A 52-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ixekizumab (LY2439821) in bDMARD Naive Patients With Nonradiographic Axial Spondyloarthritis
Phase: PHASE3
Conditions: Axial Spondyloarthritis
Sponsor: Eli Lilly and Company

I1F-MC-RHBX Protocol b 
 
A 52-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Ixekizumab (LY2439821) in bDMARD-Naive Patients with 
Nonradiographic Axial Spondyloarthritis 
 
NCT02757352 
 
Approval Date: 05-Oct-2018 
 
 
 

I1F-MC-RHBX(b) Clinical Protocol 
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LY2439821 
 
Protocol I1F-MC-RHBX(b) 
A 52-Week Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety 
of Ixekizumab (LY2439821) in bDMARD-Naive Patients with 
Nonradiographic Axial Spondyloarthritis 
  
Confidential Information 
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ixekizumab (LY2439821), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Ixekizumab (LY2439821) 
Study I1F-MC-RHBX is a Phase 3, multicenter, randomized, double-blind, and 
placebo-controlled, parallel-group, outpatient study examining the efficacy and safety of 
subcutaneous (SC) ixekizumab (LY2439821) treatment regimens (80 mg every 2 weeks 
[Q2W] and 80 mg every 4 weeks [Q4W] with an 80-mg or 160-mg starting dose) as 
compared to SC placebo in patients with active nonradiographic ax
ial spondyloarthritis 
(axSpA) who are biological disease-modifying antirheumatic drug (bDMARD)-naive, during 
a 52-week treatment period. 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol Electronically Signed and Approved by Lilly:  18 January 2016 
Amendment (a) Electronically Signed and Approved by Lilly:  05 August 2016 
Amendment (b) Electronically Signed and Approved by Lilly 
on approval date provided below. 
 
 
Approval Date: 05-Oct-2018 GMT
 

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Table of Contents
Section
Page
1.
Protocol Synopsis..............................................................................................................10
2.
Introduction ......................................................................................................................14
2.1.
Background..................................................................................................................14
2.2.
Study Rationale............................................................................................................16
3.
Objectives and Endpoints..................................................................................................17
4.
Study Design.....................................................................................................................20
4.1.
Overview of Study Design ...........................................................................................20
4.2.
End of Trial Definition.................................................................................................23
4.3.
Scientific Rationale for Study Design...........................................................................23
4.4.
Justification for Dose ...................................................................................................24
4.5.
Benefit/Risk Assessment..............................................................................................25
5.
Study Population...............................................................................................................26
5.1.
Inclusion Criteria..........................................................................................................26
5.2.
Exclusion Criteria ........................................................................................................28
5.3.
Screen Failures.............................................................................................................33
5.4.
Study RHBX Screening of Patients Who Were Ineligible for 
Study RHBV................................................................................................................34
5.5.
Lifestyle and/or Dietary Requirements .........................................................................34
6.
Treatment..........................................................................................................................35
6.1.
Treatments Administered .............................................................................................35
6.1.1.
Administration of Investigational Product ............................................................38
6.2.
Method of Treatment Assignment ................................................................................38
6.2.1.
Selection and Timing of Doses.............................................................................39
6.3.
Blinding .......................................................................................................................39
6.4.
Packaging and Labelling ..............................................................................................40
6.5.
Preparation/Handling/Storage.......................................................................................40
6.6.
Dose Modification........................................................................................................40
6.6.1.
Special Treatment Considerations ........................................................................40
6.7.
Treatment Compliance .................................................................................................41
6.8.
Concomitant Therapy...................................................................................................42
6.8.1.
Concomitant Medications During Week 0 to Week 16 .........................................42
6.8.2.
Concomitant Medications at or after Week 16 for Treatment 
Modifications (after Completion of Week 16 Assessments)..................................43
6.9.
Treatment after Study Completion................................................................................44
6.9.1.
Study Extensions..................................................................................................44

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6.9.2.
Continued Access.................................................................................................44
7.
Discontinuation Criteria ....................................................................................................45
7.1.
Discontinuation from Study Treatment.........................................................................45
7.1.1.
Permanent Discontinuation from Study Treatment ...............................................45
7.1.2.
Discontinuation of Inadvertently Enrolled Patients...............................................47
7.1.3.
Permanent Discontinuation from the Study ..........................................................47
7.1.4.
Patients Lost to Follow-Up...................................................................................47
8.
Study Assessments and Procedures ...................................................................................49
8.1.
Efficacy Assessments...................................................................................................49
8.1.1.
Primary Efficacy Assessments:  ASAS40.............................................................49
8.1.2.
Secondary Efficacy Assessments..........................................................................49
8.1.2.1.
ASAS20, ASAS Individual Components, ASAS Partial 
Remission, and ASAS5/6................................................................................49
8.1.2.1.1.
ASAS20 ...................................................................................................49
8.1.2.1.2.
ASAS Partial Remission ...........................................................................50
8.1.2.1.3.
ASAS5/6 ..................................................................................................50
8.1.2.2.
Patient Global (Assessment of Disease Activity) ............................................50
8.1.2.3.
Spinal Pain .....................................................................................................50
8.1.2.4.
Bath Ankylosing Spondylitis Disease Activity Index......................................50
8.1.2.5.
Bath Ankylosing Spondylitis Functional Index ...............................................50
8.1.2.6.
Bath Ankylosing Spondylitis Metrology Index—Spinal 
Mobility .........................................................................................................51
8.1.2.7.
Chest Expansion.............................................................................................51
8.1.2.8.
Occiput to Wall Distance................................................................................51
8.1.2.9.
Ankylosing Spondylitis Disease Activity Score ..............................................51
8.1.2.10.
Maastricht Ankylosing Spondylitis Enthesitis Score .......................................52
8.1.2.11.
SPARCC Enthesitis Score ..............................................................................52
8.1.2.12.
Peripheral Arthritis .........................................................................................52
8.1.2.12.1.
Tender Joint Count ...................................................................................52
8.1.2.12.2.
Swollen Joint Count..................................................................................53
8.1.2.13.
NSAID Intake.................................................................................................53
8.1.2.14.
Clinically Meaningful Changes in Concomitant 
Medication(s) or Background Therapy............................................................53
8.1.2.15.
Assessment of Spondyloarthritis International Society 
Health Index...................................................................................................53
8.1.2.16.
Medical Outcomes Study 36-Item Short-Form Health 
Survey............................................................................................................54
8.1.2.17.
Fatigue Severity Numeric Rating Scale...........................................................54

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8.1.2.18.
Work Productivity and Activity Impairment 
Questionnaire—Spondyloarthritis...................................................................54
8.1.2.19.
Jenkins Sleep Questionnaire ...........................................................................54
8.1.2.20.
Laboratory Tests Used for Efficacy Measures and 
Disease Diagnosis...........................................................................................54
8.1.2.20.1.
High Sensitivity C-Reactive Protein..........................................................54
8.1.2.21.
Imaging Used for Efficacy Measures and Disease 
Diagnosis........................................................................................................55
8.1.2.21.1.
Imaging Used for Efficacy Measures and Disease 
Diagnosis..................................................................................................55
8.1.2.21.2.
Spondyloarthritis Research Consortium of Canada–
MRI Score for Sacroiliac Joints ................................................................55
8.1.2.21.3.
Spondyloarthritis Research Consortium of Canada–
SIJ Structural Score (SSS) ........................................................................56
8.1.3.
Other Assessments...............................................................................................56
8.1.3.1.
European Quality of Life—5 Dimensions 5-Level ..........................................56
8.1.3.2.
Healthcare Resource Utilization......................................................................56
8.2.
Adverse Events ............................................................................................................56
8.2.1.
Serious Adverse Events........................................................................................57
8.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................58
8.2.2.
Adverse Events of Special Interest .......................................................................58
8.2.3.
Complaint Handling.............................................................................................59
8.3.
Treatment of Overdose.................................................................................................59
8.4.
Safety Assessments ......................................................................................................59
8.4.1.
Electrocardiograms ..............................................................................................59
8.4.2.
Vital Signs ...........................................................................................................60
8.4.3.
Laboratory Tests ..................................................................................................60
8.4.4.
Physical Examination...........................................................................................60
8.4.5.
Eye Symptom Assessment ...................................................................................60
8.4.6.
Chest X-Ray and Tuberculosis Testing.................................................................61
8.4.7.
Quick Inventory of Depressive Symptomatology–Self-
Report (16 Items) .................................................................................................62
8.4.8.
Columbia Suicide Severity Rating Scale...............................................................62
8.4.9.
Immunogenicity...................................................................................................63
8.4.10.
Safety Monitoring ................................................................................................63
8.4.10.1.
Neutropenia....................................................................................................63
8.4.10.1.1.
During Treatment (Period 2).....................................................................63
8.4.10.1.2.
At Early Termination Visit........................................................................64
8.4.10.1.3.
Post-Study Follow-Up ..............................................................................65
8.4.10.2.
Hepatitis B Monitoring...................................................................................65

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8.4.10.3.
Hypertension ..................................................................................................66
8.5.
Pharmacokinetics .........................................................................................................66
8.6.
Pharmacodynamics ......................................................................................................66
8.7.
Genetics .......................................................................................................................66
8.8.
Biomarkers...................................................................................................................67
8.8.1.
Samples for Immunogenicity Research.................................................................68
8.9.
Health Economics ........................................................................................................68
9.
Statistical Considerations and Data Analysis.....................................................................69
9.1.
Determination of Sample Size ......................................................................................69
9.2.
General Statistical Considerations ................................................................................69
9.2.1.
General Considerations for Analyses during the Blinded 
Treatment Dosing (Period 2)................................................................................70
9.2.2.
General Considerations for Analyses during Period 3 
(Post-Study Follow-Up Period) ............................................................................72
9.2.3.
Analysis Populations............................................................................................72
9.2.4.
Missing Data Imputation......................................................................................73
9.2.4.1.
Nonresponder Imputation for Clinical Response.............................................73
9.2.4.2.
Modified Baseline Observation Carried Forward ............................................73
9.2.4.3.
Last Observation Carried Forward..................................................................74
9.2.5.
Adjustment for Multiple Comparisons..................................................................74
9.3.
Treatment Group Comparability...................................................................................74
9.3.1.
Patient Disposition...............................................................................................74
9.3.2.
Patient Characteristics..........................................................................................74
9.3.3.
Concomitant Therapy...........................................................................................75
9.3.4.
Treatment Compliance .........................................................................................75
9.4.
Primary and Secondary Analyses .................................................................................75
9.4.1.
Primary Analyses.................................................................................................75
9.4.2.
Secondary Analyses .............................................................................................75
9.4.2.1.
Major Secondary Analyses .............................................................................75
9.4.2.2.
Other Secondary Efficacy Analyses................................................................77
9.4.2.2.1.
Period 2 (Blinded Treatment Dosing Period).............................................77
9.4.3.
Other Exploratory Analyses .................................................................................78
9.5.
Safety Analyses............................................................................................................78
9.5.1.
Adverse Events ....................................................................................................78
9.5.2.
Clinical Laboratory Tests .....................................................................................79
9.5.3.
Vital Signs, Physical Findings, and Other Safety Evaluations...............................79
9.6.
Pharmacokinetic/Pharmacodynamic/Immunogenicity Analyses ...................................80
9.7.
Other Analyses.............................................................................................................80

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9.7.1.
Health Economics ................................................................................................80
9.7.2.
Subgroup Analyses ..............................................................................................81
9.7.3.
Immunogenicity...................................................................................................81
9.8.
Interim Analyses ..........................................................................................................82
10.
Study Governance Considerations.....................................................................................83
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...........................................................................................................83
10.1.1.
Informed Consent.................................................................................................83
10.1.2.
Ethical Review.....................................................................................................83
10.1.3.
Regulatory Considerations ...................................................................................83
10.1.4.
Investigator Information.......................................................................................84
10.1.5.
Protocol Signatures ..............................................................................................84
10.1.6.
Final Report Signature .........................................................................................84
10.2. Data Quality Assurance................................................................................................84
10.2.1.
Data Capture System............................................................................................85
10.3. Study and Site Closure .................................................................................................85
10.3.1.
Discontinuation of Study Sites .............................................................................85
10.3.2.
Discontinuation of the Study................................................................................85
11.
References ........................................................................................................................86

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List of Tables
Table
Page
Table RHBX.1.
Objectives and Endpoints...............................................................................17
Table RHBX.2.
Treatment Regimens from Week 0 to Week 50 (Blinded Treatment 
Dosing Period [Period 2])..............................................................................37
Table RHBX.3.
Imaging Requirements for Sacroiliac Joints and Spine...................................55
Table RHBX.4.
Power Estimates for Week 52 ........................................................................69
Table RHBX.5.
Primary and Major Secondary Outcome Analyses..........................................77

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List of Figures
Figure
Page
Figure RHBX.1. Illustration of study design for Clinical Protocol I1F-MC-RHBX...................22

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................95
Appendix 2.
Schedule of Activities..................................................................................101
Appendix 3.
Clinical Laboratory Tests.............................................................................110
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................112
Appendix 5.
Spondyloarthritis Features ...........................................................................113
Appendix 6.
Protocol Amendment I1F-MC-RHBX(b) Summary:  A 52-Week 
Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Ixekizumab (LY2439821) in 
bDMARD-Naive Patients with Nonradiographic Axial 
Spondyloarthritis .........................................................................................114

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1.
Protocol Synopsis
Title of Study:  
A 52-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety 
of Ixekizumab (LY2439821) in bDMARD-Naive Patients with Nonradiographic Axial Spondyloarthritis  
Rationale:  
Ixekizumab (LY2439821) is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (MAb) that 
neutralizes the cytokine interleukin-17A (IL-17A, also known as IL-17).  Compelling scientific evidence exists 
indicating an important role of the IL-23/IL-17 pathway in axial spondyloarthritis (axSpA) pathogenesis.  Recently 
disclosed data from Phase 3 studies with secukinumab (Cosentyx®), a drug with a similar mechanism of action 
(MoA) as ixekizumab, have demonstrated the effectiveness of inhibiting IL-17A in patients with radiographic-axial 
spondyloarthritis (rad-axSpA, also called Ankylosing Spondylitis) who were biological disease-modifying 
antirheumatic drug (bDMARD)-naive or had previously received tumor necrosis factor (TNF) inhibitors.  The 
present study evaluates the efficacy and safety of ixekizumab in nonradiographic-axSpA (nonrad-axSpA) patients 
who are bDMARD-naive.  
Objective(s)/Endpoints:  
There are 2 primary objectives in this study to accommodate regional regulatory requirements. 
Objectives
Endpoints
Primary
The primary objective is to compare both ixekizumab 
regimens (80 mg every 2 weeks [Q2W] or 80 mg 
every 4 weeks [Q4W]) versus placebo in patients with 
active nonradiographic axial spondyloarthritis 
(nonrad-axSpA).

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40 
(ASAS40) response at Week 16
(for regulatory agencies that accept Week 16 as 
primary endpoint)

Proportion of patients achieving an ASAS40 
response at Week 52
(for regulatory agencies that require Week 52 as 
primary endpoint)
Secondary
The major secondary objective is:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W) versus placebo in patients 
with active nonrad-axSpA at Week 16 and Week 
52

Change from baseline in Ankylosing Spondylitis 
Disease Activity Score (ASDAS) at Week 16

Change from baseline in ASDAS at Week 52

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Week 16

Change from baseline in BASFI at Week 52

Proportion of patients achieving ASDAS inactive 
disease at Week 16

Proportion of patients achieving ASDAS inactive 
disease at Week 52

Change from baseline in magnetic resonance 
imaging (MRI) of the sacroiliac joints (SIJ)
(Spondyloarthritis Research Consortium of 
Canada [SPARCC] score) at Week 16

Percent of patients without clinically meaningful
changes in background therapy at Week 52

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Summary of Study Design:  
Study I1F-MC-RHBX (RHBX) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, outpatient study examining the efficacy and safety of 2 SC ixekizumab treatment regimens (80 mg 
Q2W and 80 mg Q4W) as compared to SC placebo in patients with active nonrad-axSpA who are bDMARD-naive, 
during a double-blind, 52-week treatment period (Period 2).  Patients will complete a Post-Study Follow-Up Period 
(Period 3) over a 12-week period.  
Treatment Groups and Duration:  
Study RHBX has 3 treatment groups during the 52-week Blinded Treatment Dosing Period:  80 mg ixekizumab 
Q4W, 80 mg ixekizumab Q2W, and placebo at a 1:1:1 ratio.  In each ixekizumab treatment group, half of the 
patients will receive an 80-mg starting dose and half a 160-mg starting dose (1:1 randomization).  Randomization 
will be stratified by country and screening MRI/CRP status (positive MRI and elevated C-reactive protein [CRP]; 
positive MRI and nonelevated CRP; negative MRI and elevated CRP). All doses are administered via SC injection.  
At baseline (Week 0), all patients will receive 2 injections.  Patients assigned to an ixekizumab treatment regimen
with a 160-mg ixekizumab starting dose will receive 160 mg of ixekizumab as two 80-mg SC injections.  Patients 
assigned to an ixekizumab treatment regimen with an 80-mg starting dose will receive 80 mg of ixekizumab as 1 SC 
injection and 1 SC injection of placebo.  Patients assigned to the placebo treatment group will receive 2 SC 
injections of placebo.  After Week 0 and through Week 50, all patients will receive 1 injection every 2 weeks.  
Beginning at Week 16 and up to Week 44, any patient, regardless of their original treatment group, may be 
identified by an investigator based on clinical judgment as an inadequate responder.  At such time, changes in 
background therapy and/or addition of biologic rescue therapy (ixekizumab 80 mg Q2W) can be made at the 
discretion of the investigator, while remaining blinded to the original randomization treatment assignment. Changes 
in ongoing medications at that time can include changes in dose of nonsteroidal anti-inflammatory drugs (NSAIDs)
or nonbiological disease-modifying antirheumatic drugs (DMARDs), including the introduction of new medications.  
The investigator may also decide to use biologic rescue with ixekizumab 80 mg Q2W with an 80-mg starting dose. 
General treatment guidelines recommend a minimum period of 12 weeks to evaluate effect of biologic treatment 
modifications; however, if in the opinion of the investigator, a patient does not show any clinical improvement after 
at least 8 weeks of the ixekizumab 80 mg Q2W rescue treatment, then the investigator may consider discontinuation 
of the patient from ixekizumab treatment.  Such patients may then receive other medical therapies (potentially 
including a TNF inhibitor) that are prescribed by their physician and are to remain in the study. The study duration 
will be up to 1 year (52 weeks).  Patients who have taken at least 1 study dose and who discontinue study treatment 
prior to Week 16 (Visit 8) or study participation (regardless of timing) are to complete an early termination visit 
(ETV) and enter into post-study follow-up for at least 12 weeks after the ETV date or the last regularly scheduled 
visit.  Patients whose ETV or last regularly scheduled visit is longer than 12 weeks after their last investigational 
study medication dose are not required to enter into the Post-Study Follow-Up Period. Patients who complete Study 
RHBX, if eligible, may enroll in a long-term extension study for up to 2 additional years of ixekizumab treatment.  
Study Population:  
This study will include approximately 300 randomized patients.  The study population will include patients with a 
physician’s diagnosis of active nonrad-axSpA, who meet the ASAS classification criteria for nonrad-axSpA either 
by the presence of sacroiliitis on MRI (based on central reading) accompanied by at least 1 spondyloarthritis (SpA) 
feature OR by being human leukocyte antigen (HLA)-B27 positive and having at least 2 additional SpA features.  
Patients will present with a history of back pain ≥3 months with age at onset <45 years and have active 
nonrad-axSpA defined as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, and total back pain ≥4 
on a numeric rating scale (NRS) at screening and baseline as well as objective signs of inflammation at screening by 
the presence of sacroiliitis on MRI (as defined by ASAS/OMERACT) and/or presence of elevated CRP (defined as 
CRP >5.00 mg/L).  Patients must also have a history of inadequate response to 2 or more NSAIDs at the therapeutic 
dose range for a total duration of at least 4 weeks or have a history of intolerance to NSAIDs.  Patients must also 
have a history of prior therapy for axSpA of at least 12 weeks prior to screening and not have received conventional 

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DMARDs (cDMARDs) and/or other therapies or other immunosuppressive agents for at least 4 weeks prior to 
baseline randomization, except for methotrexate [MTX] (oral or parenteral up to 25 mg/week), sulfasalazine (up to 
3 g/day), hydroxychloroquine (up to 400 mg/day), or oral corticosteroids (not to exceed 10 mg/day of prednisone or 
equivalent) that may be allowed if treated at a stable dose for at least 4 weeks prior to baseline randomization.  If 
used, cDMARDs are not to be in any combination with other cDMARDs.  
Statistical Analysis:  
Approximately 300 patients will be randomized at a 1:1:1 ratio in the Blinded Treatment Dosing Period (Period 2) to 
ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W, and placebo.  In the active treatment groups, half the patients 
will be given a 160-mg starting dose and the other half will be given an 80-mg starting dose.  With 100 patients per 
treatment group, this study will have approximately 98% power to test the superiority of ixekizumab Q2W to 
placebo for ASAS40 at Week 16 .  The following assumptions were used for the power calculations for ASAS40 
response rates at Week 16 regardless of ixekizumab starting dose: 46% for ixekizumab 80 mg Q2W treatment 
group and 18% for the placebo group.  A 2-sided Fisher’s exact test at the 0.05 level is assumed.  
There is little data from similarly designed 52-week placebo-controlled trials regarding the ASAS40 response rate 
for active and placebo treated patients to guide power estimation at Week 52.  With 100 patients per treatment 
group, this study will have approximately 66-99% power to test the superiority of ixekizumab Q2W to placebo for 
ASAS40 at Week 52, assuming various ASAS40 response rates for ixekizumab Q2W and placebo at Week 52.  A 
2 sided Fisher’s exact test at the 0.05 level is assumed.
The efficacy analyses for the Blinded Treatment Dosing Period will be conducted on the intent-to-treat (ITT) 
population and safety analyses will be conducted on the safety population.  
Comparisons between each ixekizumab treatment group (80 mg Q2W or 80 mg Q4W) and placebo will be 
performed for all analyses in the Blinded Treatment Dosing Period.  Unless otherwise specified, the ixekizumab 
80 mg Q2W and 80 mg Q4W groups will be analyzed without regard to starting dose.  The primary analysis method 
for treatment group comparisons of categorical efficacy and health outcomes variables will be a logistic regression 
analysis with treatment, geographic region, and screening MRI/CRP status (positive MRI and elevated CRP; 
positive MRI and nonelevated CRP; negative MRI and elevated CRP) as factors, using the Nonresponder Imputation 
(NRI) method.  
Under NRI, all nonresponders at Week 16 (Visit 8), as well as all patients who discontinue study treatment at any 
time prior to Week 16 for any reason, will be defined as nonresponders for the NRI analysis at Week 16.  NRI will 
be applied to Week 52 (Visit 15) in a similar method.  Patients who are deemed as inadequate responders by the 
investigator after Week 16 but remain on blinded study treatment and only have modifications in concomitant 
medications will not be automatically imputed as nonresponders.  However, patients who discontinue originally 
assigned blinded study treatment and use rescue ixekizumab 80 mg Q2W will be analyzed as nonresponders for the 
Week 52 analysis. Randomized patients without any postbaseline observation will also be defined as nonresponders 
for the NRI analysis.  
A multiple testing strategy for the primary and major secondary objectives will be implemented to control the 
family-wise type I error rate at a 2-sided α level of 0.05.  
The primary analyses for the continuous efficacy and health outcomes variables will be made using mixed-effects 
model of repeated measures (MMRM) analysis with treatment, geographic region, screening MRI/CRP status, 
baseline value, visit, baseline value-by-visit, and treatment-by-visit interactions as fixed factors.  
A secondary analysis for continuous efficacy and health outcomes variables will be made using analysis of 
covariance (ANCOVA) with treatment, geographic region, screening MRI/CRP status, and baseline.  

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Fisher’s exact test will be used for all adverse events (AEs), baseline, discontinuation, and other categorical safety 
data.  Continuous vital sign and laboratory values will be analyzed by an ANCOVA with treatment and baseline 
value.  
Patients who discontinue study treatment after Week 16 will continue to be followed for all regularly scheduled 
visits for safety and efficacy assessment.  The data collected after discontinuation of study treatment will be 
summarized separately.  

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2.
Introduction
2.1.
Background
Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly affecting the 
axial skeleton (sacroiliac joints and spine) with onset of symptoms that typically appear in the 
second or third decade of life (Poddubnyy 2013). AxSpA is recognized as a single disease 
entity, with a patient subset defined by the presence of radiographically defined structural 
damage of the sacroiliac joints (rad-axSpA) and a patient subset without clear structural damage 
radiographically (nonrad-axSpA) (Deodhar et al. 2014).  When comparing axSpA with 
rheumatoid arthritis (RA) it can be noted that while RA can be divided into erosive and 
nonerosive or seropositive and seronegative subsets, it is well accepted that these subsets still 
represent 1 disease.  AxSpA, in a similar fashion, can be considered a single disease, with rad-
axSpA and nonrad-axSpA subsets (Deodhar et al. 2014).  
AxSpA affects up to 1.4% of the Caucasian adult population worldwide (Braun and Sieper 2007; 
Reveille et al. 2012; Strand et al. 2013).  The proportion of nonrad-axSpA patients among all 
axSpA patients ranges from 40% to 60% according to several national and international referral 
programs (Rudwaleit and Sieper 2012; Poddubnyy et al. 2012). 
Until recently, axSpA patients without radiographically defined sacroiliitis but with evidence of 
sacroiliitis from magnetic resonance imaging (MRI) imaging or other characteristics of disease 
have been less well diagnosed despite sharing a similar burden of disease and the same common 
features as patients with rad-axSpA, such as spinal inflammation, chronic back pain, positivity 
for human leukocyte antigen (HLA)-B27, and extraarticular manifestations.  Delays in the 
diagnosis of axSpA can postpone administration of suitable treatment by several years (Haibel et 
al. 2008; Landewé et al. 2012; Rudwaleit et al. 2009c; van der Heijde et al. 2006).  The 
Assessment of Spondyloarthritis International Society (ASAS) criteria for axSpA (Rudwaleit et 
al. 2009a, 2009b) have been developed, in addition to a diagnostic algorithm (van den Berg et al. 
2013), to facilitate earlier recognition of axSpA and to identify axSpA patients with and without 
radiographic sacroiliitis (Rudwaleit et al. 2004, 2005) using x-rays and MRI.  Adoption of the 
ASAS criteria has the potential to lead to earlier identification of patients with axSpA (Rudwaleit 
et al. 2004), early in the disease course, and to result in more timely therapeutic intervention.  
The subgroup of nonrad-axSpA patients with objective signs of inflammation (defined as active 
inflammation on MRI and/or elevated C-reactive protein [CRP]) is considered the appropriate 
target population for biologic treatment given the higher observed progression rates (up to 20% 
over a 2-year period) relative to approximately 10% progression rate over the same period in 
nonrad-axSpA patients without such objective signs of inflammation. In addition, studies from 
(TNF) inhibitors in nonrad-axSpA demonstrated that minimal to no treatment effect is observed 
in nonrad-axSpA patients without objective signs of inflammation at baseline (Poddubnyy et al. 
2012; Rudwaleit and Sieper 2012; Sieper et al. 2013; Sieper and van der Heijde 2013).  

