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A Long Term Extension Study of Ixekizumab (LY2439821) in Participants With Axial Spondyloarthritis

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03129100
Collaborator
(none)
773
Enrollment
127
Locations
3
Arms
48.6
Actual Duration (Months)
6.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate, in participants having achieved a state of sustained remission, if the ixekizumab treatment groups are superior to the placebo group in maintaining response during the randomized withdrawal-retreatment period in participants with axial spondyloarthritis.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
773 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Long-Term Extension Study of 104 Weeks, Including a Double-Blind, Placebo-Controlled 40-Week Randomized Withdrawal-Retreatment Period, to Evaluate the Maintenance of Treatment Effect of Ixekizumab (LY2439821) in Patients With Axial Spondyloarthritis
Actual Study Start Date :
May 9, 2017
Actual Primary Completion Date :
May 26, 2020
Actual Study Completion Date :
May 27, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ixekizumab (IXE) 80Q4W

Participants received 80 milligram (mg) of Ixekizumab subcutaneously (SC) every four weeks (Q4W).

Drug: Ixekizumab
Administered SC
Other Names:
  • LY2439821

    		•
    Experimental: Ixekizumab (IXE) 80Q2W

    Participants received 80 milligram (mg) of Ixekizumab subcutaneously (SC) every two weeks (Q2W).

    Drug: Ixekizumab
    Administered SC
    Other Names:
  • LY2439821

    		•
    Placebo Comparator: Placebo

    Participants received subcutaneous dose of placebo.

    Drug: Placebo
    Administered SC

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Who do Not Experience a Flare (Combined Ixekizumab Treatment) [Week 64]

      A flare is defined as Ankylosing Spondylitis Disease Activity Score (ASDAS ≥2.1) at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2. ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with high sensitivity C-reactive protein (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.

    Secondary Outcome Measures

    1. Percentage of Participants Who do Not Experience a Flare [Week 64]

      A flare is defined as Ankylosing Spondylitis Disease Activity Score (ASDAS ≥2.1) at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2. ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with high sensitivity C-reactive protein (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.

    2. Change From Baseline in Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) [Baseline, 2 Years]

      The mSASSS is a four-point scoring system for lateral radiographs of the lumbar and cervical spine and has been shown to reliably track disease progression over time, where: 0 = normal; 1 = sclerosis, squaring or erosion; 2 = syndesmophyte; 3 = bony bridge. By the scoring system of mSASSS of the spinal x-rays, a total of 24 sites were scored on the lateral cervical and lumbar spine: the anterior corners of the vertebrae from lower border of C2 to upper border T1 (inclusive), and from lower border of T12 to upper border of S1 (inclusive). Each corner was scored from 0 to 3, resulting in a range from 0 [no change] to 72 [progression].

    3. Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS)20 Response [Week 64]

      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. The following ASAS domains are used: 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 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Q5 & Q6 (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).

    4. Percentage of Participants Achieving an ASAS40 Response [Week 64]

      ASAS40 is defined as a ≥40% improvement and an absolute improvement from baseline of ≥2 units (range of 0 to 10) in at least 3 of the following 4 domains without any worsening in the remaining domain. The following ASAS domains are used: 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 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Q5 & Q6 (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).

    5. Percentage of Participants With Change of Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥1.1 Units [Week 64]

      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 the score worse the disease activity.

    6. Percentage of Participants With Inactive Disease on the ASDAS (<1.3 Units) [Week 64]

      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 the score worse the disease activity.

    7. Change From Baseline in the Individual Components of the ASAS Criteria [Baseline, Week 64]

      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). LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    8. Percentage of Participants Achieving Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) Response [Week 64]

      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.

    9. Change From Baseline in the Measure of High Sensitivity C-Reactive Protein (CRP) [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    10. Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) [Baseline, Week 64]

      BASMI is a combined index comprising of the following 5 clinical measurements of spinal mobility in participants 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 participant's limitation of movement due to their AS. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    11. Change From Baseline in Chest Expansion in Centimeters [Baseline, Week 64]

      Chest expansion is the difference, in centimeter (cm), between the circumference of the chest in maximal inspiration and maximal expiration. While participants 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    12. Change From Baseline in Occiput to Wall Distance [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    13. Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    14. Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Score [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    15. Change From Baseline in Severity of Peripheral Arthritis by Tender Joint Count (TJC) Score of 46 Joints [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    16. Change From Baseline in Severity of Peripheral Arthritis by Swollen Joint Count (SJC) Score of 44 Joints [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    17. Percentage of Participants With Anterior Uveitis or Uveitis Flares [Week 64]

      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.

    18. Change From Baseline in the Fatigue Numeric Rating Scale (NRS) Score [Baseline, Week 64]

      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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    19. Change From Baseline on the Quick Inventory of Depressive Symptomatology Self-Report-16 (QIDS-SR16) [Baseline, Week 64]

      The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    20. Change From Baseline in 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS) Score [Baseline, Week 64]

      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. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    21. Change From Baseline in SF-36 Mental Component Summary (MCS) Score [Baseline, Week 64]

      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. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    22. Change From Baseline in ASAS Health Index (ASAS HI) [Baseline, Week 64]

      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 participant 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    23. Change From Baseline in the European Quality of Life - 5 Dimensions 5 Level (EQ-5D-5L) UK Population-based Index Score [Baseline, Week 64]

      The European Quality of Life - 5 Dimensions 5 Level (EQ-5D-5L) is a standardized measure of health status used to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of 2 components: a descriptive system of the respondent's health and a rating of his/her current health state using a 0- to 100-mm visual analog scale (VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    24. Change From Baseline in the Work Productivity Activity Impairment Spondyloarthritis (WPAI-SpA) Scores [Baseline, Week 64]

      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 participant 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, originating study, baseline value and Week 24 value as fixed factors.

    25. Change From Baseline in the Jenkins Sleep Evaluation Questionnaire (JSEQ) [Baseline, Week 64]

      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. Participants 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.

    26. Percentage of Participants With No New Syndesmophyte Formation [Week 56]

      Percentage of participants with no new syndesmophyte formation was measured using the average of 2 selected readers of 3 readers.

    27. Percentage of Participants With Anti-Ixekizumab Antibodies [Baseline, Week 64]

      A treatment emergent - antidrug antibody (TE-ADA) positive participant is defined as: a) a participant with a >= 4-fold increase over a positive baseline antibody titer; or b) for a negative baseline titer, a participant 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%.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Have completed the final study visit in Study RHBV (NCT02696785), RHBW (NCT02696798), or RHBX (NCT02757352).

    (Note: Participants from Study RHBX are not eligible if they permanently discontinued ixekizumab and were receiving a tumor necrosis factor [TNF] inhibitor).

    • Must agree to use a reliable method of birth control.
    Exclusion Criteria:

    • Have significant uncontrolled disorders or abnormal laboratory values that, in the opinion of the investigator, pose an unacceptable risk to the participant if investigational product continues to be administered.

    • Have a known hypersensitivity to ixekizumab or any component of this investigational product.

    • Had investigational product permanently discontinued during a previous ixekizumab study.

    • Had temporary investigational product interruption at any time during or at the final study visit of a previous ixekizumab study and, in the opinion of the investigator, restarting ixekizumab poses an unacceptable risk for the participant's participation in the study.

    • Have any other condition that, in the opinion of the investigator, renders the participant unable to understand the nature, scope, and possible consequences of the study or precludes the participant from following and completing the protocol.

