A Multicenter, Long-Term Extension Study of 104 Weeks, Including a Double-Blind, Placebo-Controlled 40-Week Randomized Withdrawal-Retreatment Period, to Evaluate the Maintenance of Treatment Effect of Ixekizumab (LY2439821) in Patients With Axial Spondyloarthritis
Phase: PHASE3
Conditions: Axial Spondyloarthritis
Sponsor: Eli Lilly and Company

Protocol: I1F-MC-RHBY (a)
A Multicenter, Long-Term Extension Study of 104 Weeks, Including a Double-Blind, Placebo-Controlled 
40-Week Randomized Withdrawal-Retreatment Period, to Evaluate the Maintenance of Treatment Effect of 
Ixekizumab (LY2439821) in Patients With Axial Spondyloarthritis
NCT03129100  
Approval Date: 27-Jun-2017

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1
L Y 2 4 3 9 8 2 1
Pr ot o c ol I 1 F -M C -R H B Y ( a)
A M ulti c e nt er, L o n g -T er m E xt e n si o n St u d y  of 1 0 4 W e e k s, 
I n cl u di n g a D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d 4 0 -W e e k 
R a n d o mi z e d Wit h dr a w al – R etr e at m e nt P eri o d, t o E v al u at e t h e 
M a i nt e n a n c e of Tr e at m e nt Eff e ct of I x e ki z u m a b ( L Y 2 4 3 9 8 2 1) 
i n P ati e nt s wit h Axi al S p o n d y l o art hriti s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
i x e ki z u m a b ( L Y 2 4 3 9 8 2 1), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt
wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
I x e ki z u m a b ( L Y 2 4 3 9 8 2 1)
St u d y I 1 F -M C -R H B Y ( R H B Y) i s a P h a s e 3, m ulti c e nt er, l o n g -t er m e xt e n si o n st u d y of  1 0 4 
w e e k s i n p ati e nt s wit h a xi al s p o n d yl o art hriti s t h at i n cl u d e s a d o u bl e-bli n d, pl a c e b o -
c o ntr oll e d, r a n d o mi z e d wit h dr a w al – r etr e at m e nt p eri o d .  T h e  st u d y d ur ati o n will b e u p t o 2 
y e ar s f or i x e ki z u m a b a d mi ni str ati o n, a n d u p t o 2 y e ar s a n d 6 m o nt h s f or st u d y p arti ci p ati o n 
o v er 4 p eri o d s.
A p pr o v al D at e: 2 7- J u n- 2 0 1 7 G M T
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 2 6 A u g u st 2 0 1 6
A m e n d m e nt ( a ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d 
b el o w.

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Table of Contents
Section
Page
1.
Synopsis ...........................................................................................................................10
2.
Schedule of Activities .......................................................................................................17
3.
Introduction ......................................................................................................................24
3.1.
Study Rationale............................................................................................................24
3.2.
Background..................................................................................................................25
3.3.
Benefit/Risk Assessment..............................................................................................26
4.
Objectives and Endpoints..................................................................................................28
5.
Study Design.....................................................................................................................32
5.1.
Overall Design .............................................................................................................32
5.2.
Number of Participants.................................................................................................37
5.3.
End of Study Definition ...............................................................................................38
5.4.
Scientific Rationale for Study Design...........................................................................38
5.5.
Justification for Dose ...................................................................................................39
6.
Study Population...............................................................................................................40
6.1.
Inclusion Criteria..........................................................................................................40
6.2.
Exclusion Criteria ........................................................................................................41
6.3.
Lifestyle Restrictions....................................................................................................42
6.4.
Screen Failures.............................................................................................................42
7.
Treatments........................................................................................................................43
7.1.
Treatments Administered .............................................................................................43
7.1.1.
Administration of Investigational Product ............................................................49
7.1.2.
Special Treatment Considerations ........................................................................49
7.1.3.
Packaging and Labelling ......................................................................................50
7.2.
Method of Treatment Assignment ................................................................................50
7.2.1.
Selection and Timing of Doses.............................................................................51
7.3.
Blinding .......................................................................................................................51
7.4.
Dosage Modification....................................................................................................53
7.5.
Preparation/Handling/Storage/Accountability...............................................................54
7.6.
Treatment Compliance .................................................................................................54
7.7.
Concomitant Therapy...................................................................................................54
7.8.
Treatment after the End of the Study............................................................................59
7.8.1.
Continued Access.................................................................................................59
8.
Discontinuation Criteria ....................................................................................................60
8.1.
Discontinuation from Study Treatment.........................................................................60

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8.1.1.
Permanent Discontinuation from Study Treatment ...............................................60
8.1.2.
Temporary Discontinuation from Study Treatment...............................................62
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................62
8.2.
Discontinuation from the Study....................................................................................62
8.3.
Lost to Follow-Up........................................................................................................63
9.
Study Assessments and Procedures ...................................................................................64
9.1.
Efficacy Assessments...................................................................................................64
9.1.1.
Primary Efficacy Assessments .............................................................................64
9.1.2.
Secondary Efficacy Assessments..........................................................................64
9.1.2.1.
Ankylosing Spondylitis Disease Activity Score ..............................................64
9.1.2.2.
Imaging Used for Efficacy Measures and Disease 
Diagnosis........................................................................................................65
9.1.2.2.1.
Radiographic Imaging of the Spine ...........................................................65
9.1.2.2.2.
Spondyloarthritis Research Consortium of Canada 
MRI Score for Sacroiliac Joints ................................................................65
9.1.2.2.3.
Ankylosing Spondylitis Spinal Magnetic Resonance 
Imaging Activity.......................................................................................65
9.1.2.3.
ASAS20, ASAS40, ASAS5/6, ASAS Partial Remission.................................65
9.1.2.3.1.
ASAS20 ...................................................................................................65
9.1.2.3.2.
ASAS40 ...................................................................................................66
9.1.2.3.3.
ASAS5/6 ..................................................................................................66
9.1.2.3.4.
ASAS Partial Remission ...........................................................................66
9.1.2.4.
Patient Global (Assessment of Disease Activity) ............................................66
9.1.2.5.
Spinal Pain .....................................................................................................66
9.1.2.6.
Bath Ankylosing Spondylitis Functional Index ...............................................66
9.1.2.7.
Bath Ankylosing Spondylitis Disease Activity Index......................................66
9.1.2.8.
Bath Ankylosing Spondylitis Metrology Index—Spinal 
Mobility .........................................................................................................67
9.1.2.9.
Chest Expansion.............................................................................................67
9.1.2.10.
Occiput to Wall Distance................................................................................67
9.1.2.11.
Maastricht Ankylosing Spondylitis Enthesitis Score .......................................67
9.1.2.12.
SPARCC Enthesitis Score ..............................................................................68
9.1.2.13.
Peripheral Arthritis .........................................................................................68
9.1.2.13.1.
Tender Joint Count ...................................................................................68
9.1.2.13.2.
Swollen Joint Count..................................................................................68
9.1.2.14.
Laboratory Tests Used for Efficacy Measures and 
Disease Diagnosis...........................................................................................69
9.1.2.14.1.
High Sensitivity C-Reactive Protein..........................................................69
9.1.2.15.
Health Outcomes Measures ............................................................................69

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 4
L Y 2 4 3 9 8 2 1
C CI
9. 1. 2. 1 5. 1.
Heal t hcare Res o urce Utilizati o n ................................................................6 9
9. 1. 2. 1 5. 2.
Fat i g ue Se verity N u meri c Rat i n g Scale.....................................................6 9
9. 1. 2. 1 5. 3.
Me dical O utc o mes St u d y  3 6-It e m S h ort-F or m  Healt h 
S ur ve y ......................................................................................................6 9
9. 1. 2. 1 5. 4.
Assess me nt of S p o n d yl o art hritis I nter nati onal 
S o ci et y Heal t h I n de x.................................................................................6 9
9. 1. 2. 1 5. 5.
E ur o pea n Q ualit y of  Life-5 Di me nsi o ns 5 -Le vel .......................................7 0
9. 1. 2. 1 5. 6.
W o r k Pr o d ucti vit y a n d Act i vity I mp ai r me nt 
Q uest i on naire — S p o n d yl o art hri tis .............................................................7 0
9. 1. 2. 1 5. 7.
Je n ki ns Slee p Q uesti on naire ......................................................................7 0
9. 2.
A d verse E ve nts ............................................................................................................7 1
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................7 2
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................7 2
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................7 3
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................7 3
9. 3.
Treat me nt of O ver d ose ................................................................................................. 7 4
9. 4.
S af et y ...........................................................................................................................7 4
9. 4. 1.
Electr oca r dio gr a m s ..............................................................................................7 4
9. 4. 2.
Vi t al Si g ns........................................................................................................... 7 4
9. 4. 3.
La b orat or y  Tests..................................................................................................7 4
9. 4. 4.
P h ysical E xa mi nat i on ...........................................................................................7 4
9. 4. 5.
E y e S y m pt o m Assess me nt ...................................................................................7 5
9. 4. 6.
T u berc ul osis Test i n g............................................................................................7 5
9. 4. 7.
Q ui c k I n ve nt or y of De pressi ve S y m pt o mat olo g y — Self -
Re p ort ( 1 6 Ite ms) ................................................................................................. 7 6
9. 4. 8.
C ol u m bia S uici de Se veri t y Rati n g Scale ...............................................................7 6
9. 4. 9.
I mm u n o ge nicit y ...................................................................................................7 6
9. 4. 1 0.
S af et y M o ni t ori n g ................................................................................................7 7
9. 4. 1 0. 1.
Ne utr o pe nia ....................................................................................................7 7
9. 4. 1 0 . 1. 1.
D uri n g Treat m e nt .....................................................................................7 7
9. 4. 1 0. 1. 2.
Earl y Ter mi nat i on Visit ............................................................................7 8
9. 4. 1 0. 1. 3.
P os t-Treat me nt F oll o w -U p ........................................................................7 9
9. 4. 1 0. 2.
He pati tis B M o nit ori n g ...................................................................................7 9
9. 4. 1 0. 3.
H y perte nsi o n ..................................................................................................7 9
9. 5.
P har mac o ki net ics .........................................................................................................8 0
9. 6.
P har mac o d y na mics ......................................................................................................8 0
9. 7. 1.
S a m ples f or I m m u n o ge nicit y Researc h ................................................................. 8 0
9. 8.
Heal t h Ec o n o mics........................................................................................................8 1

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10.
Statistical Considerations ..................................................................................................82
10.1. Sample Size Determination ..........................................................................................82
10.2. Populations for Analyses..............................................................................................82
10.3. Statistical Analyses ......................................................................................................83
10.3.1.
General Statistical Considerations ........................................................................83
10.3.1.1.
General Considerations for Analyses during the 
Combined Periods 1, 2, and 3 .........................................................................83
10.3.1.1.1.
Lead-In Period Safety Population..............................................................83
10.3.1.1.2.
Long-Term Ixekizumab Treatment Efficacy 
Population ................................................................................................83
10.3.1.2.
General Considerations for Analyses during Period 2 
(Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment)...............................................................................83
10.3.1.2.1.
Randomized Withdrawal ITT Population..................................................83
10.3.1.2.2.
Flare Population........................................................................................84
10.3.1.3.
General Considerations for Analyses at Week 56 for the 
2-Year Radiographic Progression in Spine Assessments.................................84
10.3.1.4.
General Considerations for Analyses during the 
Post-Treatment Follow-Up (Period 4).............................................................85
10.3.1.5.
Missing Data Imputation ................................................................................85
10.3.1.5.1.
Nonresponder Imputation for Clinical Response .......................................85
10.3.1.5.2.
Modified Nonresponder Imputation for Clinical 
Response ..................................................................................................85
10.3.1.5.3.
Modified Baseline Observation Carried Forward ......................................85
10.3.1.5.4.
Multiple Imputation..................................................................................86
10.3.1.6.
Adjustment for Multiple Comparisons ............................................................86
10.3.2.
Treatment Group Comparability...........................................................................86
10.3.2.1.
Patient Disposition..........................................................................................86
10.3.2.2.
Patient Characteristics ....................................................................................86
10.3.2.3.
Concomitant Therapy .....................................................................................87
10.3.2.4.
Treatment Compliance....................................................................................87
10.3.3.
Efficacy Analyses ................................................................................................87
10.3.3.1.
Primary Analyses ...........................................................................................87
10.3.3.2.
Major Secondary Analyses .............................................................................87
10.3.3.3.
Other Secondary Efficacy Analyses................................................................88
10.3.3.3.1.
Combined Periods 1, 2, and 3....................................................................88
10.3.3.3.2.
Period 2 (Extension Period, Including Blinded, 
Randomized Withdrawal–Retreatment).....................................................88
10.3.3.4.
Tertiary/Exploratory Analyses ........................................................................89
10.3.4.
Safety Analyses....................................................................................................89

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10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................89
10.3.6.
Other Analyses.....................................................................................................89
10.3.6.1.
Health Outcomes ............................................................................................89
10.3.6.2.
Subgroup Analyses.........................................................................................90
10.3.6.3.
Immunogenicity..............................................................................................90
10.3.7.
Interim Analyses..................................................................................................91
11.
References ........................................................................................................................92
12.
Appendices .....................................................................................................................100

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List of Tables
Table
Page
Table RHBY.1.
Objectives and Endpoints...............................................................................28
Table RHBY.2.
Summary of Treatment Regimens
Study RHBY .................................................................................................45
Table RHBY.3.
Dosage Modification for Group B during Period 2 and Period 3 ....................54
Table RHBY.4.
Concomitant Treatment with NSAIDs and Analgesics, Conventional 
DMARDs, and Corticosteroids
Study RHBY .................................................................................................56
Table RHBY.5.
Major Patient Populations for Study RHBY...................................................82

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List of Figures
Figure
Page
Figure RHBY.1. Illustration of study design for Clinical Protocol I1F-MC-RHBY...................35

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions......................................................................101
Appendix 2.
Clinical Laboratory Tests.............................................................................106
Appendix 3.
Study Governance Considerations................................................................109
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................113
Appendix 5.
Protocol Amendment I1F-MC-RHBY(a) Summary:  A Multicenter, 
Long-Term Extension Study of 104 Weeks, Including a Double-Blind, 
Placebo-Controlled 40-Week Randomized Withdrawal-Retreatment 
Period, to Evaluate the Maintenance of Treatment Effect of Ixekizumab 
(LY2439821) in Patients with Axial Spondyloarthritis.................................115