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Although the exact etiology is unknown, genetic factors and several loci are likely to be involved 
in susceptibility to axSpA (Reveille 2011).  There is a strong association with the major 
histocompatibility complex, HLA–B27.  The risk of developing axSpA is as high as about 5% in 
HLA-B27 positive individuals. Similar findings are obtained in the HLA-B27–positive relatives 
of such patients (Braun and Sieper 2007).  Up to approximately 70% of patients with nonrad-
axSpA have been reported to be positive for HLA-B27 (Gulfe et al. 2014).  Most of the other 
known genetic susceptibility comes from genes involved in cytokine production, specifically 
including genes in the T helper (Th)17 pathway (Maksymowych 2010; Reveille 2011).  
Current standard of care for nonrad-axSpA includes regular exercise, physical therapy, and 
nonsteroidal anti-inflammatory drugs (NSAIDs). TNF inhibitors have also demonstrated 
efficacy in nonrad-axSpA; however, they are not yet approved globally for this indication (Braun 
et al. 2011; Robinson et al. 2014; Ward et al. 2015), and approximately 40% of patients only 
obtain a partial response on TNF inhibitors (Sieper at al. 2012, 2013; Landewé et al. 2012; 
Dougados et al. 2014).  Corticosteroid injections may also be of some benefit.  Though NSAIDs 
are the first line of drug treatment for axSpA, they are not effective or well tolerated in all 
patients (Braun and Sieper 2009).  In contrast to patients with RA, patients with axSpA do not 
respond well to conventional disease-modifying antirheumatic drugs (cDMARDs) or systemic 
corticosteroids (Braun and Sieper 2009; Haibel and Specker 2009). 
TNF inhibitors have demonstrated efficacy across the axSpA spectrum and may be prescribed 
for nonrad-axSpA when NSAID treatment has failed or cannot be tolerated (Braun et al. 2014) 
and where regulatory approval has been obtained for this population.  To date few treatment
options are globally available for nonrad-axSpA (van der Heijde et al. 2006; Heiberg et al. 2008; 
Inman et al. 2008; Glintborg et al. 2010).  
TNF inhibitors, the only available biologic therapy for axSpA, have been associated in various 
diseases, including axSpA, with potential safety concerns, such as opportunistic infections, 
demyelinating disorders, blood dyscrasias, reactivation of tuberculosis (TB), and exacerbation of 
congestive heart failure (Singh et al. 2011; Ruderman 2012; Deepak et al. 2013; Maxwell et al. 
2015).  There remains, therefore, a significant unmet need for safer, more effective treatments for 
patients with axSpA (Dougados and Baeten 2011).  
Ixekizumab (LY2439821) is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal 
antibody (MAb) that neutralizes the cytokine interleukin-17A (IL-17A, also known as IL-17).  
Ixekizumab treatment is administered by subcutaneous (SC) injections.  Compelling scientific 
information to date suggests an important role of the IL-23/IL-17 pathway in the pathogenesis of 
axSpA (Baeten et al. 2010; Maksymowych 2010; Baraliakos et al. 2011; Reveille 2011; Baeten 
et al. 2013, 2014; Yeremenko et al. 2014).  The demonstration of increased IL-17 producing 
TH17 lymphocyte numbers and serum IL-17 levels in rad-axSpA is consistent with a direct role 
of TH17 lymphocytes in this disease (Wendling et al. 2007; Jandus et al. 2008; Mei et al. 2011).  
IL-17 secreting cells have also been detected in situ in the bone marrow of facet joints obtained 
from patients with rad-axSpA (Appel et al. 2008).  

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Selectively targeting IL-17A with ixekizumab is hypothesized to provide therapeutic benefit 
without unduly impacting host defenses. As such, ixekizumab may offer a therapeutic option for 
patients who have failed NSAIDs and for patients who have lost response, failed to respond, or 
are intolerant to current marketed drugs. Ixekizumab may offer a more favorable safety profile 
compared to currently marketed therapies.  
2.2.
Study Rationale
Lilly is investigating ixekizumab as a treatment option for nonrad-axSpA based on its 
mechanism of action, selectively blocking IL-17A (as detailed in the Investigator’s Brochure
[IB]).  The following 2 SC ixekizumab treatment regimens will be studied in this trial:  80 mg 
every 4 weeks (Q4W) or 80 mg every 2 weeks (Q2W).  Starting doses of 80 mg and 160 mg (at 
Week 0) will be evaluated for each ixekizumab regimen.  
A wide range of dosing regimens was evaluated in both Phase 2 psoriasis (Ps) and rheumatoid 
arthritis (RA) studies, and ixekizumab demonstrated efficacy in both indications (Leonardi et al. 
2012, Genovese et al. 2014). The 80 mg Q2W and 80 mg Q4W treatment regimens with a 
160-mg starting dose were evaluated in pivotal Phase 3 studies in Ps and psoriatic arthritis (PsA) 
and demonstrated efficacy with a favorable benefit/risk profile (Gottlieb et al. 2015; Griffiths et 
al. 2015; Mease et al. 2015). Recently disclosed data from Phase 3 studies with secukinumab 
(Cosentyx®), a drug with a similar mechanism of action (MoA) as ixekizumab, selectively 
inhibiting IL-17A, have demonstrated the effectiveness of inhibiting IL-17A in patients with rad-
axSpA who were biological disease-modifying antirheumatic drug (bDMARD)-naive or had 
previously received TNF inhibitors (Sanford and McKeage 2015).  The ixekizumab clinical 
development program for axSpA also includes 2 previously initiated Phase 3 studies of 
ixekizumab in rad-axSpA patients (Study I1F-MC-RHBV and Study I1F-MC-RHBW). 

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3.
Objectives and Endpoints
Table RHBX.1 shows the objectives and endpoints of the study.
Table RHBX.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective is to compare both ixekizumab 
regimens (80 mg Q2W or 80 mg Q4W) versus placebo 
in patients with active nonrad-axSpA 

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40 
(ASAS40) response at Week 16 (for regulatory 
agencies that require Week 16 as the primary 
endpoint)

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40 
(ASAS40) response at Week 52 (for regulatory 
agencies that require Week 52 as the primary 
endpoint)
Secondary
The major secondary objectives are:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W versus placebo in patients with 
active nonrad-axSpA at Week 16 and Week 52

Change from baseline in Ankylosing Spondylitis 
Disease Activity Score (ASDAS) at Week 16

Change from baseline in ASDAS at Week 52

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Week 16

Change from baseline in BASFI at Week 52

Proportion of patients achieving ASDAS inactive 
disease at Week 16

Proportion of patients achieving ASDAS inactive 
disease at Week 52

Change from baseline in magnetic resonance 
imaging (MRI) of the sacroiliac joints (SIJ)
(Spondyloarthritis Research Consortium of Canada
[SPARCC] score) at Week 16

Percent of patients without clinically meaningful
changes in background therapy at Week 52
Other secondary objectives are:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W) to placebo during the 52-
week period

Proportion of patients who achieve ASAS20, 
ASAS40, ASAS5/6, and partial remission by ASAS 
criteria

Change from baseline in the individual components 
of the ASAS criteria

Change from baseline in Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI)

Proportion of patients reaching BASDAI50

Change from baseline in ASDAS

Proportion of patients who experience 
clinically-important improvement (change of 
ASDAS from baseline ≥1.1), major improvement 
(change of ASDAS from baseline ≥2.0), or inactive 

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Objectives
Endpoints
disease (ASDAS <1.3)

Change from baseline in the measure of CRP

Change from baseline in BASFI

Change from baseline in mobility
o
Bath Ankylosing Spondylitis Metrology Index 
(BASMI) (linear) and individual components
o
Chest expansion
o
Change from baseline in occiput to wall 
distance

Change from baseline in MRI of the SIJ (SPARCC 
score)  

Change from baseline in SPARCC SIJ Structural 
Score (SSS)

Change from baseline in Maastricht Ankylosing 
Spondylitis Enthesitis Score (MASES)

Change from baseline in SPARCC Enthesitis Score 

The incidence and severity of peripheral arthritis by 
tender and swollen joint count scores of 46/44 joints

Incidence rate of anterior uveitis or uveitis flares

Change from baseline in the following health 
outcomes measures:  Fatigue NRS score, ASAS-HI 
score, Jenkins Sleep Evaluation Questionnaire 
(JSEQ), Work Productivity Activity Impairment—
Spondyloarthritis (WPAI-SpA) scores, SF-36 (both 
physical component [PCS] and mental component 
scores [MCS]), and Quick Inventory of Depressive 
Symptomatology–Self-Report (16 Items) (QIDS-
SR16) score. 

NSAID intake (ASAS-NSAID score and % of 
patients taking NSAIDs)

To explore the effect of starting dose (160 mg 
compared to 80 mg)

Onset of action and treatment response (ASAS, 
ASDAS, CRP, BASFI)

To evaluate the incidence of anti-ixekizumab 
antibodies and its relationship to efficacy of 
ixekizumab 

Efficacy response rates listed below at Weeks 16 
and 52 by treatment-emergent anti-drug antibody 
(TE-ADA) status and by neutralizing anti-drug 
antibody (NAb) status
o
Proportion of patients achieving ASAS40
o
Proportion of patients achieving ASAS20
o
Proportion of patients achieving ASDAS 
inactive disease

To measure ixekizumab exposure and assess the 
relationship between exposure and efficacy and 
exposure and immunogenicity

Serum trough concentrations of ixekizumab

Model parameters for the exposure-response 
relationship between ixekizumab serum trough 
concentrations and efficacy endpoints (for example, 
ASAS20, ASAS40) at Week 16 and/or Week 52

Ixekizumab serum trough concentrations associated 
with anti-drug antibody (ADA) titer 
Exploratory Objective

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Objectives
Endpoints

 
 
 
CCI

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4.
Study Design
4.1.
Overview of Study Design
Study I1F-MC-RHBX (RHBX) is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient study examining the efficacy and safety of 
2 ixekizumab treatment regimens (80 mg Q2W and 80 mg Q4W SC) as compared to placebo SC 
in patients with active nonrad-axSpA who are bDMARD-naive, during a double-blind, 52-week 
treatment period (Period 2).  
Figure RHBX.1 illustrates the study design. Within the active treatment groups, half the patients 
will be given a 160-mg starting dose and the other half will be given an 80-mg starting dose. All 
treatment groups and administration of the investigational product are described in Section 6.1, 
and the Study Drug Administration Log is described in Section 6.2.1.
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Appendix 2).  Selected study procedures are to be performed 
before administration of the investigational product, as applicable.  
For each patient, x-rays and magnetic resonance imaging (MRIs) will be collected according to 
Section 8.1.2.21.1 and the Schedule of Activities (Appendix 2).
Appendix 3 lists the specific laboratory tests that will be performed for this study.  At or after 
Week 16, patients who are deemed inadequate responders may receive rescue therapies as 
described in Section 6.1.1.  Patients discontinuing study treatment after Week 16 are to remain in 
the study and follow the regular visit schedule.  
Patients who have taken at least 1 study dose and who discontinue study treatment prior to 
Week 16 or study participation (regardless of timing) are to complete an early termination visit 
(ETV) and enter into post-study follow-up for at least 12 weeks after the ETV date or the last 
regularly scheduled visit. Patients whose ETV or last regularly scheduled visit is longer than 
12 weeks after their last investigational study medication dose are not required to enter into the 
Post-Study Follow-Up Period (Period 3).  For the management of patient safety, patients are to 
be monitored through the Post-Study Follow-Up Period as indicated on the Schedule of 
Activities (Appendix 2).  
Patients who complete Study RHBX may be eligible to enroll into a long-term extension study 
(Study I1F-MC-RHBY [RHBY]) for up to 2 additional years.  
Excluded and concomitant medications are detailed in Section 6.8.  
Pharmacokinetic (PK) sampling is detailed in Section 8.5.  
Section 9.8 outlines the information regarding the interim analyses.

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Abbreviations:  DMARD = disease-modifying antirheumatic drug; ETV = early termination visit; LV = last visit; LY = ixekizumab; 
n = number; NSAID = nonsteroidal anti-inflammatory drug; Q2W = every 2 weeks; Q4W = every 4 weeks; SC = subcutaneous; 
TNF = tumor necrosis factor; V = study visit; W = study week.
a
All patients will receive 2 injections at baseline at Week 0 to maintain the blind with an 80-mg or 160-mg starting dose of 
ixekizumab or placebo.
b
Beginning at Week 16 and up to Week 44, any patient, regardless of their original treatment group, may be identified by an 
investigator based on clinical judgment as an inadequate responder and receive rescue treatment. At such time changes in 
background therapy (including, but not limited to NSAIDs, nonbiological DMARDs or the use of rescue biologic treatment) can be 
made at the discretion of the investigator, while remaining blinded to the original randomization treatment assignment. Changes in 
ongoing medications at that time can include changes in dose of NSAIDS or nonbiological DMARDs, including the introduction of 
new medications.  Investigator may also decide to use biologic rescue of ixekizumab 80 mg Q2W with an 80-mg starting dose.

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c
Following any treatment modifications, investigators are to reevaluate the clinical status of the patient as appropriate to assess 
effect of treatment modification. Treatment guidelines recommend a minimum period of 12 weeks to evaluate effect of biologic 
treatment modifications; however, if in the opinion of the investigator, a patient does not show any clinical improvement after at 
least 8 weeks of the ixekizumab 80 mg Q2W treatment modification, then the investigator may consider discontinuation of the 
patient from ixekizumab treatment. Such patients may then receive other medical therapies (potentially including a TNF inhibitor) 
that are prescribed by their physician and are to remain in the study until Week 52 per study schedule.
d
Patients who have taken at least 1 study dose and who discontinue study treatment prior to Week 16 or study participation 
(regardless of timing) are to complete an ETV and enter into post-study follow-up for at least 12 weeks after the ETV date or the 
last regularly scheduled visit.  Patients whose ETV or last regularly scheduled visit is longer than 12 weeks after their last 
investigational study medication dose are not required to enter into the Post-Study Follow-Up Period. V801 and V802 are required 
for patients in the Post-Study Follow-Up Period; V803 may be needed depending on neutrophil counts.  
Figure RHBX.1.
Illustration of study design for Clinical Protocol I1F-MC-RHBX.

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4.2.
End of Trial Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Appendix 2) for the last patient in the trial.
4.3.
Scientific Rationale for Study Design
Two treatment regimens of ixekizumab 80 mg (Q2W and Q4W) will be studied as detailed in 
Section 6.1. The dose justification is outlined in Section 4.4.  The study blind is maintained as 
described in Section 6.3.  The impact of ixekizumab starting dose on speed of onset and through 
the primary efficacy endpoint assessment at Week 16 will be evaluated by providing a 160-mg 
starting dose to half of the patients and an 80-mg starting dose to the remaining half of the 
patients.  
The placebo-controlled Blinded Treatment Dosing Period is designed to minimize bias in the 
evaluation of ixekizumab in patients with nonrad-axSpA for both efficacy and safety
assessments.  Patients randomized to placebo may still receive treatment in the form of the 
allowed concomitant medications as described in the study inclusion and exclusion criteria 
(Sections 5.1 and 5.2) and concomitant therapy sections (Section 6.8).  A placebo control period
up to Week 52 is in accordance with United States (US) Regulatory advice for nonrad-axSpA 
and is considered globally acceptable given that as of Week 16, investigators may decide to offer 
rescue treatment based on their judgement of the appropriate clinical approach for the individual 
patient.  Such rescue treatments may include changes in concomitant medications (as specified in 
Section 6.8) and/or the use of ixekizumab 80 mg Q2W.  To maintain the blind, the rescue 
treatment of ixekizumab 80 mg Q2W will be given across all treatment groups. The use of 
rescue ixekizumab therapy 80 mg Q2W allows patients who were on placebo to receive active 
treatment, patients who were on ixekizumab 80 Q4W to increase dose, and patients who were on 
ixekizumab Q2W more time to further improve their response. Studies with TNF inhibitors
indicate that there is a proportion of patients who have a delayed response and may benefit from 
more time to reach an optimal response (Maksymowych et al. 2015a). 
General guidelines recommend a minimum period of 12 weeks to evaluate effect of biologic 
treatment modifications. However, if in the opinion of the investigator, a patient does not show 
any clinical improvement after at least 8 weeks of the ixekizumab 80 mg Q2W treatment 
modification, then the investigator may consider discontinuation of the patient from ixekizumab 
treatment.  Such patients may then receive other medical therapies (potentially including a TNF 
inhibitor) that are prescribed by their physician and are to remain in the study.  
The effectiveness of ixekizumab in treating nonrad-axSpA will be assessed primarily by the 
ASAS40 response rate at Week 16 for regulatory agencies that require Week 16 as the primary 
endpoint, and by the ASAS40 response rate at Week 52 for regulatory agencies that require 
Week 52 as the primary endpoint.  The ASAS40 response at Week 16 endpoints are in alignment 
with efficacy endpoints for currently approved axSpA therapies and with regulatory guidance 
(EMEA 2009).  The ASAS40 response at Week 52 and other Week 52 endpoints are in line with 
regulatory advice received by Lilly from the Food and Drug Administration for nonrad-axSpA 
(2015, 2018).  Steady-state exposure of ixekizumab is expected to be reached by Week 16.  

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Based on previous studies with ixekizumab in patients with Ps, RA, and PsA, it is anticipated 
that maximum or near maximum clinical effect in nonrad-axSpA patients willbe achieved for 
the majority of patients within this timeframe for both ixekizumab treatment regimensregardless 
of the starting dose.  
Nonrad-axSpA patients with objective signs of inflammation, defined as sacroiliitis on MRI 
and/or elevated CRP,are at increased risk of disease progression. In the present study sacroiliitis 
on MRI is defined by ASAS/OMERACTcriteria (Rudwaleit et al. 2009b, 2009d)and elevated 
CRP is defined as CRP >5.00 mg/L.  In addition, biologic treatment of patients with these 
objective signs of inflammationhas been reported to result in consistently better clinical 
responses (compared with placebo) relative to the subpopulation of nonrad-axSpA patients with 
no evidence of sacroiliitis by MRI and a normal CRP level at baseline(Poddubnyyet al. 2012; 
Sieper et al. 2013; Sieper et al. 2015; Maksymowych et al. 2014).  Therefore the following strata 
(positive MRI and elevated CRP; positive MRI and nonelevatedCRP; negative MRI and 
elevated CRP)have been defined to ensure balanceacross treatmentgroupsand greater 
comparability of treatment groups at baseline.  
The Post-StudyFollow-Up Period isimportantfor safety monitoring following administration of 
the last study treatment.  The duration of the Post-StudyFollow-Up Period (Period 3) is 
approximately 12 weeks to allow for monitoring during ixekizumab clearance and reflects atime 
period equivalent to approximately 5 half-lives of ixekizumab.  
4.4. Justification for Dose 
CCI
Lilly considers it appropriate to evaluate 2 treatment regimens in Study RHBX to enable 
appropriate evaluation of the relative benefit/risk balance associated with continuous ixekizumab
therapy in nonrad-axSpA patients.  
 
 
 
 
 
  
The ixekizumab 80 mg Q2W and80 mg Q4Wtreatment regimens with a 160-mg starting dose 
have also been tested in pivotal Phase 3 studies and demonstrated efficacy with favorable 
benefit-risk profile in Ps (Griffiths et al. 2015) and PsA (Gottlieb et al. 2015; Mease et al. 2015).  
Othertherapies (most TNF inhibitors and secukinumab) have demonstrated efficacy usinga
similar treatment regimen across various rheumatological conditions (RA, PsA, axSpA) 
(Humira® package insert, 2015 [WWW]; Enbrel® package insert, 2015 [WWW]; Simponi® 
package insert, 2013[WWW]; Cimzia® package insert, 2015 [WWW]; Cosentyx® package 
insert, 2015 [WWW], Sanford and McKeage 2015).  

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Treatment effect size has been reported to be similar between rad-axSpA and nonrad-axSpA 
patients treated with TNF-inhibitors compared with placebo comparator groups, using the same 
dose regimen across the axSpA spectrum (Callhoff et al. 2015).  
The impact of an ixekizumab starting dose on speed of onset and through the primary efficacy 
endpoint assessment at Week 16 will be evaluated by providing a 160-mg starting dose to half of 
the patients and an 80-mg starting dose to the remaining half of the patients. 
As referred to above, the current internal (ixekizumab) and external (TNF inhibitors and 
secukinumab) scientific data in this area support the rationale for studying ixekizumab in both 
rad-axSpA and nonrad-axSpA patients with the proposed treatment regimens.  
4.5.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of ixekizumab are to be found in the IB.  

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5.
Study Population
The study population will include patients with a physician’s diagnosis of active nonrad-axSpA,
who meet the ASAS classification criteria for nonrad-axSpA either by the presence of sacroiliitis 
on MRI (based on central reading) accompanied by at least 1 spondyloarthropathy (SpA) feature 
OR by being HLA–B27 positive and having at least 2 additional SpA features (Appendix 5) and 
who have given written informed consent.  
Study investigator(s) will review patient history and screening test results from Visit 1 (all 
criteria) and Visit 2 as per the Schedule of Activities (Appendix 2) to determine if the patient 
meets all inclusion and none of the exclusion criteria to qualify for randomization in the study.  
All screening activities must be completed and reviewed before the patient is randomized.  
Patients may be rescreened in the circumstances described in Section 5.3.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.  
In this protocol section, the following definitions apply:  

Screening is defined as Visit 1, up to 42 days before baseline randomization.  