    • Are currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Arthritis & Rheumatology Research Phoenix Arizona United States 85032
    2 Care Access Research - Huntington Beach Huntington Beach California United States 92648
    3 Desert Medical Advances Palm Desert California United States 92260
    4 Arthritis Assoc. & Osteoporosis Ctr of Colorado Springs, LLC Colorado Springs Colorado United States 80920
    5 Clinical Research Center of CT/NY Danbury Connecticut United States 06810
    6 Arthritis Rheumatic Disease Specialties Aventura Florida United States 33180
    7 Sarasota Arthritis Center Sarasota Florida United States 34239
    8 Marietta Rheumatology Marietta Georgia United States 30060
    9 Institute of Arthritis Research Idaho Falls Idaho United States 83404
    10 Center for Arthritis & Osteoporosis Elizabethtown Kentucky United States 42701
    11 Klein and Associates MD, PA Cumberland Maryland United States 21502
    12 Klein and Associates MD, PA Hagerstown Maryland United States 21740
    13 Arthritis Consultants Inc. Saint Louis Missouri United States 63141
    14 Glacier View Research Institute Kalispell Montana United States 59901
    15 Physician Research Collaboration, LLC Lincoln Nebraska United States 68516
    16 Shanahan Rheumatology & Immunotherapy, PLLC Raleigh North Carolina United States 27617
    17 Carolina Arthritis Associates Wilmington North Carolina United States 28401
    18 Oregon Health and Science University Portland Oregon United States 97239
    19 Altoona Center for Clinical Research Duncansville Pennsylvania United States 16635
    20 Articularis Healthcare Group, INC dba Columbia Arthritis Ctr Columbia South Carolina United States 29204
    21 Articularis Healthcare d/b/a/ Low Country Rheumatology, PA Summerville South Carolina United States 29486
    22 Univ of Texas Health Science Center - Houston Houston Texas United States 77030
    23 Arthritis Northwest PLLC Spokane Washington United States 99204
    24 Clinica Adventista de Belgrano Ciudad de Buenos Aires Buenos Aires Argentina C1430EGF
    25 CER Instituto Medico Quilmes Buenos Aires Argentina B1878DVC
    26 Centro de Enfermedades del Higado y Aparato Digestivo Rosario Santa Fe Argentina S2000CFJ
    27 Centro Medico Privado de Reumatologia San Miguel de Tucuman Tucuman Argentina T4000AXL
    28 Consultorios Reumatologicos Pampa Ciudad Autonoma de Buenos Aire Argentina C1428DZF
    29 CIR Centro de Investigacions Reumatologicas San Miguel de Tucuman Argentina 4000
    30 KH der Barmherzigen Schwestern Wien BetriebsGesmbH Wien Austria 1060
    31 CMIP - Centro Mineiro de Pesquisa Juiz de Fora Minas Gerais Brazil 36010-570
    32 EDUMED - Educação em Saúde Ltda. Curitiba Paraná Brazil 80440-080
    33 LMK Serviços Médicos S/S Porto Alegre Rio Grande Do Sul Brazil 90540-000
    34 CCBR Brasil Centro de Analises e Pesquisas Clínicas LTDA Rio de Janeiro RJ Brazil 22271-100
    35 Hospital de Clinicas de Porto Alegre Porto Alegre RS Brazil 90035-903
    36 Cpclin Centro de Pesquisas Clinicas Sao Paulo São Paulo Brazil 01228-200
    37 CIP - Centro Internacional de Pesquisa Goiás Brazil 74110-120
    38 University of Alberta Hospital Edmonton Alberta Canada T6G 2B7
    39 St. Clare's Mercy Hospital St. John's Newfoundland and Labrador Canada A1C 5B8
    40 Centre de Recherche Musculo-Squelettique Trois-Rivieres Quebec Canada G8Z 1Y2
    41 Group de recherche en maladies osseuses Quebec Canada G1V 3M7
    42 Revmaclinic, s.r.o Brno Czechia 611 41
    43 Interni a revmatologicka ambulance, Inrea s.r.o. Ostrava Czechia 703 00
    44 Arthrohelp s.r.o Pardubice Czechia 530 02
    45 Revmatologicky ustav Praha 2 Czechia 128 50
    46 MEDICAL PLUS, s.r.o. Uherske Hradiste Czechia 686 01
    47 Helsinki University Hospital, HYKS Helsinki Finland 00029
    48 Terveystalo Kamppi Helsinki Finland 00100
    49 Kiljava Medical Research Hyvinkaa Finland 05800
    50 Hôpital Trousseau, CHRU de Tours Chambray-lès-Tours France 37170
    51 Centre hospitalier universitaire Lapeyronie Montpellier Cedex 5 France 34295
    52 Nouvel Hôpital Orléans La Source Orleans CEDEX 2 France 45067
    53 Rheumazentrum Prof. Neeck Bad Doberan Mecklenburg-Vorpommern Germany 18209
    54 Rheumazentrum Ruhrgebiet Herne Nordrhein-Westfalen Germany 44649
    55 Charité Universitätsmedizin Berlin Berlin Germany 12203
    56 HRF Hamburger Rheuma Forschungszentrum Hamburg Germany 20095
    57 Revita Reumatologiai Kft. Budapest Hungary 1027
    58 Vital Medical Center Veszprem Hungary 8200
    59 Barzilai Medical Center Ashkelon Israel 7830604
    60 Rambam Medical Center Haifa Israel 3109601
    61 Rabin Medical Center Petach Tikva Israel 4941492
    62 Tel Aviv Sourasky Medical Center Tel Aviv Israel 6423906
    63 Arcispedale Santa Maria Nuova Azienda Ospedaliera di Reggio Emilia Reggio Emilia Italy 42123
    64 Hokkaido University Hospital Sapporo Hokkaido Japan 060-8648
    65 Kagawa University Hospital Kita-gun Kagawa Japan 761-0793
    66 Kochi Medical School Hospital Nankoku Kochi Japan 783-8505
    67 Kuwana City Medical Center Kuwana Mie Japan 511-0061
    68 Sasebo Chuo Hospital Sasebo Nagasaki Japan 857-1195
    69 Osaka University Hospital Suita-shi Osaka Japan 565 0871
    70 Juntendo University Hospital Bunkyo-ku Tokyo Japan 113-8431
    71 St. Lukes International Hospital Chuo-Ku Tokyo Japan 104 8560
    72 Japanese Red Cross Okayama Hospital Okayama Japan 700-8607
    73 Osaka City General Hospital Osaka Japan 534-0021
    74 Osaka City University Hospital Osaka Japan 545-8586
    75 Yamagata University Hospital Yamagata Japan 990-9585
    76 Kyung Hee University Hospital Seoul Korea Korea, Republic of 02447
    77 Seoul St. Mary's Hospital Seoul Korea Korea, Republic of 06591
    78 Asan Medical Center Songpa-gu Seoul Korea, Republic of 05505
    79 Chungnam National University Hospital Daejeon Korea, Republic of 35015
    80 Seoul National University Hospital Seoul Korea, Republic of 03080
    81 Hanyang University Medical Center Seoul Korea, Republic of 04763
    82 Konkuk University Hospital Seoul Korea, Republic of 05030
    83 Kyunghee University Hospital at Gangdong Seoul Korea, Republic of 05278
    84 Gangnam Severance Hospital Seoul Korea, Republic of 06273
    85 Seoul Municipal Boramae Hospital Seoul Korea, Republic of 07061
    86 Ctro Inv en Artritis y Osteoporosis SC Mexicali Baja California Mexico 21200
    87 Unidad de Investigacion en Enfermedades Cronico Degenerative Guadalajara Jalisco Mexico 44620
    88 Clinica en Investigación en Reumatologia y Obesidad S.C. Guadalajara Jalisco Mexico 44650
    89 Hospital Universitario de Monterrey Monterrey Nuevo Leon Mexico 64460
    90 Centro de Alta Especialidad Reumatologia Inv del Potosi SC San Luis Potosi SLP Mexico 78213
    91 Medical Care and Research, S.A. de C.V. Merida Yucatan Mexico 97070
    92 Investigación y Biomedicina de Chihuahua, SC Chihuahua Mexico 31000
    93 Academisch Medisch Centrum Amsterdam Netherlands 1105 AZ
    94 Antonius Ziekenhuis Sneek Netherlands 8601 ZK
    95 NZOZ ZDROWIE Osteo-Medic Bialystok Poland 15-351
    96 Szpital Uniwersytecki nr 2 im. dr J. Biziela Bydgoszcz Poland 85-168
    97 Centrum Kliniczno-Badawcze Elblag Poland 82-300
    98 Centrum Leczenia Osteoporozy Klinika Zdrowej Kosci Lodz Poland 90-558
    99 Lecznica MAK-MED, NZOZ Nadarzyn Poland 05-830
    100 Prywatna Praktyka Lekarska P. Hrycaj Poznan Poland 61-397
    101 Lubelskie Centrum Diagnostyczne Swidnik Poland 21-040
    102 Reumatika Centrum Reumatologii Warszawa Poland 02-691
    103 Centrum Medyczne AMED Warszawa Poland 03-291
    104 GCM Medical Group PSC San Juan Puerto Rico 00909
    105 Latin Clinical Trial Center San Juan Puerto Rico 00909
    106 Mindful Medical Research San Juan Puerto Rico 00918
    107 Spitalul Clinic Sf Maria Bucuresti Bucuresti Romania 011172
    108 Sp Clinic Judetean de Urgenta Sf.Apostol Andrei Constanta Constanta Romania 900591
    109 V.A. Nasonova Research Institute of Rheumatology Moscow Russian Federation 115522
    110 City Clinical Hospital N1 Moscow Russian Federation 119049
    111 Ryazan Regional Clinincal Cardiology Dispensary Ryazan Russian Federation 390026
    112 Saratov State Medical University Saratov Russian Federation 410026
    113 Clinical Rheumatology Hospital # 25 St. Petersburg Russian Federation 190068
    114 Clinical Hospital for Emergency Care Yaroslavl Russian Federation 150003
    115 Centro de Salud Mental Parc Tauli Sabadell Barcelona Spain 08208
    116 Hospital General Universitario Gregorio Marañon Madrid Spain 28007
    117 Hospital Infanta Luisa Sevilla Spain 41010
    118 Chang Gung Memorial Hospital - Kaohsiung Kaohsiung Taiwan 83301
    119 Chung Shan Medical University Hospital Taichung City Taiwan 40201
    120 China Medical University Hospital Taichung Taiwan 40447
    121 National Taiwan University Hospital Taipei Taiwan 10002
    122 Chi-Mei Medical Center Yongkang City Taiwan 71004
    123 Wythenshawe Hospital Wythenshawe Manchester United Kingdom M23 9LT
    124 Norfolk and Norwich Hospital Norwich Norfolk United Kingdom NR4 7UY
    125 Haywood Hospital Stoke on Trent Staffordshire United Kingdom ST6 7AG
    126 New Cross Hospital Wolverhampton West Midlands United Kingdom WV10 0QP
    127 Solihull Hospital Solihull West Midland United Kingdom B91 2JL