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1.
Synopsis
Title of Study:
A Multicenter, Long-Term Extension Study of 104 Weeks, Including a Double-Blind, Placebo-Controlled 40-Week 
Randomized Withdrawal–Retreatment Period, to Evaluate the Maintenance of Treatment Effect of Ixekizumab 
(LY2439821) in Patients with Axial Spondyloarthritis
Rationale:
In the context of long-term treatment, it is important to understand the long-term efficacy and safety of ixekizumab 
treatment in patients with axial spondyloarthritis (axSpA). The current 2-year study will, together with the 
preceding 1-year originating studies I1F-MC-RHBV (RHBV), I1F-MC-RHBW (RHBW), and I1F-MC-RHBX 
(RHBX), provide efficacy and safety data of ixekizumab after long-term treatment for patients with axSpA, 
including both radiographic axSpA (rad-axSpA) and nonradiographic axSpA (nonrad-axSpA) patients, and 
biological disease modifying antirheumatic drug (bDMARD)-naive as well as tumor necrosis factor 
(TNF)-experienced patients.  Therefore, data generated from the current study will provide further information on
the long-term efficacy and safety profile of ixekizumab.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate in patients having achieved a state 
of sustained remission whether the combined
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
Period 2

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during Period 2
Objectives
Endpoints
Major Secondary

To compare the combined ixekizumab 
treatment group to historical control for 2-year
radiographic progression in spine in patients 
with active radiographic axSpA (rad axSpA)

Change in modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS) score

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg every 2 weeks (Q2W) treatment group 
or ixekizumab 80 mg every 4 weeks (Q4W)
treatment group is superior to placebo in 
maintaining response after randomized 
withdrawal

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during Period 2

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response after 
randomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during Period 2

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LY2439821
Objectives
Endpoints

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg Q2W treatment group or ixekizumab 80 
mg Q4W treatment group is superior to placebo 
in maintaining response after randomized 
withdrawal

Time to flare for patients in the randomized 
withdrawal population during Period 2
Objectives
Endpoints
Other Secondary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
Period 2

The proportion of patients in the randomized
withdrawal population with Assessment of 
Spondyloarthritis International Society
(ASAS)20, ASAS40, ASAS 5/6, ASAS partial 
remission, clinically-important improvement 
(change of Ankylosing Spondylitis Disease 
Activity Score [ASDAS] ≥1.1 units), major 
improvement (change of ASDAS ≥2.0 units), 
and inactive disease (ASDAS <1.3) during 
Period 2

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 with Bath Ankylosing 
Spondylitis Disease Activity Index 50 
(BASDAI50) response

Change from baseline in ASDAS

Change from baseline in the measure of high 
sensitivity C-reactive protein (CRP)

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI)

Change from baseline in the measures of spinal 
mobility 
o
Bath Ankylosing Spondylitis 
Metrology Index (BASMI) (linear), 
and BASMI individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline in Maastricht Ankylosing 
Spondylitis Enthesitis Score (MASES) and 
Spondyloarthritis Research Consortium of 
Canada Score (SPARCC)

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

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Objectives
Endpoints

Change from baseline in the following health 
outcomes measures
o
Fatigue numeric rating scale (NRS)  
score
o
Quick Inventory of Depressive 
Symptomatology Self-Report-16 
(QIDS-SR16)
o
SF-36 (both physical and mental 
component scores)
o
Assessments of Spondyloarthritis 
International Society–Health Index 
(ASAS-HI)
o
European Quality of Life – 5 
Dimensions 5 Level (EQ-5D-5L)
o
Work Productivity Activity 
Impairment-Spondyloarthritis 
(WPAI-SpA)
o
Jenkins Sleep Evaluation 
Questionnaire (JSEQ)

To assess the efficacy of retreatment with 
ixekizumab following a flare during Period 2

Proportion of patients who regain ASDAS <1.3 
within 16 weeks after ixekizumab retreatment

Proportion of patients who regain ASDAS <2.1 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve/maintain an 
ASAS20, ASAS40, ASAS5/6, ASAS partial 
remission, ASDAS major improvement, and 
ASDAS clinically important improvement
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve an ASAS20, 
ASAS40, ASAS5/6, ASAS partial remission, 
ASDAS major improvement, ASDAS clinically 
important improvement, and ASDAS-inactive 
disease through Week 64

To determine the long-term treatment effect of 
80 mg ixekizumab Q2W and 80 mg ixekizumab 
Q4W through Week 104

The proportion of patients with ASAS20, 
ASAS40, ASAS 5/6, ASAS partial remission, 
clinically important improvement, major 
improvement, and inactive disease

Change from baseline in the individual 
components of the ASAS criteria

Change from baseline in BASDAI

Proportion of patients with BASDAI50
response

Change from baseline in ASDAS

Change from baseline in the measure of CRP

Change from baseline in BASFI

Change from baseline in the measures of spinal 
mobility
o
BASMI (linear), and BASMI 

I1F-MC-RHBY(a) Clinical Protocol
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LY2439821
Objectives
Endpoints
individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline in MASES and SPARCC

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

Proportion of patients with change in mSASSS 
score <2 from baseline of originating study  to
Week 56 in RHBY

Proportion of patients with no new 
syndesmophyte formation from baseline of
originating study to Week 56 in RHBY

Change from baseline in the following health 
outcomes measures
o
Fatigue NRS score
o
QIDS SR16 
o
SF-36 (both physical and mental 
component scores) 
o
ASAS-HI
o
EQ-5D-5L
o
WPAI-SpA 
o
JSEQ

To evaluate the development of 
anti-ixekizumab antibodies and its impact on 
the efficacy of ixekizumab

Efficacy response rates listed below at Week 64
and Week 104 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
Summary of Study Design:
Study I1F-MC-RHBY (RHBY) is a Phase 3, multicenter, long-term extension study that provides patients who have 
completed any of the originating studies (RHBV, RHBW, and RHBX) an opportunity to continue ixekizumab 
(LY2439821) treatment for up to 2 additional years.  Study RHBY includes 4 study periods:

Lead-In [Period 1]:  24 weeks (Week 0 to Week 24)

Extension Period including Double-Blind, Placebo-Controlled, Randomized Withdrawal–Retreatment 
[Period 2]:  40 weeks (Week 24 to Week 64)

Long-Term Extension Period [Period 3]:  40 weeks (Week 64 to Week 104)

Post-Treatment Follow-Up [Period 4]:  at least 12 weeks and up to 24 weeks after the date of the patient’s 
early termination visit (ETV) or last regularly scheduled visit

I1F-MC-RHBY(a) Clinical Protocol
Page 14
LY2439821
Treatment Arms and Duration:
The study duration will be up to 2 years for ixekizumab administration (80 mg Q2W or 80 mg Q4W), and up to 2 
years and 6 months for study participation over 4 periods:

During the Lead-In Period (Period 1; 24 weeks), patients will receive active treatment in the form of 
ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W (open label or blinded depending on the previous 
originating study).

During the Extension Period, including blinded, randomized withdrawal–retreatment (Period 2; 40 weeks):
(Group A): Patients who do not meet entry criteria for participation in the randomized withdrawal–
retreatment period will continue to receive uninterrupted ixekizumab 80 mg Q2W or ixekizumab 80 mg 
Q4W.
(Group B):  For patients having achieved a state of sustained remission who do meet the criteria for 
participation in the 40-week double-blind placebo-controlled randomized withdrawal–retreatment period
o
Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized to either 
ixekizumab 80 mg Q2W or placebo.  Patients who experience a flare will receive ixekizumab 
80 mg Q2W.
o
Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized to either 
ixekizumab 80 mg Q4W or placebo.  Patients who experience a flare will receive ixekizumab 
80 mg Q4W.

During the Long-Term Extension Period (Period 3; 40 weeks),
o
(Group A): Patients in Group A will continue their assigned treatment regimen uninterrupted. 
Patients in Group A receiving ixekizumab 80 mg Q4W may have their dose escalated to 
ixekizumab 80 mg Q2W if the investigator determines that the patient may benefit from an 
increase in frequency of dosing to achieve adequate disease control.
o
(Group B):  Patients in Group B will continue the same treatment that they were receiving at the 
end of Period 2.  However, if a patient experiences a flare and meets criteria for retreatment, the 
patient will be retreated with the ixekizumab treatment regimen (ixekizumab 80 mg Q2W or 
ixekizumab 80 mg Q4W) that he or she was receiving prior to withdrawal to evaluate whether the 
patient can regain his or her original response.  During the Long-Term Extension Period, patients 
in Group B receiving ixekizumab 80 mg Q4W may also have their dose escalated to ixekizumab 
80 mg Q2W if the investigator determines that the patient may benefit from an increase in 
frequency of dosing to achieve adequate disease control.  Escalation to ixekizumab 80 mg Q2W 
may occur only after the patient has been retreated upon flare with the ixekizumab treatment 
regimen received during Period 1 (ixekizumab 80 mg Q4W) for at least 12 weeks.

All patients receiving at least 1 dose of investigational product will enter the Post-Treatment Follow-Up 
(Period 4) for a minimum of 12 weeks and up to 24 weeks after their last regularly scheduled visit (or the 
date of their ETV).
Number of Patients:
It is estimated that approximately 750 patients will enter the long-term extension study (RHBY) after completion of 
studies RHBV, RHBW, or RHBX and that 30% of these patients (i.e., approximately 200 patients) will meet the 
criteria to enter the double-blind randomized withdrawal–retreatment period.  Approximately 100 patients who 
achieved a state of sustained remission on ixekizumab Q2W will be randomized to ixekizumab 80 mg Q2W or 

I1F-MC-RHBY(a) Clinical Protocol
Page 15
LY2439821
placebo, and approximately 100 patients who achieved a state of sustained remission on ixekizumab Q4W will be 
randomized to ixekizumab 80 mg Q4W or placebo.  Study RHBY will include patients who have completed one of 
the originating studies (RHBV, RHBW, and RHBX), and will include rad-axSpA and nonrad-axSpA patients, as 
well as bDMARD-naive and TNF-experienced patients.
Statistical Analysis:
Approximately 100 patients who achieved a state of sustained remission on ixekizumab 80 mg Q4W will be 
randomized in a 2:1 ratio to ixekizumab 80 mg Q4W or placebo, and approximately 100 patients who achieved a 
state of sustained remission on ixekizumab 80 mg Q2W will be randomized in a 2:1 ratio to ixekizumab 80 mg 
Q2W or placebo in the double-blind randomized withdrawal–retreatment period.  This total sample size of 200 will 
provide over 99% power to detect a difference in the proportion of patients who do not experience a flare between 
the combined ixekizumab treatment group (including Q2W and Q4W) and placebo using a 2-sided Fisher’s exact 
test at the 0.05 level, assuming the flare rates are 10% for ixekizumab and 70% for placebo.
During Period 2, the primary analysis (the proportion of patients in the combined ixekizumab treatment group who 
do not experience a flare during Period 2 compared with placebo) will be based on the Randomized Withdrawal ITT 
Population.  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 regions, 
and originating study in the model.  The odds ratio and 95% confidence intervals (CIs) will be reported; treatment 
difference and 95% CIs will also be reported.  Secondary analysis will be conducted using a Fisher’s exact test.
For the primary analysis, missing data will be imputed using the nonresponder imputation (NRI) method.  Patients 
will be considered a nonresponder (having a flare) for the NRI analysis if they do not meet the clinical response 
criteria at any specified analysis time point.  All nonresponders at any specified time point as well as all patients 
who discontinue study treatment before the specified analysis time point, for any reason, will be defined as a 
nonresponder for the NRI analysis. Patients without at least 1 observation on study treatment will also be defined as 
a nonresponder for the NRI analysis.  The NRI may be applied at any time point specified for analysis.
The primary outcome of proportion of patients who do not experience a flare will be tested for ixekizumab versus 
placebo at a 2-sided α=0.05.  The comparison of major secondary objectives 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.
The Kaplan-Meier product limit method will be used to estimate the survival curves for time-to-flare for the patients 
who are randomized to the randomized withdrawal–retreatment period. Treatment comparisons will be performed 
using the stratified log-rank test with treatment, geographic region, and originating study in the model.
The analysis for all continuous efficacy and health outcome variables will be made using analysis of covariance 
(ANCOVA) with treatment, baseline value, geographic region, and originating study in the model. Missing data 
will be imputed using modified baseline observation carried forward (mBOCF).  Type III sums of squares for the 
least-squares (LS) means will be used for the statistical comparison; the 95% CI will also be reported.
Fisher’s exact test will be used for all adverse events (AEs), baseline, discontinuation, and other categorical safety 
data.  Continuous vital signs and laboratory values will be analyzed by an ANCOVA with treatment and baseline 
values in the model.

I1F-MC-RHBY(a) Clinical Protocol
Page 16
LY2439821
For patients who are randomized and subsequently experience a flare in Period 2, efficacy, health outcomes, and 
safety data collected between time of flare and the end of Period 2 will be summarized for ixekizumab 80 mg Q2W 
or ixekizumab Q4W without inferential statistics.