Baseline randomization visit is defined as Visit 2 (Week 0).
5.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening or as specified:  
Type of Patient and Disease Characteristics
[1]
Presence of sacroiliitis on MRI (according to ASAS/OMERACT criteria and 
based on central reading) (Rudwaleit et al. 2009d) and have at least 1 SpA 
feature
OR
Are positive for HLA-B27 and have at least 2 additional SpA features, 
according to the ASAS criteria (Sieper et al. 2009; Rudwaleit et al. 2009a);
SpA features listed in Appendix 5.  
[2]
Patients have a history of back pain ≥3 months with age at onset <45 years.  
[3]
Have active nonrad-axSpA defined as BASDAI ≥4 and total back pain ≥4 on 
a NRS at screening and baseline (Sieper et al. 2009)  
[4]
Patients have objective signs of inflammation by presence of sacroiliitis on 
MRI (as defined by ASAS/OMERACT) or presence of elevated CRP (defined 
as CRP >5.00 mg/L).  
[5]
Must have had an inadequate response, as determined by the investigator, to 2 
or more NSAIDs at the therapeutic dose range for a total duration of at least 
4 weeks OR have a history of intolerance to NSAIDs  

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[6]
Patients must have a history of prior therapy for axSpA of at least 12 weeks 
prior to screening.  Examples of prior therapy may include but are not limited 
to physical therapy and NSAID treatment.  
Patient Characteristics
[7]
Are ambulatory male or female patients 18 years or older at time of screening  
[8]
Must agree to use a reliable method of birth control  

If a male patient, patient agrees to use a reliable method of birth control 
during the study and for at least 12 weeks following the last dose of 
investigational product, whichever is longer.  Methods of birth control 
include, but are not limited to, condoms with spermicide and male 
sterilization.  
OR

If a female patient is a woman of childbearing potential who tests negative 
for pregnancy and agrees to use a reliable method of birth control or 
remain abstinent during the study and for at least 12 weeks following the 
last dose of investigational product, whichever is longer.  Methods of 
contraception including but are not limited to: oral contraceptives, 
contraceptive patch, injectable or implantable contraceptives, intrauterine 
device, vaginal ring, diaphragm with contraceptive gel, or condom with 
contraceptive foam.  
OR

If a female patient is a woman of nonchildbearing potential, she is not 
required to use any method of birth control.  Nonchildbearing potential is 
defined as follows:  
Women who have had surgical sterilization (hysterectomy or 
bilateral oophorectomy or tubal ligation)  
OR
Women who are ≥60 years of age.  
OR
Women ≥40 and <60 years of age who have had a cessation of 
menses for ≥12 months and a follicle stimulating hormone (FSH) 
test confirming nonchildbearing potential (≥40 mIU/mL or 
≥40 IU/L).  
Informed Consent
[9]
Are able and have given informed consent approved by Lilly, or its designee, 
and the Investigational Review Board/Ethical Review Board (IRB/ERB)
governing the site  

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5.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening or as specified:  
Medical Conditions
[10] Fulfillment of the modified New York (mNY) criteria (van der Linden et al. 
1984) with sacroiliitis defined radiographically, based on central reading:  
sacroiliitis grade ≥2 bilaterally or grades 3 to 4 unilaterally  
[11] Have a history of other systemic inflammatory diseases (such as but not 
limited to lupus, vasculitis, or RA), or other chronic pain conditions (such as 
but not limited to fibromyalgia) that might confound the evaluations of benefit 
from ixekizumab therapy.
Note:  Patients with psoriasis who have never received and do not require 
systemic treatment for psoriasis, such as but not limited to oral agents or 
biologic therapies, can be included provided these patients fulfill the study 
entry criteria.  
[12] Have active Crohn’s disease (CD) or active ulcerative colitis (UC)  
Note:  Patients may be enrolled if they have had a history of inflammatory 
bowel disease (IBD), including CD and UC, but have had no exacerbation for 
≥6 months prior to baseline, and, if currently on treatment, must be on stable 
treatment for ≥6 months prior to baseline.  
[13] Have evidence of active anterior uveitis (an acute episode) within the last 
4 weeks prior to baseline randomization 
Note:  These patients may be rescreened only one time ≥4 weeks after 
resolution of acute symptoms.
[14] Have current or a history of lymphoproliferative disease, or signs or 
symptoms of lymphoproliferative disease, within 5 years prior to baseline 
randomization; or have active or history of malignant disease within 5 years 
prior to baseline randomization  
[15] Have a history of fluid overload, myocardial infarction (MI), uncompensated 
heart failure, or evidence of new-onset ischemic heart disease or, in the 
opinion of the investigator, other serious cardiac disease, within 12 weeks 
prior to baseline randomization  
[16] Presence of significant uncontrolled cerebrocardiovascular events (for 
example, unstable angina, unstable arterial hypertension, moderate-to-severe 
heart failure [New York Heart Association class III/IV], or cerebrovascular 
accident) at screening that, in the opinion of the investigator, pose an 
unacceptable risk to the patient if participating in the study or of interfering 
with the interpretation of data  

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[17] Presence of any comorbid respiratory, hepatic, renal, gastrointestinal, 
endocrine, or hematologic disorders at screening that, in the opinion of the 
investigator, pose an unacceptable risk to the patient if participating in the 
study or of interfering with the interpretation of data  
[18] Presence of any neurologic or neuropsychiatric disorders at screening that, in 
the opinion of the investigator, pose an unacceptable risk to the patient if 
participating in the study or of interfering with the interpretation of data  
[19] Presence of significant uncontrolled neuropsychiatric disorder; have a recent 
history of a suicide attempt (within 30 days prior to screening visit [Visit 1] 
and any time between screening visit [Visit 1] and baseline randomization 
[Visit 2]); or have a score of 3 on Item 12 (Thoughts of Death or Suicide) of 
the Quick Inventory of Depressive Symptomatology-Self-Report (16 Items) 
(QIDS-SR16) at screening or baseline randomization or are clinically judged 
by the investigator to be at risk for suicide.
[20] Patients who have 

in the past 12 weeks prior to baseline randomization:
o
had a serious infection (for example, pneumonia, cellulitis),
o
have been hospitalized for an infection,
o
or have received intravenous antibiotics for an infection,

in the past 24 weeks prior to baseline randomization had a serious 
bone or joint infection,

or have ever had:
o
an infection of an artificial joint
o
or had an infection that occurs with increased incidence in an 
immunocompromised host (including, but not limited to, 
Pneumocystis jirovecii pneumonia, symptomatic histoplasmosis, or 
coccidioidomycosis)  
[21] Have a known immunodeficiency or who are immunocompromised to an 
extent such that participation in the study would pose an unacceptable risk to 
the patient  
[22] Have or had a herpes zoster or any other clinically apparent varicella-zoster 
virus infection within 12 weeks of baseline randomization  
[23] Have any other active or recent infection within 4 weeks of baseline 
randomization that, in the opinion of the investigator, would pose an 
unacceptable risk to the patient if participating in the study  
Note:  These patients may be rescreened once ≥4 weeks after resolution of 
symptoms.  

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[24] Have a known allergy or hypersensitivity to any biologic therapy that would 
pose an unacceptable risk to the patient if participating in this study  
[25] Have had surgical treatment of a joint that is to be assessed in the study within 
8 weeks prior to baseline randomization or will require surgical treatment of a 
joint that is to be assessed in the study during the first 16 weeks of the trial  
[26] Have had any major surgery within 8 weeks prior to baseline randomization or 
will require major surgery during the study that, in the opinion of the 
investigator and in consultation with Lilly or its designee, would pose an 
unacceptable risk to the patient  
Prior/Concurrent Therapy or Clinical Trial Experience
[27] Patients who are taking NSAIDs or cyclooxygenase-2 (COX-2) inhibitors and 
are not on a stable dose for at least 2 weeks prior to baseline randomization 
are excluded.  
[28] Have received cDMARDs and/or other therapies such as, but not limited to, 
gold salts, cyclosporine, azathioprine, dapsone, 6-mercaptopurine, 
mycophenolate mofetil, or any other immunosuppressive agents within 
4 weeks prior to baseline randomization 
Exception: the following cDMARDs:  MTX (oral or parenteral up to 
25 mg/week), sulfasalazine (up to 3 g/day), or hydroxychloroquine (up to 
400 mg/day) may be allowed IF at stable dose for at least 4 weeks prior to 
baseline randomization,  
AND
if used, are not to be in any combination with other cDMARDs.
Note: If MTX is used, local standard of care is to be followed for 
concomitant administration of folic or folinic acid with MTX.  
[29] Current use of oral corticosteroids greater than 10 mg per day of prednisone or 
equivalent  
Note:  If patients are taking prednisone or its equivalent and the dose is less 
than or equal to 10 mg/day, the dose must be stable for at least 4 weeks prior 
to baseline randomization.  
[30] Have received any prior, or are currently receiving, treatment with biologic or 
other immunomodulatory agents, including investigational therapies (such as,
but not limited to, Janus kinase inhibitors, TNF inhibitors, IL-1, IL-6, IL-
12/23, IL-17 [including ixekizumab], IL-17R, T cell, or B cell targeted 
therapies)  
[31] Are currently enrolled in, have participated in, or discontinued from a clinical 
trial involving an investigational product or nonapproved use of a drug or 
device within the last 30 days prior to screening or a period of at least 
5 half-lives of the last administration of the drug (whichever is longer)  

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Note:  Investigational products that are biologic or other immunomodulatory 
agents are not permitted regardless of wash-out period (described in criterion 
above).  
[32] 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  
[33] Are currently receiving or have received treatment with denosumab within 
6 months prior to baseline randomization
[34] Have received any parenteral glucocorticoid administered by intraarticular, 
intramuscular, or intravenous injection within 6 weeks prior to baseline 
randomization; or are planning to receive a parenteral injection of 
glucocorticosteroids during the Blinded Treatment Dosing Period (Period 2) 
of the study  
[35] Use of any opiate analgesic at average daily doses of >30 mg/day of morphine 
or its equivalent or use of variable doses of any opiate analgesic within 
6 weeks prior to baseline randomization.  Exception for patients with pain that 
may interfere with undergoing an MRI:  patient may receive premedication of 
≤30 mg of morphine or equivalent, on the day of the MRI, for significant pain 
as judged by the investigator.  
[36] Had a live vaccination within 12 weeks prior to baseline randomization, 
intend to have a live vaccination during the course of the study or within 
12 weeks of completing treatment in this study, or have participated in a 
vaccine clinical study within 12 weeks prior to baseline randomization.  
Investigators must review the vaccination status of their patients and follow 
the local guidelines for adult vaccination with nonlive vaccines intended to 
prevent infectious disease prior to therapy.  
Note:  Killed/inactive or subunit vaccines are expected to be safe; however, 
their efficacy with concomitant ixekizumab treatment is unknown.  
[37] Had a vaccination with Bacillus Calmette-Guérin (BCG) within 12 months 
prior to baseline randomization or intend to have this vaccination with BCG 
during the course of the study or within 12 months of completing treatment in 
this study  
Diagnostics Assessments
[38] Have a body temperature ≥38°C (100.5°F) at baseline randomization  
Note:  These patients may be rescreened once ≥4 weeks after documented 
resolution of elevated temperature.
[39] Have evidence or suspicion of active or latent TB (refer to Section 5.3 for 
rescreening and Section 8.4.6 for details on determining full TB exclusion 
criteria)  

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[40] Are positive for human immunodeficiency virus (HIV) serology; ie, positive 
for human immunodeficiency virus antibody (HIVAb)  
[41] Have evidence of or test positive for hepatitis B virus (HBV) by testing 
positive for 1) HBV surface antigen (HBsAg+) OR 2) anti-hepatitis B core 
antibody positive (HBcAb+) and are HBV DNA positive  
Note:  Patients who are HBcAb+ and HBV DNA negative may be enrolled in 
the study.  Patients who meet these criteria at screening will be identified by 
the central laboratory and monitored during the study as detailed in 
Section 8.4.10.2.  
[42] Have evidence of or test positive for hepatitis C virus (HCV).  A positive test 
for HCV is defined as:  1) positive for hepatitis C antibody (anti–HCV Ab) 
and 2) positive via a confirmatory test for HCV (for example, 
HCV-polymerase chain reaction).  
[43] Have electrocardiogram (ECG) abnormalities that are considered clinically 
significant by the investigator and would pose an unacceptable risk to the 
patient if participating in the study  
[44] Have contraindications to MRI (for example, claustrophobia, pacemakers, 
aneurysm clips, intraocular metallic fragments).  
Note:  For claustrophobia, premedication with benzodiazepine is allowed 
(investigator should assess for potential interactions with other concomitant 
medication(s) such as opiates).
Laboratory tests are not to be repeated unless there is a technical error or clinical reason to 
believe a result may need to be retested, within the screening period.  Laboratory tests can be 
repeated a maximum of 1 time, and results must be received and reviewed by study site 
personnel prior to randomization.  For eligibility, the most recent lab test results must not meet 
any of the following criteria:
[45] At screening, have a neutrophil count <1500 cells/μL (<1.50x103/µL or 
<1.50 GI/L)  
[46] At screening, have a lymphocyte count <800 cells/μL (<0.80x103/µL or 
<0.80 GI/L)  
[47] At screening, have a platelet count <100,000 cells/μL (<100x103/µL or 
<100 GI/L)  
[48] At screening, have aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)
[49] At screening, have a total white blood cell (WBC) count <3000 cells/μL 
(<3.00x103/µL or <3.00 GI/L)  
[50] At screening, have hemoglobin <8.5 g/dL (85.0 g/L) for male patients and 
<8.0 g/dL (80 g/L) for female patients  

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[51] Have other clinical laboratory test results at screening that are outside the 
normal reference range for the population and are considered clinically 
significant, per investigator assessment 
Other Exclusions
[52] Have donated blood of more than 450 mL within the last 4 weeks prior to 
screening or intend to donate blood during the course of the study  
Note:  Patients who have donated blood may be rescreened 1 time after 
≥4 weeks have passed since initial screening.  
[53] Are women who are lactating or breastfeeding  
[54] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.  
[55] Are Lilly employees or its designee or are employees of third-party 
organizations (TPOs) involved in the study  
[56] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the patient  
[57] Have any other condition that precludes the patient from following and
completing the protocol, in the opinion of the investigator  
5.3.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened in the following circumstances: Patients who test positive for latent TB at screening 
may be rescreened following appropriate treatment as described in Section 8.4.6; patients who do 
not qualify at screening under Exclusion Criteria [13], [23], [38], or [52] may be rescreened one 
time, ≥4 weeks after documented resolution of symptoms or from time of blood donation.  
The screening MRI must be completed ≤30 days prior to baseline randomization (Visit 2).  After 
consultation with Lilly medical, patients may be rescreened if screening MRI of the SIJ was 
>30 days prior to baseline randomization.  
If a patient is unable to complete all screening procedures within the screening period, the patient 
may be rescreened after consultation with Lilly medical.
When rescreening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number.  To ensure that all eligibility criteria are met, all 
screening procedures must be repeated unless previously conducted within timeframes specified 
in the Schedule of Activities (Appendix 2).

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5.4.
Study RHBX Screening of Patients Who Were Ineligible for 
Study RHBV
Study RHBV is a Phase 3, multicenter, randomized, double-blind, active- and placebo-
controlled, parallel-group, outpatient study examining the efficacy and safety of ixekizumab 
compared to placebo SC in patients with active rad-axSpA who are bDMARD-naive.  Patients 
ineligible for Study RHBV because of an absence of radiographic evidence of axSpA may be 
eligible for Study RHBX.  
Patients who were initially screened for Study RHBV and were excluded because their x-ray of 
the SIJ did not meet mNY criteria but who may meet entry criteria for Study RHBX, may give 
consent for Study RHBX.  Timeframe guidelines for screening procedures are as follows:
MRI:

If ≤30 days between the Study RHBV screening MRI of the SIJ and Study RHBX 
randomization (Visit 2): MRI of the SIJ does not need to be repeated.  

If >30 days between the Study RHBV screening MRI of the SIJ and Study RHBX
baseline randomization (Visit 2):  MRI of the SIJ must be repeated.  
Other procedures:

If ≤42 days between the Study RHBV screening visit (Visit 1) and the Study RHBX 
baseline randomization (Visit 2):  data collected at the Study RHBV screening visit (for 
example, laboratory data, TB testing, and patient questionnaires) may be used to 
determine eligibility for Study RHBX.  

If >42 days between the Study RHBV screening visit (Visit 1) and the Study RHBX 
baseline randomization (Visit 2):  laboratory tests will need to be repeated, but x-rays 
may not need to be repeated if conducted within timeframes specified in the Schedule of 
Activities (Appendix 2).  
Patients must have discontinued from screening of Study RHBV prior to entering into
Study RHBX.
5.5.
Lifestyle and/or Dietary Requirements
Not applicable.  

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6.
Treatment
6.1.
Treatments Administered
The Blinded Treatment Dosing Period (Period 2) involves a comparison of ixekizumab at 
2 treatment regimens (80 mg Q2W and 80 mg Q4W) with placebo treatment.  Each ixekizumab 
treatment regimen will include patients receiving an 80-mg or a 160-mg starting dose; patients 
will be randomized to a starting dose at a 1:1 ratio.  All doses are administered via SC injection.  
Table RHBX.2 shows the treatment regimens.  
At baseline (Week 0), all patients will be randomized to a treatment group and receive 
2 injections.  Patients assigned to an ixekizumab treatment regimen with a 160-mg ixekizumab
starting dose will receive 160-mg of ixekizumab as 2 SC injections (80 mg per SC injection).  
Patients assigned to an ixekizumab treatment regimen with an 80-mg starting dose will receive 
80 mg of ixekizumab as 1 SC injection and 1 SC injection of placebo.  Patients assigned to the 
placebo treatment group will receive 2 SC injections of placebo.  After Week 0 and through 
Week 50, all patients will receive 1 injection every 2 weeks.  Details of the patient treatment 
regimens are provided in Table RHBX.2.  
Beginning at Week 16 and up to Week 44, any patient, regardless of their original treatment 
group, may be identified by an investigator based on clinical judgment as an inadequate 
responder.  At such time, changes in background therapy and/or addition of biologic rescue 
therapy (ixekizumab 80 mg Q2W) can be made at the discretion of the investigator, while 
remaining blinded to the original randomization treatment assignment. Changes in ongoing 
medications at that time can include changes in dose of NSAIDs or nonbiological disease-
modifying antirheumatic drugs (DMARDs), including the introduction of new medications.  The 
investigator may also decide to use biologic rescue of ixekizumab 80 mg Q2W with an 80-mg 
starting dose, which is a blinded decision as to whether the patient will be initiating ixekizumab, 
increasing the dose, or remaining on the same treatment regimen.  
Investigators who believe a patient needs rescue ixekizumab 80 mg Q2W treatment will indicate 
such via interactive web-response system (IWRS), and these patients will receive ixekizumab 
80 mg Q2W with an 80-mg starting dose.  This option specifically means the following:  

Placebo inadequate responders will switch to ixekizumab 80 mg Q2W.

Ixekizumab 80 mg Q4W inadequate responders will switch to ixekizumab 80 mg Q2W.

Ixekizumab 80 mg Q2W inadequate responders will continue on the same regimen of 
ixekizumab 80 mg Q2W to allow more time to improve their response.  
General treatment guidelines recommend a minimum period of 12 weeks to evaluate effect of 
biologic treatment modifications; however, if, in the opinion of the investigator, a patient does 
not show any clinical improvement after at least 8 weeks of the ixekizumab 80 mg Q2W rescue 
treatment, then the investigator may consider discontinuation of the patient from ixekizumab 
treatment.  Such patients may then receive medical therapies as per local standard of care, which 
may include a TNF inhibitor, as prescribed by their physician, and are to remain in the study per 
the Schedule of Activities (Appendix 2). If an investigator decides to initiate a TNF inhibitor in 

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patients who fail rescue ixekizumab therapy, it is recommended that, for the timing of the first 
TNF inhibitor injection, investigators take into account the half-life of ixekizumab 
(approximately 13 days) and apply appropriate clinical judgement in balancing the need for 
treatment (eg, introducing a TNF inhibitor) with potential safety considerations.  For patients 
who are prescribed a TNF inhibitor by the investigator after failing rescue ixekizumab therapy, 
the patient’s specific TNF inhibitor may be provided to him/her during his/her participation in 
the trial up to Week 52 in an unblinded method either by direct supply or by reimbursement, 
depending upon local policy and procedures.  
Details of the treatment regimens for patients responding to study treatment are summarized in 
Table RHBX.2.  
To maintain blinding throughout the study, each patient will receive at least 1 SC injection Q2W 
regardless of his/her assigned treatment regimen (that is, placebo will be administered every 
other week as necessary for the Q4W treatment group) until the patient discontinues 
investigational product.  
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational product to the patient/patient caretaker

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing, collection, and 
administration

returning all unused medication to Lilly or its designee at the end of the study
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.  
Further instructions and special considerations for the administration of the investigational 
product are provided in Sections 6.1.1, 6.2.1, and 6.6.1.  

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6.1.1. Administration of Investigational Product
Injections will be self-administered SC by the patient or caregiver after training by the clinical 
staff.  
Training:  At Week 0 (baseline, Visit 2) each patient is scheduled to receive 2 injections of 
blinded investigational product.  For training purposes, the proper procedures for administration 
of the initial injection will be performed by clinical staff, and the second injection of 
investigational product at that visit will be administered by the patient or caregiver under the 
supervision of clinical staff.  If additional training is necessary, an injection may be 
self-administered by the patient or caregiver under the supervision of clinical staff at Week 2 
(Visit 4).  
Administration:  If the patient is unable to perform the injection, a caregiver, who will also be 
trained under supervision of site staff, may administer the investigational product.  All 
subsequent injections of investigational product will be administered, unsupervised, by the 
patient or caregiver.  It is recommended that these injections be administered away from the 
investigational site, except when the injections have to be done at the site for postdose 
monitoring.  If the patient or caregiver is not able to administer the second injection of the 
starting dose or any dose throughout the study, study site staff may administer that injection.  
Refer to the appropriate Manual Syringe Directions for Use provided by the sponsor for the 
investigational product.  Note that in case a study drug injection is performed in an arm, it is not 
to be given in the same arm from which patient blood samples, including PK samples, are drawn 
at relevant visits.  
Study Drug Administration Logs will be dispensed to each patient for recording pertinent data 
about each injection; details of the use of these logs are provided in Section 6.2.1.  
Possible injection sites are identified in the Manual Syringe Directions for Use.  The injection 
site may be rotated to another area for subsequent doses.  
Observation:  For safety monitoring patients are to remain under observation for at least 1 hour 
after dosing at Week 0 (Visit 2) and at any visit on or after Week 16 in which a patient receives
the initial injection of ixekizumab as rescue therapy.  This initial injection of rescue ixekizumab 
will be administered by the patient or caregiver at the clinical site to allow for observation for 
any AEs and for collection of postinjection blood pressure (BP) and pulse measurements 
approximately 1 hour after administration of the investigational product (Section 8.4.2 and
Appendix 2).  
6.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Week 0 (Visit 2).  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an IWRS.  The IWRS will be used to assign double-blind investigational 
product to each patient.  Site personnel will confirm that they have located the correct 

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investigational product package by entering a confirmation number found on the package into 
the IWRS.  
To achieve between-group comparability, the randomization will be stratified by country and 
screening MRI/CRP status (positive MRI and elevated CRP; positive MRI and nonelevated CRP; 
negative MRI and elevated CRP).  Elevated CRP is defined as >5.00 mg/L.  
Target enrollment will be a minimum of approximately 20% for each of the MRI/CRP strata. 
Once a specific stratum is fully enrolled, the sponsor may stop further enrollment of patients 
fitting the criteria of that stratum.  
6.2.1. Selection and Timing of Doses
Investigational product is to be administered at approximately the same time each day, as much 
as possible.  If an injection is missed, the missed dose should be administered as soon as possible.  
Injection(s) for missed dose(s) should not be given within 5 days of the next scheduled dose; 
injections should be ≥5 days apart.  Dates of subsequent study visits are not to be modified 
according to this delay.  
A paper Study Drug Administration Log will be completed by randomized patients for each 
injection throughout study participation.  The data from the Study Drug Administration Log must 
be transcribed into the electronic case report form (eCRF) by site personnel.  
Patients will be instructed to contact their study site in the event of an injection problem.  In 
addition, site personnel will review all Study Drug Administration Logs at each visit to identify 
any product complaints, and they will complete a Product Complaint Form for each operation 
failure reported on a Study Drug Administration Log (see Section 8.2.3 for additional 
instructions regarding complaint handling).  
6.3.
Blinding
This is a double-blind study; patients, study site personnel, and study team will be blinded to 
study treatment randomization.  If an investigator decides to use the treatment modification of 
ixekizumab Q2W for a patient, study site personnel, the patient, and the study team will remain 
blinded to the initial randomization.  
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All actions resulting in an unblinding event are recorded and reported by the IWRS.  
If an investigator, site personnel performing assessments, or a patient is unblinded, the patient is 
to be discontinued from the study treatment.  In cases where there are ethical reasons to have the 
patient remain on study treatment, the investigator must obtain specific approval from a Lilly 
clinical research physician or Lilly clinical research scientist for the patient to continue on study 
treatment.  

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In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator is requested to make every effort to contact the Lilly clinical research 
physician/clinical research scientist prior to unblinding a patient’s treatment assignment.  If the 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  
6.4.
Packaging and Labelling
The investigational products will be supplied by the sponsor or its designee in accordance with 
current Good Manufacturing Practices (cGMP).  
Clinical trial materials will be labeled according to the country’s regulatory requirements.  All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations.  
Ixekizumab and placebo to match will be supplied as an injectable solution in 1-mL, single-dose, 
prefilled, disposable manual syringes with study specific labels.  Each syringe of ixekizumab is 
designed to deliver ixekizumab 80 mg.  The syringes (and contents) containing either 
ixekizumab or placebo will be visibly indistinguishable from each other.  Syringes will be 
supplied in cartons with the appropriate quantity of syringes specific to the planned dispensing 
schedule of the investigational product.  
6.5.
Preparation/Handling/Storage
Investigational products will be supplied by Lilly or its representative, in accordance with cGMP 
and will be supplied with lot numbers, expiry dates, and certificates of analysis, as applicable.  
The investigational product is to be stored at 2°C to 8°C (36°F to 46°F) in its original carton to 
protect from light.  Investigational product must not be frozen or shaken.  Sites will be required 
to monitor temperature of the on-site storage conditions of the investigational product.  
6.6.
Dose Modification
No investigational product dose modifications are permitted except where treatment 
modifications are recommended by the investigator because of inadequate response (refer to 
Section 6.1 for treatment modifications and Section 8.4.10.1.1 for instances where drug may be 
withheld).  
6.6.1.Special Treatment Considerations 
Patients will be screened for eligibility in the study as described in Sections 5.1 and 5.2 and will 
be informed of the study-specific restrictions and requirements of the study.  Patients who are not 
willing to comply with the study restrictions and requirements of the study will not be eligible 
for enrollment.  
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include, but are not limited to:  

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
skin rash

pruritus (itching)

urticaria (hives)

angioedema (for example, swelling of the lips and/or tongue)

anaphylactic reaction
Sometimes these reactions can be life threatening.  Proteins may also cause redness, itching, 
swelling, or pain locally at the injection site; therefore, all patients are to be closely monitored 
for signs or symptoms that could result from such reactions, educated on the signs or symptoms 
of these types of reactions, and instructed to contact the study site immediately if any of the 
symptoms are experienced following an injection.  If a patient experiences an acute 
allergic/hypersensitivity reaction after an injection of investigational product, he or she is to be 
managed appropriately and given instruction to receive relevant supportive care.  Additionally, 
for an event judged by the investigator to be a potential systemic allergic/hypersensitivity 
reaction, a blood sample is to be drawn to test for anti-drug antibodies (ADA) and PK as soon as 
possible (Section 8.4.9).  
For patients who experience a potential allergic/hypersensitivity reaction, consideration for any 
premedication for future injections will be agreed upon between the investigator and sponsor.  
Examples of potential allergic/hypersensitivity reactions that might merit premedication include 
mild-to-moderate skin rashes, mild-to-moderate generalized pruritus and/or urticaria, and 
mild-to-moderate injection site reactions (for example, injection site erythema, injection site 
pruritus, etc.).  Patients who develop clinically significant systemic allergic/hypersensitivity 
reactions following administration of investigational product that do not respond to symptomatic 
medication or result in clinical sequelae or hospitalization are to be discontinued from study 
treatment and not receive further doses of investigational product, with or without premedication 
(see Section 7.1.1).  Medications considered appropriate for premedication include, but are not 
restricted to, acetaminophen/paracetamol up to 1000 mg and antihistamines (for example, oral 
diphenhydramine 50 mg) given after all efficacy assessments have been completed for a given 
visit and 30 to 60 minutes prior to investigational product SC injection for visits where injections 
are administered at the clinic.  For all other injections, patients may self-premedicate at home 
prior to administration of investigational product, as directed by the investigator.  All such 
premedications will be recorded as concomitant medications.  Corticosteroids are not permitted 
as agents for premedication.  
6.7.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by review of the Study Drug Administration Log, return of empty or unused 
investigational product packaging, and/or direct questioning.  Deviations from the prescribed 
dosage regimen are to be recorded in the case report form (CRF).  
Compliance is defined in Section 9.3.4.

