomized participants regardless of history of anterior uveitis. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included.

Number of participants without changes in background therapy while on originally randomized treatment.

Time frame: Baseline through Week 52

Population: All randomized participants. Additional analysis not performed due to small number of participants with changes in background therapy and complete overlap with switch to open-label ixekizumab.

A treatment-emergent positive anti-drug antibody (TE-ADA+) participant will be defined as a 4-fold increase over a positive baseline antibody titer (Tier 3); or for a negative baseline titer, a participant with an increase from the baseline to a level of ≥ 1:10.

Time frame: Week 52

Population: All randomized participant who received at least one dose of ixekizumab during the study and had an evaluable baseline sample and at least 1 evaluable post baseline sample.

ASDAS is a composite index to assess disease activity in axSpA. ASDAS Inactive Disease is defined as a score of less than (\<)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.

Time frame: Week 52

Population: All randomized participants. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data was imputed using the NRI method.

ASDAS is a composite index to assess disease activity in axSpA. ASDAS low disease activity is defined as a score of \<2.1. 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.

Time frame: Week 52

Population: All randomized participants with baseline ASDAS \<2.1. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data was imputed using the NRI method.

ASDAS is a composite index to assess disease activity in axSpA. ASDAS low disease activity is defined as a score of \<2.1. 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.

Time frame: Week 16

Population: All randomized participants with baseline ASDAS \<2.1. For inadequate responders who were treated with open label ixekizumab 80 mg Q2W, only data up to the time of initiation of open label of ixekizumab 80 mg Q2W were included. Missing data was imputed using the NRI method.

PK trough serum concentration samples were collected at steady state (Ctrough ss)

Time frame: Week 52

Population: All randomized participants who had evaluable PK data.