I1F-MC-RHBY(a) Clinical Protocol
Page 17
LY2439821
2. Schedule of Activities
Schedule of Activities, Protocol I1F-MC-RHBY
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized Withdrawal–
Retreatment (Period 2)
Long-Term Extension Period 
(Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518 V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Informed consent
X
Physical 
examinationd
X
X
X
Vital signs (BP 
and pulse)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habitsg
X
X
X
Inclusion/
exclusion criteriah
X
Randomizationi
Xi
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSAID use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre-existing 
conditions and 
medical historyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Eye symptom 
assessmentk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Enter ASDASl
X
X
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Dispense IP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense SDAL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I1F-MC-RHBY(a) Clinical Protocol
Page 18
LY2439821
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized Withdrawal–
Retreatment (Period 2)
Long-Term Extension Period 
(Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518 V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Collect, review, 
and enter data 
from SDAL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Efficacy/Health Outcomes
MRI of spine plus 
SIJm
Xm
x-ray—spinen
X
Xn
Linear BASMI
X
X
X
X
X
X
X
X
X
Chest expansion
X
X
X
X
X
X
X
X
X
Occiput to wall 
distance
X
X
X
X
X
X
X
X
X
Enthesitis 
(MASES and 
SPARCC)
X
X
X
X
X
X
X
X
X
Assessment of 
TJC/SJC (46/44)
X
X
X
X
X
X
X
X
X
Patient Global 
Assessment of 
Disease Activity 
NRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spinal pain
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Healthcare 
resource 
utilization
X
X
X
X
X
X
X

I1F-MC-RHBY(a) Clinical Protocol
Page 19
LY2439821
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized Withdrawal–
Retreatment (Period 2)
Long-Term Extension Period 
(Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518 V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Fatigue NRS
X
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
X
ASAS-HI
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
WPAI-SpA
X
X
X
X
X
X
X
JSEQ
X
X
X
X
X
X
X
QIDS-SR16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm 
Supplement 
Formo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer TB 
test(s)p  
TB testing required only based on clinical assessment of TB risk (symptoms/signs/known or suspected TB exposure), and according to 
local regulations and/or local standard of care.
ECG
X
X
X
X
HBV DNAq
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy 
testr 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PTT, PT/INR
X
X
X
X
Fasting lipid 
panels
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 2 0
L Y 2 4 3 9 8 2 1
Le a d -I n Peri o d
( Peri o d 1)
E xte nsi o n Peri o d, I ncl u di n g Bli n de d, R a n d o mize d Wit h dr a w al –
Retre at me nt ( Peri o d 2)
L o n g -Ter m E xte nsi o n Peri o d 
( Peri o d 3)
E T V
Visit N o
( Gr o u p A)c
V 1 a
V 2  
V 3  
V 4
V 5 c
-
V 6
-
V 7
-
V 8
-
V 9
-
V 1 0
V 1 1
V 1 2
V 1 3
V 1 4
E T V
Visit N o
( Gr o u p B)c
V 5 0 5 c V 5 0 6
V 5 0 7
V 5 0 8
V 5 0 9
V 5 1 0 V 5 1 1 V 5 1 2 V 5 1 3 V 5 1 4
V 5 1 5
V 5 1 6
V 5 1 7
V 5 1 8
V 5 1 9
St u d y Wee k
W 0  
W 8
W 1 6
W 2 0
W 2 4
W 2 8
W 3 2  
W 3 6
W 4 0
W 4 4
W 4 8
W 5 2
W 5 6
W 6 0
W 6 4
W 7 6
W 8 8
W 1 0 0
W 1 0 4
St u d y D a y
b
5 6 
± 5 d
1 1 2
± 5 d
1 4 0
± 5 d
1 6 8
± 5 d
1 9 6
± 5 d
2 2 4
± 5 d
2 5 2
± 5 d
2 8 0
± 5 d
3 0 8
± 5 d
3 3 6
± 5 d
3 6 4
± 5 d
3 9 2
± 5 d
4 2 0
± 5 d
4 4 8
± 5 d
5 3 2
± 5 d
6 1 6
± 5 d
7 0 0
± 5 d
7 2 8
± 5 d
Ur i nal ysis  
X
X
X
X
X  
X
I m m u n o ge nicit y 
testi n gv, w
X
X
X
X
X
X  
X
P K sa m pli n g v, x
X
X
X
X
X
X  
X
C CI

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 2 4 3 9 8 2 1
P ost -Tre at me nt F oll o w -U p f or P atie nts Disc o nti n ui n g 
Tre at me nt ( Peri o d 4) y
Re q uire d F oll o w -U p Visits
As - Nee de d F oll o w-U p Visits
Visit N o
V 8 0 1
V 8 0 2
V 8 0 3 a n d O n w ar ds
St u d y Wee k
L V + 4 W
L V + 1 2 W
L V + 2 4 W
St u d y Da y
± 1 4 d
± 1 4 d
± 1 4 d
C o nc o mita nt me dicati o ns
X
X
X
Vital si g ns ( B P a n d p ulse) e
X
X
X
Wei g ht
f
X
X
X
Pree xisti n g c o n diti o ns a n d me dical hist or y j
X
X
X
A d verse e ve nts
X
X
X
C- S S R S
X
X
X
Self -Har m S u p ple me nt F or m o
X
X
X
QI D S -S R 1 6
X
X
X
H B V D N A q
X
X
Ser u m c he mistr y
X
X
X
He mat ol o g y
X
X
X
I m m u n o ge nicit y testi n gv, w
X
P K sa m pli n g v, x
X
C CI

I1F-MC-RHBY(a) Clinical Protocol
Page 22
LY2439821
Abbreviations:  ASAS-HI = Assessment of Spondyloarthritis International Society–Health Index; ASDAS = Ankylosing Spondylitis Disease Activity Score;  
BASDAI = Bath Ankylosing Spondylitis Disease Activity Index ; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing 
Spondylitis Metrology Index; BP = blood pressure; CRP = high sensitivity C-reactive protein; C-SSRS = Columbia-Suicide Severity Rating Scale; d = days; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; eCRF = electronic case report form; ePRO = electronic patient-reported outcome; EQ-5D-5L = 
European Quality of Life-5 Dimensions 5-Level; ETV = early termination visit; HBV = hepatitis B virus; INR = international normalized ratio; IP = 
investigational product; IWRS = interactive web-response system; JSEQ = Jenkins Sleep Evaluation Questionnaire; LV= last visit; MASES = Maastricht 
Ankylosing Spondylitis Enthesitis Score; MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inflammatory drug; NRS = numeric rating scale; 
PK = pharmacokinetic; PPD = purified protein derivative; PT = prothrombin time; PTT = partial thromboplastin time; QIDS-SR16 = Quick Inventory of 
Depressive Symptomatology-Self Report (16 items); RNA = ribonucleic acid; SDAL = Study Drug Administration Log; SF-36 = Short Form 36; SIJ = 
sacroiliac joints; SJC = swollen joint count; SPARCC = Spondyloarthritis Research Consortium of Canada; TB = tuberculosis; TJC = tender joint count; V = 
study visit; W = study week; WPAI-SpA = Work Productivity Activity Impairment Questionnaire-Spondyloarthritis.
a
For most patients, the final visit of the originating study (RHBV, RHBW, or RHBX) will coincide with Visit 1 (Week 0) of Study RHBY.  In these cases, any 
assessments/procedures (including laboratory tests) conducted during the patient’s final visit in the originating study should not be repeated for Visit 1 
(Week 0) of Study RHBY.  In cases where entry into Study RHBY is delayed beyond Week 52 of the originating study, assessments/procedures (including 
laboratory tests) indicated for Visit 1 (Week 0) of Study RHBY that are not conducted during the last visit (Visit 801 or Visit 802) of the originating study 
will be performed as indicated in the Schedule of Activities.
b
For most patients, the final visit of the originating study (RHBV, RHBW, or RHBX) will coincide with Visit 1 (Week 0) of Study RHBY.  However, in 
particular circumstances, the duration between the final visit of the originating study and Visit 1 (Week 0) of Study RHBY may be extended after consultation 
with the sponsor.  Therefore, there is no specified visit window for Visit 1 (Week 0) of Study RHBY.
c
Patients will be assigned to Group A or Group B at Visit 5/Visit 505 (Week 24).
d
A complete physical examination (excluding pelvic, rectal examination) will be performed at baseline.  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.
e
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.
f
Weight is only captured on eCRF at Visit 1 (Week 0), Visit 10/Visit 515 (Week 64), Visit 14/Visit 519 (Week 104), or ETV.  Body weight collected at other 
visits is used only for calculation of creatinine clearance.
g
Habits include recording of caffeine, alcohol, and tobacco consumption.
h
If patients are not eligible to enter Study RHBY at Week 52 in the originating study (e.g., due to unresolved safety concerns), then entry into Study RHBY 
may be delayed beyond Week 52 of the originating study.  See Section 6.1.
i
Patients who have achieved a state of sustained remission (Group B) will participate in randomized withdrawal–retreatment and will be randomized to their 
treatment assignment at Week 24.  See Section 5.1.
j
Evaluation includes both historical events as well as preexisting conditions which are assessed after baseline to determine any treatment-emergent worsening 
of preexisting conditions.  Adverse events that initiated in the originating study (RHBV, RHBW, or RHBX) and are ongoing by the time the patient completes 
participation in the originating study will be considered as preexisting conditions in Study RHBY.
k
Patients need to be asked about presence of eye symptoms; if eye symptoms are present then an eye examination is required.  See Section 9.4.5.

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 2 3
L Y 2 4 3 9 8 2 1
l
Sites will e nter i nt o I W R S t h e partial A S D A S sc ore pr o vi de d b y t he E P X T M w e bsite a n d t he ce ntral la b orat or y C R P val ue fr o m t his visit , as s o o n as a vaila ble.  
After Visit 5/ Visit 5 0 5 , t he partial A S D A S sc ore a n d C R P val ue will be e ntere d i nt o I W R S o nl y f or patie nts partici pati n g i n t he ra n d o mize d wit h dra wal–
retreat me nt ( Gr o u p B) .  O n ce a patie nt e x perie nces a flare (see Secti o n 5. 1 ), t he partial A S D A S sc ore a n d C R P val ue are n o l o n ger e ntere d i nt o I W R S.
m
A n M RI of t he s pi ne pl us SI J will be pe rf orme d at Wee k 2 4 (1 0 da ys) f or patie nts partici pati n g i n ra n d o mize d wit h dra wal– retreat me nt ( Gr o u p B).  If t he 
M RI was n ot c o m plete d wit hi n t he pr ot oc ol -defi ne d wi n d o w, please c o ntact Lill y me dical f or a d diti o nal g ui da nce.   See Secti o n 7. 7 f or a d diti o nal g ui da nce 
re gar di n g c o nc o mita nt t hera p y f or patie nts u n der g oi n g a n M RI.
n
Cer vical a n d l u m bar s pi ne o nl y .  A n  x-r a y is o nl y nee de d f or patie nts i nitiall y e nr olle d i n St u dies R H B V or R H B W.  If t he patie nt’s E T V occ urs pri or t o 
Visit 9 / Visit 5 1 3 ( Wee k 5 6), t he n a n x -ra y will nee d t o be perf or me d at t he E T V.  If t he patie nt’s E T V occ urs after Visit 9 / Visit 5 1 3 ( Wee k
5 6), a n x -r a y will 
o nl y  be re q uire d at E T V if a n x-ra y was n ot c ollecte d at Wee k
5 6.
o
A Self -Har m F oll o w -U p F or m m ust be c o m plete d f or eac h discrete e ve nt i de ntifie d o n t he Self -Har m S u p ple me nt F or m.
p
T B testi n g re q uire d o nl y base d o n cli nical asses s me nt of T B ris k (s y m pt o ms/si g ns/ k n o w n or s us pecte d T B e x p os ure), as deter mi ne d b y t he pr i nci pal 
i n vesti gat or, a n d acc or di n g t o l ocal re g ulati o ns a n d/ or l ocal sta n dar d of care ( Secti o n 9. 4. 6) .
q
H B V D N A m o nit ori n g will be perf or me d as i n dicate d i n t he Sc he d ule of Acti vities f or patie nts p ositi ve f or he patitis B c ore a nti b o d y at t he scree ni n g visit of 
t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) a n d w h o re q uire d H B V D N A m o nit ori n g d uri n g t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X).  If t he 
res ult of t he H B V D N A testi n g is p ositi ve, t he patie nt is t o be disc o nti n ue d fr o m t he st u d y a n d is t o recei ve a p pr o priate f oll o w-u p me dical care (refer t o 
Secti o n 9. 4. 1 0. 2 f or f urt her i nf or mati o n re gar di n g t he ti mi n g of disc o nti n uati o n).
r
O nl y f or fe males of c hil d beari n g p ote ntial .  Ur i ne pr e g na nc y test will be c ollecte d a n d rea d/a nal yze d l ocall y.  Patie nts will u n der g o uri ne pre g na nc y testi n g 
d uri n g desi g nate d sc he d ule d visits .  A d diti o nal uri ne pre g na nc y testi n g ca n be perf or me d at t he i n vesti gat or’s discreti o n.  Ur i ne testi n g f or pre g na nc y ma y 
occ ur at i nter vals m ore fre q ue ntl y t ha n acc or di n g t o t he Sc he d ule of Acti vities d uri n g t he st u d y treat me nt peri o d a n d/ or f oll o w u p peri o d if re q uire d per l ocal 
re g ulati o n.  Patie nts deter mi ne d t o be pre g na nt will be disc o nti n ue d fr o m treat me nt a n d w ill n o l o n ger be a d mi nistere d i n vesti gati o nal pr o d uct.
s
F or t he fasti n g li pi d pr ofile , patie nts are t o n ot eat or dri n k a n yt hi n g e xce pt water f or 1 2 h o urs pri or t o test.
t
W here c ollecti o n is all o we d b y l ocal re g ulati o ns.   All sa m ples ( ur i ne, ser u m, plas ma, R N A , a n d w h ole bl o o d) will be c ollecte d at t h e desi g nate d sc he d ule d 
visits.
v
A n a d diti o nal bl o o d sa m ple will be c ollecte d, w he n p ossi ble, f or a n y patie nt w h o e x perie nces a p ote ntial s yste mic a ller gic/ h y perse nsiti vit y reacti o n d uri n g t he 
st u d y as j u d ge d b y t he i n vesti gat or.
w
I m m u n o ge nicit y sa m ples are t o be c ollecte d bef ore i n vesti gati o nal pr o d uct i njecti o n.
x
P K sa m ples are t o be c ollecte d bef ore i n vesti gati o nal pr o d uct i njecti o n.
y
All patie n ts recei vi n g at least 1 d ose of i n vesti gati o nal pr o d uct will e nter t he P ost-Treat me nt F oll o w - Up ( Peri o d 4) f or a mi ni m u m of 1 2 wee ks a n d u p t o 
2 4 wee ks after t heir last re g ularl y sc he d ule d visit ( or t he date of t heir E T V ).  Patie nts w h ose E T V or last re g ularl y sc he d ule d visit is l o n ger t ha n 1 2 wee ks 
after t heir last i n vesti gati o nal st u d y me dicati o n d ose are n ot re q uire d t o e nter i nt o t he P ost -Treat me nt F oll o w -U p ( Peri o d 4).  Visits 8 0 1 a n d 8 0 2 are sc he d ule d 
at 4 a n d 1 2 wee ks (res pecti vel y) after t he date of t he last patie nt visit.  Visit 8 0 3 will occ ur if a patie nt’s ne utr o p hil c o u nts have n ot ret ur ne d t o t he criteria 
defi ne d i n Secti o n
C CI
9. 4. 1 0. 1 .