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03129100
    Other Study ID Numbers:
    • 16181
    • I1F-MC-RHBY
    • 2016-002634-69
    First Posted:
    Apr 26, 2017
    Last Update Posted:
    Jun 13, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Spondylitis
    Spondylarthritis
    Ixekizumab

    Study Results

    Participant Flow

    Recruitment Details Lead-In (Period 1): 24 weeks (Week 0 to Week 24) Extension Period including Double-Blind, Placebo-Controlled, Randomized Withdrawal-Retreatment (RWR) (Period 2): 40 weeks (Week 24 to Week 64) Long-Term Extension Period (Period 3): 40 weeks (Week 64 to Week 104) Post-Treatment Follow-Up (Period 4): at least 12 weeks and up to 24 weeks after the date of the participant's ETV or last regularly scheduled visit.
    Pre-assignment Detail In Period 2, participants who did not achieve sustained remission were assigned to Group A and continued to receive the ixekizumab(IXE) dose regimen that they were receiving during Period 1. Participants who did achieve sustained remission were assigned to Group B (Randomized Withdrawal Extension(RWE) period) and were randomized 2:1 to either continue their IXE dose or to withdraw to placebo. Participants who experienced a flare in group B were retreated with IXE in Retreatment Extension Period.
    Arm/Group Title IXE 80Q4W-Lead-in Period IXE80Q2W-Lead-in Period IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period IXE80Q2W/IXE80Q2W-Retreatment Extension Period IXE80Q4W/IXE80Q4W-Retreatment Extension Period PBO/IXE80Q2W-Retreatment Extension Period PBO/IXE80Q4W-Retreatment Extension Period IXE80Q2W-group A Long-term Extension Period IXE80Q4W-group A Long-term Extension Period IXE80Q2W-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q4W-Group B-Randomized Withdrawal Long-term Extension Period PBO-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q2W/IXE80Q2W-Retreatment Long-term Extension Period IXE80Q4W/IXE80Q4W-Retreatment Long-term Extension Period PBO/IXE80Q2W-Retreatment Long-term Extension Period PBO/IXE80Q4W-Retreatment Long-term Extension Period IXE80Q4W-Group A-Escalation Period IXE80Q4W-Randomized Withdrawal Escalation Period PBO-Randomized Withdrawal Escalation Period PBO-follow-up Period IXE80Q4W-follow-up Period IXE80Q2W-follow-up Period
    Arm/Group Description Participants received 80 milligram (mg) of Ixekizumab subcutaneously (SC) every four weeks (Q4W) for up to week 24. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) for up to week 24. Participants continued to receive uninterrupted Ixekizumab 80 mg Q4W subcutaneous dose during the extension period. Participants continued to receive uninterrupted Ixekizumab 80 mg Q2W subcutaneous dose during the extension period. Participants in the Ixekizumab 80 mg Q4W treatment group (Lead-in) were re randomized to receive Ixekizumab 80 mg Q4W subcutaneous dose at Week 24 in the randomized withdrawal extension period. Participants in the Ixekizumab 80 mg Q2W treatment group (Lead-in) were re randomized to receive subcutaneous dose of Ixekizumab 80 mg Q2W at Week 24 in the randomized withdrawal extension period. Participants were re-randomized to receive subcutaneous dose of placebo at Week 24 in the randomized withdrawal extension period. Participants in Group B who received Ixekizumab 80 mg Q2W in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long-term extension period. Participants in Group B who received Ixekizumab 80 mg Q4W in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group B who received placebo in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long term extension period. Participants in Group B who received placebo in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants from "IXE80Q2W group A extension period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q4W group A extension period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q2W-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q4W-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "Placebo-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants in Group B who received Ixekizumab 80 mg Q2W in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long-term extension period. Participants in Group B who received Ixekizumab 80 mg Q4W in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group B who received placebo in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long term extension period. Participants in Group B who received placebo in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group A receiving ixekizumab 80 mg Q4W escalated to ixekizumab 80 mg Q2W in Period 3. Participants in Group B receiving Ixekizumab 80 mg Q4W escalated to ixekizumab 80 mg Q2W. Participants in Group B, who received PBO, experienced a flare and retreated with Ixekizumab 80 mg Q4W, escalated to ixekizumab 80 mg Q2W. Participants did not receive any intervention during Follow-up period. Participants did not receive any intervention during Follow-up period. Participants did not receive any intervention during Follow-up period.
    Period Title: Lead-In Period (Period 1)
    STARTED 350 423 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Received at Least One Dose of Study Drug 348 423 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    COMPLETED 335 406 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 15 17 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 255 318 48 54 53 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Received at Least One Dose of Study Drug 0 0 255 318 47 54 53 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    COMPLETED 0 0 234 312 42 45 32 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 21 6 6 9 21 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 0 0 0 0 0 6 5 9 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    COMPLETED 0 0 0 0 0 0 0 6 5 8 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 0 0 0 0 0 0 0 0 0 306 177 45 42 30 0 0 0 0 0 0 0 0 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 287 146 40 37 21 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 19 31 5 5 9 0 0 0 0 0 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 4 11 15 0 0 0 0 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 2 11 12 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 3 0 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 77 5 4 0 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 73 5 4 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0
    Period Title: Lead-In Period (Period 1)
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 25 223 453
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 22 198 411
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 25 42