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6.8.
Concomitant Therapy
All concomitant medication taken during the study must be recorded in the electronic CRF
(eCRF).  Patients will maintain their usual medication regimen throughout the study unless 
specifically excluded in the protocol.  Patients taking permitted medications are to be on stable 
doses at the baseline visit (Week 0; Visit 2) through Week 16 as specified in inclusion/exclusion 
criteria (Sections 5.1 and 5.2).  Up to Week 16, patients should not start new medications or 
make any changes to concomitant medications unless changes need to be made for an AE or for 
safety reasons.  Beyond Week 16, some flexibility is allowed in concomitant medication as 
outlined below.
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.  If the need for concomitant medication arises, the 
investigator is to base decisions on the patient and relevant clinical factors.  Any additional 
medication, whether prescription or over-the-counter, used at baseline (Week 0, Visit 2) and/or 
during the course of the study must be documented with the start and stop dates in the eCRF.  
Other medications may be allowed, if approved by the sponsor or its designee.  
Only for patients who discontinued study treatment and have entered the Post-Study Follow-Up 
Period (Period 3), axSpA therapy with another agent previously excluded during the treatment 
period of the study may be allowed, as determined appropriate by the investigator and approved 
by Lilly medical. 
Patients requiring surgery at any time during the study are to interrupt administration of the 
investigational product beginning 8 weeks prior to the surgery, or as early as possible within 
8 weeks of surgery, and resume administration of the investigational product only after complete 
wound healing.  
TNF alpha inhibitors:
TNF alpha inhibitors are not to be used during any study period prior to discontinuation of 
investigational study medication and/or rescue ixekizumab 80 mg.  
Vaccines: 
Live vaccines are not allowed during any of the study periods.  Use of nonlive seasonal 
vaccinations and/or emergency vaccination (such as rabies or tetanus vaccinations) is allowed.  
6.8.1. Concomitant Medications During Week 0 to Week 16
NSAIDs and Analgesics:
NSAIDs, including COX-2 inhibitors, will be allowed up to the maximum recommended doses 
for pain.  Patients must be on a stable dose of NSAIDs/COX-2 inhibitors for at least 2 weeks 
prior to baseline randomization. Introduction of a new NSAID or dose adjustment to an existing 
NSAID is not permitted, unless required for safety reasons (AE).  
Short-acting analgesics with no anti-inflammatory action (such as paracetamol) are permitted.  If 
administered ad hoc as needed, they are to be withheld within the 24-hour period prior to any 

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assessment.  Aspirin (in a dose not exceeding 350 mg/day) may be taken to manage 
cardiovascular risk.  
Opiate analgesic use is allowed but is not to exceed an average daily dose of 30 mg/day of 
morphine or its equivalent.  Introduction of a new opiate analgesic or dose adjustment to an 
existing opiate analgesic is not permitted, unless required for safety reasons or as premedication 
for MRIs. 
Conventional DMARDs:
Discontinuation of excluded oral or injectable cDMARDs before study enrollment must occur at 
least 4 weeks prior to baseline.  MTX (oral or parenteral up to 25 mg/week), sulfasalazine (up to 
3 g/day), or hydroxychloroquine (up to 400 mg/day) may be allowed IF at stable dose for at least 
4 weeks prior to baseline randomization. These agents can only be used as single agent therapy 
and not in combination with other cDMARDs.  If, at any time, the investigator believes that side 
effects or laboratory abnormalities may be attributable to the cDMARD, then cDMARD dose is 
to be lowered or the medication stopped.  Local standard of care is to be followed for 
concomitant administration of folic or folinic acid if MTX is taken.  
Corticosteroids:
Oral corticosteroids:  If on oral corticosteroids, the dose must not exceed 10 mg/day of 
prednisone or its equivalent and must be stable for at least 4 weeks prior to baseline 
randomization.  Treatment alteration in oral corticosteroid dose is not to occur prior to Week 16.  
Parenteral corticosteroids (intravenous, intramuscular, intra-articular):  Treatment with any 
parenteral corticosteroids is not permitted within 6 weeks prior to baseline or up to Week 16.  
Inhaled and topical steroids:  Regular use of inhaled or topical steroids will be permitted during 
any study period.  
6.8.2. Concomitant Medications at or after Week 16 for Treatment 
Modifications (after Completion of Week 16 Assessments)
General:
Changes in therapy are discouraged in the last 8 weeks prior to 52 week assessments.
NSAIDs and Analgesics: 
Alterations of NSAIDs, including COX-2 inhibitors (dose change, introduction, or withdrawal),
are allowed.  Doses are recommended to be stable in the 2 weeks prior to an assessment.  Any 
changes in frequency and/or dose must be recorded in the eCRF.  
Short-acting analgesics with no anti-inflammatory action (such as paracetamol) are permitted. If
administered ad hoc as needed, they are to be withheld within the 24-hour period prior to any 
assessment.  Aspirin (dose not exceeding 350 mg/day) may be taken to manage cardiovascular 
risk.  

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Opiate analgesic use:  Use of variable doses of opiate analgesics is allowed but is not to exceed 
an average daily dose of 30 mg morphine or its equivalent.  
Conventional DMARDs:
Adjustment of allowed cDMARDs (eg, dose change, introduction, withdrawal of cDMARDs, or 
replacement of a current cDMARD with the introduction of a new cDMARD) is allowed after all 
assessments at Week 16 are completed.  Not more than 1 adjustment of cDMARDs at 1 time 
within 8 weeks is recommended.  cDMARD can only be used as a single agent and not in 
combination with other cDMARDs.  Any changes must be recorded in the eCRF.  
For all study periods, the maximum allowed dose is 25 mg/week for MTX, 3 g/day for 
sulfasalazine, and 400 mg/day for hydroxychloroquine.  Local standard of care is to be followed 
for concomitant administration of folic or folinic acid if MTX is taken and for administration of 
other cDMARDs.  
Oral corticosteroids:  As of Week 16, adjustments of oral corticosteroids are allowed; however,
the maximum dose is not to exceed 10 mg/day of prednisone or its equivalent at any time during 
these periods.  
Parenteral corticosteroids (intravenous, intramuscular, intra-articular):  As of Week 16,
intra-articular injection of corticosteroid may be allowed, as needed.  The joint injected must be 
designated along with the medication in the eCRF and must be recorded as unevaluable on the 
TJC/SJC assessment.  
Inhaled and topical steroids:  Regular use of inhaled or topical steroids will be permitted during 
any study period.  
Any change in medication not addressed above is to be discussed with the clinical research 
physician or clinical research scientist.  Patients must be instructed to consult the investigator or 
other appropriate study personnel at the site before taking any new medications or supplements.  
6.9.
Treatment after Study Completion
6.9.1. Study Extensions 
Patients who complete this study through Visit 15 (Week 52) may be eligible to participate in a 
long-term study (Study RHBY) offering up to an additional 2 years of treatment, if enrollment 
criteria for Study RHBY are met.  For patients who have completed Study RHBX through 
Week 52 and have exclusionary criteria for Study RHBY at Week 44 and Week 52, patients will 
complete the Post-Study Follow-Up Period (Period 3) in Study RHBX.  
6.9.2. Continued Access
Investigational product will not be made available to patients after conclusion of this study.  
However, patients who complete Study RHBX and who are eligible to continue in the long-term 
study (Study RHBY) may have access to investigational product for up to an additional 2 years.  

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7.
Discontinuation Criteria
The reason for and date of discontinuation from study treatment (investigational product) and 
reason for and date of discontinuation from study participation will be collected for all 
randomized patients. 
Patients who have taken at least 1 study dose and who discontinue study treatment prior to Week 
16 or study participation (regardless of timing) are to complete an ETV and enter into post-study 
follow-up for at least 12 weeks after the ETV date or the last regularly scheduled visit. Patients 
whose ETV or last regularly scheduled visit is longer than 12 weeks after their last 
investigational study medication dose are not required to enter into the Post-Study Follow-Up 
Period.  Patients who complete the study through Week 52 and who are not entering into Study 
RHBY are to enter into the Post-Study Follow-Up Period (Period 3) as shown in the Schedule of 
Activities (Appendix 2).  
7.1.
Discontinuation from Study Treatment
7.1.1. Permanent Discontinuation from Study Treatment
The following criteria must be followed for discontinuation from study treatment.  
[1]
Discontinuation of the investigational product for abnormal liver tests should 
be considered by the investigator when a patient meets 1 of the following 
conditions after consultation with the Lilly designated medical monitor:  

ALT or AST >8 times ULN

ALT or AST >5 times ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level >2 times ULN or 
prothrombin time >1.5 times ULN

ALT or AST >3 times ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)

alkaline phosphatase >2.5 times ULN and total bilirubin >2 times ULN

alkaline phosphatase >2.5 times ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
[2]
Other laboratory tests (Note:  Laboratory test(s) that may result in 
discontinuation based on a single result may be repeated only once if there is a 
technical error or clinical reason to believe a result may need to be retested.  
Laboratory tests can only be repeated after consultation with Lilly medical.  
Investigational product should not be administered in these cases until retest 
result is available.):  

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
Neutrophil (segmented) counts (see safety monitoring for neutropenia 
in Section 8.4.10.1):  
o
<500 cells/L (<0.50x103/µL or <0.50 GI/L)
o
≥500 and <1000 cells/L (≥0.50x103/µL and <1.00x103/µL or 
≥0.50 GI/L and <1.00 GI/L) (based on 2 test results; the second 
test performed within 1 week from knowledge of the initial 
result)
o
≥1000 and <1500 cells/L (≥1.00x103/µL and <1.50x103/µL
or ≥1.00 GI/L and <1.50 GI/L) (based on 3 test results as 
specified in Section 8.4.10.1)
- AND -  a concurrent infection

Total WBC count <2000 cells/L (<2.00x103/µL or <2.00 GI/L)

Lymphocyte count <500 cells/μL (<0.50x103/µL or <0.50 GI/L)

Platelet count <50,000 cells/μL (<50x103/µL or <50 GI/L)
[3]
The patient experiences a severe AE, an SAE, or a clinically significant 
change in a laboratory value that, in the opinion of the investigator, merits the 
discontinuation of the investigational product and appropriate measures being 
taken.  In this case, Lilly or its designee is to be notified immediately.  Refer 
to Adverse Events, Section 8.2.  
[4]
Clinically significant systemic hypersensitivity reaction following SC 
administration of investigational product that does not respond to 
symptomatic medication or results in clinical sequelae  
[5]
The patient becomes pregnant.  
[6]
The patient develops a malignancy.  
Note:  Patients may be allowed to continue if they develop no more than 
2 nonmelanoma skin cancers during the study.  
[7]
Enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study  
[8]
It is recommended that the subject be assessed by a psychiatrist or 
appropriately trained professional to assist in deciding whether the subject is 
to be discontinued from the study in the following circumstances:  
The patient, at any time during the study, scores a 3 for Item 12 (Thoughts of 
Death or Suicide) on the QIDS-SR16; 
OR 

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develops active suicidal ideation with some intent to act with or without a 
specific plan (yes to question 4 or 5 on the “Suicidal Ideation” portion of the 
Columbia-Suicide Severity Rating Scale [C-SSRS]); 
OR 
develops suicide-related behaviors as recorded on the C-SSRS. 
[9]
The investigator or attending physician decides that the patient is to be 
withdrawn from study treatment.  
[10] The patient requests to be withdrawn from study treatment.  
[11] Lilly or its designee stops the patient’s participation in the study or Lilly stops 
the study for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and good clinical practice (GCP).  
[12] The patient becomes HBV DNA positive.  The patient is to be referred to a 
specialist physician.  Discussion of discontinuation from study treatment and 
from the study is provided in Section 8.4.10.2.  
7.1.2. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the sponsor or investigator identify a 
patient who did not meet enrollment criteria and was inadvertently enrolled, a discussion must 
occur between the sponsor clinical research physician and the investigator to determine if the 
patient may continue in the study.  If both agree it is medically appropriate to continue, the 
investigator must obtain documented approval from the sponsor clinical research physician to 
allow the inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product.
7.1.3. Permanent Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:  

Enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.

Participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

Patient Decision:  the patient requests to be withdrawn from the study.
Patients who discontinue the study participation early will have end-of-study procedures 
performed as shown in the Schedule of Activities (Appendix 2).  
7.1.4. Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make due 

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diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.  

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8.
Study Assessments and Procedures
Appendix 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).  
Appendix 3 lists the laboratory tests that will be performed for this study.  
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.  
8.1.
Efficacy Assessments
Below are brief descriptions on key aspects of scales used in the study.  Complete assessments 
are included in site training materials.  
The following ASAS domains are used to determine ASAS20, ASAS40, ASAS partial 
remission, and ASAS5/6 (Sieper et al. 2009, ASAS Handbook):  
1) Patient Global (Section 8.1.2.2)
2) Spinal Pain (Section 8.1.2.3)
3) Function (Section 8.1.2.5) 
4) Inflammation (mean of BASDAI questions 5 and 6) (Section 8.1.2.4) 
5) CRP (Section 8.1.2.20.1), and 
6) Spinal Mobility (lateral spinal flexion) (Section 8.1.2.6).
8.1.1. Primary Efficacy Assessments: ASAS40
The ASAS40 response (Anderson et al. 2001; Brandt et al. 2004; Sieper et al. 2009) is derived 
from patient-reported assessments.  The ASAS40 is defined as a ≥40% improvement and an 
absolute improvement from baseline of ≥2 units (range 0 to 10) in ≥3 of the following 4 domains 
(Patient Global, Spinal Pain, Function, and Inflammation) without any worsening in the 
remaining domain.  
8.1.2. Secondary Efficacy Assessments 
8.1.2.1.
ASAS20, ASAS Individual Components, ASAS Partial Remission, and 
ASAS5/6 
The ASAS20, ASAS individual components, ASAS partial remission, and ASAS5/6 responses 
(Davis et al. 2003; Sieper et al. 2009) are secondary efficacy assessments that are calculated as 
improvements in respective response rates in multiple disease domains.  
Complete definitions of each assessment are provided below.  
8.1.2.1.1. ASAS20
The ASAS20 response is derived from patient-reported assessments.  An ASAS20 response is 
defined as a ≥20% improvement and an absolute improvement from baseline of ≥1 units 

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(range 0 to 10) in ≥3 of the following 4 domains (Patient Global, Spinal Pain, Function, and 
Inflammation) and no worsening of ≥20% and ≥1 unit (range 0 to 10) in the remaining domain.  
8.1.2.1.2. ASAS Partial Remission
The ASAS partial remission is derived from patient-reported assessments.  An ASAS partial 
remission is defined as a value not above 2 units (range 0 to 10, NRS) in each of the following 
4 domains: Patient Global, Spinal Pain, Function, and Inflammation.  
8.1.2.1.3. ASAS5/6
The ASAS5/6 includes assessment of all 6 individual ASAS domains listed above (Section 8.1) 
and represents improvement of ≥20% in at least 5 domains.  
8.1.2.2.
Patient Global (Assessment of Disease Activity)
From the ASAS handbook (Sieper et al. 2009), the patient is asked to respond to the following 
question:  
“How active was your spondylitis on average during the last week?”
The answer is recorded on a NRS and is rated between “0” (not active) and “10” (very active).  
8.1.2.3.
Spinal Pain
From the ASAS handbook (Sieper et al. 2009), the patient is asked to respond to the following 
2 questions (on average, last week):  
1. “How much pain of your spine due to ankylosing spondylitis do you have?”
2. “How much pain of your spine due to ankylosing spondylitis do you have at night?”
The answers are recorded on a NRS and are each rated between “0” (no pain) and “10” (most 
severe pain).  The first question is used to calculate derived scores (ie, ASAS40, ASAS20, etc.)
and defines the total back pain for inclusion criteria [3].  
8.1.2.4.
Bath Ankylosing Spondylitis Disease Activity Index
The BASDAI is a patient-reported assessment.  The BASDAI is an instrument consisting of 
6 questions that relate to 5 major symptoms relevant to axSpA (Garrett et al. 1994; Sieper et al. 
2009):  1) Fatigue, 2) Spinal pain, 3) Peripheral arthritis, 4) Enthesitis, 5) Intensity, and 6) 
Duration of morning stiffness.  Patients need to score each item with a score from 0 to 10 (NRS).  
Higher score represents worse disease activity.
The BASDAI50 represents an improvement of ≥50% of the BASDAI score from baseline.  
8.1.2.5.
Bath Ankylosing Spondylitis Functional Index
The BASFI is a patient-reported assessment.  The BASFI establishes a patient’s functional 
baseline and subsequent response to treatment (Calin et al. 1995).  To complete the BASFI, a 
patient will be asked to rate the difficulty associated with 10 individual basic functional activities.  
Patients respond to each question using an NRS (range 0 to 10), with a higher score indicating 
worse functioning.  
The patient’s final BASFI score is the mean of the 10 item scores completed on an NRS.  

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8.1.2.6.
Bath Ankylosing Spondylitis Metrology Index—Spinal Mobility
The BASMI is a combined index comprising the following 5 clinical measurements of spinal 
mobility in patients with axSpA (Jenkinson et al. 1994).  

Lateral spinal flexion

Tragus-to-wall distance

Lumbar flexion (modified Schrober)

Maximal intermalleolar distance

Cervical rotation.
The BASMI includes these 5 measurements which are each scaled to a score of 0 to 10 
depending on the result of the assessment (BASMI linear function).  The average score of the 
5 assessments gives the BASMI linear result (van der Heijde et al. 2008; Sieper et al. 2009).  
The BASMI must be assessed by a rheumatologist or health care provider who meets the 
qualifications for study assessment.
8.1.2.7.
Chest Expansion
While patients have their hands resting on or behind the head, the assessor will measure the chest 
encircled length by centimeter (cm) at the fourth intercostal level anteriorly.  The difference 
between maximal inspiration and expiration in centimeters will be recorded. Two tries will be 
recorded.  The better (larger difference) measurement of 2 tries (in centimeters) will be used for 
analyses.
The measurement of chest expansion must be assessed by a rheumatologist or health care 
provider who meets the qualifications for study assessment.  
8.1.2.8.
Occiput to Wall Distance
The patient is to make a maximum effort to touch the head against the wall when standing with 
heels and back against the wall.  Tip of nose and tragus must be at the same horizontal line to 
avoid neck extension.  Then the distance from occiput to the wall is measured.  Two tries will be 
recorded.  The better (smaller) measurement of 2 tries (in centimeters) will be used for analyses.  
The measurement of occiput to wall distance must be assessed by a rheumatologist or health care 
provider who meets the qualifications for study assessment.  
8.1.2.9.
Ankylosing Spondylitis Disease Activity Score
The ASDAS is a composite index to assess disease activity in AS (Machado et al. 2011a, 2011b; 
Zochling et al. 2011).  The parameters used for the ASDAS (with high-sensitivity CRP [hsCRP]
as acute phase reactant):  
1) Total back pain (BASDAI question 2)
2) Patient Global (Section 8.1.2.2)
3) Peripheral pain/swelling (BASDAI question 3)
4) Duration of morning stiffness (BASDAI question 6)
5) CRP in mg/L

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ASDAScrp:  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) (Machado et al. 2015).  
Note:  CRP is in mg/liter, the range of other variables is from 0 to 10; Ln represents the natural 
logarithm. 
Four disease activity states have been defined by ASAS consensus (Machado et al. 2011c):  

ASDAS <1.3 defines inactive disease; 

1.3 ≤ ASDAS <2.1 defines moderate disease activity; 

2.1≤ ASDAS ≤3.5 defines high disease activity; and 

ASDAS >3.5 defines very high disease activity.
Clinically important improvement is defined as change ≥1.1 units, and major improvement is 
defined as change ≥2.0 units (Machado et al. 2011b).  
8.1.2.10. Maastricht Ankylosing Spondylitis Enthesitis Score
The MASES is an index used to measure the severity of enthesitis (Hueft-Dorenbosch et al. 
2003).  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 of scores:  0 to 13), higher scores indicate more severe enthesitis.  
The MASES is to be assessed by a rheumatologist or health care provider who meets study 
qualifications for study assessment.  
8.1.2.11. SPARCC Enthesitis Score
The SPARCC enthesitis is an index used to measure the severity of enthesitis (Maksymowych 
et al. 2009).  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 of scores:  0 to 16).  Higher scores indicate 
more severe enthesitis.  
The SPARCC is to be assessed by a rheumatologist or health care provider who meets study 
qualifications for study assessments.  
8.1.2.12. Peripheral Arthritis
8.1.2.12.1.Tender Joint Count
The number of tender and painful joints will be determined by examination of 46 joints (23 joints 
on each side of the patient’s body).  The 46 joints to be assessed and classified as tender or not 
tender are detailed in site training materials.  Any joints that require intra-articular injections 

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during the study (according to Section 6.8) must be excluded from evaluation from the time of 
the injection to the conclusion of the study.  
Joint assessments will be performed by an experienced rheumatologist or skilled and trained 
assessor.  To minimize interobserver variation, particularly during the Blinded Treatment Dosing 
Period (Period 2), it is recommended that the same assessor performs the TJC for a given patient.  
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
Screening Visit and will be excluded from evaluation during the study.  
The TJC data will be collected electronically.  
8.1.2.12.2.Swollen Joint Count
The number of swollen joints will be determined by examination of 44 joints (22 joints on each 
side of the patient’s body).  The 44 joints to be assessed and classified as swollen or not swollen 
are detailed in site training materials.  Any joints that require intra-articular injections during the 
study (according to Section 6.8) must be excluded from evaluation from the time of the injection 
to the conclusion of the study.  
Joint assessment is to be performed by an experienced rheumatologist or health care provider
who meets the qualifications for study assessments.  To minimize interobserver variation, 
particularly during the Blinded Treatment Dosing Period (Period 2), it is recommended that the 
same assessor performs the SJC for a given patient.  Missing, replaced, ankylosed, or arthrodesed 
joints will be identified by the investigator at the Screening Visit and will be excluded from 
evaluation during the study.  
The SJC data will be collected electronically.  
8.1.2.13. NSAID Intake
Information regarding NSAIDs intake will be collected in the eCRF, and the ASAS-NSAID 
score will be calculated at baseline and through Week 52 (Dougados et al. 2011).  
8.1.2.14. Clinically Meaningful Changes in Concomitant Medication(s) or 
Background Therapy
Information regarding changes in concomitant medication or background therapy will be 
collected at baseline and through Week 52.  A detailed definition of what are considered 
clinically meaningful changes in concomitant medication(s) or background therapy will be 
provided in the SAP.  
8.1.2.15. Assessment of Spondyloarthritis International Society Health Index
The ASAS-HI is a disease specific health-index instrument designed to assess the impact of 
interventions for SpA, including axSpA.  This broader concept of Health is included in the 
International Classification of Functioning Disability and Health (ICFD) which has been 
published by World Health Organization (WHO).  The ASAS has applied the ICFD as a basis to 
define a core set of items relevant for patients with axSpA.  The 17-item instrument has scores 
ranging from 0 (good Health) to 17 (poor Health) (Kiltz et al. 2015).  Each item consists of 
1 question that the patient needs to respond to with either “I agree” (score 1) or “I do not agree 

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(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. 
8.1.2.16. Medical Outcomes Study 36-Item Short-Form Health Survey
The SF-36 is a 36-item patient-administered measure designed to be a short, multipurpose 
assessment of health in the areas of physical functioning, role – physical, role – emotional, 
bodily pain, vitality, social functioning, mental health, and general health.  The 2 overarching 
domains of mental well-being and physical well-being are captured by the Mental Component 
Summary and Physical Component Summary scores.  The summary scores range from 0 to 100; 
higher scores indicate better levels of function and/or better health.  Items are answered on Likert 
scales of varying lengths.  The SF-36 version 2 (acute version) will be used, which utilizes a 
1-week recall period (Ware 2000).  
8.1.2.17. Fatigue Severity Numeric Rating Scale
The fatigue severity NRS is a patient-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” (Naegeli et al. 2013).  Patients 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.  
8.1.2.18. Work Productivity and Activity Impairment Questionnaire—
Spondyloarthritis
The WPAI-SpA consists of 6 questions to determine employment status, hours missed from 
work because of spondyloarthritis, hours missed from work for other reasons, hours actually 
worked, the degree to which spondyloarthritis affected work productivity while at work, and the 
degree to which spondyloarthritis affected activities outside of work.  The WPAI-SpA has been 
validated in the rad-axSpA patient population (Reilly et al. 2010).  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.  Greater scores indicate greater impairment 
(Reilly Associates Health Outcomes Research [WWW]).  
8.1.2.19. Jenkins Sleep Questionnaire
The JSEQ is a 4-item scale designed to estimate sleep problems in clinical research.  The JSEQ 
assesses the frequency of sleep disturbance in 4 categories:  1) trouble falling asleep, 2) waking 
up several times during the night, 3) having trouble staying asleep (including waking up far too 
early), and 4) waking up after the usual amount of sleep feeling tired and worn out.  Patients 
report the numbers of days they experience each of these problems in the past month on a 6-point 
Likert Scale ranging from 0 = “no days” to 5 = “22-30 days.”  The total JSEQ score ranges from 
0 to 20, with higher scores indicating greater sleep disturbance (Deodhar et al. 2010).  
8.1.2.20. Laboratory Tests Used for Efficacy Measures and Disease Diagnosis
8.1.2.20.1.High Sensitivity C-Reactive Protein
High-sensitivity C-reactive protein (hsCRP) will be the measure of acute phase reactant.  It will 
be measured with a high sensitivity assay at the central laboratory to help assess the effect of 

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ixekizumab on disease activity.  The results will not be shared with the investigative sites after 
baseline randomization to maintain study blind.  
8.1.2.21. Imaging Used for Efficacy Measures and Disease Diagnosis
8.1.2.21.1.Imaging Used for Efficacy Measures and Disease Diagnosis
For each patient, x-ray and MRI images will be collected according to the Schedule of Activities 
(Appendix 2) and Table RHBX.3 and will follow the study specific recommendations included 
in the site training materials for the study.  The x-ray of the SIJ will be used to exclude patients 
with radiographic sacroiliitis as defined by the mNY criteria.  MRI of the SIJ, collected at 
screening, Week 16, and Week 52 will generate objective data for the investigational drug on the 
anti-inflammatory effect as well as data on the evolution of structural changes in the SIJ.  The
screening x-ray of the spine will serve as baseline for later evaluation of change from baseline in 
structural progression in the long-term study (Study RHBY).  All reading of x-ray and MRI
images is done centrally.  
Table RHBX.3.
Imaging Requirements for Sacroiliac Joints and Spine 
Time Pointa
Type of Imageb
Purpose
Reading
Other Readers
Screening 
X-ray of the SIJd
Eligibility to 
exclude rad-axSpA 
(per mNY criteria)a
Centrally readc
Send to central reader. 
Results must be received from 
central reader prior to baseline 
randomization.
Screening
X-ray of the spine 
(cervical and lumbar)
Provides baseline 
for later evaluation 
of structural 
progression in spine 
Centrally read
Send to central readers (as 
baseline for later structure 
assessments in LTE study).
Screening, 
Week 16, and 
Week 52
MRI of the SIJ
Eligibility (to 
confirm sacroiliitis 
on MRI)c
Assess efficacy 
Centrally read
Send to central reader. 
Results must be received from 
central reader prior to baseline 
randomization.  
Abbreviations:  LTE = long-term extension study; mNY = modified New York; MRI = magnetic resonance 
imaging; nonrad-axSpA = nonradiographic axial spondyloarthritis; rad-axSpA = radiographic axial 
spondyloarthritis; SIJ = sacroiliac joints.
a
Screening procedures must be conducted within timeframes specified in the Schedule of Activities (Appendix 2).
b
Imaging to be reviewed and approved for quality; imaging that does not pass the quality assessment must be  
repeated prior to randomization.
c
Patient cannot be randomized until centrally read results are received by site.
8.1.2.21.2.Spondyloarthritis Research Consortium of Canada–MRI Score for 
Sacroiliac Joints
Both left and right SIJ are scored for bone marrow edema.  Total SIJ SPARCC scores can range 
from 0 to 72 with higher scores reflecting worse disease (Maksymowych et al. 2005).  Scoring 
will be performed by central readers.  