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3.
Introduction
3.1.
Study Rationale
The clinical development plan to evaluate the efficacy and safety of ixekizumab in patients with 
axial spondyloarthritis (axSpA) includes three Phase 3 studies (I1F-MC-RHBV [RHBV], 
I1F-MC-RHBW [RHBW], and I1F-MC-RHBX [RHBX]; hereafter referred to as the originating 
studies).  The current study (I1F-MC-RHBY [RHBY]) is an extension study and offers patients 
who have completed any of these originating studies an opportunity to continue ixekizumab 
(LY2439821) treatment for up to 2 additional years.
Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) high-affinity monoclonal 
antibody (MAb) that selectively targets the cytokine interleukin-17A (IL-17A, also known as 
IL-17).  Ixekizumab treatment is administered by subcutaneous (SC) injections.  The 
demonstration of increased IL-17 producing Th17 lymphocyte numbers and serum IL-17 levels 
in radiographic axSpA (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).  Compelling scientific information exists to date suggesting 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).
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 with axSpA who have failed nonsteroidal anti-inflammatory drugs (NSAIDs), and for 
patients with axSpA 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.
Axial spondyloarthritis requires long-term and often life-long treatment and data from 
withdrawal studies with tumor necrosis factor alpha inhibitors (TNF inhibitors) have shown that 
in most patients with axSpA, treatment needs to be maintained long-term in order to maintain 
response (Baraliakos et al. 2005, 2007; Brandt et al. 2003, 2005). In patients with early disease, 
the likelihood of maintaining response after treatment withdrawal may be somewhat higher 
(Haibel et al. 2008; Barkham et al. 2009; Haibel et al. 2010; and Sieper et al. 2014).
Inhibition of IL-17A represents a newer therapeutic class for the treatment of axSpA. 
Accordingly, there is clinical utility in understanding whether an alternative 
mechanism-of-action other than inhibition of TNF may offer durability in maintaining an 
achieved response following the withdrawal of treatment. During the double-blind,
placebo-controlled, randomized withdrawal–retreatment period, the current study (RHBY) will 
evaluate what happens with patients who achieved sustained remission on ixekizumab treatment 
when they are discontinued from treatment, as well as how long it takes for these patients to 
relapse.  In addition, the study will evaluate the effect of ixekizumab on structure progression in 
the spine approximately 2 years post-baseline of the originating Phase 3 study.

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3.2.
Background
Axial spondyloarthritis, a chronic inflammatory disease predominantly affecting the axial 
skeleton (sacroiliac joints [SIJ] and spine) (Poddubnyy 2013), is now recognized as a single 
disease entity, with a subset defined by the presence of radiographically (rad-axSpA) defined 
structural damage of the SIJ and a subset without clear structural damage defined 
radiographically (nonradiographic axSpA [nonrad-axSpA]).  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 it is still one disease.  
AxSpA, in a similar fashion, also has subsets, and can nonetheless be considered a single disease 
(Deodhar et al. 2014).
Radiographic axSpA, also called ankylosing spondylitis (AS), represents a disease in which there 
is evidence of disease features on radiographic imaging.  It is a chronic inflammatory disease 
characterized by chronic inflammation of the axial skeleton and variable involvement of the 
peripheral joints (Braun and Sieper 2007).  As the disease progresses, it can lead to new bone 
formation in the form of syndesmophytes and joint ankylosis, primarily in the axial skeleton.  
Patients with rad-axSpA may also have extra-articular manifestations of the disease such as 
enthesitis, anterior uveitis, psoriasis, and inflammatory bowel disease (IBD), as well as 
comorbidities of aortitis or cardiac conduction abnormalities.  Compared with the general 
population, patients with rad-axSpA have increased rates of work disability, unemployment, and 
mortality (Boonen and van der Linden 2006).
According to several national and international referral programs (Rudwaleit and Sieper 2012; 
Poddubnyy et al. 2012), the proportion of nonrad-axSpA patients among all axSpA patients 
ranges from 40% to 60%.
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 -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.
Axial spondyloarthritis affects up to 1.4% of the adult population worldwide (Braun and Sieper 
2007; Reveille et al. 2012; Strand et al. 2013).  Current standard of care for rad-axSpA includes 
regular exercise, physical therapy, NSAIDs, and TNF inhibitors (Braun et al. 2011; Ward et al. 
2015).  In addition, recently completed registration studies of secukinumab (an IL-17A 

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antagonist like ixekizumab) have also demonstrated efficacy in patients with rad-axSpA (Baeten 
et al. 2015; Braun et al. 2015).  For patients with nonrad-axSpA, the current standard of care 
includes regular exercise, physical therapy, and NSAIDs.  TNF inhibitors have also 
demonstrated efficacy in nonrad-axSpA; however, although they are approved in some 
geographies, 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) including methotrexate (MTX) or systemic 
corticosteroids (Braun and Sieper 2009; Haibel and Specker 2009).
TNF inhibitors have demonstrated efficacy across the axSpA spectrum and may be prescribed 
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).  While TNF inhibitors have proven to be effective treatments for 
axSpA, an unmet need remains, as not all patients respond well to or tolerate TNF inhibitor 
treatments (van der Heijde et al. 2006; Heiberg et al. 2008; Inman et al. 2008; Glintborg et al. 
2010).  While TNF inhibitors have demonstrated significant impact on signs and symptoms, 
function, and quality of life, they have not been able to demonstrate significant effect on 
structural progression in prospective clinical studies.  The use of these biologic therapies in 
various diseases also is associated with safety concerns, such as opportunistic infections, 
demyelinating disorders, blood dyscrasias, reactivation of tuberculosis (TB), and exacerbation of 
congestive heart failure (Moreland 2005; Smith et al. 2009).  There remains, therefore, a 
significant unmet need for safer, more effective treatments for patients with axSpA (Dougados 
and Baeten 2011).
3.3.
Benefit/Risk Assessment
The 2 ixekizumab treatment regimens in Study RHBY (ixekizumab 80 mg every 2 weeks [Q2W]
and ixekizumab 80 mg every 4 weeks [Q4W]) have also been tested in pivotal Phase 3 studies in 
patients with psoriasis (Ps) and psoriatic arthritis (PsA), and demonstrated efficacy with 
favorable benefit-risk profile in patients with Ps (Griffiths et al. 2015) and in patients with PsA 
(Gottlieb et al. 2015; Mease et al. 2015).  Other therapies (most TNF inhibitors and 
secukinumab) have demonstrated efficacy with common dose regimens across various 
rheumatological conditions (RA, PsA, axSpA) (Humira® package insert, 2016 [WWW]; Enbrel®
package insert, 2015 [WWW]; Simponi® package insert, 2016 [WWW]; Cimzia® package insert 
2016, [WWW]; Cosentyx® package insert 2016, [WWW]; Sanford and McKeage 2015).  The 
collective data from ixekizumab and secukinumab on efficacy of IL-17A inhibition across 
various indications support a reasonable expectation of efficacy for ixekizumab in patients with 
rad-axSpA, both short and long-term.  As up to 40% of the patients do not get appropriate benefit 

I1F-MC-RHBY(a) Clinical Protocol
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from TNF inhibitors and TNF inhibitors have failed to demonstrate significant effect on 
structural progression, there is a need for additional alternative therapies.
Eli Lilly and company (Lilly) has considerable experience with ixekizumab across indications, 
and more than 4950 patients (4209 Ps patients, 532 RA patients, and 209 PsA patients) have 
been treated with at least 1 dose of ixekizumab.  Across 3 disease states (RA, PsA, and Ps), no 
notable safety concerns have been observed with the currently proposed dose regimens that 
would preclude the study of ixekizumab for the treatment of patients with axSpA.  Events 
identified as important potential risks for ixekizumab include serious infections, serious 
hypersensitivity, and IBD.  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 Investigator’s Brochure (IB).  The protocol for Study RHBY includes 
appropriate inclusion/exclusion criteria to minimize enrolling patients with greater safety risks, 
as well as criteria to discontinue those patients who develop potentially increased safety risks 
during the study.  Regular review of blinded safety data and risk mitigation actions by Lilly or its 
designee are intended to assist in identification and reduction of potential risks associated with 
ixekizumab administration.  In addition, patients participating in Study RHBY will already have 
successfully completed one of the originating 1-year axSpA studies.
The current benefit/risk profile of ixekizumab therefore supports further research of ixekizumab 
in axSpA.

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4.
Objectives and Endpoints
Table RHBY.1 shows the objectives and endpoints of the study.
Table RHBY.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during
Period 2

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during Period 2
Objectives and Endpoints
Objectives
Endpoints
Major Secondary

To compare the combined ixekizumab 
treatment group to historical control for 2-year 
radiographic progression in spine in patients 
with active radiographic axSpA (rad-axSpA)

Change in modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS score)

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg every 2 weeks (Q2W) treatment group 
or ixekizumab 80 mg every 4 weeks (Q4W) 
treatment group is superior to placebo in 
maintaining response after randomized
withdrawal

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during Period 2

To evaluate in patients having achieved a state 
of sustained remission whether the combined
ixekizumab treatment group is superior to the 
placebo group in maintaining response after 
randomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during Period 2

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg Q2W treatment group or ixekizumab 
80 mg Q4W treatment group is superior to 
placebo in maintaining response after 
randomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during Period 2

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Objectives
Endpoints
Other Secondary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
Period 2

The proportion of patients in the randomized 
withdrawal population with ASAS20, ASAS40, 
ASAS 5/6, ASAS partial remission, clinically
important improvement (change of Ankylosing 
Spondylitis Disease Activity Score [ASDAS] 
≥1.1 units), major improvement (change of 
ASDAS ≥2.0 units), and inactive disease 
(ASDAS <1.3) during Period 2

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 with Bath Ankylosing 
Spondylitis Disease Activity Index 50 
(BASDAI50) response

Change from baseline in (ASDAS)

Change from baseline in the measure of high 
sensitivity C-reactive protein (CRP)

Change from baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI)

Change from baseline in the measures of spinal
mobility:
o
Bath Ankylosing Spondylitis 
Metrology Index (BASMI) (linear), 
and BASMI individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline in Maastricht Ankylosing 
Spondylitis Enthesitis Score (MASES) and
Spondyloarthritis Research Consortium of 
Canada Score (SPARCC)

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

Change from baseline in the following health 
outcomes measures:
o
Fatigue numeric rating scale (NRS) 
score
o
Quick Inventory of Depressive 
Symptomatology Self-Report-16 
(QIDS-SR16)
o
SF-36 (both physical and mental 
component scores)
o
Assessments of Spondyloarthritis 

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Objectives
Endpoints
International Society–Health Index 
(ASAS-HI)
o
European Quality of Life -
5 Dimensions 5 Level (EQ-5D-5L)
o
Work Productivity Activity 
Impairment-Spondyloarthritis 
(WPAI-SpA)
o
Jenkins Sleep Evaluation 
Questionnaire (JSEQ)

To assess the efficacy of retreatment with 
ixekizumab following a flare during Period 2

Proportion of patients who regain ASDAS <1.3 
within 16 weeks after ixekizumab retreatment 

Proportion of patients who regain ASDAS <2.1 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve/maintain an 
ASAS20, ASAS40, ASAS5/6, ASAS partial 
remission, ASDAS major improvement, and 
ASDAS clinically important improvement 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve an ASAS20, 
ASAS40, ASAS5/6, ASAS partial remission, 
ASDAS major improvement, ASDAS clinically 
important improvement, and ASDAS-inactive 
disease through Week 64

To determine the long-term treatment effect of 
80 mg ixekizumab Q2W and 80 mg ixekizumab 
Q4W through Week 104

The proportion of patients with ASAS20, 
ASAS40, ASAS 5/6, ASAS partial remission, 
clinically important improvement, major 
improvement, and inactive disease

Change from baseline in the individual 
components of the ASAS criteria

Change from baseline in BASDAI

Proportion of patients with BASDAI50
response

Change from baseline in ASDAS

Change from baseline in the measure of CRP

Change from baseline in BASFI

Change from baseline in the measures of spinal 
mobility:
o
BASMI (linear), and BASMI 
individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline in MASES and SPARCC

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 3 1
L Y 2 4 3 9 8 2 1
O bjecti ves
E n d p oi nts

Pr o p orti o n of patie nts wit h c ha n ge i n m S A S S S 
sc ore < 2 fr o m baseli ne of ori gi nati n g st u d y t o 
Wee k 5 6 i n R H B Y

Pr o p orti o n of patie nts wit h n o ne w 
s yn des m o p h y te f or mati o n fr o m baseli ne of 
or i gi nati n g st u d y t o Wee k 5 6 i n R H B Y

C ha n ge f r om baseli ne i n t he f oll o wi n g healt h 
o utc o mes meas ures :
o
Fati g ue N R S sc ore
o
QI D S S R 1 6
o
S F -3 6 ( b ot h p h ysical a n d me ntal 
c o m p o ne nt sc ores)
o
A S A S -HI
o
E Q - 5 D- 5 L
o
W P AI -S p A
o
J S E Q

T o e val uate t he de vel o p me nt of 
a nti -i xe kiz u ma b a nti b o dies a n d its i m pact o n 
t he efficac y of i xe kiz u ma b

Efficac y res p o nse rates liste d bel o w at 
Wee k s 6 4 a n d 1 0 4 b y treat me nt-e mer ge nt a nti -
dr u g a nti b o d y ( T E -A D A ) stat us a n d b y 
ne utralizi n g a nti -dr u g a nti b o d y ( N A b ) stat us:
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 4 0
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 2 0
o
Pr o p orti o n of patie nts ac hie vi n g A S D A S 
i nacti ve disease
C CI

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5.
Study Design
5.1.
Overall Design
Study I1F-MC-RHBY (RHBY) is a Phase 3, multicenter, long-term extension study that includes 
a double-blind, placebo-controlled, randomized withdrawal–retreatment period. The study 
duration will be up to 2 years for ixekizumab administration, and up to 2 years and 6 months for 
study participation over 4 study periods:

Lead-In [Period 1]:  24 weeks (Week 0 to Week 24)

Extension Period including Double-Blind, Placebo-Controlled, Randomized Withdrawal–
Retreatment [Period 2]:  40 weeks (Week 24 to Week 64)

Long-Term Extension Period [Period 3]:  40 weeks (Week 64 to Week 104)

Post-Treatment Follow-Up [Period 4]:  at least 12 weeks and up to 24 weeks after the 
date of the patient’s early termination visit [ETV] or last regularly scheduled visit).
Patients who completed an originating study (RHBV, RHBW, or RHBX) through Week 52 may 
be eligible for enrollment into Study RHBY provided they fulfill study entry criteria for Study 
RHBY (see Section 6).
Study RHBY will evaluate the sustainability of clinical benefits, safety, and tolerability of 
ixekizumab treatment as well as the impact of ixekizumab on structural progression in patients 
with axSpA. In addition, maintenance of response after treatment withdrawal will be evaluated 
in those patients having achieved a state of sustained remission, defined as one of the following:

Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 at Weeks 16 and 20,
OR

ASDAS <1.3 at Week 16 and ASDAS <2.1 at Week 20,
OR

ASDAS <2.1 at Week 16 and ASDAS <1.3 at Week 20.
Figure RHBY.1 illustrates the study design.  During the 24-Week Lead-In Period [Period 1]), all 
patients will receive active treatment in the form of ixekizumab 80 mg Q4W or ixekizumab 
80 mg Q2W.
[Group A]:  Patients who DO NOT meet entry criteria for participation in the 40-week 
double-blind, placebo-controlled, randomized withdrawal–retreatment period will continue to 
receive the ixekizumab dose regimen that they were receiving at Week 24 during Periods 2 and 
3.
[Group B]:  For patients who DO meet entry criteria for participation in the 40-week double-
blind, placebo-controlled, randomized withdrawal–retreatment period (i.e., patients having 
achieved a state of sustained remission),

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
Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized to either 
ixekizumab 80 Q2W or placebo at 2:1 ratio and will be stratified by geographic region 
and originating study.

Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized to either 
ixekizumab 80 mg Q4W or placebo at 2:1 ratio and will be stratified by geographic
region and originating study.
After completion of the 40-week randomized withdrawal–retreatment period, patients will 
continue the same treatment that they were receiving at the end of Period 2, and will continue in 
the Long-Term Extension Period (Period 3).  All treatment groups and administration of the 
investigational product are described in Section 7.1, and the Study Drug Administration Log is 
described in Section 7.2.1.
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Section 2).  Selected study procedures are to be performed before 
administration of the investigational product, as applicable.  Appendix 2 lists the specific 
laboratory tests that will be performed for this study.
Patients who have taken at least 1 study dose and who discontinue study treatment are to 
complete an ETV and enter into Post-Treatment Follow-Up Period (Period 4) for at least 12 
weeks and up to 24 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 study dose 
are not required to enter into the Post-Treatment Follow-Up Period. For the management of 
patient safety, patients are to be monitored through the Post-Treatment Follow-Up Period as 
indicated on the Schedule of Activities (Section 2).  Excluded and concomitant medications are 
detailed in Section 7.7.  Immunogenicity testing and pharmacokinetic (PK) sampling are detailed 
in Section 9.4.9 and Section 9.5, respectively.  Section 10.3.7 outlines the information regarding 
the interim analyses.

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Lead-In 
Period 
(Period 1)
Post
Treatment
Follow-up 
(Period 4)
W0e
24 weeks
W24
ixekizumab
80 mg Q2W
104
ixekizumab
80 mg Q4W
ixekizumab 80 mg Q4W
placebo
Retreatc
Retreatc
continuous ixekizumab 80 mg Q4W
Extension Period, Including Blinded, 
Randomized Withdrawal-Retreatment 
(Period 2)
ixekizumab 80 mg Q2W
placebo
continuous ixekizumab 80 mg Q2W
Up to 
24 weeks
Long-Term Extension Period 
(Period 3)
W64
Group Bb
40 weeks
40 weeks
Retreatc
Retreatc
Group Aa
Group Aa
Group Bb
ixekizumab 80 mg Q2W
Escalated
Escalated

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Abbreviations:  Q2W = once every 2 weeks; Q4W = once every 4 weeks; W = week.
a
Patients in Group A will continue to receive the same ixekizumab dose regimen that they were receiving during Period 1.
b
Only patients having achieved a state of sustained remission (Group B) are eligible for participation in the randomized 
withdrawal–retreatment period.
c
Patients who experience a flare will be retreated with the ixekizumab treatment regimen that they were receiving prior to 
withdrawal.
d
As of Week 64, patients receiving ixekizumab 80 mg Q4W during Period 3 may have their dose escalated to ixekizumab 
80 mg Q2W if the investigator determines that the patient may benefit from an increase in frequency of dosing to achieve 
adequate disease control.  However, for patients in Group B, escalation to ixekizumab 80 mg Q2W may occur only after the 
patient has been retreated upon flare with the ixekizumab treatment regimen received during Period 1 (ixekizumab 80 mg 
Q4W) for at least 12 weeks.
e
For patients who were receiving ixekizumab in the originating study, the dose in the 24-week Lead-In Period (Period 1) will 
be based on the current dosing in the originating study.  For patients in Study RHBX who were on placebo, patients will
receive ixekizumab 80 mg Q4W.
Figure RHBY.1.
Illustration of study design for Clinical Protocol I1F-MC-RHBY.

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Lead-In Period (Period 1):  Patients who were previously receiving ixekizumab treatment 
during Studies RHBV and RHBW will, as of Week 0 in Study RHBY, continue to receive the 
same ixekizumab treatment regimen they were on at the end of the originating study, but now in 
open-label fashion.
For patients in Study RHBX, treatment during the Lead-In Period will be assigned as follows:

Patients who were rescued to ixekizumab 80 mg Q2W will remain on ixekizumab 80 mg 
Q2W in open-label fashion.

Patients who were receiving blinded treatment with either ixekizumab 80 mg Q2W or 
ixekizumab 80 mg Q4W will continue on their ixekizumab dose regimen in blinded 
fashion.

Patients who were receiving blinded treatment with placebo will be assigned to receive 
blinded treatment with ixekizumab 80 mg Q4W.
Note:  Patients from Study RHBX on blinded therapy in Period 1 of Study RHBY will continue 
on blinded treatment until at least the Week 52 datalock has occurred for Study RHBX.
Patients, site personnel, and the Sponsor will remain blinded to the initial treatment patients were 
assigned to in Studies RHBV, RHBW, and RHBX until after completion of datalock for the 
respective originating study (i.e., Week 16 datalock for Studies RHBV and RHBW, and Week 52 
datalock for Study RHBX).
Screening for eligibility for Study RHBY should occur during the last visit (Week 52) of the 
originating study.  However, in particular circumstances, entry into Study RHBY may occur after 
Week 52 of the originating study after consultation with the sponsor (see Section 6.1).  More 
details on treatment groups and administration of the investigational product are described in 
Section 7.1.
Extension Period, Including Blinded, Randomized Withdrawal–Retreatment (Period 2):
Eligibility criteria for participation in randomized withdrawal are defined as one of the 
following:

ASDAS <1.3 at Weeks 16 and 20,
OR

ASDAS <1.3 at Week 16 and ASDAS <2.1 at Week 20,
OR

ASDAS <2.1 at Week 16 and ASDAS <1.3 at Week 20.
Patients who DO NOT meet entry criteria for participation in the 40-week double-blind,
placebo-controlled, randomized withdrawal–retreatment period (i.e., patients who have not 
achieved a state of sustained remission) will continue to receive uninterrupted ixekizumab 
therapy and are referred to as Group A.

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Patients who DO meet entry criteria for participation in the 40-week double-blind,
placebo-controlled, randomized withdrawal–retreatment period (i.e., patients having achieved a 
state of sustained remission) are referred to as Group B and will be re-randomized at Week 24 as 
follows:

Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized 2:1 at 
Week 24 to either ixekizumab 80 mg Q2W or placebo.  Patients who experience a flare 
will return to treatment with ixekizumab 80 mg Q2W.

Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized 2:1 at 
Week 24 to either ixekizumab 80 mg Q4W or placebo.  Patients who experience a flare 
will return to treatment with ixekizumab 80 mg Q4W.
A flare is defined as follows:

ASDAS ≥2.1 at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2 and/or 
Period 3.
Long-Term Extension Period (Period 3):
Group A: All patients will continue to receive uninterrupted ixekizumab therapy.  During Period 
3, patients in Group A receiving ixekizumab 80 mg Q4W may have their dose escalated to 
ixekizumab 80 mg Q2W if the investigator determines that the patient may benefit from an 
increase in frequency of dosing to achieve adequate disease control.
Group B:  Patients in Group B will continue the same treatment that they were receiving at the 
end of Period 2.  However, if a patient experiences a flare, the patient will be retreated with the 
ixekizumab treatment regimen (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W) that he or 
she was receiving prior to withdrawal to evaluate whether the patient can regain his or her 
original response.
During Period 3, patients in Group B receiving ixekizumab 80 mg Q4W may also have their 
dose escalated to ixekizumab 80 mg Q2W if the investigator determines that the patient may 
benefit from an increase in frequency of dosing to achieve adequate disease control.  Escalation 
to ixekizumab 80 mg Q2W may occur only after the patient has been retreated upon flare with 
the ixekizumab treatment regimen received during Period 1 (ixekizumab 80 mg Q4W) for at 
least 12 weeks.
Post-Treatment Follow-Up (Period 4):  All patients receiving at least 1 dose of investigational 
product will enter the Post-Treatment Follow-Up (Period 4) for a minimum of 12 weeks and up 
to 24 weeks after their last regularly scheduled visit (or the date of their ETV).
5.2.
Number of Participants
It is estimated that approximately 750 patients will enter the long-term extension study (RHBY) 
after completion of studies RHBV, RHBW, or RHBX.  This sample size is estimated based on 
the 1-year retention rates from ixekizumab Ps studies and from 1 secukinumab rad-axSpA study 
(Baeten et al. 2015), which had a retention rate of approximately 85%.

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5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient in the trial.
5.4.
Scientific Rationale for Study Design
In the context of long-term treatment, it is important to understand the long-term efficacy and 
safety of ixekizumab treatment in patients with axSpA. The current 2-year study will, together 
with the preceding 1-year studies RHBV, RHBW, and RHBX, provide descriptive data about 
efficacy and safety of ixekizumab after long-term treatment, up to 3 years (including the 1-year 
duration of the originating study), for patients with axSpA, including both rad-axSpA and 
nonrad-axSpA patients, and biological disease modifying antirheumatic drug (bDMARD)-naive
as well as TNF inhibitor-experienced patients. Therefore, data generated from the current study 
will help to provide further information on the long-term efficacy and safety profile of 
ixekizumab.
As axSpA is a chronic condition that may require long-term treatment, there is increasing interest 
in evaluating the need for long-term uninterrupted treatment compared to temporary treatment 
withdrawal after achieving clinical response, followed by retreatment if there is loss of clinical 
response (i.e., flare).  Data from withdrawal studies with TNF inhibitors have shown that in most 
patients with axSpA, treatment needs to be maintained long-term in order to maintain response 
(Baraliakos et al. 2005, 2007; Brandt et al. 2003, 2005). In patients with early axSpA, the 
likelihood of success of this approach may be somewhat higher (Haibel et al. 2008; Barkham et 
al. 2009; Haibel et al. 2010; Sieper et al. 2014).  The potential of ixekizumab (with a mechanism 
of action [MOA] different from TNF inhibitors) to maintain response after treatment withdrawal 
will be evaluated in the current study during a double blind placebo-controlled randomized 
withdrawal period (Period 2).
To increase the likelihood of successful withdrawal without immediate relapse, only patients 
having achieved a state of sustained remission will participate in the randomized withdrawal–
retreatment period. It is anticipated that approximately 30% of the 750 patients will meet the 
entry criteria for randomized withdrawal (Sieper et al. 2015).  These patients will be 
re-randomized in blinded fashion to either continue their current regimen or receive placebo.
Patients randomized to placebo may still receive treatment in the form of the allowed 
concomitant medications as described in the concomitant therapy section (Section 7.7).
The monthly visit schedule for patients participating in the randomized withdrawal–retreatment
period (Group B) allows these patients to be followed closely and ixekizumab treatment to be 
resumed upon signs of relapse.
The length of the randomized withdrawal period is 40 weeks and considered sufficiently long 
based on previous randomized withdrawal studies of TNF inhibitors in RA and axSpA (Haibel et 
al. 2008; Barkham et al. 2009; Haibel et al. 2010; Sieper et al. 2014; Smolen et al. 2014).  It is 
anticipated that the majority of patients who no longer receive active treatment will relapse 
within that time frame.

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The Long-Term Extension Period (Period 3) allows for collection of data for the continued 
assessment of longer-term safety data and maintenance of efficacy with ixekizumab treatment.
The Post-Treatment Follow-Up Period (Period 4) is important for safety monitoring following 
administration of the last study treatment.  The duration of the Post-Treatment Follow-Up Period 
is at least 12 weeks and up to 24 weeks to allow for monitoring during ixekizumab clearance and 
reflects a time period equivalent to approximately 5 half-lives of ixekizumab.
A repeat x-ray of the cervical and lumbar spine will be taken at Week 56 in Study RHBY 
(approximately 2 years after baseline of the originating study) to evaluate the potential effect of 
ixekizumab treatment on structural progression.  The x-ray at Week 56 is only needed for 
patients initially enrolled in Studies RHBV or RHBW (see Schedule of Activities, Section 2).  
As structural progression in axSpA is slow, a 2-year time interval between consecutive x-rays is 
appropriate for such evaluation in patients with radiographic axSpA and avoids radiographic 
overexposure for patients.
5.5.
Justification for Dose
Study RHBY is a long-term extension study for patients who have completed Week 52 of any of 
the following originating studies: RHBV, RHBW, or RHBX. The ixekizumab dose regimens 
used in Study RHBY (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W) are the same as 
those used in studies RHBV, RHBW, and RHBX.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
The study population for Study RHBY will include patients from any of the originating studies 
(RHBV, RHBW, or RHBX), and will therefore include patients with rad-axSpA and patients 
with nonrad-axSpA, with or without prior use of TNF inhibitors.
For most patients, Week 52 of the originating study (RHBV, RHBW, or RHBX) will coincide 
with Week 0 (Visit 1) for Study RHBY.  Study investigator(s) will review patient data from 
Week 52 in the respective originating study to determine if the patient meets all inclusion and 
none of the exclusion criteria to qualify for participation in Study RHBY.  If, at Week 52 in the 
originating study, a patient is not able to enter Study RHBY (e.g., due to unresolved safety 
concerns), investigational product will be temporarily interrupted and the patient will be 
evaluated in the originating study for up to 12 weeks beyond Week 52 (i.e., Visit 802 in the 
originating study) to determine whether treatment with investigational product can resume.  If, in 
the opinion of the investigator, restarting ixekizumab does not pose an unacceptable risk, the 
patient can begin participation in Study RHBY (Visit 1 [Week 0]).
Patients are eligible to be included in the study only if they meet the following criteria:
[1.]
Have completed the final study visit in Study RHBV, RHBW, or RHBX.  
(Note: Patients from Study RHBX are not eligible if they permanently 
discontinued ixekizumab and were receiving a TNF inhibitor).
[2.]
Must agree to use a reliable method of birth control.