    Baseline Characteristics

    Arm/Group Title IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period Total
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) for up to week 24. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) for up to week 24. Participants in the Ixekizumab 80 mg Q4W treatment group (Lead-in) were re randomized to receive Ixekizumab 80 mg Q4W subcutaneous dose at Week 24 in the randomized withdrawal extension period. Participants in the Ixekizumab 80 mg Q2W treatment group (Lead-in) were re randomized to receive subcutaneous dose of Ixekizumab 80 mg Q2W at Week 24 in the randomized withdrawal extension period. Participants were re-randomized to receive subcutaneous dose of placebo at Week 24 in the randomized withdrawal extension period. Total of all reporting groups
    Overall Participants 255 318 48 54 53 728
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    240
    94.1%
    302
    95%
    48
    100%
    53
    98.1%
    52
    98.1%
    695
    95.5%
    >=65 years
    15
    5.9%
    16
    5%
    0
    0%
    1
    1.9%
    1
    1.9%
    33
    4.5%
    Sex: Female, Male (Count of Participants)
    Female
    68
    26.7%
    95
    29.9%
    10
    20.8%
    14
    25.9%
    15
    28.3%
    202
    27.7%
    Male
    187
    73.3%
    223
    70.1%
    38
    79.2%
    40
    74.1%
    38
    71.7%
    526
    72.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    61
    23.9%
    86
    27%
    7
    14.6%
    14
    25.9%
    11
    20.8%
    179
    24.6%
    Not Hispanic or Latino
    166
    65.1%
    204
    64.2%
    31
    64.6%
    35
    64.8%
    39
    73.6%
    475
    65.2%
    Unknown or Not Reported
    28
    11%
    28
    8.8%
    10
    20.8%
    5
    9.3%
    3
    5.7%
    74
    10.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    14
    5.5%
    11
    3.5%
    2
    4.2%
    5
    9.3%
    4
    7.5%
    36
    4.9%
    Asian
    54
    21.2%
    50
    15.7%
    15
    31.3%
    15
    27.8%
    13
    24.5%
    147
    20.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    2
    0.6%
    0
    0%
    0
    0%
    0
    0%
    2
    0.3%
    White
    183
    71.8%
    247
    77.7%
    31
    64.6%
    31
    57.4%
    35
    66%
    527
    72.4%
    More than one race
    3
    1.2%
    8
    2.5%
    0
    0%
    3
    5.6%
    1
    1.9%
    15
    2.1%
    Unknown or Not Reported
    1
    0.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.1%
    Region of Enrollment (Count of Participants)
    Argentina
    11
    4.3%
    18
    5.7%
    1
    2.1%
    1
    1.9%
    2
    3.8%
    33
    4.5%
    Romania
    1
    0.4%
    3
    0.9%
    0
    0%
    1
    1.9%
    0
    0%
    5
    0.7%
    Hungary
    3
    1.2%
    2
    0.6%
    1
    2.1%
    1
    1.9%
    0
    0%
    7
    1%
    United States
    14
    5.5%
    30
    9.4%
    1
    2.1%
    3
    5.6%
    2
    3.8%
    50
    6.9%
    Czechia
    37
    14.5%
    35
    11%
    5
    10.4%
    4
    7.4%
    4
    7.5%
    85
    11.7%
    Japan
    7
    2.7%
    9
    2.8%
    1
    2.1%
    3
    5.6%
    1
    1.9%
    21
    2.9%
    United Kingdom
    4
    1.6%
    6
    1.9%
    0
    0%
    1
    1.9%
    0
    0%
    11
    1.5%
    Spain
    5
    2%
    4
    1.3%
    0
    0%
    1
    1.9%
    0
    0%
    10
    1.4%
    Russia
    16
    6.3%
    30
    9.4%
    6
    12.5%
    7
    13%
    6
    11.3%
    65
    8.9%
    Canada
    3
    1.2%
    2
    0.6%
    1
    2.1%
    0
    0%
    2
    3.8%
    8
    1.1%
    Netherlands
    0
    0%
    2
    0.6%
    0
    0%
    0
    0%
    0
    0%
    2
    0.3%
    South Korea
    28
    11%
    23
    7.2%
    10
    20.8%
    7
    13%
    8
    15.1%
    76
    10.4%
    Austria
    1
    0.4%
    1
    0.3%
    0
    0%
    1
    1.9%
    0
    0%
    3
    0.4%
    Taiwan
    17
    6.7%
    16
    5%
    3
    6.3%
    5
    9.3%
    2
    3.8%
    43
    5.9%
    Finland
    0
    0%
    5
    1.6%
    0
    0%
    1
    1.9%
    2
    3.8%
    8
    1.1%
    Brazil
    7
    2.7%
    16
    5%
    0
    0%
    0
    0%
    0
    0%
    23
    3.2%
    Poland
    50
    19.6%
    67
    21.1%
    13
    27.1%
    7
    13%
    13
    24.5%
    150
    20.6%
    Italy
    0
    0%
    1
    0.3%
    0
    0%
    0
    0%
    0
    0%
    1
    0.1%
    Mexico
    40
    15.7%
    38
    11.9%
    5
    10.4%
    11
    20.4%
    8
    15.1%
    102
    14%
    Israel
    5
    2%
    3
    0.9%
    0
    0%
    0
    0%
    1
    1.9%
    9
    1.2%
    France
    4
    1.6%
    4
    1.3%
    0
    0%
    0
    0%
    0
    0%
    8
    1.1%
    Germany
    2
    0.8%
    3
    0.9%
    1
    2.1%
    0
    0%
    2
    3.8%
    8
    1.1%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who do Not Experience a Flare (Combined Ixekizumab Treatment)
    Description A flare is defined as Ankylosing Spondylitis Disease Activity Score (ASDAS ≥2.1) at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2. ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with high sensitivity C-reactive protein (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 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title Combined IXE Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) and every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 102 53
    Number [Percentage of participants]
    83.3
    32.7%
    54.7
    17.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.35
    Confidence Interval (2-Sided) 95%
    2.03 to 9.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Percentage of Participants Who do Not Experience a Flare
    Description A flare is defined as Ankylosing Spondylitis Disease Activity Score (ASDAS ≥2.1) at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2. ASDAS is a composite index to assess disease activity in AS. The parameters used for the ASDAS (with high sensitivity C-reactive protein (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 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of participants]
    83.3
    32.7%
    83.3
    26.2%
    54.7
    114%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.28
    Confidence Interval (2-Sided) 95%
    1.66 to 11.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.42
    Confidence Interval (2-Sided) 95%
    1.77 to 11.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in Modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS)
    Description The mSASSS is a four-point scoring system for lateral radiographs of the lumbar and cervical spine and has been shown to reliably track disease progression over time, where: 0 = normal; 1 = sclerosis, squaring or erosion; 2 = syndesmophyte; 3 = bony bridge. By the scoring system of mSASSS of the spinal x-rays, a total of 24 sites were scored on the lateral cervical and lumbar spine: the anterior corners of the vertebrae from lower border of C2 to upper border T1 (inclusive), and from lower border of T12 to upper border of S1 (inclusive). Each corner was scored from 0 to 3, resulting in a range from 0 [no change] to 72 [progression].
    Time Frame Baseline, 2 Years