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8.1.2.21.3.Spondyloarthritis Research Consortium of Canada–SIJ Structural 
Score (SSS)
Structural lesions in MRIs of the SIJ were assessed using the SPARCC SSS method in which the 
presence or absence of lesions is scored in SIJ quadrants (for fat metaplasia and erosion) or SIJ 
halves (for backfill and ankylosis).  Scoring ranges are fat metaplasia (0 to 40), erosions (0 to 
40), backfill (0 to 20), and ankylosis (0 to 20) (Maksymowych et al. 2015b).  Scoring will be 
performed by central readers.
8.1.3. Other Assessments
8.1.3.1.
European Quality of Life—5 Dimensions 5-Level
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.  The respondent is 
asked to indicate his/her health state by ticking (or placing a cross) in the box associated with the 
most appropriate statement in each of the 5 dimensions.  It should be noted that the numerals 1 to 
5 have no arithmetic properties and are not to be used as a cardinal score.  The VAS records the 
respondent’s self-rated health on a vertical VAS in which the endpoints are labeled “best 
imaginable health state” and “worst imaginable health state.”  This information can be used as a 
quantitative measure of health outcome.  The EQ-5D-5L health states, defined by the EQ-5D-5L 
descriptive system, may be converted into a single summary index by applying a formula that 
essentially attaches values (also called weights) to each of the levels in each dimension (The 
EuroQol Group 2011).  
8.1.3.2.
Healthcare Resource Utilization
Healthcare resource utilization data regarding the number of visits to medical care providers, 
such as general practitioners, specialists, physical, or occupational therapists, and other 
nonphysical care providers for services outside of the clinical trial; emergency room admissions, 
hospital admissions, and concomitant medications will be recorded by the investigator in the 
study’s CRF.  These data will be collected to support economic evaluations of treatment.  
8.2.
Adverse Events
An AE is defined as follows: any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment.  An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  

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Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of patients during the study.  
Investigators must document their review of each laboratory safety report.  
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient is to be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.  
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish treatment effect.  
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record via CRF any change 
in the condition(s) and any new conditions as AEs. Investigators are to record their assessment 
of the potential relatedness of each AE to protocol procedure, investigational product, via CRF.  
The investigator decides whether he or she interprets each AE as reasonably possibly related to 
the study product, study procedure, disease under study, or other concomitant medications, or 
pathologies. To assess the relationship of the AEs, the following is defined:  
Reasonably Possibly Related: Reasonable possibility that there is a cause and effect 
relationship between the study product and/or study procedure and the AE.  
The investigator answers yes/no when making this assessment.  
Planned surgeries and nonsurgical interventions are not to be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.  
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via electronic data entry, clarifying if possible, the 
circumstances leading to any dosage modifications or discontinuations of treatment.  
Accurate start and stop dates (and times, where required) are to be reported via electronic data 
entry for all AEs.  Only AEs that are ongoing at the last study visit and/or communication are to 
be documented as “ongoing.”  
8.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

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
a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.
If an SAE occurs after signing the ICF, but prior to receiving investigational product, it needs to 
be reported ONLY if it is considered reasonably possibly related to study procedure.  
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy (during maternal 
or paternal exposure to investigational product) must be reported following the SAE process and 
data are to be collected on the outcome for both mother and fetus.  
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  
8.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Lilly has procedures that will be followed for the recording and expedited reporting of suspected 
unexpected serious adverse events (SUSARs) that are consistent with global regulations and the 
associated detailed guidances.  
8.2.2. Adverse Events of Special Interest
The following adverse events of special interest (AESIs) will be used to determine the safety and 
tolerability of ixekizumab over the range of doses selected for this clinical study.  
AESIs for ixekizumab are:  

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

clinically significant hepatic events and/or significant elevations in liver function test 
changes/enzyme elevations (ALT, AST, bilirubin, and alkaline phosphatase)

infections

injection-site reactions

allergic reactions/hypersensitivities

cerebrocardiovascular events 

malignancies

IBD

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
depression.
Sites will provide details on some of these AEs as instructed on the CRF.  Investigators will also 
educate patients and/or caregivers about the symptoms of allergic/hypersensitivity reactions and 
will provide instructions on dealing with these reactions (see also Section 6.6.1).  A blood 
sample will be collected as soon as possible for any patient who experiences an AE of a potential 
systemic allergic /hypersensitivity reaction during the study as judged by the investigator.  
Data on preferred terms associated with cerebrocardiovascular events (defined as death, cardiac 
ischemic events including MI and hospitalization for unstable angina, hospitalization for heart 
failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization procedure, stroke/transient ischemic attack, peripheral revascularization 
procedure, peripheral arterial event, and hospitalization for hypertension) will be collected, and 
these events and any deaths will be adjudicated by an external clinical events committee (CEC) 
made up of a chairman, 2 cardiologists, and a neurologist.  
Data on suspected IBD, as identified by events possibly indicative of ulcerative colitis and 
Crohn’s disease, will be collected and the events will be adjudicated by an external CEC with 
expertise in IBD. 
The role of external CECs is to adjudicate defined clinical events in a blinded, consistent, and 
unbiased manner throughout the course of a study.  The purpose of the CEC for adjudication of 
cerebrocardiovascular events and the CEC for adjudication of suspected IBD events is to ensure 
that all reported events are evaluated uniformly by a single group.
8.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.  
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.  
8.3.
Treatment of Overdose
Refer to the IB.
8.4.
Safety Assessments
8.4.1. Electrocardiograms
For each patient, 12-lead ECGs must be collected locally at screening (Appendix 2).  Patients are 
to be resting for 5 minutes prior to the ECG.  It is recommended that patients be in a supine 
position.  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational treatment are to be reported to Lilly or its 

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designee as an AE via CRF.  Any clinically significant ECG findings prior to receiving drug are 
to be reported as a preexisting condition.  
8.4.2. Vital Signs
For each patient, vital signs measurements are to be conducted according to the Schedule of 
Activities (Appendix 2).  Vital signs include BP, pulse, and temperature.  Patients are to be 
resting for a minimum of 5 minutes prior to vital sign collection.  
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment are to be reported to Lilly or 
its designee as an AE via CRF.  
8.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 3) will be sent to central laboratory for 
processing and are to be conducted according to the Schedule of Activities (Appendix 2).  Please 
reference the central laboratory manual for specific instructions.  
Urine pregnancy test and PPD/T-SPOT® will be collected and read/analyzed locally.  
QuantiFERON®-TB Gold test will be collected and read/analyzed either centrally or locally.  
If required per local regulations, urine testing for pregnancy may occur at intervals as required 
during the study treatment period and/or follow-up period.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product are to be reported to Lilly or its 
designee as an AE via CRF.  
8.4.4. Physical Examination
For each patient, a complete physical examination must be conducted according to the Schedule 
of Activities (Appendix 2).  
Any clinically significant finding from a complete physical examination that results in a 
diagnosis and that occurs after the patient receives the first dose of study treatment is to be 
reported to Lilly or its designee as an AE via CRF.  
8.4.5. Eye Symptom Assessment
At each study visit, study healthcare providers will evaluate the patient for any symptoms of 
anterior uveitis as specified in the Schedule of Activities (Appendix 2).  If the patient has no 
prior ophthalmologist diagnosed anterior uveitis and develops eye pain or discomfort, eye 
redness, blurring of vision, or any other symptoms suggestive of anterior uveitis, the patient must 
be evaluated by an ophthalmologist.  If a patient has prior history of ophthalmologist diagnosed 
anterior uveitis, then she/he must be evaluated by a physician for recurrence of anterior uveitis 
(whenever possible, diagnosis is to be confirmed by an ophthalmologist).  

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8.4.6. Chest X-Ray and Tuberculosis Testing
For each patient, a posterior anterior chest x-ray and TB testing must be conducted according to 
the Schedule of Activities (Appendix 2).  
The posterior anterior chest x-ray or results will be reviewed by the investigator or designee prior 
to baseline randomization to exclude patients with active TB infection.  
Any clinically significant findings from a posterior anterior chest x-ray or TB testing that result 
in a new diagnosis and that occur after the patient receives the first dose of study treatment is to 
be reported to Lilly or its designee as an AE via CRF.  
Patients with no TB test (Purified Protein Derivative [PPD] and/or Interferon-Gamma 
Release Assay) results on file:  These patients will be tested at screening as indicated on the 
Schedule of Activities (Appendix 2) for evidence of active or latent TB indicated by a positive 
PPD skin test response, defined as ≥5 mm diameter of induration, between approximately 2 and 
3 days after test application, regardless of BCG vaccination history.  In countries where the 
Interferon-Gamma Release Assay (QuantiFERON®-TB Gold test, or T-SPOT®) is available 
and, in the judgment of the investigator, preferred as an alternative to the PPD skin test for the 
evaluation of TB infection, it may be used instead of the PPD test (positive tests excluded).  The 
QuantiFERON-TB Gold test may be read locally or centrally, while the T-SPOT must be read 
locally.  If the QuantiFERON-TB Gold test is indeterminate or the T-SPOT is invalid or 
borderline, 1 retest is allowed.  If the retest for the QuantiFERON-TB Gold test is indeterminate 
or the retest for the T-SPOT is invalid or borderline, then the patient is excluded from enrolling 
in the study.  
However, patients with a PPD skin test ≥5 mm induration or a positive QuantiFERON-TB Gold 
or positive T-SPOT test at screening but no other evidence of active TB may be rescreened 
1 time and may be enrolled without repeating a PPD or QuantiFERON-TB Gold test or T-SPOT 
(TB test) if the following conditions are met:  

after receiving at least 4 weeks of appropriate latent TB infection (LTBI) therapy.

with no evidence of hepatotoxicity (ALT/AST must remain ≤2xULN) upon retesting of 
serum ALT/AST prior to randomization.  Such patients must complete appropriate latent 
TB infection (LTBI) therapy during the course of the study in order to remain eligible.

meet all other inclusion/exclusion criteria for participation.
If rescreening occurs within 6 months of the initial screening posterior anterior chest x-ray, there 
is no necessity for repeat of the chest x-ray for considering enrollment.  
Patients with negative TB test results on file:  Patients with documentation of a negative test 
result within 3 months prior to baseline (Week 0; Visit 2) do not need a TB screen at Visit 1.  
Documentation of a PPD test result must include a record of the size of the induration response 
documenting either no induration or induration measuring <5mm in diameter.  A PPD test 
recorded as negative without documenting the size of induration will result in a required test at 
screening to determine patient eligibility.  

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Patients with positive TB test results on file:  Patients with prior history of a positive TB test 
are not to have a TB test at Visit 1.  Documentation of this history and of at least 4 weeks of 
appropriate latent TB treatment prior to baseline (Week 0, Visit 2) and continued treatment 
during the study is required to attain and maintain study eligibility.  Patients who have a 
documented history of completing an appropriate TB treatment regimen with no history of 
re-exposure to TB since their treatment was completed and no evidence of active TB are eligible 
to participate in the study.  Patients who have had household contract with a person with active 
TB are excluded, unless appropriate and documented prophylaxis for TB was completed.  
8.4.7. Quick Inventory of Depressive Symptomatology–Self-Report 
(16 Items)
For each patient, a QIDS-SR16 assessment will be collected according to the Schedule of 
Activities (Appendix 2).  
Any clinically significant findings from the QIDS-SR16 assessment that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment are to be reported to Lilly or 
its designee as an AE via CRF.  
The QIDS-SR16 is a self-administered 16-item instrument intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association’s 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (APA 1994).  A patient is 
asked to consider each statement as it relates to the way they have felt for the past 7 days.  There 
is a 4-point scale for each item ranging from 0 to 3.  The 16 items corresponding to 9 depression 
domains that are summed to give a single score ranging from 0 to 27, with higher scores 
denoting greater symptom severity.  The domains assessed by the instrument are (1) sad mood, 
(2) concentration, (3) self-criticism, (4) suicidal ideation, (5) interest, (6) energy/fatigue, 
(7) sleep disturbance (initial, middle, and late insomnia or hypersomnia), (8) decrease/increase in 
appetite/weight, and (9) psychomotor agitation/retardation.  Additional information and the 
QIDS-SR16 questions may be found at the University of Pittsburgh IDS/QIDS internet page 
(IDS/QIDS home page [WWW]).  
8.4.8. Columbia Suicide Severity Rating Scale
The C-SSRS (Posner et al. 2007, C-SSRS web site [WWW]) is a scale that captures the 
occurrence, severity, and frequency of suicide-related ideations and behaviors during the 
assessment period.  The C-SSRS must be administered by appropriately trained site personnel.  
The tool was developed by the National Institute of Mental Health (NIMH) Treatment of 
Adolescent Suicide Attempters (TASA) trial group for the purpose of being a counterpart to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) categorization of suicidal 
events.  Patients will be assessed according to the Schedule of Activities (Appendix 2).  
The Self-Harm Supplement Form is a 1 question eCRF questionnaire that is completed at any 
visit, including baseline visits, asking for the number of suicidal or nonsuicidal self-injurious 
behaviors the patient experienced since last assessment. For each unique event identified, a 

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questionnaire (Self-Harm Follow-Up Form) which collects supplemental information on the 
self-injurious behavior must be completed. This information is then documented in the eCRF.  
8.4.9. Immunogenicity
For each patient, an immunogenicity sample will be collected according to the Schedule of 
Activities (Appendix 2).  
Additionally, a blood sample will be collected, as soon as possible, for any patient who 
experiences a potential systemic allergic/hypersensitivity reaction during the study as judged by 
the investigator.  These samples will be tested for immunogenicity and PK, while other 
laboratory tests may be performed as needed to elucidate the cause of the 
allergic/hypersensitivity reaction.  
8.4.10. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  
If a study patient experiences elevated ALT ≥3xULN, alkaline phosphatase ≥2xULN, or elevated 
total bilirubin ≥2xULN, clinical and laboratory monitoring is to be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  For other AESIs or abnormal lab results, please refer to the appropriate 
protocol section that addresses these topics.  To ensure patient safety and comply with regulatory 
guidance, the investigator is to consult with the Lilly clinical research physician/clinical research 
scientist regarding collection of specific recommended clinical information and follow-up 
laboratory tests.  See Appendix 4.  
8.4.10.1. Neutropenia
8.4.10.1.1.During Treatment (Period 2)
During treatment with investigational product, patients with neutrophil counts <1500 cells/L 
(<1.50x103/µL or <1.50 GI/L) are to be managed for neutropenia as follows:

<500 cells/L (<0.50x103/µL or <0.50 GI/L), see Discontinuation Criteria 
(Section 7.1)

≥500 cells/L and <1000 cells/L (≥0.50x103/µL and <1.00x103/µL or 
≥0.50 GI/L and <1.00 GI/L), see Discontinuation Criteria (Section 7.1)

≥1000 cells/L and <1500 cells/L (≥1.00x103/µL and <1.50x103/µL or 
≥1.00 GI/L and <1.50 GI/L), and the patient has a concurrent infection that 
requires systemic anti-infective therapy (for example, antibiotic, antifungal agent, 
antiviral agent):  

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o
The dose of investigational product is to be withheld, the patient is to receive 
appropriate medical care, and a repeat test for neutrophil count is to be 
performed within 4 weeks from knowledge of the initial report.  If the repeat 
neutrophil count has returned to ≥1500 cells/L (≥1.50x103/µL or 
≥1.50x103/µL) and the infection has resolved or is resolving, the patient may 
resume dosing of investigational product and evaluation at scheduled visits.  If 
the neutrophil count remains ≥1000 cells/L and <1500 cells/L 
(≥1.00x103/µL and <1.50x103/µL or ≥1.00 GI/L and <1.50 GI/L), 
investigational product is to continue to be withheld and a repeat neutrophil 
count is to again be performed within another 4 weeks.  If, after 2 repeat tests, 
the neutrophil count still remains ≥1000 cells/L and <1500 cells/L 
(≥1.00x103/µL and <1.50x103/µL or ≥1.00 GI/L and <1.50 GI/L), and:

the infection has not fully resolved; the patient will be discontinued from 
the study treatment.

the infection has resolved; the patient may resume dosing and evaluation 
at scheduled visits.  However, if resumption of dosing is not deemed 
appropriate by the investigator, the patient will be discontinued from the 
study treatment.

≥1000 cells/L and <1500 cells/L (≥1.00x103/µL and <1.50x103/µL or ≥1.00 
GI/L and <1.50 GI/L), and the patient has no concurrent infection that requires 
systemic anti-infective therapy (for example, antibiotic, antifungal agent, antiviral 
agent):  
o
Dosing may continue, and a repeat neutrophil count is to be performed 4 to 
8 weeks from knowledge of the initial report.  Testing may be at a regularly 
scheduled visit or at an unscheduled visit, as necessary.  
Repeat testing is to be performed at 4- to 8-week intervals until the neutrophil 
count has returned to ≥1500 cells/L (≥1.50x103/µL or ≥1.50 GI/L).  If the 
patient has 3 or more postbaseline neutrophil counts of ≥1000 cells/L 
(≥1.00x103/µL or ≥1.00 GI/L) and <1500 cells/L (<1.50x103/µL or 
<1.50 GI/L), no value of <1000 cells/L (<1.00 x103/µL or <1.00 GI/L), and 
no postbaseline infection requiring systemic anti-infective therapy, the patient 
may continue or resume further evaluation at scheduled visits, as deemed 
appropriate by the investigator.  
If a patient without initial concurrent infection develops an infection that requires systemic 
anti-infective therapy, then the patient is to be managed as indicated above for patients with 
concurrent infection.  
8.4.10.1.2.At Early Termination Visit
For patients not enrolling in Study RHBY:  If, at the last scheduled study visit, the patient’s 
neutrophil count is <1500 cells/L (<1.50x103/µL or <1.50 GI/L) and less than the patient’s 
baseline neutrophil count, the following measures are to be taken:  

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
Patients with Concurrent Infection:  If there is a concurrent infection that requires 
systemic anti-infective therapy, the patient must receive appropriate medical care 
and a repeat test for neutrophil count is to be performed at least Q4W (or sooner 
as appropriate) until resolution of infection.  Upon resolution of infection, the 
neutrophil count is to be monitored using the required study visits in the 
Post-Study Follow-Up Period (Period 3) design at Visits 801 (4 weeks post-
resolution of infection), 802 (8 weeks after Visit 801 unless otherwise specified), 
and 803 (if necessary; 12 weeks after Visit 802); additional visits may be required 
depending on the degree of neutropenia. For patients with a neutrophil count 
below the above mentioned threshold at Week 52 who have already enrolled in 
Study RHBY, requirements for repeat test for neutrophil count will be specified in 
the Study RHBY protocol.

Patients without Concurrent Infection:  If there is no concurrent infection that 
requires systemic anti-infective therapy, the neutrophil count is to be monitored 
using the required study visits in the Post-Study Follow-Up Period (Period 3) 
design, Visits 801 (4 weeks post-ETV or last regularly scheduled visit), 802, and 
803 (if necessary); additional visits may be required depending on the degree of 
neutropenia.
8.4.10.1.3.Post-Study Follow-Up
For patients not enrolling in Study RHBY, at Visit 801 and subsequent visits, the following 
monitoring applies:  

As long as a patient’s neutrophil count is <1000 cells/L (<1.00x103/µL or 
<1.00 GI/L) at any follow-up visit, the patient is to return for visits at least 
Q4W (may require unscheduled visits).  

As long as a patient’s neutrophil count is ≥1000 cells/L and <1500 cells/L 
(≥1.00x103/µL and <1.50x103/µL or ≥1.00 GI/L and <1.50 GI/L) at any 
follow-up visit, the patient is to return for additional visit(s) at least every 4 to 
8 weeks (may require unscheduled visits).  

If, at Visit 802 or Visit 803, the patient’s neutrophil count is ≥1500 cells/L 
(≥1.50x103/L or ≥1.50 GI/L) or greater than or equal to the patient’s baseline 
neutrophil count (whichever is lower), the patient’s participation in the study 
will be considered complete unless the investigator deems additional 
follow-up may be necessary.  
If, at Visit 803, the patient’s neutrophil count remains <1500 cells/L (<1.50x103/µL or 
<1.50 GI/L) and less than the patient’s baseline neutrophil count, or if the investigator deems 
additional follow-up may be necessary, the investigator in consultation with Lilly, or qualified 
designee, will determine the appropriate management of the patient and the appropriate timing of 
additional contact(s) or visit(s).  
8.4.10.2. Hepatitis B Monitoring
Patients who are HBcAb+ at screening, regardless of other hepatitis B testing results, will have a
serum HBV DNA specimen obtained to be analyzed by the central laboratory. Such patients 

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who are determined to be HBV DNA negative (undetectable) may be enrolled into the study with
required HBV DNA monitoring every 3 to 4 months during treatment and 12 weeks after the last
dose of ixekizumab. Patients who are found to be HBV DNA positive (detectable) at screening
will be excluded from the trial.  
If the result of any subsequent HBV DNA testing is positive, the patient is to be discontinued
from the study treatment, is to continue safety follow-up, and is to receive appropriate follow-up
medical care, including consideration for antiviral therapy.  A specialist physician in the care of 
patients with hepatitis (for example, infectious disease or hepatologist subspecialists) should be 
consulted and potentially start antiviral therapy prior to discontinuation of any 
immunosuppressant therapy (including investigational drug). Timing of discontinuation from 
the study treatment and of any immunosuppressant therapy/immunomodulatory therapy 
(including investigational product) needs to be based on the recommendations of the consulting 
specialist physician in conjunction with the investigator and medical guidelines/standard of care.  
8.4.10.3. Hypertension
Patients who experience changes in BP (systolic BP at ≥160 mm Hg plus ≥20 mm Hg increase 
from baseline [Week 0; Visit 2]; and/or diastolic BP at ≥100 mm Hg plus ≥10 mm Hg increase 
from baseline) on 2 consecutive visits are to receive intervention for the management of 
hypertension.  Intervention could include the maximal intervention of withholding the dose of 
investigational product and/or the introduction of antihypertensive agent(s) as medically 
appropriate.  
8.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Appendix 2), blood samples of 
approximately 4 mL each will be collected to determine the serum concentrations of ixekizumab.  
These blood samples for PK analysis are matched to the timing of samples for the assessment of 
immunogenicity.  It is expected that these PK samples will allow sufficient description of 
ixekizumab PK profiles at steady state throughout the study. Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.  
Samples collected for PK analysis will be tested at a laboratory approved by Lilly or its designee.  
Concentrations of immunoreactive ixekizumab in human serum will be determined by a 
validated method.  
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.  
8.6.
Pharmacodynamics
Refer to Section 9.6. 
8.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Appendix 2) where local regulations and ERBs allow.