If the patient is male, the patient must agree 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 the patient is female and is a woman of childbearing potential who tests 
negative for pregnancy, the patient must agree 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 birth control include, but are not limited to, oral 
contraceptives, contraceptive patch, injectable or implantable 
contraceptives, intrauterine device, vaginal ring, or diaphragm with 
contraceptive gel.

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(Note: Where required by regulation, a highly effective method of birth 
control is required.  A highly effective method of birth control is defined 
as one that results in a low failure rate [that is, <1% per year] when used 
consistently and correctly, such as male sterilization, oral contraceptives, 
contraceptive patch, injectable or implantable contraceptives, intrauterine 
device, or vaginal ring).
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:
Women who have had surgical sterilization (hysterectomy, 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).
[3.]
Have given written informed consent approved by Lilly or its designee, and 
the Investigational Review Board (IRB)/Ethical Review Board (ERB) 
governing the site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
[4.]
Have significant uncontrolled cerebro-cardiovascular (e.g., myocardial 
infarction [MI], unstable angina, unstable arterial hypertension, severe heart 
failure, or cerebrovascular accident), respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematologic, neuropsychiatric disorders, or 
abnormal laboratory values that developed during the originating ixekizumab
study (RHBV, RHBW, or RHBX) that, in the opinion of the investigator, pose 
an unacceptable risk to the patient if investigational product continues to be 
administered.
[5.]
Have a known hypersensitivity to ixekizumab or any component of this 
investigational product.
[6.]
Had investigational product permanently discontinued during a previous 
ixekizumab study.

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[7.]
Had temporary investigational product interruption at any time during or at 
the final study visit of the originating ixekizumab study (RHBV, RHBW, or 
RHBX) and, in the opinion of the investigator, restarting ixekizumab poses an 
unacceptable risk for the patient’s participation in the study.
[8.]
Have any other condition that, in the opinion of the investigator, renders the 
patient unable to understand the nature, scope, and possible consequences of 
the study or precludes the patient from following and completing the protocol.
[9.]
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.
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened.

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7. Treatments
7.1.
Treatments Administered
During the Lead-In Period (Period 1; Week 0 to Week 24), patients will receive active treatment 
in the form of ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W (open-label or blinded 
depending on the previous originating study; Table RHBY.2).  
During the Extension Period, including blinded, randomized withdrawal–retreatment (Period 2; 
Week 24 to Week 64), patients who do not meet entry criteria for participation in the randomized 
withdrawal–retreatment period (Group A) will continue to receive uninterrupted ixekizumab 80 
mg Q2W or ixekizumab 80 mg Q4W (Table RHBY.2).  
For patients having achieved a state of sustained remission who do meet the criteria for 
participation in the 40-week double-blind, placebo-controlled, randomized withdrawal–
retreatment period (Group B)

Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized to either 
ixekizumab 80 mg Q2W or placebo.  Patients who experience a flare (see Section 5.1) 
will receive ixekizumab 80 mg Q2W. 

Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized to either 
ixekizumab 80 mg Q4W or placebo.  Patients who experience a flare (see Section 5.1) 
will receive ixekizumab 80 mg Q4W. 
During the Long-Term Extension Period (Period 3; Week 64 to Week 104), patients in Group A 
will continue their assigned treatment regimen. Patients in Group A receiving ixekizumab 80 mg 
Q4W may have their dose escalated to ixekizumab 80 mg Q2W if the investigator determines 
that the patient may benefit from an increase in frequency of dosing to achieve adequate disease 
control (see Section 7.4).  
During the Long-Term Extension Period, patients in Group B will continue the same treatment 
that they were receiving at the end of Period 2.  However, if a patient experiences a flare and 
meets criteria for retreatment (see Section 5.1), the patient will be retreated with the ixekizumab 
treatment regimen (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W) that he or she was 
receiving prior to withdrawal to evaluate whether the patient can regain his or her original 
response.  As of Week 64 and during the Long-Term Extension Period, patients in Group B 
receiving ixekizumab 80 mg Q4W may also have their dose escalated to ixekizumab 80 mg 
Q2W, if the investigator determines that the patient may benefit from an increase in frequency of 
dosing to achieve adequate disease control. Escalation to ixekizumab 80 mg Q2W may occur 
only after the patient has been retreated with the ixekizumab treatment regimen received during 
Period 1 (ixekizumab 80 mg Q4W) for at least 12 weeks (see Section 7.4).
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

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
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 they have 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 7.1.1 and 7.1.2.

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Table RHBY.2.
Summary of Treatment Regimens
Study RHBY
Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
RHBV or
RHBW
ixekizumab 80 
mg Q2W
ixekizumab 80 mg Q2W 
(open-label)
[Dose: 1 ixekizumab 80-mg 
Q2W injection (beginning at 
Week 0)]
Group A: open-label
ixekizumab 80 mg Q2W
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindeda,d
ixekizumab 80 mg Q2W (blinded)
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
ixekizumab 80 
mg Q4W
ixekizumab 80 mg Q4W 
(open-label)
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0)] 
Group A: open-labelc
ixekizumab 80 mg Q4W
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24)] 
Group B: blindedb,d
ixekizumab 80 mg Q4W (blinded)
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24)]
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q4W (beginning at Week 24)]

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Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
RHBX
rescued to 
ixekizumab 80 
mg Q2W
ixekizumab 80 mg Q2W 
(open-label)
[Dose: 1 ixekizumab 80-mg 
Q2W injection (beginning at 
Week 0)]
Group A: open-label
ixekizumab 80 mg Q2W
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindeda,d
ixekizumab 80 mg Q2W (blinded)
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
ixekizumab 80 
mg Q2W 
(blinded) 
ixekizumab 80 mg Q2W 
(blinded)e
[Dose: 1 ixekizumab 80-mg 
Q2W injection (beginning at 
Week 0)]
Group A: blindede
ixekizumab 80 mg Q2W 
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindeda,d,e
ixekizumab 80 mg Q2W (blinded)
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]

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Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
ixekizumab 80 
mg Q4W 
(blinded) 
ixekizumab 80 mg Q4W 
(blinded)e
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0);  
and 1 placebo for ixekizumab 
injection Q4W (beginning at 
Week 2)]
Group A: blindedc,e
ixekizumab 80 mg Q4W 
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24);  
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]
Group B: blindedb,d,e
ixekizumab 80 mg Q4W (blinded)
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]  
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
placebo 
(blinded)
ixekizumab 80 mg Q4W 
(blinded)e
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0); 
and 1 placebo for ixekizumab 
injection Q4W (beginning at 
Week 2)]
Group A: blindedc,e
ixekizumab 80 mg Q4W 
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]
Group B: blinded b,d,e
ixekizumab 80 mg Q4W (blinded)
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)] 
or
placebo (blinded)
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]

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Abbreviations:  Q2W = every 2 weeks; Q4W = every 4 weeks.
a
Patients who experience a flare and meet the criteria for retreatment during Period 2 or Period 3 will receive ixekizumab 80 mg Q2W.
b
Patients who experience a flare and meet the criteria for retreatment during Period 2 or Period 3 will receive ixekizumab 80 mg Q4W.  As of Week 64, 
patients in Group B may have their dose escalated to ixekizumab 80 mg Q2W only after the patient was retreated upon flare with ixekizumab 80 mg Q4W for 
at least 12 weeks (Section 7.4).
c
As of Week 64, patients in Group A receiving ixekizumab 80 mg Q4W may have their dose escalated to ixekizumab 80 mg Q2W (Section 7.4).  Dose 
escalation may begin at the next scheduled visit or at an unscheduled visit prior to the next scheduled visit.
d
All patients in Group B will remain on blinded study drug from Week 24 until the completion of the study or time of flare (Section 7.3).
e
For patients entering Study RHBY from Study RHBX who were receiving blinded treatment at the end of the originating study, patients will continue to 
receive blinded treatment in Study RHBY until the 52-week datalock for Study RHBX is achieved.

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7.1.1. Administration of Investigational Product
Administration:  Injections will be self-administered SC by the patient or caregiver.  It is 
recommended that these injections be administered away from the investigational site.  If the 
patient or caregiver is not able to administer 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 the 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 7.2.1.
Possible injection sites are identified in the Manual Syringe Directions for Use.  The injection 
site may be rotated to another area for subsequent doses.
7.1.2. Special Treatment Considerations
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include, but are not limited to:

skin rash

pruritus (itching)

urticaria (hives)

angioedema (e.g., 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 will be drawn as soon as possible for immunogenicity and PK testing 
(Section 9.4.9).
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 (e.g., injection site erythema, injection site pruritus, 
etc.).  Patients who develop clinically significant systemic allergic/hypersensitivity reactions 

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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 8.1.1).  Medications considered appropriate for premedication include, but are not 
restricted to, acetaminophen/paracetamol up to 1000 mg and antihistamines (e.g., oral 
diphenhydramine 50 mg) given after all efficacy assessments have been completed for a given 
visit.  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.
7.1.3. 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.
7.2.
Method of Treatment Assignment
During the Lead-In Period (Period 1), patients who were previously receiving ixekizumab 
treatment during Studies RHBV and RHBW will, as of Week 0 in Study RHBY, continue to 
receive the same ixekizumab treatment regimen they were on at the end of the originating study, 
but now in open-label fashion.
For patients who were previously in Study RHBX, treatment during the Lead-In Period will be 
assigned as follows:

Patients who were rescued to open-label ixekizumab 80 mg Q2W will remain on 
ixekizumab 80 mg Q2W in open-label fashion.

Patients who were receiving blinded treatment with either ixekizumab 80 mg Q2W or 
ixekizumab 80 mg Q4W will continue on their ixekizumab dose regimen in blinded 
fashion.

Patients who were receiving blinded treatment with placebo will be assigned to receive 
blinded treatment with ixekizumab 80 mg Q4W.
During the Extension Period (Period 2), patients in Group A who do not meet entry criteria for 
randomized withdrawal–retreatment will continue to receive the same ixekizumab dose regimen 

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that they were receiving during the Lead-In Period (ixekizumab 80 mg Q2W or ixekizumab 80 
mg Q4W).
During the Extension Period (Period 2), patients in Group B, who have achieved a state of 
sustained remission, and meet the criteria for randomized withdrawal–retreatment (see 
Section 5.1), will be assigned to treatment groups as follows by a computer-generated random 
sequence using an interactive web-response system (IWRS).

Patients in the ixekizumab 80 mg Q2W treatment group will be re-randomized to either 
ixekizumab 80 Q2W or placebo at 2:1 ratio allocation and will be stratified by region and 
originating study.

Patients in the ixekizumab 80 mg Q4W treatment group will be re-randomized to either 
ixekizumab 80 mg Q4W or placebo at 2:1 ratio allocation and will be stratified by region 
and originating study.
During the Extension Period, the IWRS will be used to assign double-blind investigational 
product to each patient in Group B. Site personnel will confirm that they have located the 
correct investigational product package by entering a confirmation number found on the package 
into the IWRS.
7.2.1. Selection and Timing of Doses
Investigational product is to be administered at approximately the same time each day, as much 
as possible.  For injections not administered on the scheduled day of the week from Week 0 to 
Week 104, 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 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 9.2.3 for additional 
instructions regarding complaint handling).
7.3.
Blinding
Patients, study site personnel, and study team in Study RHBY will remain blinded to the initial 
treatment assigned in the originating study (RHBV, RHBW, or RHBX) until the time of datalock 
for the respective originating study (i.e., Week 16 datalock for Studies RHBV and RHBW, and 
Week 52 datalock for Study RHBX).
During the Lead-In Period (Period 1), all patients from studies RHBV and RHBW will receive 
treatment with either ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W in open-label fashion.  
For patients from Study RHBX, patients who were rescued to open-label treatment with 

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ixekizumab 80 mg Q2W will continue to receive open-label treatment with ixekizumab 80 mg 
Q2W during the Lead-In Period.  All other patients from Study RHBX will continue on blinded 
treatment in the extension Study RHBY until Week 52 datalock has occurred for Study RHBX.
During the Extension Period (Period 2), including blinded, randomized withdrawal–retreatment, 
patients who do not meet entry criteria for participation in the randomized withdrawal–
retreatment period (Group A) will continue to receive ixekizumab 80 mg Q2W or ixekizumab 80 
mg Q4W.  Patients having achieved a state of sustained remission and do meet the criteria 
outlined in Section 5.1 (Group B) will participate in the double-blind, placebo-controlled, 
randomized withdrawal–retreatment period.  During the randomized withdrawal–retreatment 
period, patients in Group B, study site personnel, and study team will be blinded to study 
treatment randomization.  Patients participating in the randomized withdrawal–retreatment 
period will continue to receive blinded treatment until the completion of the study or time of 
flare.  Upon flare, patients will be retreated with the ixekizumab treatment regimen assigned in 
Period 1 in an open-label fashion.  Patients who experience a flare and were originally from 
Study RHBX will not receive open-label treatment until the Week 52 datalock has occurred for 
Study RHBX.
During the Long-Term Extension Period (Period 3), patients from Group A will continue to 
receive ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W.  Patients from Group B will 
continue the same treatment they were receiving at the end of Period 2 (ixekizumab 80 mg Q2W, 
ixekizumab 80 mg Q4W, or placebo) in blinded fashion until the completion of the study or time 
of flare.  Upon flare, patients will be retreated with the ixekizumab treatment regimen assigned 
in Period 1 in an open-label fashion.  As of Week 64, patients initially treated with ixekizumab
80 mg Q4W during Period 1 may have their dose escalated to ixekizumab 80 mg Q2W, in an 
open-label fashion, only after the patient has experienced a flare and been subsequently retreated 
with ixekizumab 80 mg Q4W for at least 12 weeks.
Patients who experience a flare and were originally from Study RHBX will not receive 
open-label treatment until the Week 52 datalock has occurred for Study RHBX.
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 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.
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 

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physician/clinical research scientist prior to unblinding a patient’s treatment assignment unless 
this could delay emergency treatment of the patient.  If the patient’s treatment assignment is 
unblinded, Lilly must be notified immediately.
7.4.
Dosage Modification
As described in Section 5.1, if a patient who has achieved a state of sustained remission (Group 
B) during the randomized withdrawal–retreatment period experiences a flare and meets the 
criteria for retreatment, the patient will be retreated with the ixekizumab treatment regimen that 
he or she was receiving prior to withdrawal (ixekizumab 80 mg Q2W or ixekizumab 80 mg 
Q4W).  During Period 2, retreatment will begin at the next scheduled visit.  During Period 3, 
given the longer interval between visits, retreatment may begin at the next scheduled visit or at 
an unscheduled visit prior to the next scheduled visit.
As of Week 64, patients in Group A receiving ixekizumab 80 mg Q4W may have their dose 
escalated to ixekizumab 80 mg Q2W in Period 3 if the investigator determines that the patient 
may benefit from an increase in frequency of dosing to achieve adequate disease control.  Dose 
escalation may begin at the next scheduled visit or at an unscheduled visit prior to the next 
scheduled visit.
As of Week 64, patients in Group B (Table RHBY.3):

who are receiving placebo will remain on placebo, and will be monitored per the 
Schedule of Activities (Section 2) for eligibility (i.e., flare) to be retreated with the 
ixekizumab treatment regimen they were receiving prior to withdrawal (ixekizumab 
80 mg Q2W or ixekizumab 80 mg Q4W).

who are receiving ixekizumab 80 mg Q4W may have their dose escalated to 
ixekizumab 80 mg Q2W in Period 3 if the investigator determines that the patient 
may benefit from an increase in dosing to achieve adequate disease control.  
Escalation to ixekizumab 80 mg Q2W may occur only after the patient has been
retreated upon flare with the ixekizumab treatment regimen received during Period 1
(ixekizumab 80 mg Q4W) for at least 12 weeks.

who are receiving ixekizumab 80 mg Q2W will remain on this dose until completion 
of the study or early discontinuation.