    Outcome Measure Data

    Analysis Population Description
    Ixekizumab structure population who have been treated with ixekizumab for at least 24 months.
    Arm/Group Title IXE80Q4W IXE80Q2W Combined IXE
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W). Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W). Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) and two weeks (Q2W).
    Measure Participants 115 115 230
    Mean (Standard Deviation) [Units on a Scale]
    0.41
    (2.102)
    0.23
    (1.387)
    0.32
    (1.779)
    4. Secondary Outcome
    Title Percentage of Participants Achieving an Assessment of Spondyloarthritis International Society (ASAS)20 Response
    Description 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. The following ASAS domains are used: 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 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Q5 & Q6 (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).
    Time Frame Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of participants]
    81.3
    31.9%
    81.5
    25.6%
    50.9
    106%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.51
    Confidence Interval (2-Sided) 95%
    1.78 to 11.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.61
    Confidence Interval (2-Sided) 95%
    1.88 to 11.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Percentage of Participants Achieving an ASAS40 Response
    Description ASAS40 is defined as a ≥40% improvement and an absolute improvement from baseline of ≥2 units (range of 0 to 10) in at least 3 of the following 4 domains without any worsening in the remaining domain. The following ASAS domains are used: 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 mean of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Q5 & Q6 (mean of intensity & duration of stiffness): Score ranges from "0" (none) and "10" (very severe).
    Time Frame Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of Participants]
    79.2
    31.1%
    79.6
    25%
    43.4
    90.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.17
    Confidence Interval (2-Sided) 95%
    2.11 to 12.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.23
    Confidence Interval (2-Sided) 95%
    2.20 to 12.47
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Percentage of Participants With Change of Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥1.1 Units
    Description 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 the score worse the disease activity.
    Time Frame Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of participants]
    79.2
    31.1%
    74.1
    23.3%
    45.3
    94.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.60
    Confidence Interval (2-Sided) 95%
    1.90 to 11.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 3.55
    Confidence Interval (2-Sided) 95%
    1.56 to 8.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Percentage of Participants With Inactive Disease on the ASDAS (<1.3 Units)
    Description 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 the score worse the disease activity.
    Time Frame Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of participants]
    60.4
    23.7%
    53.7
    16.9%
    24.5
    51%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.92
    Confidence Interval (2-Sided) 95%
    2.07 to 11.72
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 3.61
    Confidence Interval (2-Sided) 95%
    1.57 to 8.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline in the Individual Components of the ASAS Criteria
    Description 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). LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Patient Global
    -5.1
    (0.38)
    -5.0
    (0.36)
    -3.0
    (0.36)
    Spinal Pain
    -5.1
    (0.39)
    -4.8
    (0.37)
    -3.0
    (0.36)
    BASFI
    -4.35
    (0.316)
    -4.19
    (0.301)
    -2.79
    (0.301)
    Inflammation
    -5.20
    (0.336)
    -4.83
    (0.319)
    -3.03
    (0.317)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments Patient Global
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.1
    Confidence Interval (2-Sided) 95%
    -3.1 to -1.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.51
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments Patient Global
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.0
    Confidence Interval (2-Sided) 95%
    -2.9 to -1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.49
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments Spinal Pain
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.1
    Confidence Interval (2-Sided) 95%
    -3.1 to -1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.51
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments Spinal Pain
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.8
    Confidence Interval (2-Sided) 95%
    -2.8 to -0.8
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.49
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments BASFI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.55
    Confidence Interval (2-Sided) 95%
    -2.39 to -0.72
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.421
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments BASFI
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.40
    Confidence Interval (2-Sided) 95%
    -2.20 to -0.59
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.409
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments Inflammation
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.17
    Confidence Interval (2-Sided) 95%
    -3.05 to -1.28
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.448
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments Inflammation
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.80
    Confidence Interval (2-Sided) 95%
    -2.66 to -0.95
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.433
    Estimation Comments
    9. Secondary Outcome
    Title Percentage of Participants Achieving Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) Response
    Description 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.
    Time Frame Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the nonresponder imputation (NRI) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of participants]
    81.3
    31.9%
    75.9
    23.9%
    45.3
    94.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.34
    Confidence Interval (2-Sided) 95%
    2.13 to 13.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.07
    Confidence Interval (2-Sided) 95%
    1.75 to 9.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Change From Baseline in the Measure of High Sensitivity C-Reactive Protein (CRP)
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [milligram per liter (mg/L)]
    -12.952
    (1.4666)
    -11.074
    (1.3861)
    -5.094
    (1.3696)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -7.858
    Confidence Interval (2-Sided) 95%
    -11.729 to -3.987
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.9586
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -5.979
    Confidence Interval (2-Sided) 95%
    -9.655 to -2.304
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.8600
    Estimation Comments
    11. Secondary Outcome
    Title Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI)
    Description BASMI is a combined index comprising of the following 5 clinical measurements of spinal mobility in participants 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 participant's limitation of movement due to their AS. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [Units on a scale]
    -0.69
    (0.080)
    -0.73
    (0.075)
    -0.50
    (0.073)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.062
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.20
    Confidence Interval (2-Sided) 95%
    -0.40 to 0.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.104
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.018
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.24
    Confidence Interval (2-Sided) 95%
    -0.43 to -0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.099
    Estimation Comments
    12. Secondary Outcome
    Title Change From Baseline in Chest Expansion in Centimeters
    Description Chest expansion is the difference, in centimeter (cm), between the circumference of the chest in maximal inspiration and maximal expiration. While participants 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [centimeter (cm)]
    0.77
    (0.256)
    0.53
    (0.243)
    0.67
    (0.236)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.757
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.10
    Confidence Interval (2-Sided) 95%
    -0.56 to 0.77
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.335
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.670
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.14
    Confidence Interval (2-Sided) 95%
    -0.77 to 0.50
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.322
    Estimation Comments
    13. Secondary Outcome
    Title Change From Baseline in Occiput to Wall Distance
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [cm]
    -0.78
    (0.260)
    -0.66
    (0.239)
    -0.38
    (0.235)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.236
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.40
    Confidence Interval (2-Sided) 95%
    -1.07 to 0.27
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.338
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.373
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.28
    Confidence Interval (2-Sided) 95%
    -0.92 to 0.35
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.319
    Estimation Comments
    14. Secondary Outcome
    Title Change From Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B), and with Baseline MASES score >0. Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 29 36 35
    Least Squares Mean (Standard Error) [Units on a scale]
    -3.55
    (0.352)
    -3.62
    (0.315)
    -3.48
    (0.302)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.885
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.07
    Confidence Interval (2-Sided) 95%
    -0.98 to 0.85
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.459
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.735
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.14
    Confidence Interval (2-Sided) 95%
    -0.95 to 0.68
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.410
    Estimation Comments
    15. Secondary Outcome
    Title Change From Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Score
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B), and with baseline SPARCC score >0. Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 22 30 30
    Least Squares Mean (Standard Error) [Units on a scale]
    -3.23
    (0.388)
    -3.34
    (0.338)
    -2.71
    (0.335)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.294
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.53
    Confidence Interval (2-Sided) 95%
    -1.53 to 0.47
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.501
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.164
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.64
    Confidence Interval (2-Sided) 95%
    -1.54 to 0.27
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.453
    Estimation Comments
    16. Secondary Outcome
    Title Change From Baseline in Severity of Peripheral Arthritis by Tender Joint Count (TJC) Score of 46 Joints
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B), and with baseline TJC >0. Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 27 33 23
    Least Squares Mean (Standard Error) [Units on a scale]
    -6.1
    (0.76)
    -5.3
    (0.74)
    -4.0
    (0.85)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.063
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -2.1
    Confidence Interval (2-Sided) 95%
    -4.3 to 0.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.10
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.211
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.3
    Confidence Interval (2-Sided) 95%
    -3.3 to 0.7
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.02
    Estimation Comments
    17. Secondary Outcome
    Title Change From Baseline in Severity of Peripheral Arthritis by Swollen Joint Count (SJC) Score of 44 Joints
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B), and with baseline SJC >0. Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 16 21 15
    Least Squares Mean (Standard Error) [Units on a scale]
    -3.6
    (0.67)
    -3.9
    (0.59)
    -2.7
    (0.73)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.334
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.9
    Confidence Interval (2-Sided) 95%
    -2.7 to 0.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.90
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.168
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -1.2
    Confidence Interval (2-Sided) 95%
    -3.0 to 0.5
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.88
    Estimation Comments
    18. Secondary Outcome
    Title Percentage of Participants With Anterior Uveitis or Uveitis Flares
    Description 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 Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B), and regardless of history of anterior uveitis.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Number [Percentage of Participants]
    4.2
    1.6%
    5.6
    1.8%
    5.7
    11.9%
    19. Secondary Outcome
    Title Change From Baseline in the Fatigue Numeric Rating Scale (NRS) Score
    Description 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    -4.2
    (0.31)
    -4.3
    (0.29)
    -3.5
    (0.28)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.100
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.7
    Confidence Interval (2-Sided) 95%
    -1.5 to 0.1
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.40
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.047
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.8
    Confidence Interval (2-Sided) 95%
    -1.5 to -0.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.38
    Estimation Comments
    20. Secondary Outcome
    Title Change From Baseline on the Quick Inventory of Depressive Symptomatology Self-Report-16 (QIDS-SR16)
    Description The 16-item QIDS-SR16 version is a widely used validated scale designed to assess the severity of depressive symptoms. The participant was asked to rate the severity and frequency of specific symptoms present over the last 7 days. The QIDS-SR16 total scores range from 0 to 27, where higher scores indicate higher severity of symptoms. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    -3.68
    (0.362)
    -3.28
    (0.344)
    -2.80
    (0.342)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.068
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.88
    Confidence Interval (2-Sided) 95%
    -1.83 to 0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.479
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.307
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.48
    Confidence Interval (2-Sided) 95%
    -1.40 to 0.44
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.465
    Estimation Comments
    21. Secondary Outcome
    Title Change From Baseline in 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS) Score
    Description 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. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    13.2954
    (1.1210)
    13.1030
    (1.0457)
    10.6934
    (1.0366)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.079
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 2.6021
    Confidence Interval (2-Sided) 95%
    -0.3011 to 5.5053
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.4684
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.087
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 2.4096
    Confidence Interval (2-Sided) 95%
    -0.3541 to 5.1734
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.3978
    Estimation Comments
    22. Secondary Outcome
    Title Change From Baseline in SF-36 Mental Component Summary (MCS) Score
    Description 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. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    3.1766
    (0.8968)
    4.6404
    (0.8369)
    2.3396
    (0.8314)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.477
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.8370
    Confidence Interval (2-Sided) 95%
    -1.4864 to 3.1605
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.1752
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.042
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 2.3009
    Confidence Interval (2-Sided) 95%
    0.0880 to 4.5138
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.1192
    Estimation Comments
    23. Secondary Outcome
    Title Change From Baseline in ASAS Health Index (ASAS HI)
    Description 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 participant 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    -4.64
    (0.393)
    -4.37
    (0.368)
    -3.64
    (0.370)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.058
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.99
    Confidence Interval (2-Sided) 95%
    -2.02 to 0.04
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.520
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.147
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.72
    Confidence Interval (2-Sided) 95%
    -1.71 to 0.26
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.497
    Estimation Comments
    24. Secondary Outcome
    Title Change From Baseline in the European Quality of Life - 5 Dimensions 5 Level (EQ-5D-5L) UK Population-based Index Score
    Description The European Quality of Life - 5 Dimensions 5 Level (EQ-5D-5L) is a standardized measure of health status used to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of 2 components: a descriptive system of the respondent's health and a rating of his/her current health state using a 0- to 100-mm visual analog scale (VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. LS mean was determined by ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    0.2877
    (0.0252)
    0.2847
    (0.0235)
    0.2459
    (0.0237)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.213
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0418
    Confidence Interval (2-Sided) 95%
    -0.0329 to 0.1164
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.0334
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.225
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0388
    Confidence Interval (2-Sided) 95%
    -0.0324 to 0.1101
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.0319
    Estimation Comments
    25. Secondary Outcome
    Title Change From Baseline in the Work Productivity Activity Impairment Spondyloarthritis (WPAI-SpA) Scores
    Description 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 participant 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, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    -43.58
    (3.329)
    -40.10
    (3.115)
    -32.96
    (3.099)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments Percentage of Activity Impairment
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.017
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -10.62
    Confidence Interval (2-Sided) 95%
    -19.28 to -1.95
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.383
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments Percentage of Activity Impairment
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.091
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -7.14
    Confidence Interval (2-Sided) 95%
    -15.44 to 1.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 4.199
    Estimation Comments
    26. Secondary Outcome
    Title Change From Baseline in the Jenkins Sleep Evaluation Questionnaire (JSEQ)
    Description 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. Participants 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 ANCOVA with treatment, geographic region, originating study, baseline value and Week 24 value as fixed factors.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved a state of sustained remission and were randomized to 40-week double-blind placebo controlled RWR period (Group B). Missing data was imputed using the modified baseline observation carried forward (mBOCF) method.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 48 54 53
    Least Squares Mean (Standard Error) [units on a scale]
    -4.0
    (0.50)
    -3.8
    (0.47)
    -3.6
    (0.47)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combined IXE, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.531
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.4
    Confidence Interval (2-Sided) 95%
    -1.7 to 0.9
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.66
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.743
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.2
    Confidence Interval (2-Sided) 95%
    -1.4 to 1.0
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.62
    Estimation Comments
    27. Secondary Outcome
    Title Percentage of Participants With No New Syndesmophyte Formation
    Description Percentage of participants with no new syndesmophyte formation was measured using the average of 2 selected readers of 3 readers.
    Time Frame Week 56