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Samples will notbe used to create a biobank for conducting unspecified disease or population 
genetic research either now or in the future.  Samples may be used to investigate variable 
response to ixekizumab and to investigate genetic variants and epigenetic changes thought to 
play a role in nonrad-axSpAand/or associated autoimmune/inflammatoryconditions.
Assessment of variable response may include evaluation of AEsor differences in efficacy.  
These studies may include,but are not limited to,axSpA and/or associated 
autoimmune/inflammatoryconditions to evaluate their association with observed response to 
ixekizumab.  
All pharmacogenetic samples will be coded with the patient number.These samples and any 
data generated can be linked back to the patient only by the investigator site personnel.Samples 
will be destroyed according to a process consistent with local regulations.  
Samples will be retained for a maximum of 15 years following the last patient visitfor the study, 
or for a shorter period, iflocal regulations and/orERBs impose shorter time limits, at a facility 
selected by the sponsor.This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in drug development or when the drug is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and,therefore,
cannot be specifically named.However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, candidate gene studies, and epigenetic 
analyses.Regardless of technology utilized genotyping data generated will be used only for the 
specific research scope described here.  
8.8. Biomarkers
CCI
 
  
 
 
  
 
  
 
 
  

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8.8.1. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
against the investigational product(s) as specified in the Schedule of Activities 
(Appendix 2). Immunogenicity will be assessed using a validated assay designed to detect ADA 
in the presence of the investigational product(s).  Antibodies may be further characterized and/or 
evaluated for their ability to neutralize the activity of the investigational product(s).  
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period, if regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
ixekizumab.  
8.9.
Health Economics
Refer to Section 8.1.3.

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9.
Statistical Considerations and Data Analysis
9.1.
Determination of Sample Size
Approximately 300 patients will be randomized at a 1:1:1 ratio in the Blinded Treatment Dosing 
Period (Period 2) to ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W, and placebo.  With 
100 patients per treatment group, this study will have approximately 98% power to test the 
superiority of ixekizumab Q2W to placebo for the ASAS40 at Week 16.  The following 
assumptions were used for the power calculations for ASAS40 response rates at Week 16 
regardless of starting dose:  46% for ixekizumab 80 mg Q2W treatment group and 18% for the 
placebo group.  A 2-sided Fisher’s exact test at the 0.05 level is assumed. These assumptions are 
based on the data from historical clinical studies in nonrad-axSpA patients with objective signs
of inflammation (etanercept, adalimumab, certolizumab, and golimumab [Sieper et al. 2013; 
Dougados et al. 2014; Landewé et al. 2014; Sieper et al. 2015]).    
There is little data from similarly designed 52-week placebo-controlled trials regarding the 
ASAS40 response rate for active and placebo treated patients to guide power estimation at 
Week 52.  Table RHBX.4 provides power estimates to test the superiority of ixekizumab Q2W to 
placebo for the ASAS40 at Week 52, assuming various ASAS40 response rates for ixekizumab 
Q2W and placebo at Week 52. A 2-sided Fisher’s exact test at the 0.05 level is assumed. 
Table RHBX.4.
Power Estimates for Week 52
ASAS40 Response Rates (%) at Week 52
Power (%)
Ixekizumab Q2W
(N = 100)
Placebo
(N = 100)
50
10
99
40
10
99
30
10
93
50
15
99
40
15
97
30
15
66
Abbreviations:  ASAS = Assessment of Spondyloarthritis International Society; N = number of subjects;
Q2W = every 2 weeks.
9.2.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly.  
Continuous data will be summarized in terms of the mean, standard deviation, minimum, 
maximum, median, and number of observations.  Categorical data will be summarized as 
frequency counts and percentages.  
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 

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in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.  
Complete details of the planned analyses will be documented in the SAP.  
9.2.1. General Considerations for Analyses during the Blinded 
Treatment Dosing (Period 2)
Comparisons between each ixekizumab regimen (80 mg Q2W or 80 mg Q4W) and placebo will 
be performed for all analyses in Period 2.  
Period 2 starts at the first injection of study treatment at Week 0 (Visit 2) and ends at Week 52 
(Visit 15) or the ETV (between Weeks 0 and 52).  For patients who are deemed as inadequate 
responders by investigators after Week 16 and for whom the investigator indicates the need to 
use ixekizumab 80 mg Q2W, only data prior to the assignment of modified treatment by 
ixekizumab 80 mg Q2W will be included in the Period 2 primary analyses to avoid falsely 
ascribing benefit from the modified biologic treatment to the initially randomized treatment. For 
patients who are deemed as inadequate responders by investigators after Week 16 and for whom 
the treatment modifications are limited to concomitant medication only, all data from Period 2 
will be included (from time of first injection of study treatment at Week 0 [Visit 2] up to and 
including Week 52 [Visit 15] or the ETV [between Weeks 0 and 52]).  
Baseline will be defined as the last available value before the first injection for efficacy, health 
outcome, and safety analyses.  In most cases, this will be the measure recorded at Week 0 
(Visit 2).  For efficacy measures, if the patient does not take any injection, the last available 
value on or prior to the randomization date will be used.  Change from baseline will be 
calculated as the visit value of interest minus the baseline value. For safety analyses using a 
baseline period, the baseline period is defined as the time from Visit 1 to the date/time of the first 
injection.  
The randomization to treatment groups is stratified by country and screening MRI/CRP status 
(positive MRI and elevated CRP; positive MRI and nonelevated CRP; negative MRI and 
elevated CRP) as described in Section 6.2.  The countries will be categorized into geographic 
regions for analysis.  Geographic regions will be defined in the SAP upon country finalization. 
Unless otherwise specified, the statistical analysis models will adjust for geographic region and 
screening MRI/CRP status.  
Unless otherwise specified, treatment groups of ixekizumab 80 mg Q2W and 80 mg Q4W will 
be analyzed without regard to starting dose.  
The primary analysis method for treatment comparisons of categorical efficacy and health 
outcomes variables at specific time points will be made using a logistic regression analysis with 
treatment, geographic region, and screening MRI/CRP status in the model.  The odds ratio and 
95% confidence intervals (CIs) will be reported.  Treatment difference and 95% CI will also be 
reported.  Secondary analysis will be conducted using a Fisher’s exact test.  

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As a secondary analysis for the primary and major secondary categorical efficacy measures, a 
categorical mixed-effects model of repeated measures (categorical MMRM) estimating the 
percentage of patients achieving response across postbaseline visits may be used.  The model 
will include treatment, geographic region, screening MRI/CRP status, visit, treatment-by-visit as 
fixed factors, as well as the continuous, fixed covariate of baseline value and baseline 
value-by-visit interaction (when appropriate).  The binomial distribution and the logit link will be 
used.  An unstructured covariance matrix will be used to model the within-patient 
variance-covariance errors.  The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom.  The Newton-Raphson with ridging optimization technique will 
be used to aid with convergence. The probability of response, the corresponding 2-sided 95% 
CI, and the p-value for treatment comparisons at Week 16 (Visit 8), Week 52 (Visit 15), and all 
other postbaseline visits will be reported.  
If the unstructured covariance matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure, followed by the heterogeneous autoregressive covariance 
structure, followed by the compound symmetry will be used.  This order is specified according to 
a decreasing number of covariance parameters in the structure.  The sandwich estimator (Diggle 
et al. 1994) for the covariance estimation will be used by specifying the EMPIRICAL option in 
SAS PROC MIXED.  When sandwich estimation is used, the Kenward-Roger approximation for 
denominator degrees of freedom cannot be used.  Instead, DDFM=BETWITHIN option will be 
used to estimate denominator degrees of freedom.  
The primary analyses for continuous efficacy and health outcomes variables will be made using 
MMRM.  A secondary analysis for continuous efficacy and health outcomes variables will be 
made using analysis of covariance (ANCOVA).  
When the MMRM is used, the model will include treatment, geographic region, screening
MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interaction 
as fixed factors.  The covariance structure to model the within-patient errors will be unstructured.  
If the unstructured covariance matrix results in a lack of convergence, the similar approach 
specified above for categorical MMRM will be used.  The Kenward-Roger method will be used 
to estimate the denominator degrees of freedom.  Type III tests for the least-squares (LS) means 
will be used for the statistical comparison; the 95% CI will also be reported. Treatment group 
comparisons with placebo at Week 16 (Visit 8), Week 52 (Visit 15), and all other visits will be 
tested.  
When the ANCOVA is used, the model will include treatment, geographic region, screening
MRI/CRP status and baseline value.  Type III sums of squares for the LS means will be used for 
the statistical comparison; the 95% CI will also be reported.  
The impact of ixekizumab starting dose of 160 mg versus 80 mg on time to onset (focusing on 
Week 4) and treatment response during Blinded Treatment Dosing Period will be summarized 
and evaluated. Details will be specified in the SAP.  
For variables that are not collected at each postbaseline visit, data may exist at visits where the 
variable was not scheduled to be collected due to early discontinuation visits.  In these situations, 

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data from the early discontinuation visit that does not correspond to the planned collection 
schedule will be excluded from the MMRM and Categorical MMRM analyses.  However, the 
data will still be used in other analyses, including shift analyses, change from baseline to last-
observation carried forward (LOCF) or modified baseline observation carried forward (mBOCF) 
endpoint analyses, and other categorical analyses.  
Fisher's exact test will be used for all AE, baseline, discontinuation, and other categorical safety 
data.  Continuous vital sign and laboratory values will be analyzed by an ANCOVA with 
treatment and baseline value in the model.  
Patients who discontinue study treatment after Week 16 will continue to be followed for the 
scheduled visits for safety and efficacy assessment.  The data collected post discontinuation of 
study treatment will be summarized separately.  
9.2.2. General Considerations for Analyses during Period 3 
(Post-Study Follow-Up Period)
For the safety analyses during Period 3, baseline is defined as the last nonmissing assessment on 
or prior to entering Period 3, that is, on or prior to Week 52 (Visit 15) or ETV.  
Safety data collected will be summarized using descriptive statistics.  
9.2.3. Analysis Populations
The following analysis populations will be used; additional analysis populations will be specified 
in the SAP:
Intent-to-Treat Population (ITT): Unless otherwise specified, efficacy and health outcomes 
analyses for Period 2 (Blinded Treatment Dosing Period) will be conducted on the ITT 
population, defined as all randomized patients, even if the patient does not take the assigned 
treatment, does not receive the correct treatment, or otherwise does not follow the protocol.  
Patients will be analyzed according to the treatment to which they were assigned.  
Per-Protocol Set (PPS): In addition, the primary efficacy analysis will be repeated using the 
PPS, which is defined as all randomized patients who are compliant with therapy, who do not
have significant protocol deviations, and whose investigator site does not have significant GCP 
issues that require a report to the regulatory agencies prior to Week 52 (Visit 15).  Compliance 
with therapy is defined to be missing no more than 20% of expected doses, not missing 
2 consecutive doses (all injections at a visit is counted as 1 dose), and not have any occurrence of 
double-dosing (that is, took more injections at the same time point than specified in the protocol) 
during Period 2 (Blinded Treatment Dosing Period).  For patients who are deemed as inadequate 
responders by investigators after Week 16 and for whom the investigator indicates the need for
modified treatment by the use of rescue ixekizumab 80 mg Q2W, the requirements for PPS only 
apply during the treatment period prior to the assignment of modified treatment by ixekizumab 
80 mg Q2W.
Significant protocol deviations will be described in the SAP.  Patients will be analyzed according 
to the treatment to which they were assigned.  

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Safety Population: Safety analyses for Period 2 will be conducted on the safety population, 
defined as all randomized patients who received at least 1 dose of study treatment.  Patients will 
be analyzed according to the treatment to which they were assigned in that period.  
Follow-up Population:  Safety analyses for Period 3 (Post-Study Follow-Up Period) will be 
conducted on the follow-up population, defined as all randomized patients who received at least 
1 dose of study treatment and have entered the Post-Study Follow-Up Period.  Patients will be 
analyzed according to the treatment they received before entering the follow-up period.  
9.2.4. Missing Data Imputation
In accordance with precedent set with other Phase 3 axSpA trials (van der Heijde et al. 2006; 
Inman et al. 2008), the following methods for imputation of missing data will be used:  
9.2.4.1.
Nonresponder Imputation for Clinical Response
Analysis of categorical efficacy and health outcomes variables will be assessed using a 
nonresponder imputation (NRI) method.  Patients will be considered a nonresponder for the NRI 
analysis if they do not meet the clinical response criteria or have missing clinical response data at 
the primary analysis time point.  All nonresponders at Week 16 (Visit 8), as well as all patients 
who discontinue study treatment at any time prior to Week 16 for any reason, will be defined as 
nonresponders for the NRI analysis at Week 16.  Similarly, all nonresponders at Week 52 
(Visit 15), as well as patients who discontinue study treatment at any time prior to Week 52 for 
any reason, will be defined as nonresponders for the NRI analysis at Week 52.  Patients who are 
deemed as inadequate responders by the investigator after Week 16 but remain on blinded study 
treatment and only have modifications in concomitant medications will not be automatically 
imputed as nonresponders.  However, patients who discontinue originally assigned blinded study 
treatment and use rescue ixekizumab 80 mg Q2W will be analyzed as nonresponders for the 
Week 52 analysis.  Randomized patients without at least 1 postbaseline observation will also be 
defined as nonresponders for the NRI analysis.  
The NRI may be applied at any time point specified for analysis.  
9.2.4.2.
Modified Baseline Observation Carried Forward
An mBOCF analysis will be performed on efficacy and health outcomes variables in the major 
and other secondary objectives.  For patients discontinuing study drug due to an AE, the baseline 
observation will be carried forward to the corresponding time point for evaluation.  For patients 
discontinuing study drug for any other reason, the last nonmissing observation before 
discontinuation will be carried forward to the corresponding time point for evaluation, with the 
following exception:  for patients who discontinue originally assigned blinded study treatment 
and use rescue ixekizumab 80 mg Q2W, the last nonmissing observations prior to the use of 
rescue ixekizumab 80 mg Q2W will be carried forward to subsequent time points.  Randomized 
patients without at least 1 postbaseline observation will not be included for evaluation with the 
exception of patients discontinuing study treatment because of an AE.  

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9.2.4.3.
Last Observation Carried Forward
A LOCF analysis will be performed on continuous efficacy and health outcomes variables in the 
major secondary objectives.  This approach is identical to the mBOCF approach, with 
1 exception:  for patients discontinuing study drug because of an AE, the last nonmissing 
postbaseline observation before discontinuation will be carried forward to the corresponding 
endpoint for evaluation.  For patients who discontinue originally assigned blinded study 
treatment and use rescue ixekizumab 80 mg Q2W, their last nonmissing observations prior to the 
use of rescue ixekizumab 80 mg Q2W will be carried forward to subsequent time points. 
Randomized patients without any postbaseline observation will not be included for evaluation.  
9.2.5. Adjustment for Multiple Comparisons
The primary outcome of ASAS40 at Week 16 will be tested for ixekizumab 80 mg Q2W versus 
placebo at a 2-sided α=0.05.  The primary outcome of ASAS40 at Week 52 will also be tested 
for ixekizumab 80 mg Q2W versus placebo at a 2-sided α=0.05.  Because this study has a 
different primary endpoint for different regulatory agencies, the significances of both primary 
endpoints will not be required in order for the study to be considered successful. No multiplicity 
adjustment will be made for the 2 primary endpoints. The comparison of ASAS40 for 
ixekizumab 80 mg Q4W versus placebo at Weeks 16 and Week 52 and the major secondary 
objectives (Section 3) will be tested using an appropriate multiple testing approach providing 
strong control of the familywise error rate (for the primary and major secondary tests) at a 2-
sided α=0.05.  Details of the specific testing methodology (including testing order, 
interrelationships, type I error allocation, and the associated propagation) will be specified in the 
SAP.  
There will be no adjustment for multiple comparisons for any other analyses.  
9.3.
Treatment Group Comparability
9.3.1. Patient Disposition
All patients who discontinue from the study treatment and the study will be identified, and the 
extent of their participation in the study will be reported.  
Patient disposition will be summarized with reasons for discontinuation.  The reasons for 
discontinuation during Period 2 (Blinded Treatment Dosing Period) will be compared between 
treatment groups using Fisher’s exact test.  
9.3.2. Patient Characteristics
Patient characteristics and baseline clinical measures will be summarized.  Baseline 
characteristics will include sex, age, age category, weight, body mass index, race, geographic 
region, country, baseline disease activity (BASDAI), duration of disease, HLA-B27 positivity, 
baseline CRP (% of nonelevated or elevated), screening MRI status, screening MRI/CRP status,
and history of extra-axial disease manifestations.  Baseline clinical measurements may include 
ASDAS, CRP, BASFI, BASMI, chest expansion, Fatigue NRS, Patient Global NRS, total back 

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pain, spinal pain at night, spinal pain, inflammation (mean of questions 5 and 6 of BASDAI), 
MASES, enthesitis SPARCC, TJC, and SJC.  
Treatment group comparisons in Period 2 (Blinded Treatment Dosing Period) will be conducted 
using Fisher’s exact test for categorical data and an ANOVA with treatment as a factor for 
continuous data.  
9.3.3. Concomitant Therapy
Previous and concomitant medications will be summarized for patients who enter treatment 
period and will be presented by WHO Anatomic Therapeutic Class Level 4 and WHO preferred 
term.  Concomitant DMARDs, concomitant oral corticosteroids, and concomitant NSAIDs will 
also be summarized.  Treatment group comparisons in Period 2 (Blinded Treatment Dosing 
Period) will be conducted using Fisher’s exact test.  
9.3.4. Treatment Compliance
Treatment compliance with investigational product will be summarized for patients who enter 
the treatment period.  A patient will be considered overall compliant for treatment period if 
he/she is missing no more than 20% of the expected doses, does not miss 2 consecutive doses,
and does not over-dose (that is, take more injections at the same time point than specified in the 
protocol).  
Proportions of patients compliant by visit and overall will be compared between treatment 
groups during Period 2 (Blinded Treatment Dosing Period) using Fisher’s exact test.  
9.4.
Primary and Secondary Analyses
9.4.1. Primary Analyses
The primary analysis, the proportion of patients with ASAS40 at Week 16 or at Week 52 treated 
with ixekizumab compared with placebo, will be based on the ITT population.  In addition, an 
analysis of the PPS population will be used to support the primary efficacy analysis.  
Treatment comparisons between each ixekizumab treatment group and placebo in the proportion 
of patients achieving an ASAS40 response at Week 16 (Visit 8) or Week 52 (Visit 15) will be 
analyzed using the logistic regression model defined in Section 9.2.1.  Missing data will be 
imputed using the NRI method described in Section 9.2.4.  
Secondary analyses for ASAS40 will be conducted using Categorical MMRM and Fisher’s exact 
test as described in Section 9.2.1.  
9.4.2. Secondary Analyses
9.4.2.1.
Major Secondary Analyses
The major secondary analyses at Weeks 16 and 52 will be based on the ITT population for 
Blinded Treatment Dosing Period (Period 2).  The major secondary comparisons will be based 
on the multiple testing procedures described in Section 9.2.5.  Treatment comparisons in the 

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proportion of patients achieving a categorical response at Week 16 (Visit 8) and Week 52 
(Visit 15) will be analyzed using the logistic regression model defined in Section 9.2.1. For 
categorical responses, missing data will be imputed using the NRI method described in 
Section 9.2.4.  Treatment comparisons in the continuous measures will be analyzed using the 
MMRM model defined in Section 9.2.1.  
Table RHBX.5 summarizes the primary and major secondary outcomes and analysis methods.  
All analyses will be performed based on ITT population unless otherwise specified.  

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Table RHBX.5.
Primary and Major Secondary Outcome Analyses
Outcomes Measure
Primary Analysis Method
Secondary Analysis Method
ASAS40 at Week 16 (primary efficacy 
outcome for regulatory agencies who 
accept Week 16 as the primary 
endpoint)
Logistic regression analysis 
with NRI 
Categorical MMRM
Fisher’s exact test with NRI
Logistic regression analysis with NRI on 
PPS 
ASAS40 at Week 52 (primary efficacy 
outcome for regulatory agencies who 
require Week 52 as the primary 
endpoint)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
Logistic regression analysis with NRI on 
PPS
Change from baseline in ASDAS at
Week 16 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in ASDAS at 
Week 52 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in BASFI at 
Week 16 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in BASFI at 
Week 52 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
ASDAS inactive disease at Week 16 
(major secondary outcome)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
ASDAS inactive disease at Week 52 
(major secondary outcome)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
Change from baseline in MRI of the 
SIJ [SPARCC Score] at Week 16 
(major secondary outcome)
ANCOVA with observed 
case analysisa
Secondary analysis maybe specified in 
SAP
Percent of patients without clinically 
meaningful changes in background 
therapy at Week 52 (major secondary 
outcome)
Logistic regression analysis
Fisher’s exact test
Abbreviations:  ANCOVA = analysis of covariance; ASAS = Assessment of Spondyloarthritis International Society; 
ASDAS = Ankylosing Spondylitis Disease Activity Score; BASFI = Bath Ankylosing Spondylitis Functional 
Index; LOCF = last observation carried forward; mBOCF = modified baseline observation carried forward; 
MMRM = mixed-effects model of repeated measures; MRI = magnetic resonance imaging; NRI = nonresponder 
imputation; PPS = per-protocol set; SAP = statistical analysis plan; SIJ = sacroiliac joints; SPARCC = 
Spondyloarthritis Research Consortium of Canada Score.
a
Only patients with both baseline and Week 16 MRI scores will be included in the observed case analysis.  
9.4.2.2.
Other Secondary Efficacy Analyses
There will be no adjustment for multiple comparisons.  Analyses will be conducted for the other
secondary efficacy objectives defined in Section 3.  Specific details of analyses will be specified 
in the SAP.  
9.4.2.2.1. Period 2 (Blinded Treatment Dosing Period)
Unless otherwise specified, the other secondary analyses during Period 2 will be based on the 
ITT population.  

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Treatment comparisons in the proportion of patients achieving a categorical response at specified 
time point will be analyzed using the logistic regression model defined in Section 9.2.1. Missing 
data will be imputed using the NRI method described in Section 9.2.4. 
For all continuous efficacy variables that are collected at repeated visits, treatment group 
comparisons will be analyzed using the MMRM model defined in Section 9.2.1.  No imputation 
methods are applied to MMRM analysis.  Additional analysis will be conducted using ANCOVA 
model defined in Section 9.2.1.  Missing data will be imputed by the mBOCF method as 
described in Section 9.2.4.  
9.4.3. Other Exploratory Analyses
Details about exploratory analyses will be included in the SAP or appropriate biomarker analysis 
plan.  
9.5.
Safety Analyses
Safety will be assessed by summarizing and analyzing AEs including adjudicated 
cerebrocardiovascular events, laboratory analytes including neutrophil counts, QIDS-SR16, 
C-SSRS, and vital signs.  The duration of treatment exposure will also be summarized.  
For Period 2 (Blinded Treatment Dosing Period), safety data will be summarized for the safety 
population.  Treatment group comparisons on categorical safety data will be performed using 
Fisher’s exact test as described in Section 9.2.1. Continuous safety data will be analyzed by an 
ANCOVA model as described in Section 9.2.1.  
For patients who are deemed as inadequate responders by investigators after Week 16 and for 
whom the investigator indicates the need for modified treatment by the use of rescue ixekizumab 
80 mg Q2W, safety data collected after initiation of modified treatment by ixekizumab 80 mg 
Q2W will be summarized separately.
Safety data collected after study treatment discontinuation will be summarized separately.
For post-study follow-up (Period 3), safety data will be summarized according to the treatment 
patients were on prior to entering the Post-Study Follow-Up Period. 
The categorical safety measures will be summarized with incidence rates.  The mean change of 
the continuous safety measures will be summarized by visits.  
Further details will be described in the SAP.  
9.5.1. Adverse Events
Adverse events are classified based upon the Medical Dictionary for Regulatory Activities 
(MedDRA).  A treatment-emergent adverse event (TEAE) is defined as an event that first 
occurred or worsened in severity after baseline and on or prior to the date of the last visit within 
the treatment period.  Both the date/time of the event and the date/time of the injection are 
considered when determining TEAEs.  TEAEs will be assigned to the treatment period in which 
they first occurred or worsened.  A follow-up emergent adverse event (FEAE) is defined as an 

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event that first occurred or worsened in severity after the date of Week 52 (Visit 15) or the ETV.  
For events that are gender specific, the denominator and computation of the percentage will 
include only patients from the given gender.  
An overall summary of AEs will be provided for the treatment period, including the number and 
percentage of patients who experienced TEAE, TEAE by maximum severity, death, SAE, TEAE 
related to study drug, discontinuations from the treatment due to an AE, and treatment-emergent 
AESI.  TEAEs (all, by maximum severity, and TEAEs possibly related to study drug by the 
investigator), SAEs including deaths, AEs that lead to treatment discontinuation will be 
summarized and analyzed by MedDRA system organ class (SOC) and preferred term (PT).  
In addition to general safety parameters, safety information on specific topics of AESIs will also 
be presented.  Potential AESI will be identified by a standardized MedDRA query (SMQ) or a 
Lilly defined MedDRA preferred term listing.  
FEAEs, SAEs including deaths, AEs that lead to study discontinuation will be summarized for 
Period 3.  
9.5.2. Clinical Laboratory Tests
Laboratory assessments will be presented as mean changes from baseline and as incidence of 
treatment-emergent abnormal, high, or low laboratory values (see below).  Shift tables will be 
presented for selected parameters.  

For categorical lab tests: 
o
Treatment-emergent abnormal value = a change from normal at all baseline visits 
to abnormal at any time postbaseline

For continuous lab tests: 
o
Treatment-emergent high value = a change from a value less than or equal to the 
high limit at all baseline visits to a value greater than the high limit at any time 
postbaseline
o
Treatment-emergent low value = a change from a value greater than or equal to 
the low limit at all baseline visits to a value less than the low limit at any time 
postbaseline
9.5.3. Vital Signs, Physical Findings, and Other Safety Evaluations
Vital signs will be presented as mean changes from baseline and as incidence of 
treatment-emergent high or low values (see below) and will be summarized both pre- and 
postdose at Week 0 (Visit 2) and postbaseline visits, as applicable.  

For treatment-emergent high and low:  
o
A treatment-emergent high result is defined as a change from a value less than 
or equal to the high limit at baseline to a value greater than the high limit at 
any time that meets the specified change criteria during the treatment period.