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Table RHBY.3.
Dosage Modification for Group B during Period 2 and Period 3
Period 1
(Open-Label)
Period 2
(Blinded)
Period 3
(Blinded)
If Flare during Period 2 or 3,
Retreat (Open-Label)
12 Weeks after Retreat, 
Escalate (Period 3)
(Open-Label)
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
N/A
placebo
placebo
ixekizumab
80 mg Q2W
N/A
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q2W
placebo
placebo
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q2W
Abbreviations:  N/A = not applicable; Q2W = every 2 weeks; Q4W = every 4 weeks.
Note:  Patients from Group B who experience a flare and meet criteria for retreatment during Period 2 or Period 3 
will be retreated with the ixekizumab treatment regimen received during Period 1 in an open-label fashion.  As of 
Week 64, patients initially treated with ixekizumab 80 mg Q4W during Period 1 may have their dose escalated to 
ixekizumab 80 mg Q2W, in an open-label fashion, only after the patient has experienced a flare and been 
subsequently retreated with ixekizumab 80 mg Q4W for at least 12 weeks.  Patients who experience a flare and 
were originally from Study RHBX will not receive open-label treatment until the Week 52 datalock has occurred 
for Study RHBX.
In addition, Section 9.4.10.1 describes instances where drug may be withheld.
Other than these exceptions, investigational product dose modifications are not permitted.
7.5.
Preparation/Handling/Storage/Accountability
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.
7.6.
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 10.3.2.4.
7.7.
Concomitant Therapy
All concomitant medication taken during the study must be recorded in the eCRF. Additional 
drugs are to be avoided during the study unless required to treat an AE or for the treatment of an 
ongoing medical problem. Patients will maintain their usual medication regimen for other 
concomitant diseases throughout the study unless specifically excluded in the protocol. 
During the randomized withdrawal–retreatment phase of Period 2, patients in Group B are 
requested to not have any changes to concomitant medications during the 40-week observation 

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period except for the defined retreatment medication or changes needing to be made for an AE or 
for safety reasons.
Patients undergoing an MRI at Week 24 (see Schedule of Activities, Section 2) may receive 
premedication of ≤30 mg of morphine or equivalent or other NSAIDs/cyclooxygenase-2
inhibitors, on the day of the MRI, for significant pain as judged by the investigator.  Patients with 
claustrophobia may receive premedication with benzodiazepine; the investigator should assess 
for potential interactions with other concomitant medication(s), such as opiates.
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.
Conventional DMARDs and/or other therapies such as, but not limited to, gold salts, 
cyclosporine, azathioprine, dapsone, 6 mercaptopurine, mycophenolate mofetil, or any other 
immunosuppressive agents are prohibited (see Table RHBY.4 for additional information 
regarding methotrexate).  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) are also 
prohibited.
Additional information regarding concomitant treatment with NSAIDs and analgesics, 
conventional DMARDs, and corticosteroids is provided in Table RHBY.4.

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Table RHBY.4.
Concomitant Treatment with NSAIDs and Analgesics, Conventional DMARDs, and Corticosteroids
Study RHBY 
Period 1
Period 2 
Period 3
NSAIDs and 
Analgesics
NSAIDs, including COX-2 inhibitors, 
will be allowed up to the maximum 
recommended doses for pain.  Patients 
are to be on stable dose during Period 1. 
Introduction of a new NSAID or dose 
adjustment to an existing NSAID is not 
permitted, unless required for safety 
reasons.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed and 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.  Patients are to be on stable 
dose during Period 1.  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.
Group A:
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 arthritis assessment.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed but 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.
Group B (participating in randomized
withdrawal): Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A:
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 arthritis assessment.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed but 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.
Group B (participating in randomized
withdrawal): Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 3.

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Period 1
Period 2 
Period 3
Conventional 
DMARDs
Methotrexate (oral or parenteral up to 
25 mg/week), sulfasalazine (up to 
3 g/day), or hydroxychloroquine (up to 
400 mg/day) is allowed.
During Period 1, alteration of cDMARD 
dose or route, and/or introduction of a 
new cDMARD are not permitted, unless 
required for safety reasons.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs.  Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group A:  Methotrexate (oral or 
parenteral up to 25 mg/week), 
sulfasalazine (up to 3 g/day), or 
hydroxychloroquine (up to 400 mg/day) 
may be allowed, and adjustment of 
allowed cDMARDs (e.g., dose change, 
introduction, withdrawal of cDMARDs 
or replacement of a current cDMARD 
with the introduction of a new 
cDMARD) is permitted.  Not more than 
1 adjustment of cDMARDs at 1 time 
within 12 weeks is recommended.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs. Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A:
Methotrexate (oral or parenteral up to 
25 mg/week), sulfasalazine (up to 
3 g/day), or hydroxychloroquine (up to 
400 mg/day) may be allowed, and 
adjustment of allowed cDMARDs (e.g., 
dose change, introduction, withdrawal of 
cDMARDs or replacement of a current 
cDMARD with the introduction of a new 
cDMARD) is permitted. Not more than 
1 adjustment of cDMARDs at 1 time 
within 12 weeks is recommended.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs. Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group B (participating in randomized
withdrawal): Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 3.

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Period 1
Period 2 
Period 3
Corticosteroids
Oral corticosteroids:  If on oral 
corticosteroids, the dose must not exceed 
10 mg/day of prednisone or its 
equivalent at any time during the study.
During Period 1, treatment alterations in 
oral corticosteroid dose are strongly 
discouraged.
Parenteral corticosteroids (intravenous, 
intramuscular):  Treatment with 
intravenous or intramuscular 
corticosteroids is not permitted.
Parenteral corticosteroids 
(intra-articular): Intra-articular injection 
of corticosteroid may be allowed on a 
limited basis: It is recommended that 
there be no more than 1 injection within 
any 1 year period.  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.
Group A:
Oral corticosteroids:
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 the 
study.
Parenteral corticosteroids (intravenous, 
intramuscular, intra-articular):
Treatment with parenteral corticosteroids 
is not recommended.  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.
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A:
Oral corticosteroids:
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 the 
study.
Parenteral corticosteroids (intravenous, 
intramuscular, intra-articular):
Treatment with parenteral corticosteroids 
is not recommended.  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.
Group B (participating in randomized
withdrawal): Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 3.
Abbreviations: cDMARD = conventional disease modifying antirheumatic drug; COX-2 = cyclooxygenase-2; eCRF = electronic case report form; 
MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; SJC = swollen joint count; TJC = tender joint count.

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Other Concomitant Medications:
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.
If the need for concomitant medication arises, the investigator is to base decisions on the patient 
and on clinical factors. Any additional medication, whether prescription or over-the-counter, 
used at baseline and/or during the course of the study, must be documented with the start and 
stop dates in the eCRF.  Additional systemic drugs are to be avoided during the study, unless 
required to treat an AE.  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-Treatment 
Follow-up Period, 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.
Any changes in medications not addressed above are to be discussed with the investigator.  
Patients must be instructed to consult the investigator or other appropriate study personnel at the 
site before taking any new medications or supplements.
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
Investigational product will not be made available to patients after conclusion of this study.

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8.
Discontinuation Criteria
The reason for and date of discontinuation from study treatment (investigational product) and 
study participation will be collected for all patients in the study.
Patients who have taken at least 1 study dose and who discontinue study treatment are to 
complete an ETV and enter into post-treatment follow-up for at least 12 weeks and up to 24 
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-Treatment Follow-Up Period. For the management of 
patient safety, patients are to be monitored through the Post-Treatment Follow-Up Period as 
indicated on the Schedule of Activities (Section 2).
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
The following criteria must be followed for discontinuation from study treatment.  Patients will 
enter into the Post-Treatment Follow-Up Period (Period 4) if they discontinue 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:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
>8x upper limit of normal (ULN)

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3x ULN and total bilirubin level >2xULN or 
prothrombin time >1.5xULN

ALT or AST >3xULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)

alkaline phosphatase >2.5xULN and total bilirubin >2xULN

alkaline phosphatase >2.5xULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
[2]
Other Laboratory tests:

neutrophil (segmented) counts (see safety monitoring for neutropenia 
in Section 9.4.10.1):
o
<500 cells/L (<0.50x103/µL or <0.50 GI/L)

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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 9.4.10.1)
- AND - a concurrent infection

total white blood count (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)
Note:  Laboratory test(s) that may result in discontinuation based on a single result may be 
repeated 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.
[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 AEs, Section 9.2.
[4]
Any positive TB test that indicates TB test conversion since prior testing 
(based on patient medical history), AND the patient does not receive 
appropriate treatment for latent TB; or there is evidence of active TB infection 
at any time.
[5]
Clinically significant systemic hypersensitivity reaction following SC 
administration of investigational product that does not respond to 
symptomatic medication or results in clinical sequelae.
[6]
The patient becomes pregnant.
[7]
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.
[8]
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.

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[9]
It is recommended that the patient is assessed by a psychiatrist or 
appropriately trained professional to assist in deciding whether the patient 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 Quick Inventory of Depressive Symptomatology-self 
report (16 items) (QIDS-SR16);
OR 
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 suicidal behaviors as recorded on the C-SSRS.
[10] The investigator or attending physician decides that the patient is to be 
withdrawn from study treatment.
[11] The patient requests to be withdrawn from study treatment.
[12] 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).
[13] The patient becomes hepatitis B virus (HBV) deoxyribonucleic acid (DNA)
positive.  The patient is to be referred to a specialist physician.  Discussion of 
the timing of discontinuation from study treatment and from the study is 
provided in Section 9.4.10.2.
8.1.2. Temporary Discontinuation from Study Treatment
Section 9.4.10.1 describes instances where drug may be withheld.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the sponsor or investigator identifies 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.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

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
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 (Section 2).
8.3.
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 
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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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 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.
9.1.
Efficacy Assessments
Below are brief descriptions on key aspects of efficacy assessments used in the study.  Complete 
assessments are included in site training materials.
9.1.1. Primary Efficacy Assessments
As described in Section 10.3.3.1, the primary efficacy endpoint is the proportion of patients in 
the randomized withdrawal population who do not experience a flare (a flare is defined as 
ASDAS ≥2.1 at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2).  The ASDAS 
is a composite index to assess disease activity in axSpA (Machado et al. 2011a, 2011b; Zochling 
2011).  The parameters used for the ASDAS (with high sensitivity C-reactive protein [CRP] as 
acute phase reactant) are the following: 
1) Total back pain (BASDAI question 2)
2) Patient global assessment (Section 9.1.2.4)
3) Peripheral pain/swelling (BASDAI question 3)
4) Duration of morning stiffness (BASDAI question 6)
5) CRP in mg/L
The ASDAScrp is calculated with the following equation:  0.121 × total back pain + 0.110 × 
patient global + 0.073 × peripheral pain/swelling + 0.058 × duration of morning stiffness + 0.579 
× Ln(CRP+1) (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.)
9.1.2. Secondary Efficacy Assessments
9.1.2.1.
Ankylosing Spondylitis Disease Activity Score
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

ASDAS >3.5 defines very high disease activity

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Secondary efficacy assessments will include evaluation of patients who meet the criteria for 
inactive disease (ASDAS <1.3; Machado et al. 2011c), clinically important improvement 
(defined as change ≥1.1 units), and major improvement (defined as change ≥2.0 units; Machado 
et al. 2011b).
9.1.2.2.
Imaging Used for Efficacy Measures and Disease Diagnosis
9.1.2.2.1. Radiographic Imaging of the Spine
The radiographic image (x-ray) of the spine is used to evaluate structure progression.
At Week 56, a spinal x-ray, plain radiograph of the lateral views of cervical and lumbar spine, 
will be centrally read; the x-ray at Week 56 is only needed for patients initially enrolled in 
Studies RHBV or RHBW.  The data set will be scored by the modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS; Wanders 2004; Creemers 2005).
By the scoring system of mSASSS of the spinal x-rays, a total of 24 sites are scored on the lateral 
cervical and lumbar spine: the anterior corners of the vertebrae from lower border of C2 to 
upper border T1 (inclusive), and from lower border of T12 to upper border of S1 (inclusive). 
Each corner can be scored from 0 to 3, resulting in a range from 0 to 72 for the total mSASSS.  
The example of scoring according to the mSASSS, 0 = normal; 1 = sclerosis, squaring or 
erosion; 2 = syndesmophyte; 3 = bony bridge.
9.1.2.2.2. Spondyloarthritis Research Consortium of Canada MRI Score for 
Sacroiliac Joints
At Week 24 (Group B:  Visit 505), an MRI of both left and right SIJ is collected.  Both left and 
right SIJ are scored for bone marrow edema.  Total SIJ Spondyloarthritis Research Consortium 
of Canada (SPARCC) scores can range from 0 to 72 with higher scores reflecting worse disease.  
Scoring will be performed by a central reader.
9.1.2.2.3. Ankylosing Spondylitis Spinal Magnetic Resonance Imaging Activity
At Week 24 (Group B:  Visit 505), an MRI of the spine is collected.  All 23 disco-vertebral units 
of the spine (from C2 to S1) are scored for bone marrow edema with a validated scoring method.  
Scoring will be performed by a central reader.
9.1.2.3.
ASAS20, ASAS40, ASAS5/6, ASAS Partial Remission
The following ASAS domains are used to determine ASAS20, ASAS40, ASAS 5/6, and ASAS 
partial remission (Sieper et al. 2009; ASAS Handbook):
1) Patient Global (Section 9.1.2.4)
2) Spinal Pain (Section 9.1.2.5)
3) Function (Section 9.1.2.6)
4) Inflammation (mean of BASDAI questions 5 and 6) (Section 9.1.2.7)
5) CRP (Section 9.1.2.14.1)
6) Spinal mobility (lateral spinal flexion) (Section 9.1.2.8)
9.1.2.3.1. 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 (from originating 