    Outcome Measure Data

    Analysis Population Description
    Ixekizumab structure population who have been treated with Ixekizumab for at least 24 months
    Arm/Group Title IXE80Q4W IXE80Q2W
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W). Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W).
    Measure Participants 115 115
    Number [Percentage of participants]
    80.9
    31.7%
    87.8
    27.6%
    28. Secondary Outcome
    Title Percentage of Participants With Anti-Ixekizumab Antibodies
    Description A treatment emergent - antidrug antibody (TE-ADA) positive participant is defined as: a) a participant with a >= 4-fold increase over a positive baseline antibody titer; or b) for a negative baseline titer, a participant 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%.
    Time Frame Baseline, Week 64

    Outcome Measure Data

    Analysis Population Description
    All randomized participants from Group B, who received at least one dose of study drug.
    Arm/Group Title IXE80Q4W IXE80Q2W Placebo
    Arm/Group Description Participants received 80 mg of Ixekizumab subcutaneously every four weeks (Q4W) during the randomized withdrawal extension period. Participants received 80 mg of Ixekizumab subcutaneously (SC) every two weeks (Q2W) during the randomized withdrawal extension period. Participants received placebo subcutaneously during the randomized withdrawal extension period.
    Measure Participants 43 51 45
    Number [Percentage of participants]
    4.7
    1.8%
    2.0
    0.6%
    20.0
    41.7%