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o
A treatment-emergent low result is defined as a change from a value greater 
than or equal to the low limit at baseline to a value less than the low limit at 
any time that meets the specified change criteria during the treatment period.
The maximum postbaseline QIDS-SR16 total score will be summarized by treatment group, and 
a shift table will be produced for the change from baseline in QIDS-SR16 total score category.  
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent, based 
on the C-SSRS, will be listed by patient.
9.6.
Pharmacokinetic/Pharmacodynamic/Immunogenicity Analyses
Observed ixekizumab serum concentrations will be summarized by treatment group, visits, and 
corresponding time when sampling occurred.  
As appropriate, the PK and the exposure-response relationship between ixekizumab exposure 
and clinically important efficacy measures (for example, ASAS20 or ASAS40) may be explored 
using graphical methods and/or a modeling approach.  Pharmacokinetic and/or exposure-
response data from this study may be combined with existing PK and/or exposure-response data 
from other studies, if considered appropriate.  
If a trend or statistically significant difference between the ixekizumab dose cohorts and/or the 
placebo cohort is noted in any safety endpoint, the exposure relationship for this endpoint may be 
explored graphically.  
In addition, the potential impact of immunogenicity on ixekizumab exposure and/or efficacy 
responses may be evaluated by graphical assessments, as appropriate, to compare drug exposure 
or efficacy responses between ADA negative and ADA positive patients at corresponding visits, 
or before and after ADA development for patients who developed ADA.  Both 
treatment-emergent only and all ADA positive/negative patients may be explored.  A similar 
approach may be taken if patients become NAb positive.  The effect of immunogenicity may be 
evaluated as a covariate in the population PK and exposure-response analyses, if applicable.  
9.7.
Other Analyses
9.7.1. Health Economics
There will be no adjustment for multiple comparisons.  Analyses will be conducted for the other 
secondary health outcomes objectives as defined in Section 3.  
Period 2 (Blinded Treatment Dosing Period):  
Unless otherwise specified, the other secondary analyses during Period 2 will be based on the 
ITT population.  
Treatment comparisons in the proportion of patients achieving a categorical response at a 
specified time point will be analyzed using the logistic regression model defined in Section 9.2.1. 
Missing data will be imputed using the NRI method described in Section 9.2.4. 

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For all continuous health outcomes variables that are collected at repeated visits, treatment group 
comparisons will be analyzed using the MMRM model defined in Section 9.2.1.  No imputation 
methods are applied to MMRM analysis.  Additional analysis will be conducted using ANCOVA 
model defined in Section 9.2.1.  Missing data will be imputed by the mBOCF method as 
described in Section 9.2.4. 
Additional analyses of health outcomes measures will be specified in the SAP.  
9.7.2. Subgroup Analyses
Subgroup analysis will be conducted for ASAS40 and selective major secondary outcomes 
(defined in SAP) at Week 16 (Visit 8) and Week 52 (Visit 15) using the ITT population.  
Subgroup analyses may be conducted based on gender, age category, race, baseline disease 
severity, country, geographic region, baseline CRP status, baseline MRI status, screening
MRI/CRP status, and presence of HLA-B27.  
For ASAS40, a logistic regression model with treatment, subgroup, and the interaction of 
subgroup-by-treatment included as factors will be used.  The subgroup-by-treatment interaction 
will be tested at the significance level of 0.10.  Treatment group differences will be evaluated 
within each category of the subgroup using Fisher’s exact test, regardless of whether the 
interaction is statistically significant.  Missing data will be imputed using NRI as described in 
Section 9.2.4.  If any group within the subgroup is <10% of the total population, only summaries 
of the efficacy data will be provided (that is, no inferential testing).  
For continuous efficacy outcome (eg, mean change from baseline in ASDAS), an ANCOVA 
model with treatment, baseline value, subgroup, and the interaction of subgroup-by-treatment 
will be used.  The subgroup-by-treatment interaction will be tested at the significance level of 
0.10.  Treatment group differences will be evaluated within each category of the subgroup using 
an ANCOVA model with treatment and baseline value as a covariate, regardless of whether the 
interaction is statistically significant.  Missing data will be imputed using mBOCF method as 
described in Section 9.2.4. 
Detailed description of the subgroup variables will be provided in the SAP.  Additional subgroup 
analyses on efficacy or subgroup analyses on safety may be performed as deemed appropriate 
and necessary.  
9.7.3. Immunogenicity
The analyses of ADA effects will be conducted on all evaluable patients within the defined 
safety population.  Evaluable patients will be defined as either a) patients with an evaluable 
baseline sample and at least 1 evaluable postbaseline sample (that is, sample after administration 
of study drug) or b) patients with no evaluable baseline sample whose evaluable postbaseline 
samples were all ADA negative.  
A treatment-emergent positive anti-drug antibody (TE-ADA+) patient will be defined as any 
occurrence of a greater than or equal to 4-fold or 2 dilution increase in immunogenicity titer over 

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the baseline titer.  This is equivalent to an increase in titer to ≥1:10, in the case of a negative 
result at baseline.  
The frequency and percentage (incidence) of patients with positive, negative, or inconclusive 
ADA at baseline and postbaseline (and NAbs at baseline and postbaseline) will be summarized 
by treatment group.  Patients who are TE-ADA positive, TE-ADA persistent positive, and 
TE-ADA transient positive will also be summarized.  
The potential impact of immunogenicity on ixekizumab exposure and/or efficacy responses will 
be evaluated, as appropriate.  
Assessment of immunogenicity with respect to safety will include comparison of patients who 
experience TEAEs of systemic allergy/hypersensitivity and of injection-site reactions and who 
also develop treatment-emergent anti-ixekizumab antibody positivity with patients who 
experience the same types of TEAEs but who remain treatment-emergent anti-ixekizumab 
antibody negative.  Anti-ixekizumab antibody titers will also be evaluated in anti-ixekizumab 
antibody positive patients who experience these events.  
9.8.
Interim Analyses
An interim database lock and unblinding will occur, and the analysis will be performed at the 
time (that is, a cut-off date) the last patient completes Visit 15 (Week 52) or ETV.  This interim 
database lock will include all data collected by the cut-off date including follow-up data from 
patients who have begun the Post-Study Follow-Up Period (Period 3).  Because the study will 
still be ongoing for the Post-Study Follow-Up Period at the time of this database lock, the 
analysis will be referred to as an interim analysis.  The analyses from the Week 52 lock will be 
treated as a primary analysis because all primary and major secondary study objectives will be 
assessed at this time.  
In addition to the Week 52 lock, an internal Lilly data review committee or a data monitoring 
committee not in direct contact with the study sites may have access to unblinded data once all 
patients complete the Week 16 time point for regulatory submission or for a business purpose. 
The study will not be terminated early on the basis of efficacy assessment following the Week 16
analyses. Information that may unblind the study during the Week 16 analysis will not be
reported to study sites or blinded study team until after the study has been unblinded at the 
Week 52 lock.  All investigators, patients, and study team will remain blinded to treatment 
assignment until after all patients complete Week 52 or are discontinued from the study.
Unblinding details are specified in the blinding/unblinding plan.  

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10. Study Governance Considerations
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process
10.1.1. Informed Consent
The investigator is responsible for ensuring:  

that the patient understands the potential risks and benefits of participating in 
the study.

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of 
investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the trial.
10.1.2. Ethical Review
The investigator must give assurance that the ERB was properly constituted and convened as 
required by International Conference on Harmonisation (ICH) guidelines and other applicable 
laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on GCP.  
The study site’s ERB(s) will be provided with the following:  

the current IB and updates during the course of the study

ICF

relevant curricula vitae
10.1.3. Regulatory Considerations
This study will be conducted in accordance with:  

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines.

applicable ICH GCP Guidelines.

applicable laws and regulations.
Some of the obligations of the sponsor may be assigned to a third-party.  

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10.1.4. Investigator Information
Licensed physicians with a specialty in rheumatology (for Japan:  specialty in rheumatology or 
orthopedic surgery) will participate as investigators in this clinical trial.  
10.1.5. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.  
10.1.6. Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.  
The CSR coordinating investigator will be selected by the sponsor.  If this investigator is unable 
to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.  
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.  
10.2. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection.

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.  

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The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.  
10.2.1. Data Capture System
An electronic data capture system and an electronic source system will be used in this 
study. The site maintains a separate source for the data entered by the site into the 
sponsor-provided electronic data capture system. Some or all of a patient’s data will be directly 
entered into the eCRF at the time that the information is obtained. In instances where direct data 
entry is not used, the site will maintain source documentation in the trial files, and the patient’s 
data will be transcribed into the eCRF. Paper documentation provided by the patient will serve 
as the source document, including a study drug administration log and an event-medication 
diary, that will be identified and documented by each site in that site’s study file.
In this study, patient-rated scales/questionnaires will be collected at office visits (or even at 
home) directly via an electronic patient-reported outcome (ePRO) tablet device as part of an 
ePRO/Clinical Outcome Assessment (COA) system. Data entered into the ePRO/COA system 
will serve as the source data.  The ePRO records are stored at a third party site.  Investigator sites 
will have continuous access to the source data during the study and will receive an archival copy 
at the end of the study for retention.  Any data collected within the ePRO instrument will serve 
as the source data and will be identified and documented by each site in that site’s study file.  
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system. Data will subsequently be transferred from the central 
vendor to the Lilly generic labs system.  
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.  
10.3. Study and Site Closure
10.3.1. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.  
10.3.2. Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.  

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product
AESI
adverse events of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AS
ankylosing spondylitis:  currently referred to as radiographic axial spondyloarthritis 
(rad-axSpA)
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASAS
Assessment of Spondyloarthritis International Society
ASAS-HI
Assessment of Spondyloarthritis International Society Health Index
AST
aspartate aminotransferase
axSpA
axial spondyloarthritis:  a single disease entity with a subset defined by the presence of 
clear structural damage (rad-axSpA) and a subset with no clear structural damage as 
defined by conventional x-rays (nonrad-axSpA)
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASDAI50
Bath Ankylosing Spondylitis Disease Activity Index 50
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BCG
Bacillus Calmette- Guérin
bDMARD
biological disease-modifying antirheumatic drug

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Term
Definition
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BP
blood pressure
CD
Crohn’s disease
cDMARD
conventional disease-modifying antirheumatic drug
CEC
clinical events committee
cGMP
current Good Manufacturing Practices
CI
confidence interval
COA
Clinical Outcome Assessment
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
COX-2
cyclooxygenase-2
CRF/eCRF
case report form/electronic case report form
CRP
C-reactive protein
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
DMARD
disease-modifying antirheumatic drug
ECG
electrocardiogram
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life–5 Dimensions 5-Level
ETV
early termination visit
FEAE
follow-up emergent adverse event

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Term
Definition
FSH
follicle stimulating hormone
GCP
good clinical practice
HBC
hepatitis C virus
HBcAb+
anti-hepatitis B core antibody positive
HBsAg+
hepatitis B virus surface antigen
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HIVAb
human immunodeficiency virus antibody
HLA
human leukocyte antigen
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IBD
inflammatory bowel disease (eg, Crohn’s disease and ulcerative colitis)
IBP
inflammatory back pain
ICF
informed consent form
ICFD
International Classification of Functioning Disability and Health
ICH
International Conference on Harmonisation
IgG4
immunoglobulin G subclass 4
IL-17A
interleukin-17A, also known as IL-17
inadequate responder
patient who, as determined by the investigator, shows inadequate improvement in 
disease signs or symptoms or a failure to adequately respond following treatment with a 
therapeutic agent
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB/ERB
Investigational Review Board/Ethical Review Board

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Term
Definition
ITT
intent-to-treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web-response system
JSEQ
Jenkins Sleep Evaluation Questionnaire
LOCF
last observation carried forward
LS
least-squares
MAb
monoclonal antibody
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
mBOCF
modified baseline observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
mixed-effects model of repeated measures
mNY
modified New York criteria
MOA
mechanism of action
MRI
magnetic resonance imaging
MTX
methotrexate
NAb
neutralizing anti-drug antibody
nonrad-axSpA
nonradiographic axial spondyloarthritis:  a subset of axSpA in which there is no clear 
structural damage as defined by conventional radiographic imaging.
NRI
nonresponder imputation
NRS
numeric rating scale
NSAIDS
nonsteroidal anti-inflammatory drugs
OMERACT
outcome measures in rheumatology
PK/PD
pharmacokinetics/pharmacodynamics
PPD
purified protein derivative

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Term
Definition
PPS
per-protocol set:  The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
Ps
psoriasis
PsA
psoriatic arthritis
PT
preferred term
Q2W
every 2weeks 
Q4W
every 4 weeks
QIDS-SR16
Quick Inventory of Depressive Symptomatology–Self-Report (16 Items)
RA
rheumatoid arthritis
rad-axSpA
radiographic axial spondyloarthritis:  a subset of axSpA in which there is evidence of 
disease features on radiographic imaging
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SF-36 MCS
Short Form 36 mental component score
SF-36 PCS
Short Form 36 physical component score
SIJ
sacroiliac joints
SJC
swollen joint count
SOC
system organ class
SpA
spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SPARCC SSS
Spondyloarthritis Research Consortium of Canada–SIJ Structural Score
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis

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Term
Definition
TE-ADA
treatment-emergent anti-drug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment.
TJC
tender joint count
TNF inhibitor
tumor necrosis factor inhibitor 
TPO
third-party organization
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
VAS
visual analog scale
WBC
white blood count
WHO
World Health Organization
WPAI-SpA
Work Productivity Activity Impairment—Spondyloarthritis

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Appendix 2.
Schedule of Activities

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regularly scheduled visit is longer than 12 weeks after their last investigational study medication dose are not required to enter into the Post-Study Follow-Up 
Period (Period 3).  
b
Demographics includes recording of year of birth, sex, race, and ethnicity.
c
One complete physical examination (excluding pelvic, rectal examination) will be performed at screening.  All physical examinations throughout the study are 
to include a symptom-directed physical as well as examination of heart, lungs, abdomen, eyes and visual examination of the skin.
d
Patients are to be resting for a minimum of 5 minutes prior to vital sign collection.  Blood pressure and pulse will be measured in sitting position and will be 
recorded before IP dosing at all visits (Section 8.4.2).  For safety monitoring, patients are to remain under observation for at least 1 hour after dosing at 
Week 0 (Visit 2) and at any visit on or after Week 16 in which a patient receives the initial injection of ixekizumab as rescue therapy.  This initial injection of 
rescue ixekizumab will be administered by the patient or caregiver at the clinical site to allow for observation for any AEs and for collection of postinjection 
BP and pulse measurements approximately 1 hour after administration of the IP (Section 8.4.2).  
e
Habits include recording of caffeine, alcohol, and tobacco consumption.
f
A posterior anterior chest x-ray will be taken locally at screening unless one has been obtained within 6 months of screening (Visit 1) (provided the x-ray 
and/or report are available for review).  Refer to Section 8.4.6 for more details.
g
Refer to rescreening guidance as appropriate (Section 5.3).
h
Evaluation includes both historical events as well as preexisting conditions which are assessed after Visit 2 to determine any treatment-emergent worsening of 
preexisting conditions.
i
Patients need to be asked about presence of eye symptoms; if eye symptoms are present then an eye examination is required.  Refer to Section 8.4.5 for 
specific instructions.
j
Refer to Section 6.1.1 for specific IP administration instructions.  Note that at or after Week 16, treatment modifications may occur per the investigator 
decision by a change in concomitant medication and/or a decision to use ixekizumab 80 mg Q2W.  The treatment modification of ixekizumab 80 mg Q2W 
requires that the dose is administered on site; patients to stay an additional hour for on-site observation after the initial injection of rescue ixekizumab therapy. 
k
The Week 16 MRI may be collected up to 10 days prior to Week 16 (Visit 8).  It is strongly recommended that the Week 16 MRI be collected prior to the 
Week 16 (Visit 8) dosing.  If patients discontinue study participation prior to Week 16, MRI of the SIJ should be collected at ETV.  For ETV, MRI 
requirements are dependent on the timing of study discontinuation.  If discontinuation is:

at or before Visit 5, no MRI is required at ETV.  

after Visit 5 up to and including Visit 8 (Week 16), MRI is required at ETV. 

after Visit 8, MRI is required only if ETV occurs on or after Visit 12.
l
An x-ray of the SIJ will be performed during the Screening Period (Period 1) unless an x-ray taken within 6 months prior to screening is available and of good 
quality.  All x-rays require central reading ONLY, regardless of date taken.  Central reading will define eligibility using the mNY criteria to exclude patients 
with definite sacroiliitis on x-ray.
m Cervical and lumbar spine only; serves as baseline for potential later assessments of structural changes. X-ray does not need to be repeated if one is available 
that was taken ≤3 months prior to screening (Visit 1; refer to Sections 5.2 and 5.3) and has passed quality assessment by central reading vendor.
n
A Self-Harm Follow-Up Form must be completed for each discrete event identified on the Self-Harm Supplement Form.
o
HLA-B27 test will be performed centrally.
p
Approval from the Lilly clinical research physician or clinical research scientist must be obtained before a CRP retest is permitted.  If the CRP lab is retested, 
the most recent value will be used for randomization.

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q
TB test(s) include PPD, QuantiFERON®-TB Gold, and T-SPOT®.  See Section 8.4.6 for detailed description of TB testing.  In countries where the 
QuantiFERON-TB Gold test or T-SPOT is available, either test may be used instead of the PPD TB test.  The QuantiFERON-TB Gold test may be performed 
locally or centrally; the T-SPOT must be performed locally.  PPD tests must be read 2 to 3 days after Visit 1.
r
For female patients ≥40 and <60 years of age who have had a cessation of menses for at least 12 months, an FSH test will be performed to confirm 
nonchildbearing potential (FSH ≥40 mIU/mL).  FSH test will be performed centrally.
s
All patients will be tested for HBV at screening.  Patients who are HBcAb+ at screening, regardless of HBsAb status, will have a serum HBV DNA obtained 
by the central laboratory. Patients who are found to be HBV DNA positive (detectable) at screening will be excluded from the trial. Patients who are HBV 
DNA negative (undetectable) may be enrolled into the study with required HBV DNA monitoring every 3 months during treatment and 12 weeks after the last 
dose of ixekizumab.  If the result of the HBV DNA testing is positive, the patient must be discontinued from the study treatment and should receive 
appropriate follow-up medical care (refer to Section 8.4.10.2 for further information regarding the timing of discontinuation).
t
Only for females of childbearing potential.  Serum pregnancy test will be done at Visit 1 only and will be performed centrally.  Patients determined to be 
pregnant will be discontinued from treatment and will no longer be administered investigational product (see Section 7.1).  Patients will undergo urine 
pregnancy testing at the clinic during designated scheduled visits through Week 52.  Additional urine pregnancy testing can be performed at the investigator’s 
discretion.  If required per local regulations, urine testing for pregnancy may occur at intervals as required during the study treatment period and/or follow-up 
period.
u
For the fasting lipid profile patients are to not eat or drink anything except water for 12 hours prior to test.
v
Where collection is allowed by local regulations.
w Only serum and plasma are collected at this visit..
x
Immunogenicity samples may also be analyzed for ixekizumab serum concentration to facilitate in the interpretation of immunogenicity data.  An additional 
blood sample will be collected, when possible, for any patient who experiences a potential systemic allergic/hypersensitivity reaction during the study as 
judged by the investigator.
y
PK samples are to be collected before investigational product injection.
z
The Week 52 MRI may be collected up to 10 days prior to Week 52 (Visit 15).
aa Patients who have taken at least 1 study dose and who discontinue study treatment prior to Week 16 or study participation (regardless of timing) are to 
complete an ETV and enter into post-study follow-up for at least 12 weeks after the ETV date or the last regularly scheduled visit. Patients whose ETV or last 
regularly scheduled visit is longer than 12 weeks after their last investigational study medication dose are not required to enter into the Post-Study Follow-Up 
Period (Period 3).  Patients who complete the study through Week 52 and who are not entering into Study RHBY are to enter into the Post-Study Follow-Up 
Period (Period 3). Visits 801 and 802 are scheduled at 4 and 12 weeks (respectively) after the date of the last patient visit.  Visit 803 will occur if a patient’s 
neutrophil counts have not returned to the criteria defined in Section 8.4.10.1.
bb Weight is only captured on eCRF at V2, V8, V10, V15, and/or ETV.  Body weight collected at other visits is used only for calculation of creatinine 
clearance.
cc If not completed at Visit 2, the sample should be collected as soon as possible at the next scheduled visit.
dd If MRI is conducted on the same day as study visit, ensure that any scales/questionnaires are completed prior to administering any premedication to facilitate 
patient undergoing an MRI (for example, morphine or equivalent for significant pain as judged by the investigator or a benzodiazepine for claustrophobia).  
ee For all patients, screening MRI of the SIJ must be completed ≤30 days prior to randomization (refer to Sections 5.3 and 5.4).

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Appendix 3.
Clinical Laboratory Tests 
Clinical Laboratory Tests
Hematologya:
Serum Chemistrya:
Hemoglobin
   Sodium
Hematocrit
   Potassium
Erythrocyte count (RBC)
   Bicarbonate
Mean cell volume (MCV)
   Chloride
Mean cell hemoglobin concentration (MCHC)
   Phosphorus
Leukocytes (WBC)
   Total bilirubin
Platelets
   Direct bilirubin
Absolute counts of: 
   Alkaline phosphatase
Neutrophils, segmented
   Alanine aminotransferase (ALT/SGPT)
Neutrophils, juvenile (bands)
   Aspartate aminotransferase (AST/SGOT)
Lymphocytes
   Blood urea nitrogen (BUN)
Monocytes
   Uric acid
Eosinophils
   Creatinine
Basophils
   Calcium
Urinalysis (dipstick)a:
   Glucose
Color
   Albumin
Specific gravity
   Cholesterol (total)
pH
   Total protein
Protein
   Calculated creatinine clearance
Glucose
   Creatine phosphokinase (CPK)
Ketones
   Triglycerides
Bilirubin
   Gamma-glutamyl transferase (GGT)
Urobilinogen
Blood
Lipid Panelc
Nitrite
   Low density lipoprotein (LDL)
Urine creatinine
   High density lipoprotein (HDL)
Leukocyte esterase
   Very low density lipoprotein (VLDL)
Other Tests:
Human immunodeficiency virus antibody (HIV)f
Pregnancy test (serum)d
Hepatitis B surface antigen (HBsAg)f
Follicle-stimulating hormone (FSH)e
Anti–hepatitis B surface antibody (HBsAb)f
Thyroid-stimulating hormone (TSH) and free T4
Anti–hepatitis B core antibody (HBcAb)f
Ixekizumab serum concentration (pharmacokinetic)
Anti–hepatitis C antibodyf,h
Partial thromboplastin time (PTT)
HBV DNAg
Prothrombin time/international normalized ratio
High-sensitivity C-reactive protein (hsCRP)
Exploratory storage samples (urine, serum, plasma, 
RNA, and whole blood)
Purified protein derivative (PPD)i
Urine pregnancy testd (assayed by clinical study site)
Pharmacogenetic sample (DNA)
QuantiFERON®-TB Gold testi
Immunogenicity testing (anti-ixekizumab Ab)
T-SPOT®i
HLA-B27

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Clinical Laboratory Tests
Abbreviations:  Ab = antibody; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; HCV = hepatitis C virus; 
IgA = immunoglobulin A; RNA = ribonucleic acid; RBC = red blood cells; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; T4 = thyroxine; WBC = white blood cells.
a
Unscheduled blood chemistry, hematology, and urinalysis panels may be performed at the discretion of the 
investigator.
b
Cockcroft-Gault calculation is used for the calculated creatinine clearance.
c
For the fasting lipid profile, patients are not to eat or drink anything except water for 12 hours prior to test.  
Fasting is not required for the Screening Visit.
d
Serum pregnancy test for all women <60 years of age who are still of childbearing potential at Visit 1; after 
Visit 1, urine pregnancy test performed locally for women of childbearing potential.
e
Women ≥40 and <60 years of age who have had a cessation of menses for ≥12 months will have an FSH test 
confirming nonchildbearing potential (≥40 mIU/mL).
f
Test required at Visit 1 to determine eligibility of patient for the study.  
g
HBV DNA testing will be done in those patients who HBcAb+ at any time
h
See exclusion criteria (Section 5.2) specific to Hepatitis C antibody.  A confirmatory test for HCV will be 
performed if the patient is positive for HCV antibody.
i
In countries where the QuantiFERON®-TB Gold test or T-SPOT® is available, either test may be used instead 
of the PPD TB test.  The QuantiFERON-TB Gold test may be performed locally or centrally; the T-SPOT must 
be performed locally.

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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Spondyloarthritis Features
To be included in Study RHBX, patients must fulfill the ASAS criteria for nonrad-axSpA either 
by:  
(a) presence of sacroiliitis on MRI (according to ASAS/OMERACT criteria and 
based on central reading) (Rudwaleit et al. 2009d) and have at least 1 SpA feature 
from the bulleted list below.
OR
(b) being HLA-B27 positive and have at least 2 additional SpA features from the bulleted 
list below.
SpA features:

Inflammatory back pain (IBP): IBP according to experts:  four out of five of the 
following parameters present:  (1) onset before the age of 40 years, (2) insidious onset, 
(3) improvement with exercise, (4) no improvement with rest, (5) pain at night (with 
improvement upon getting up).

Arthritis: Past or present active synovitis diagnosed by a doctor.

Enthesitis (heel): Heel enthesitis:  past or present spontaneous pain or tenderness at 
examination at the site of the insertion of the Achilles tendon or plantar fascia at the 
calcaneus.

Uveitis: Past or present uveitis anterior, confirmed by an ophthalmologist.

Dactylitis: Past or present dactylitis diagnosed by a doctor.

Psoriasis: Past or present psoriasis diagnosed by a doctor

Crohn’s/Colitis:  Past or present Crohn’s disease or ulcerative colitis diagnosed by a 
doctor

Good response to NSAIDs: At 24 to 48 h after a full dose of NSAID the back pain was 
not present anymore or much better.
Note:  As patients enrolling into the study should have failed 2 NSAIDs or be intolerant
to NSAIDs, a doctor should assess whether patients had “good” prior response to 
NSAIDs.

Family history for SpA: Presence in first-degree or second-degree relatives of any of 
the following:  (a) ankylosing spondylitis, (b) psoriasis, (c) uveitis, (d) reactive arthritis, 
(e) IBD.
Note:  A doctor should confirm with his/her patient there was a clear diagnosis (not 
self-diagnosis) for any of these in first- or second-degree relatives.

HLA-B27: positive testing according to standard laboratory techniques

Elevated CRP: CRP >5.00 mg/L in the presence of back pain, after exclusion of other 
causes for elevated CRP concentration
References:  Rudwaleit et al. 2009d; Sieper et al. 2009; Aydin et al. 2012.

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Appendix 6.
Protocol Amendment I1F-MC-RHBX(b) 
Summary:  A 52-Week Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Ixekizumab (LY2439821) in bDMARD-Naive 
Patients with Nonradiographic Axial Spondyloarthritis
Protocol I1F-MC-RHBX, A 52-Week Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Ixekizumab (LY2439821) in bDMARD-
Naive Patients with Nonradiographic Axial Spondyloarthritis, has been amended.  The new 
protocol is indicated by amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

There are now two primary objectives to accommodate regional regulatory requirements. 

Proportion of patients achieving ASAS40 response at Week 52 is removed from the 
secondary objective and added as a primary objective. Power estimations were added for 
this objective. 

Clarified that we will use screening MRI/CRP status and not baseline. 
Other minor typographical corrections and clarifications not affecting content have been made in 
the document.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 1.  Protocol Synopsis
Objective(s)/Endpoints:  
There are 2 primary objectives in this study to accommodate regional regulatory requirements.
Objectives
Endpoints
Primary
The primary objective is to compare both ixekizumab 
regimens (80 mg every 2 weeks [Q2W] or 80 mg 
every 4 weeks [Q4W]) versus placebo in patients with 
active nonradiographic axial spondyloarthritis 
(nonrad-axSpA) at Week 16.  

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40  
(ASAS40) response at Week 16
(for regulatory agencies that accept Week 16 as 
primary endpoint)

Proportion of patients achieving an ASAS40 
response at Week 52 
(for regulatory agencies that require Week 52 as 
primary endpoint)
Secondary
The major secondary objective is:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W) versus placebo in patients 
with active nonrad-axSpA at Week 16 and Week 
52

Proportion of patients achieving an ASAS40 
response at Week 52

Change from baseline in Ankylosing Spondylitis 
Disease Activity Score (ASDAS) at Week 16

Change from baseline in ASDAS at Week 52

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Week 16

Change from baseline in BASFI at Week 52

Proportion of patients achieving ASDAS inactive 
disease at Week 16

Proportion of patients achieving ASDAS inactive 
disease at Week 52

Change from baseline in magnetic resonance 
imaging (MRI) of the sacroiliac joints (SIJ) 
(Spondyloarthritis Research Consortium of 
Canada [SPARCC] score) at Week 16

Percent of patients without clinically meaningful
changes in background therapy at Week 52
Treatment Groups and Duration:  
Study RHBX has 3 treatment groups during the 52-week Blinded Treatment Dosing Period:  80 mg ixekizumab 
Q4W, 80 mg ixekizumab Q2W, and placebo at a 1:1:1 ratio.  In each ixekizumab treatment group, half of the 
patients will receive an 80 mg starting dose and half a 160 mg starting dose (1:1 randomization).  Randomization 
will be stratified by country and baseline screening MRI/CRP status (positive MRI and elevated C-reactive protein 
[CRP]; positive MRI and nonelevated CRP; negative MRI and elevated CRP).  All doses are administered via SC 
injection.  At baseline (Week 0), all patients will receive 2 injections.  Patients assigned to an ixekizumab treatment 
regimen with a 160 mg ixekizumab starting dose will receive 160 mg of ixekizumab as two 80 mg SC injections.  
Patients assigned to an ixekizumab treatment regimen with an 80 mg starting dose will receive 80 mg of ixekizumab 

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as 1 SC injection and 1 SC injection of placebo.  Patients assigned to the placebo treatment group will receive 2 SC 
injections of placebo.  After Week 0 and through Week 50, all patients will receive 1 injection every 2 weeks.  
Statistical Analysis:  
Approximately 300 patients will be randomized at a 1:1:1 ratio in the Blinded Treatment Dosing Period (Period 2) to 
ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W, and placebo.  In the active treatment groups, half the patients 
will be given a 160 mg starting dose and the other half will be given an 80 mg starting dose.  With 100 patients per 
treatment group, this study will have approximately 98% power to test the superiority of ixekizumab Q2W to 
placebo for ASAS40 at Week 16.  The following assumptions were used for the power calculations for ASAS40 
response rates at Week 16 regardless of ixekizumab starting dose:  46% for ixekizumab 80 mg Q2W treatment 
group and 18% for the placebo group.  A 2-sided Fisher’s exact test at the 0.05 level is assumed.  
There is little data from similarly designed 52-week placebo-controlled trials regarding the ASAS40 response rate 
for active and placebo treated patients to guide power estimation at Week 52.  With 100 patients per treatment 
group, this study will have approximately 66-99% power to test the superiority of ixekizumab Q2W to placebo for 
ASAS40 at Week 52, assuming various ASAS40 response rates for ixekizumab Q2W and placebo at Week 52.  A 2 
sided Fisher’s exact test at the 0.05 level is assumed.
The efficacy analyses for the Blinded Treatment Dosing Period will be conducted on the intent-to-treat (ITT) 
population and safety analyses will be conducted on the safety population.  
Comparisons between each ixekizumab treatment group (80 mg Q2W or 80 mg Q4W) and placebo will be 
performed for all analyses in the Blinded Treatment Dosing Period.  Unless otherwise specified, the ixekizumab 80 
mg Q2W and 80 mg Q4W groups will be analyzed without regard to starting dose.  The primary analysis method for 
treatment group comparisons of categorical efficacy and health outcomes variables will be a logistic regression 
analysis with treatment, geographic region, and baseline screening MRI/CRP status (positive MRI and elevated 
CRP; positive MRI and nonelevated CRP; negative MRI and elevated CRP) as factors, using the Nonresponder 
Imputation (NRI) method.  
Under NRI, all nonresponders at Week 16 (Visit 8), as well as all patients who discontinue study treatment at any 
time prior to Week 16 for any reason, will be defined as nonresponders for the NRI analysis at Week 16.  NRI will 
be applied to Week 52 (Visit 15) in a similar method.  Patients who are deemed as inadequate responders by the 
investigator after Week 16 but remain on blinded study treatment and only have modifications in concomitant 
medications will not be automatically imputed as nonresponders.  However, patients who discontinue originally 
assigned blinded study treatment and use rescue ixekizumab 80 mg Q2W will be analyzed as nonresponders for the 
Week 52 analysis.  Randomized patients without any postbaseline observation will also be defined as nonresponders 
for the NRI analysis.  
A multiple testing strategy for the primary and major secondary objectives will be implemented to control the 
family-wise type I error rate at a 2-sided α level of 0.05.  
The primary analyses for the continuous efficacy and health outcomes variables will be made using mixed-effects 
model of repeated measures (MMRM) analysis with treatment, geographic region, baseline screening MRI/CRP 
status, baseline value, visit, baseline value-by-visit, and treatment-by-visit interactions as fixed factors.  
A secondary analysis for continuous efficacy and health outcomes variables will be made using analysis of 
covariance (ANCOVA) with treatment, geographic region, baseline screening MRI/CRP status, and baseline.  
Fisher’s exact test will be used for all adverse events (AEs), baseline, discontinuation, and other categorical safety 
data.  Continuous vital sign and laboratory values will be analyzed by an ANCOVA with treatment and baseline 
value.  

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Patients who discontinue study treatment after Week 16 will continue to be followed for all regularly scheduled 
visits for safety and efficacy assessment.  The data collected after discontinuation of study treatment will be 
summarized separately.  
Section 3.  Objectives and Endpoints
Table RHBX.1 shows the objectives and endpoints of the study.
Table RHBX.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective is to compare both ixekizumab 
regimens (80 mg Q2W or 80 mg Q4W) versus placebo 
in patients with active nonrad-axSpA at Week 16

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40 
(ASAS40) response at Week 16 (for regulatory 
agencies that require Week 16 as the primary 
endpoint)

Proportion of patients achieving an Assessment of 
Spondyloarthritis International Society 40 
(ASAS40) response at Week 52 (for regulatory 
agencies that require Week 52 as the primary 
endpoint)
Secondary
The major secondary objectives are:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W versus placebo in patients with 
active nonrad-axSpA at Week 16 and Week 52

Proportion of patients achieving an ASAS40 
response at Week 52

Change from baseline in Ankylosing Spondylitis 
Disease Activity Score (ASDAS) at Week 16

Change from baseline in ASDAS at Week 52 

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Week 16

Change from baseline in BASFI at Week 52

Proportion of patients achieving ASDAS inactive 
disease at Week 16

Proportion of patients achieving ASDAS inactive 
disease at Week 52

Change from baseline in magnetic resonance 
imaging (MRI) of the sacroiliac joints (SIJ) 
(Spondyloarthritis Research Consortium of Canada
[SPARCC] score) at Week 16

Percent of patients without clinically meaningful 
changes in background therapy at Week 52
Other secondary objectives are:

To compare both ixekizumab regimens (80 mg 
Q2W or 80 mg Q4W) to placebo during the 52-
week period

Proportion of patients who achieve ASAS20, 
ASAS40, ASAS5/6, and partial remission by ASAS 
criteria

Change from baseline in the individual components 
of the ASAS criteria

Change from baseline in Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI)

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Objectives
Endpoints

Proportion of patients reaching BASDAI50

Change from baseline in ASDAS

Proportion of patients who experience 
clinically-important improvement (change of 
ASDAS from baseline ≥1.1), major improvement 
(change of ASDAS from baseline ≥2.0), or inactive 
disease (ASDAS <1.3)

Change from baseline in the measure of CRP

Change from baseline in BASFI

Change from baseline in mobility
o
Bath Ankylosing Spondylitis Metrology Index 
(BASMI) (linear) and individual components
o
Chest expansion
o
Change from baseline in occiput to wall 
distance

Change from baseline in MRI of the SIJ (SPARCC 
score)  

Change from baseline in SPARCC SIJ Structural 
Score (SSS)

Change from baseline in Maastricht Ankylosing 
Spondylitis Enthesitis Score (MASES)

Change from baseline in SPARCC Enthesitis Score 

The incidence and severity of peripheral arthritis by 
tender and swollen joint count scores of 46/44 joints

Incidence rate of anterior uveitis or uveitis flares

Change from baseline in the following health 
outcomes measures:  Fatigue NRS score, ASAS-HI 
score, Jenkins Sleep Evaluation Questionnaire 
(JSEQ), Work Productivity Activity Impairment—
Spondyloarthritis (WPAI-SpA) scores, SF-36 (both 
physical component [PCS] and mental component 
scores [MCS]), and Quick Inventory of Depressive 
Symptomatology–Self-Report (16 Items) (QIDS-
SR16) score.  

NSAID intake (ASAS-NSAID score and % of 
patients taking NSAIDs)

To explore the effect of starting dose (160 mg 
compared to 80 mg)

NSAID intake (ASAS NSAID score and % of 
patients taking NSAIDs)

Onset of action and treatment response (ASAS, 
ASDAS, CRP, BASFI)

To evaluate the incidence of anti-ixekizumab 
antibodies and its relationship to efficacy of 
ixekizumab 

Efficacy response rates listed below at Weeks 16 
and 52 by treatment-emergent anti-drug antibody 
(TE-ADA) status and by neutralizing anti-drug 
antibody (NAb) status
o
Proportion of patients achieving ASAS40
o
Proportion of patients achieving ASAS20
o
Proportion of patients achieving ASDAS 
inactive disease

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Objectives
Endpoints

To measure ixekizumab exposure and assess the 
relationship between exposure and efficacy and 
exposure and immunogenicity

Serum trough concentrations of ixekizumab

Model parameters for the exposure-response 
relationship between ixekizumab serum trough 
concentrations and efficacy endpoints (for example,
ASAS20, ASAS40) at Week 16 and/or Week 52

Ixekizumab serum trough concentrations associated 
with anti-drug antibody (ADA) titer 
Section 4.3.  Scientific Rationale for Study Design
The effectiveness of ixekizumab in treating nonrad-axSpA will be assessed primarily by the 
ASAS40 response rate at Week 16 for regulatory agencies that require Week 16 as the primary 
endpoint,  and by the ASAS40 response rate at Week 52 for regulatory agencies that require 
Week 16 as the primary endpoint,  and by the ASAS40 response rate at Week 52 for regulatory 
agencies that require Week 52 as the primary endpoint.  The ASAS40 response at This measure 
and the other Week 16 endpoints are in alignment with efficacy endpoints for currently approved 
axSpA therapies and with regulatory guidance (EMEA 2009).  The ASAS40 response at Week 
52 (first major secondary endpoint) and other Week 52 endpoints are in line with regulatory 
advice received by Lilly from the Food and Drug Administration for nonrad axSpA (2015, 
2018).  Steady-state exposure of ixekizumab is expected to be reached by Week 16.  Based on 
previous studies with ixekizumab in patients with Ps, RA, and PsA, it is anticipated that 
maximum or near maximum clinical effect in nonrad axSpA patients will be achieved for the 
majority of patients within this timeframe for both ixekizumab treatment regimens regardless of 
the starting dose.  
Section 6.2.  Method of Treatment Assignment
To achieve between-group comparability, the randomization will be stratified by country and 
baseline screening MRI/CRP status (positive MRI and elevated CRP; positive MRI and 
nonelevated CRP; negative MRI and elevated CRP).  Elevated CRP is defined as >5.00 mg/L.  
Section 8.1.2.9.  Ankylosing Spondylitis Disease Activity Score
ASDAScrp:  0.1216 × total back pain + 0.1106 × patient global + 0.0736 × peripheral 
pain/swelling + 0.0586 × duration of morning stiffness + 0.5796 × Ln(CRP+1) (Machado et al. 
2015).  
Section 9.1.  Determination of Sample Size
Approximately 300 patients will be randomized at a 1:1:1 ratio in the Blinded Treatment Dosing 
Period (Period 2) to ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W, and placebo.  With 
100 patients per treatment group, this study will have approximately 98% power to test the 
superiority of ixekizumab Q2W to placebo for the ASAS40 at Week 16.  The following 
assumptions were used for the power calculations for ASAS40 response rates at Week 16 
regardless of starting dose:  46% for ixekizumab 80 mg Q2W treatment group and 18% for the 
placebo group.  A 2-sided Fisher’s exact test at the 0.05 level is assumed. These assumptions are 
based on the data from historical clinical studies in nonrad-axSpA patients with objective signs 

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of inflammation (etanercept, adalimumab, certolizumab, and golimumab [Sieper et al. 2013; 
Dougados et al. 2014; Landewé et al. 2014; Sieper et al. 2015]).    
There is little data from similarly designed 52-week placebo-controlled trials regarding the 
ASAS40 response rate for active and placebo treated patients to guide power estimation at Week 
52.  Table RHBX .4. provides power estimates to test the superiority of ixekizumab Q2W to 
placebo for the ASAS40 at Week 52,  assuming various ASAS40 response rates for ixekizumab 
Q2W and placebo at Week 52.  A 2-sided Fisher’s exact test at the 0.05 level is assumed. 
Table RHBX.4.
Power Estimates for Week 52 
ASAS40 Response Rates  (%) at Week 52
Power (%)
Ixekizumab Q2W
(N = 100)
Placebo
(N = 100)
50
10
99
40
10
99
30
10
93
50
15
99
40
15
97
30
15
66
Abbreviations:  ASAS = Assessment of Spondyloarthritis International Society; N = number of subjects; Q2W = 
every 2 weeks.
Section 9.2.1.  General Considerations for Analyses during the Blinded Treatment Dosing 
(Period 2)
The randomization to treatment groups is stratified by country and baseline screening MRI/CRP 
status (positive MRI and elevated CRP; positive MRI and nonelevated CRP; negative MRI and 
elevated CRP) as described in Section 6.2.  The countries will be categorized into geographic 
regions for analysis.  Geographic regions will be defined in the SAP upon country finalization.  
Unless otherwise specified, the statistical analysis models will adjust for geographic region and 
baseline screening MRI/CRP status.  
Unless otherwise specified, treatment groups of ixekizumab 80 mg Q2W and 80 mg Q4W will
be analyzed without regard to starting dose.  
The primary analysis method for treatment comparisons of categorical efficacy and health 
outcomes variables at specific time points will be made using a logistic regression analysis with 
treatment, geographic region, and baseline screening MRI/CRP status in the model.  The odds 
ratio and 95% confidence intervals (CIs) will be reported.  Treatment difference and 95% CI will 
also be reported.  Secondary analysis will be conducted using a Fisher’s exact test.  
As a secondary analysis for the primary and major secondary categorical efficacy measures, a 
categorical mixed-effects model of repeated measures (categorical MMRM) estimating the 
percentage of patients achieving response across postbaseline visits may be used.  The model 
will include treatment, geographic region, baseline screening MRI/CRP status, visit, treatment-
by-visit as fixed factors, as well as the continuous, fixed covariate of baseline value and baseline 

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value by visit interaction (when appropriate).  The binomial distribution and the logit link will be 
used.  An unstructured covariance matrix will be used to model the within-patient variance 
covariance errors.  The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom.  The Newton-Raphson with ridging optimization technique will be used to 
aid with convergence.  The probability of response, the corresponding 2-sided 95% CI, and the 
p-value for treatment comparisons at Week 16 (Visit 8), Week 52 (Visit 15), and all other 
postbaseline visits will be reported.  
If the unstructured covariance matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure, followed by the heterogeneous autoregressive covariance 
structure, followed by the compound symmetry will be used.  This order is specified according to 
a decreasing number of covariance parameters in the structure.  The sandwich estimator (Diggle 
et al. 1994) for the covariance estimation will be used by specifying the EMPIRICAL option in 
SAS PROC MIXED.  When sandwich estimation is used, the Kenward-Roger approximation for 
denominator degrees of freedom cannot be used.  Instead, DDFM=BETWITHIN option will be 
used to estimate denominator degrees of freedom.  
The primary analyses for continuous efficacy and health outcomes variables will be made using 
MMRM.  A secondary analysis for continuous efficacy and health outcomes variables will be 
made using analysis of covariance (ANCOVA).  
When the MMRM is used, the model will include treatment, geographic region, baseline 
screening MRI/CRP status, baseline value, visit, baseline value-by-visit, and treatment-by-visit 
interaction as fixed factors.  The covariance structure to model the within-patient errors will be 
unstructured.  If the unstructured covariance matrix results in a lack of convergence, the similar 
approach specified above for categorical MMRM will be used.  The Kenward-Roger method will 
be used to estimate the denominator degrees of freedom.  Type III tests for the least-squares (LS) 
means will be used for the statistical comparison; the 95% CI will also be reported.  Treatment 
group comparisons with placebo at Week 16 (Visit 8), Week 52 (Visit 15), and all other visits 
will be tested.  
When the ANCOVA is used, the model will include treatment, geographic region, baseline 
screening MRI/CRP status and baseline value.  Type III sums of squares for the LS means will 
be used for the statistical comparison; the 95% CI will also be reported.  
The impact of ixekizumab starting dose of 160 mg versus 80 mg on time to onset (focusing on 
Week 4) and treatment response during Blinded Treatment Dosing Period will be summarized 
and evaluated.  Details will be specified in the SAP.  
For variables that are not collected at each postbaseline visit, data may exist at visits where the 
variable was not scheduled to be collected due to early discontinuation visits.  In these situations, 
data from the early discontinuation visit that does not correspond to the planned collection 
schedule will be excluded from the MMRM and Categorical MMRM analyses.  However, the 
data will still be used in other analyses, including shift analyses, change from baseline to last-
observation carried forward (LOCF) or modified baseline observation carried forward (mBOCF) 
endpoint analyses, and other categorical analyses.  

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Fisher's exact test will be used for all AE, baseline, discontinuation, and other categorical safety 
data.  Continuous vital sign and laboratory values will be analyzed by an ANCOVA with 
treatment and baseline value in the model.  
Patients who discontinue study treatment after Week 16 will continue to be followed for the 
scheduled visits for safety and efficacy assessment.  The data collected post discontinuation of 
study treatment will be summarized separately.  
Section 9.2.5.  Adjustment for Multiple Comparisons
The primary outcome of ASAS40 at Week 16 will be tested for ixekizumab 80 mg Q2W versus 
placebo at a 2-sided α=0.05.  The primary outcome of ASAS40 at Week 52 will also be tested 
for ixekizumab 80 mg Q2W versus placebo at a 2-sided α=0.05.  Because this study has a 
different primary endpoint for different regulatory agencies, the significances of both primary 
endpoints will not be required in order for the study to be considered successful. No multiplicity 
adjustment will be made for the 2 primary endpoints. The comparison of ASAS40 for 
ixekizumab 80 mg Q4W versus placebo at Weeks 16 and Week 52 and the major secondary 
objectives (Section 3) will be tested using an appropriate multiple testing approach providing 
strong control of the familywise error rate (for the primary and major secondary tests) at a 2-
sided α=0.05.  Details of the specific testing methodology (including testing order, 
interrelationships, type I error allocation, and the associated propagation) will be specified in the 
SAP.  
There will be no adjustment for multiple comparisons for any other analyses.  
Section 9.3.2.  Patient Characteristics
Patient characteristics and baseline clinical measures will be summarized.  Baseline 
characteristics will include sex, age, age category, weight, body mass index, race, geographic 
region, country, baseline disease activity (BASDAI), duration of disease, HLA-B27 positivity, 
baseline CRP (% of nonelevated or elevated), baseline screening MRI status, baseline screening
MRI/CRP status, and history of extra-axial disease manifestations.  Baseline clinical 
measurements may include ASDAS, CRP, BASFI, BASMI, chest expansion, Fatigue NRS, 
Patient Global NRS, total back pain, spinal pain at night, spinal pain, inflammation (mean of 
questions 5 and 6 of BASDAI), MASES, enthesitis SPARCC, TJC, and SJC.  
Treatment group comparisons in Period 2 (Blinded Treatment Dosing Period) will be conducted 
using Fisher’s exact test for categorical data and an ANOVA with treatment as a factor for 
continuous data.  

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Section 9.4.1.  Primary Analyses
The primary analysis, the proportion of patients with ASAS40 at Week 16 or at Week 52, will be 
based on the ITT population.  In addition, an analysis of the PPS population will be used to 
support the primary efficacy analysis.  
Treatment comparisons between each ixekizumab treatment group and placebo in the proportion 
of patients achieving an ASAS40 response at Week 16 (Visit 8) or Week 52 (Visit 15) will be 
analyzed using the logistic regression model defined in Section 9.2.1.  Missing data will be 
imputed using the NRI method described in Section 9.2.4.  
Secondary analyses for ASAS40 at Week 16 will be conducted using Categorical MMRM and 
Fisher’s exact test as described in Section 9.2.1.  
Section 9.4.2.1.  Major Secondary Analyses
Table RHBX.5.
Primary and Major Secondary Outcome Analyses
Outcomes Measure
Primary Analysis Method
Secondary Analysis Method
ASAS40 at Week 16 (primary efficacy 
outcome for regulatory agencies who 
accept Week 16 as the primary 
endpoint)
Logistic regression analysis 
with NRI 
Categorical MMRM
Fisher’s exact test with NRI
Logistic regression analysis with NRI on 
PPS 
ASAS40 at Week 52 (primary efficacy 
outcome for regulatory agencies who 
require Week 52 as the primary 
endpoint)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
Logistic regression analysis with NRI on 
PPS
Change from baseline in ASDAS at 
Week 16 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in ASDAS at 
Week 52 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in BASFI at 
Week 16 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
Change from baseline in BASFI at 
Week 52 (major secondary outcome)
MMRM
ANCOVA with mBOCF/LOCF
ASDAS inactive disease at Week 16 
(major secondary outcome)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
ASDAS inactive disease at Week 52 
(major secondary outcome)
Logistic regression analysis 
with NRI
Categorical MMRM
Fisher’s exact test with NRI
Change from baseline in MRI of the 
SIJ [SPARCC Score] at Week 16 
(major secondary outcome)
ANCOVA with observed 
case analysisa
Secondary analysis maybe specified in 
SAP
Percent of patients without clinically 
meaningful changes in background 
therapy at Week 52 (major secondary 
outcome)
Logistic regression analysis
Fisher’s exact test

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Abbreviations:  ANCOVA = analysis of covariance; ASAS = Assessment of Spondyloarthritis International Society; 
ASDAS = Ankylosing Spondylitis Disease Activity Score; BASFI = Bath Ankylosing Spondylitis Functional 
Index; LOCF = last observation carried forward; mBOCF = modified baseline observation carried forward; 
MMRM = mixed-effects model of repeated measures; MRI = magnetic resonance imaging; NRI = nonresponder 
imputation; PPS = per-protocol set; SAP = statistical analysis plan; SIJ = sacroiliac joints; SPARCC = 
Spondyloarthritis Research Consortium of Canada Score.
a
Only patients with both baseline and Week 16 MRI scores will be included in the observed case analysis.  
Section 9.7.2.  Subgroup Analyses
Subgroup analysis will be conducted for ASAS40 and selective major secondary outcomes 
(defined in SAP) at Week 16 (Visit 8) and Week 52 (Visit 15) using the ITT population.  
Subgroup analyses may be conducted based on gender, age category, race, baseline disease 
severity, country, geographic region, baseline CRP status, baseline MRI status, baseline 
screening MRI/CRP status, and presence of HLA-B27.  

PPD
Leo Document ID = 2abdbb41-ae4c-4b34-9f70-b94807fbd16a
Approver: 
Approval Date & Time: 04-Oct-2018 18:51:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Oct-2018 12:31:13 GMT
Signature meaning: Approved
PPD