    Adverse Events

    Time Frame Baseline, up to 128 weeks
    Adverse Event Reporting Description All randomized participants received at least one dose of study treatment. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Arm/Group Title IXE 80Q4W-Lead-in Period IXE80Q2W-Lead-in Period IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period IXE80Q2W/IXE80Q2W-Retreatment Extension Period IXE80Q4W/IXE80Q4W-Retreatment Extension Period PBO/IXE80Q2W-Retreatment Extension Period PBO/IXE80Q4W-Retreatment Extension Period IXE80Q2W-group A Long-term Extension Period IXE80Q4W-group A Long-term Extension Period IXE80Q2W-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q4W-Group B-Randomized Withdrawal Long-term Extension Period PBO-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q2W/IXE80Q2W-Retreatment Long-term Extension Period IXE80Q4W/IXE80Q4W-Retreatment Long-term Extension Period PBO/IXE80Q2W-Retreatment Long-term Extension Period PBO/IXE80Q4W-Retreatment Long-term Extension Period IXE80Q4W-Group A-Escalation Period IXE80Q4W-Randomized Withdrawal Escalation Period PBO-randomized Withdrawal Escalation Period PBO-follow-up Period IXE80Q4W-follow-up Period IXE80Q2W-follow-up Period
    Arm/Group Description Participants received 80 milligram (mg) of Ixekizumab subcutaneously (SC) every four weeks (Q4W) for up to week 24. Participants received 80 mg of Ixekizumab subcutaneously every two weeks (Q2W) for up to week 24. Participants continued to receive uninterrupted Ixekizumab 80 mg Q4W subcutaneous dose during the extension period. Participants continued to receive uninterrupted Ixekizumab 80 mg Q2W subcutaneous dose during the extension period. Participants in the Ixekizumab 80 mg Q4W treatment group (Lead-in) were re randomized to receive Ixekizumab 80 mg Q4W subcutaneous dose at Week 24 in the randomized withdrawal extension period. Participants in the Ixekizumab 80 mg Q2W treatment group (Lead-in) were re randomized to receive subcutaneous dose of Ixekizumab 80 mg Q2W at Week 24 in the randomized withdrawal extension period. Participants were re-randomized to receive subcutaneous dose of placebo at Week 24 in the randomized withdrawal extension period. Participants in Group B who received Ixekizumab 80 mg Q2W in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long-term extension period. Participants in Group B who received Ixekizumab 80 mg Q4W in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group B who received placebo in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long term extension period. Participants in Group B who received placebo in Period 2 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants from "IXE80Q2W group A extension period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q4W group A extension period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q2W-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "IXE80Q4W-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants from "Placebo-Group B-Randomized Withdrawal Extension Period" continued to receive same treatment that they were receiving at the end of Period 2. Participants in Group B who received Ixekizumab 80 mg Q2W in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long-term extension period. Participants in Group B who received Ixekizumab 80 mg Q4W in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group B who received placebo in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q2W during the retreatment long term extension period. Participants in Group B who received placebo in Period 3 and experienced a flare were retreated with subcutaneous dose of Ixekizumab 80 mg Q4W during the retreatment long term extension period. Participants in Group A receiving ixekizumab 80 mg Q4W escalated to ixekizumab 80 mg Q2W in Period 3. Participants in Group B receiving ixekizumab 80 mg Q4W escalated to ixekizumab 80 mg Q2W. Participants in Group B, who received PBO, experienced a flare and retreated with Ixekizumab 80 mg Q4W, escalated to ixekizumab 80 mg Q2W. Participants did not receive any intervention during Follow-up period. Participants did not receive any intervention during Follow-up period. Participants did not receive any intervention during Follow-up period.
    All Cause Mortality
    IXE 80Q4W-Lead-in Period IXE80Q2W-Lead-in Period IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period IXE80Q2W/IXE80Q2W-Retreatment Extension Period IXE80Q4W/IXE80Q4W-Retreatment Extension Period PBO/IXE80Q2W-Retreatment Extension Period PBO/IXE80Q4W-Retreatment Extension Period IXE80Q2W-group A Long-term Extension Period IXE80Q4W-group A Long-term Extension Period IXE80Q2W-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q4W-Group B-Randomized Withdrawal Long-term Extension Period PBO-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q2W/IXE80Q2W-Retreatment Long-term Extension Period IXE80Q4W/IXE80Q4W-Retreatment Long-term Extension Period PBO/IXE80Q2W-Retreatment Long-term Extension Period PBO/IXE80Q4W-Retreatment Long-term Extension Period IXE80Q4W-Group A-Escalation Period IXE80Q4W-Randomized Withdrawal Escalation Period PBO-randomized Withdrawal Escalation Period PBO-follow-up Period IXE80Q4W-follow-up Period IXE80Q2W-follow-up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/348 (0%) 0/423 (0%) 2/255 (0.8%) 0/318 (0%) 0/47 (0%) 0/54 (0%) 0/53 (0%) 0/6 (0%) 0/5 (0%) 0/9 (0%) 0/10 (0%) 0/306 (0%) 0/177 (0%) 0/45 (0%) 0/42 (0%) 0/30 (0%) 0/6 (0%) 0/4 (0%) 0/11 (0%) 0/15 (0%) 0/77 (0%) 0/5 (0%) 0/4 (0%) 0/25 (0%) 1/223 (0.4%) 0/453 (0%)
    Serious Adverse Events
    IXE 80Q4W-Lead-in Period IXE80Q2W-Lead-in Period IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period IXE80Q2W/IXE80Q2W-Retreatment Extension Period IXE80Q4W/IXE80Q4W-Retreatment Extension Period PBO/IXE80Q2W-Retreatment Extension Period PBO/IXE80Q4W-Retreatment Extension Period IXE80Q2W-group A Long-term Extension Period IXE80Q4W-group A Long-term Extension Period IXE80Q2W-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q4W-Group B-Randomized Withdrawal Long-term Extension Period PBO-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q2W/IXE80Q2W-Retreatment Long-term Extension Period IXE80Q4W/IXE80Q4W-Retreatment Long-term Extension Period PBO/IXE80Q2W-Retreatment Long-term Extension Period PBO/IXE80Q4W-Retreatment Long-term Extension Period IXE80Q4W-Group A-Escalation Period IXE80Q4W-Randomized Withdrawal Escalation Period PBO-randomized Withdrawal Escalation Period PBO-follow-up Period IXE80Q4W-follow-up Period IXE80Q2W-follow-up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/348 (2.9%) 12/423 (2.8%) 12/255 (4.7%) 11/318 (3.5%) 2/47 (4.3%) 2/54 (3.7%) 1/53 (1.9%) 1/6 (16.7%) 0/5 (0%) 0/9 (0%) 0/10 (0%) 15/306 (4.9%) 3/177 (1.7%) 1/45 (2.2%) 1/42 (2.4%) 0/30 (0%) 0/6 (0%) 0/4 (0%) 0/11 (0%) 0/15 (0%) 1/77 (1.3%) 0/5 (0%) 0/4 (0%) 0/25 (0%) 3/223 (1.3%) 2/453 (0.4%)
    Blood and lymphatic system disorders
    Neutropenia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 0/453 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 1/45 (2.2%) 1 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Cardiac failure acute 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Coronary artery stenosis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 1/177 (0.6%) 1 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Myocardial infarction 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 1/177 (0.6%) 1 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 1/77 (1.3%) 1 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Myocardial ischaemia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 1/453 (0.2%) 1
    Eye disorders
    Iridocyclitis 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Gastrointestinal disorders
    Colitis ulcerative 0/348 (0%) 0 2/423 (0.5%) 2 2/255 (0.8%) 2 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Crohn's disease 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 0/453 (0%) 0
    Inguinal hernia 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 1/177 (0.6%) 1 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Strangulated umbilical hernia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    General disorders
    Death 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Soft tissue inflammation 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 1/53 (1.9%) 1 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Hepatobiliary disorders
    Cholecystitis acute 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Infections and infestations
    Appendicitis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 3/306 (1%) 3 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Cellulitis 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Chronic tonsillitis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Clostridium difficile colitis 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Covid-19 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 0/453 (0%) 0
    Influenza 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 1/6 (16.7%) 1 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Orchitis 1/256 (0.4%) 1 0/293 (0%) 0 0/187 (0%) 0 0/223 (0%) 0 0/37 (0%) 0 0/40 (0%) 0 0/38 (0%) 0 0/4 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/8 (0%) 0 0/215 (0%) 0 0/130 (0%) 0 0/34 (0%) 0 0/33 (0%) 0 0/21 (0%) 0 0/4 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/12 (0%) 0 0/56 (0%) 0 0/3 (0%) 0 0/1 (0%) 0 0/17 (0%) 0 0/166 (0%) 0 0/317 (0%) 0
    Respiratory tract infection viral 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Sepsis 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Urinary tract infection 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Injury, poisoning and procedural complications
    Clavicle fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Comminuted fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 1/177 (0.6%) 1 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Compression fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 1/47 (2.1%) 1 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Concussion 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Contusion 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Femur fracture 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Ilium fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Ligament sprain 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Limb injury 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 2 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Lumbar vertebral fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Meniscus injury 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Pneumothorax traumatic 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Rib fracture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Spinal column injury 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Synovial rupture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Investigations
    Blood creatine phosphokinase increased 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Metabolism and nutrition disorders
    Hyperglycaemia 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Hyperkalaemia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Axial spondyloarthritis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Back pain 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 2 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Osteoarthritis 2/348 (0.6%) 2 1/423 (0.2%) 1 2/255 (0.8%) 2 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Pseudarthrosis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 0/453 (0%) 0
    Spinal ligament ossification 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Temporomandibular joint syndrome 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Tenosynovitis 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Adenocarcinoma 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Anal cancer 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Benign lung neoplasm 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Breast cancer 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Chronic lymphocytic leukaemia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 2 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Ovarian cancer 0/92 (0%) 0 1/130 (0.8%) 1 0/68 (0%) 0 0/95 (0%) 0 0/10 (0%) 0 0/14 (0%) 0 0/15 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/2 (0%) 0 0/2 (0%) 0 0/91 (0%) 0 0/47 (0%) 0 0/11 (0%) 0 0/9 (0%) 0 0/9 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/21 (0%) 0 0/2 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/57 (0%) 0 0/136 (0%) 0
    Ovarian germ cell teratoma benign 0/92 (0%) 0 0/130 (0%) 0 0/68 (0%) 0 0/95 (0%) 0 1/10 (10%) 1 0/14 (0%) 0 0/15 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/2 (0%) 0 0/2 (0%) 0 0/91 (0%) 0 0/47 (0%) 0 0/11 (0%) 0 0/9 (0%) 0 0/9 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/21 (0%) 0 0/2 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/57 (0%) 0 0/136 (0%) 0
    Papillary thyroid cancer 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Nervous system disorders
    Cerebral venous sinus thrombosis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Hypoglycaemic unconsciousness 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Myelopathy 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Radiculopathy 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Psychiatric disorders
    Depression 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Major depression 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Suicidal ideation 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Renal and urinary disorders
    Calculus urinary 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Nephrolithiasis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Renal colic 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Ureterolithiasis 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 1/42 (2.4%) 1 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Urinary incontinence 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 1/453 (0.2%) 1
    Reproductive system and breast disorders
    Dysmenorrhoea 0/92 (0%) 0 0/130 (0%) 0 0/68 (0%) 0 0/95 (0%) 0 0/10 (0%) 0 0/14 (0%) 0 0/15 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/2 (0%) 0 0/2 (0%) 0 1/91 (1.1%) 1 0/47 (0%) 0 0/11 (0%) 0 0/9 (0%) 0 0/9 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/21 (0%) 0 0/2 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/57 (0%) 0 0/136 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Haemothorax 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Urticaria 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Vascular disorders
    Venous thrombosis 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Venous thrombosis limb 0/348 (0%) 0 0/423 (0%) 0 1/255 (0.4%) 1 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Other (Not Including Serious) Adverse Events
    IXE 80Q4W-Lead-in Period IXE80Q2W-Lead-in Period IXE80Q4W-Group A Extension Period IXE80Q2W-Group A Extension Period IXE80Q4W-Group B-Randomized Withdrawal Extension Period IXE80Q2W-Group B-Randomized Withdrawal Extension Period Placebo-Group B-Randomized Withdrawal Extension Period IXE80Q2W/IXE80Q2W-Retreatment Extension Period IXE80Q4W/IXE80Q4W-Retreatment Extension Period PBO/IXE80Q2W-Retreatment Extension Period PBO/IXE80Q4W-Retreatment Extension Period IXE80Q2W-group A Long-term Extension Period IXE80Q4W-group A Long-term Extension Period IXE80Q2W-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q4W-Group B-Randomized Withdrawal Long-term Extension Period PBO-Group B-Randomized Withdrawal Long-term Extension Period IXE80Q2W/IXE80Q2W-Retreatment Long-term Extension Period IXE80Q4W/IXE80Q4W-Retreatment Long-term Extension Period PBO/IXE80Q2W-Retreatment Long-term Extension Period PBO/IXE80Q4W-Retreatment Long-term Extension Period IXE80Q4W-Group A-Escalation Period IXE80Q4W-Randomized Withdrawal Escalation Period PBO-randomized Withdrawal Escalation Period PBO-follow-up Period IXE80Q4W-follow-up Period IXE80Q2W-follow-up Period
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 79/348 (22.7%) 108/423 (25.5%) 62/255 (24.3%) 82/318 (25.8%) 8/47 (17%) 17/54 (31.5%) 16/53 (30.2%) 0/6 (0%) 4/5 (80%) 2/9 (22.2%) 1/10 (10%) 52/306 (17%) 37/177 (20.9%) 8/45 (17.8%) 6/42 (14.3%) 9/30 (30%) 0/6 (0%) 3/4 (75%) 6/11 (54.5%) 5/15 (33.3%) 6/77 (7.8%) 2/5 (40%) 0/4 (0%) 0/25 (0%) 14/223 (6.3%) 27/453 (6%)
    Blood and lymphatic system disorders
    Leukopenia 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 2/318 (0.6%) 2 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 1/5 (20%) 1 0/9 (0%) 0 0/10 (0%) 0 2/306 (0.7%) 2 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 1/4 (25%) 1 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 1/453 (0.2%) 1
    Cardiac disorders
    Tachycardia 1/348 (0.3%) 1 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 2 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 1/15 (6.7%) 1 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Eye disorders
    Iridocyclitis 8/348 (2.3%) 8 5/423 (1.2%) 5 7/255 (2.7%) 8 10/318 (3.1%) 11 2/47 (4.3%) 2 2/54 (3.7%) 3 3/53 (5.7%) 3 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 6/306 (2%) 7 6/177 (3.4%) 6 2/45 (4.4%) 2 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 5/453 (1.1%) 6
    Gastrointestinal disorders
    Abdominal pain upper 1/348 (0.3%) 1 2/423 (0.5%) 2 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 2/54 (3.7%) 2 1/53 (1.9%) 1 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 2/30 (6.7%) 2 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Crohn's disease 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 1/15 (6.7%) 1 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 1/453 (0.2%) 1
    Diarrhoea 3/348 (0.9%) 4 10/423 (2.4%) 10 6/255 (2.4%) 6 5/318 (1.6%) 6 0/47 (0%) 0 3/54 (5.6%) 3 1/53 (1.9%) 1 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 3/306 (1%) 3 2/177 (1.1%) 2 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 1/453 (0.2%) 1
    Toothache 1/348 (0.3%) 1 1/423 (0.2%) 1 1/255 (0.4%) 1 1/318 (0.3%) 1 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 1/4 (25%) 1 0/11 (0%) 0 0/15 (0%) 0 1/77 (1.3%) 1 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    General disorders
    Fatigue 0/348 (0%) 0 3/423 (0.7%) 3 1/255 (0.4%) 1 1/318 (0.3%) 1 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 2/306 (0.7%) 2 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 1/30 (3.3%) 1 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Infections and infestations
    Covid-19 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 3/306 (1%) 3 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 1/30 (3.3%) 1 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 1/5 (20%) 1 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 3/453 (0.7%) 3
    Gastrointestinal viral infection 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 1/5 (20%) 1 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Nasopharyngitis 27/348 (7.8%) 28 40/423 (9.5%) 42 27/255 (10.6%) 33 30/318 (9.4%) 32 2/47 (4.3%) 3 4/54 (7.4%) 6 7/53 (13.2%) 8 0/6 (0%) 0 1/5 (20%) 1 1/9 (11.1%) 1 0/10 (0%) 0 19/306 (6.2%) 20 17/177 (9.6%) 19 2/45 (4.4%) 4 1/42 (2.4%) 1 3/30 (10%) 3 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 2/15 (13.3%) 2 2/77 (2.6%) 2 1/5 (20%) 1 0/4 (0%) 0 0/25 (0%) 0 4/223 (1.8%) 4 6/453 (1.3%) 6
    Pharyngitis 5/348 (1.4%) 6 9/423 (2.1%) 10 9/255 (3.5%) 9 7/318 (2.2%) 7 0/47 (0%) 0 0/54 (0%) 0 3/53 (5.7%) 3 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 6/306 (2%) 7 3/177 (1.7%) 3 1/45 (2.2%) 1 1/42 (2.4%) 1 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 2/453 (0.4%) 2
    Upper respiratory tract infection 16/348 (4.6%) 19 22/423 (5.2%) 24 7/255 (2.7%) 7 13/318 (4.1%) 14 2/47 (4.3%) 3 4/54 (7.4%) 4 2/53 (3.8%) 2 0/6 (0%) 0 0/5 (0%) 0 1/9 (11.1%) 1 0/10 (0%) 0 8/306 (2.6%) 10 3/177 (1.7%) 3 2/45 (4.4%) 2 1/42 (2.4%) 1 2/30 (6.7%) 2 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 2/77 (2.6%) 2 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 2/223 (0.9%) 2 1/453 (0.2%) 1
    Vaginal infection 0/92 (0%) 0 0/130 (0%) 0 0/68 (0%) 0 0/95 (0%) 0 0/10 (0%) 0 0/14 (0%) 0 0/15 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/2 (0%) 0 0/2 (0%) 0 0/91 (0%) 0 1/47 (2.1%) 1 0/11 (0%) 0 0/9 (0%) 0 1/9 (11.1%) 1 0/2 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/21 (0%) 0 0/2 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/57 (0%) 0 1/136 (0.7%) 1
    Injury, poisoning and procedural complications
    Contusion 2/348 (0.6%) 2 0/423 (0%) 0 0/255 (0%) 0 1/318 (0.3%) 1 1/47 (2.1%) 1 0/54 (0%) 0 1/53 (1.9%) 1 0/6 (0%) 0 0/5 (0%) 0 1/9 (11.1%) 1 0/10 (0%) 0 0/306 (0%) 0 2/177 (1.1%) 3 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 0/453 (0%) 0
    Foreign body in eye 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 1/5 (20%) 1 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Tendon rupture 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Investigations
    Neutrophil count decreased 0/348 (0%) 0 1/423 (0.2%) 1 0/255 (0%) 0 0/318 (0%) 0 1/47 (2.1%) 2 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 1/5 (20%) 2 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 1/42 (2.4%) 1 0/30 (0%) 0 0/6 (0%) 0 1/4 (25%) 1 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Metabolism and nutrition disorders
    Glucose tolerance impaired 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 1/10 (10%) 1 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 8/348 (2.3%) 9 6/423 (1.4%) 6 5/255 (2%) 7 14/318 (4.4%) 16 0/47 (0%) 0 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 2/306 (0.7%) 4 4/177 (2.3%) 4 1/45 (2.2%) 1 2/42 (4.8%) 2 1/30 (3.3%) 1 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 1/77 (1.3%) 1 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 1/223 (0.4%) 1 5/453 (1.1%) 6
    Back pain 9/348 (2.6%) 9 15/423 (3.5%) 15 3/255 (1.2%) 3 3/318 (0.9%) 3 1/47 (2.1%) 1 3/54 (5.6%) 3 2/53 (3.8%) 2 0/6 (0%) 0 1/5 (20%) 1 1/9 (11.1%) 1 0/10 (0%) 0 2/306 (0.7%) 2 1/177 (0.6%) 1 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 2/223 (0.9%) 2 2/453 (0.4%) 2
    Chondrodynia 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 1/306 (0.3%) 1 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Enthesopathy 3/348 (0.9%) 3 3/423 (0.7%) 3 1/255 (0.4%) 1 0/318 (0%) 0 1/47 (2.1%) 1 1/54 (1.9%) 1 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 1/4 (25%) 2 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Musculoskeletal stiffness 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Myalgia 2/348 (0.6%) 2 0/423 (0%) 0 2/255 (0.8%) 2 3/318 (0.9%) 3 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 2/306 (0.7%) 2 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 2/30 (6.7%) 2 0/6 (0%) 0 0/4 (0%) 0 0/11 (0%) 0 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Reproductive system and breast disorders
    Ovarian cyst 0/92 (0%) 0 0/130 (0%) 0 0/68 (0%) 0 0/95 (0%) 0 1/10 (10%) 1 0/14 (0%) 0 0/15 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/2 (0%) 0 0/2 (0%) 0 0/91 (0%) 0 0/47 (0%) 0 0/11 (0%) 0 0/9 (0%) 0 0/9 (0%) 0 0/2 (0%) 0 0/1 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/21 (0%) 0 0/2 (0%) 0 0/3 (0%) 0 0/8 (0%) 0 0/57 (0%) 0 0/136 (0%) 0
    Skin and subcutaneous tissue disorders
    Cold urticaria 0/348 (0%) 0 0/423 (0%) 0 0/255 (0%) 0 0/318 (0%) 0 0/47 (0%) 0 0/54 (0%) 0 0/53 (0%) 0 0/6 (0%) 0 0/5 (0%) 0 0/9 (0%) 0 0/10 (0%) 0 0/306 (0%) 0 0/177 (0%) 0 0/45 (0%) 0 0/42 (0%) 0 0/30 (0%) 0 0/6 (0%) 0 0/4 (0%) 0 1/11 (9.1%) 1 0/15 (0%) 0 0/77 (0%) 0 0/5 (0%) 0 0/4 (0%) 0 0/25 (0%) 0 0/223 (0%) 0 0/453 (0%) 0
    Rash 1/348 (0.3%) 2 5/423 (1.2%) 5 1/255 (0.4%) 1 3/318 (0.9%) 3 0/47 (0%) 0 1/54 (1.9%) 3