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study) of ≥1 units (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.
9.1.2.3.2. 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 (from originating study) 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.
9.1.2.3.3. ASAS5/6
The ASAS5/6 includes assessment of all 6 individual ASAS domains listed above 
(Section 9.1.2.3) and represents improvement of ≥20% in at least 5 domains.
9.1.2.3.4. 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, numeric rating scale [NRS]) in 
each of the following 4 domains:  Patient Global, Spinal Pain, Function, and Inflammation.
9.1.2.4.
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 an NRS and is rated between “0” (not active) and “10” (very active).
9.1.2.5.
Spinal Pain
From the ASAS Handbook (Sieper et al. 2009), the patient is asked to respond to the following 
2 questions (on average during the 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 an NRS and are each rated between “0” (no pain) and “10” (most 
severe pain).  The first question is used to derive responses (i.e., ASAS40, ASAS20, and so on).
9.1.2.6.
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.
9.1.2.7.
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) 

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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.
9.1.2.8.
Bath Ankylosing Spondylitis Metrology Index—Spinal Mobility
The Bath Ankylosing Spondylitis Metrology Index (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.
9.1.2.9.
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 cm 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.
9.1.2.10. 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 (occiput).  Then the distance from occiput to wall is measured.  
Two tries will be recorded.  The better (smaller) measurement of 2 tries in centimeters will be 
used for analyses (Sieper et al. 2009).
The measurement of occiput to wall distance must be assessed by a rheumatologist or health care 
provider who meets the qualifications for study assessment.
9.1.2.11. Maastricht Ankylosing Spondylitis Enthesitis Score
The Maastricht Ankylosing Spondylitis Enthesitis Score (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 

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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.
9.1.2.12. 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), c 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.
9.1.2.13. Peripheral Arthritis
9.1.2.13.1.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 
during the study (according to Section 7.7) 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, randomized 
withdrawal–retreatment period (Period 2), it is recommended that the same assessor performs the 
tender joint count (TJC) for a given patient.  Missing, replaced, ankylosed, or arthrodesed joints 
will be identified by the investigator and will be excluded from evaluation during the study.  
The TJC data will be collected electronically.
9.1.2.13.2.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 7.7) 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, randomized withdrawal–retreatment period (Period 2), it is 

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recommended that the same assessor performs the swollen joint count (SJC) for a given patient.  
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator and will 
be excluded from evaluation during the study.
The SJC data will be collected electronically.
9.1.2.14. Laboratory Tests Used for Efficacy Measures and Disease Diagnosis
9.1.2.14.1.High Sensitivity C-Reactive Protein
High sensitivity C-reactive protein 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 
ixekizumab on disease activity.
9.1.2.15. Health Outcomes Measures
9.1.2.15.1.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 or 
designee in the study’s CRF.  These data will be collected to support economic evaluations of 
treatment.
9.1.2.15.2.Fatigue Severity Numeric Rating Scale
The fatigue severity NRS is a patient-reported 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.
9.1.2.15.3.Medical Outcomes Study 36-Item Short-Form Health Survey
The Short Form 36 (SF-36) is a 36-item patient-reported 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).
9.1.2.15.4.Assessment of Spondyloarthritis International Society Health Index
The ASAS–Health Index (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 

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not agree (score 0).” A score of “1” is given where the item is affirmed, indicating adverse 
health.  All item scores are summed to give a total score or index.
9.1.2.15.5.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).
9.1.2.15.6.Work Productivity and Activity Impairment Questionnaire—
Spondyloarthritis
The Work Productivity Activity Impairment Questionnaire-Spondyloarthritis (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]).
9.1.2.15.7.Jenkins Sleep Questionnaire
The Jenkins Sleep Evaluation Questionnaire (JSEQ) is a 4-item scale designed to estimate sleep 
problems in clinical research.  The JSEQ assesses the frequency of sleep disturbance in 4 
categories:  1) trouble falling asleep, 2) waking up several times during the night, 3) having 
trouble staying asleep (including waking up far too early), and 4) waking up after the usual 
amount of sleep feeling tired and worn out.  Patients report the number of days they experience 
each of these problems in the past month on a 6-point Likert Scale ranging from 0 = “no days” to 
5 = “22-30 days.”  The total JSEQ score ranges from 0 to 20, with higher scores indicating 
greater sleep disturbance (Deodhar et al. 2010).

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9.2.
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.
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 should 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 informed consent form (ICF) is signed, study site personnel will record via case report 
form (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 any change in the condition(s) and any new conditions as 
AEs. Investigators should record their assessment of the potential relatedness of each AE to 
protocol procedure, investigational product, via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment 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 should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.

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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.”
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason: important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the CRF, SAE reporting begins 
after the patient has signed the ICF and has received investigational product.  However, 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 should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients 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 patient 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.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Lilly has procedures that will be followed for the recording and expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs) that are consistent with global regulations and 
the associated detailed guidances.

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9.2.2. 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.
Adverse events of special interest for ixekizumab are as follows:

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

inflammatory bowel disease 

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 7.1.2).  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.  The role of the CEC will be to 
adjudicate these defined clinical events in a blinded, consistent, and unbiased manner throughout 
the course of a study and ensure that all events that have been reported are evaluated uniformly 
by a single group (the CEC).
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 the CEC will be to adjudicate defined clinical events, in a blinded, 
consistent, and unbiased manner throughout the course of a study and ensure that all events that 
have been reported are evaluated uniformly by a single group.
9.2.3. 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.

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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.
9.3.
Treatment of Overdose
Refer to the IB and/or the product label where applicable.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, electrocardiograms (ECGs) should be collected according to the Schedule of 
Activities (Section 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 should be reported to Lilly or its 
designee as an AE via CRF.
9.4.2. Vital Signs
For each patient, vital signs measurements (sitting) should be conducted according to the 
Schedule of Activities (Section 2).  Vital signs include blood pressure (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 should be reported to Lilly or 
its designee as an AE via CRF.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).  Please reference the central laboratory manual for specific 
instructions.
Urine pregnancy test will be collected and read/analyzed locally.  Urine testing for pregnancy 
may occur at intervals more frequently than according to the Schedule of Activities during the 
study treatment period and/or follow up period if required per local regulation.
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 should be reported to Lilly or its 
designee as an AE via CRF.
9.4.4. Physical Examination
For each patient, a complete physical examination must be conducted according to the Schedule 
of Activities (Section 2).

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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.
9.4.5. 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 (Section 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).
9.4.6. Tuberculosis Testing
Tuberculosis testing will be conducted based on clinical assessment of TB risk 
(symptoms/signs/known or suspected TB exposure), and as required by local regulations and/or 
local standard of care.
Patients with a positive TB test and/or other evidence of active TB should be 
discontinued (Section 8.1.1).
In patients with a positive TB test indicating TB test conversion since prior testing (based on 
patient medical history), but no other evidence of active TB, study treatment should be withheld.  
These patients may continue in Study RHBY and resume study treatment without repeating TB
testing if all of the following conditions are met:

a specialist in the care of patients with TB (e.g., infectious disease or pulmonary 
medicine subspecialists) is consulted and does not identify evidence of active TB, and the 
patient is assessed as having latent TB infection

a posterior-anterior view chest x-ray or results from a chest x-ray obtained within 30 days 
prior to the positive TB test does not indicate active TB infection

after receiving at least the initial 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

meet all other inclusion/exclusion criteria for participation
Such patients must complete appropriate LTBI therapy in order to remain in compliance and 
continue to participate in the study.
If a positive TB test result is believed to represent a false-positive result based on thorough 
medical assessment of the patient, the investigator should discuss further testing and 
management with Lilly medical.
Any findings of a positive TB test that occurs after the patient receives the first dose of study 
treatment are to be reported to Lilly or its designee as an AE via CRF.

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9.4.7. 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 (Section 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 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]).
9.4.8. 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  Treatment of Adolescent 
Suicide Attempters trial group for the purpose of being a counterpart to the Columbia 
Classification Algorithm of Suicide Assessment categorization of suicidal events.  Patients will 
be assessed according to the Schedule of Activities (Section 2).
The Self-Harm Supplement Form is a one-question form 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 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.
9.4.9. Immunogenicity
For each patient, an immunogenicity sample will be collected according to the Schedule of 
Activities (Section 2).  If necessary, samples may also be tested for ixekizumab drug 
concentrations to facilitate the interpretation of the immunogenicity data.
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 

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laboratory tests may be performed as needed to elucidate the cause of the 
allergic/hypersensitivity reaction.
9.4.10. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
If a study patient experiences elevated ALT ≥3x ULN, alkaline phosphatase ≥2x ULN, or 
elevated total bilirubin ≥2x ULN, 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.
9.4.10.1. Neutropenia
9.4.10.1.1.During Treatment
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 8.1)

≥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 8.1)

≥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 (e.g., antibiotic, antifungal agent, antiviral 
agent):
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.

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
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 (e.g., 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.
o
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.
9.4.10.1.2.Early Termination Visit
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:

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-Treatment Follow-Up Period (Period 4) 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.

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-Treatment Follow-Up Period (Period 4), 
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.

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9.4.10.1.3.Post-Treatment Follow-Up
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).
9.4.10.2. Hepatitis B Monitoring
Hepatitis B virus DNA monitoring will be performed as indicated in the Schedule of Activities 
(Section 2) for patients positive for hepatitis B core antibody at the screening visit of the 
originating study (RHBV, RHBW, or RHBX) and who required HBV DNA monitoring during 
the originating study (RHBV, RHBW, or RHBX).
If the result of any 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 (e.g., 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.
9.4.10.3. Hypertension
Patients who experience changes in BP (systolic BP at ≥160 mm Hg plus ≥20 mm Hg increase 
from baseline [Week 0; Visit 1]; 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.

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 8 0
L Y 2 4 3 9 8 2 1
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Sectio n 2 ) for i m m u n o ge nicit y 
sa m ples, bl o o d sa m ples o f a p pr o xi matel y 4 m L eac h will als o be c o llecte d a n d ma y be use d t o 
deter mi ne t he ser u m c o nce ntrati o ns of i xe kiz u ma b.  T hese bl o o d sa m ples ma y be use d t o ai d i n 
i nter pretatio n of  t he i m m u n o ge nicity data.  I nstr ucti ons f or t he c ollecti o n a n d ha n dli n g of bl o o d 
sa m ples will be pr o vi ded b y  t he s p o ns or.  T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of e ac h 
sa m pli n g will be rec or de d.
S a m ples c o llecte d f or P K a nal ysis will be teste d at a la b orat or y a p pr o ve d b y Lill y or its desi g nee.  
C o nce ntrati o ns of i m m u n oreacti ve i xe kiz u ma b i n h u ma n se r u m will be deter mi ne d b y a 
vali date d m et h o d.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure i n vest i gati o nal pr o d uct c o nce ntrati o n will be retai ne d 
f or a ma xi m u m of 1 year f oll o wi n g last p atie nt visit f or t he st u d y.
9. 6.
P h ar m a c o d y n a mi c s
Refer t o Secti o n  1 0. 3. 5 .
9. 7. 1.
S a m pl e s f or I m m u n o g e ni cit y R e s e ar c h
Bl o o d sa m pl es f or i m m u n o ge nicity testi n g will be c ollecte d t o deter mi ne a nti b o d y pr o d uctio n 
a gai nst t he i n vest i gati onal pr o d uct(s) as s pecifie d i n t he Sc he d ule of Act i vities 
( Sectio n 2 )
C CI
. I m m u n o ge nicity will  be assesse d usi n g a vali date d assa y desi g ne d t o detect a nti -
dr u g a nti b o dies i n t he prese nce of t he i n vesti gati o nal pr o d uct(s).  A nti b o dies ma y be f urt her 
c haracterize d a n d/ or e valu at e d f or t hei r a bilit y t o ne utralize t he acti vity of t he i n vest i gati onal 
pr o d uct (s).

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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.
9.8.
Health Economics
Refer to Section 9.1.2.15.

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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 100 patients who achieved a state of sustained remission on ixekizumab Q4W 
will be randomized in a 2:1 ratio to ixekizumab 80 mg Q4W or placebo, and approximately 
100 patients who achieved a state of sustained remission on ixekizumab Q2W will be 
randomized in a 2:1 ratio to ixekizumab 80 mg Q2W or placebo in the double-blind randomized 
withdrawal–retreatment period.  This 200 total sample size will provide over 99% power to 
detect a difference in the proportion of patients who do not experience a flare between
ixekizumab treatment (including both Q2W and Q4W) and placebo using a 2-sided Fisher’s 
exact test at the 0.05 level, assuming the flare rates are 10% for ixekizumab and 70% for 
placebo.  It is estimated that approximately 30% of total enrolled patients (i.e., approximately 
200 patients) will meet the criteria to enter the double-blind randomized withdrawal–retreatment 
period.
If less than the anticipated number of patients meet the criteria to enter the double-blind 
randomized withdrawal–retreatment period (e.g., 20%), the total number of patients 
(approximately 150) would still provide over 95% power to detect a difference between
ixekizumab treatment and placebo in the proportion of patients who do not experience a flare.
10.2. Populations for Analyses
For purposes of analysis, the following major patient populations are defined (Table RHBY.5).
Table RHBY.5.
Major Patient Populations for Study RHBY
Population
Description
Lead-In Period Safety 
Population
All patients who receive at least 1 dose of ixekizumab in Period 1.
Randomized Withdrawal 
Intent-to-Treat (ITT) Population
All patients who are randomized in Period 2 (Group B), even if the patient does 
not receive the correct treatment or does not follow the protocol.  Patients will 
be analyzed according to the treatment which they were assigned.
Randomized Withdrawal Safety 
Population
All patients in Group B who receive at least 1 dose of study treatment after 
Period 2 randomization.  Patients will be analyzed according to the treatment to 
which they were assigned.
Ixekizumab Structure Population
All patients who (i) are from either RHBV or RHBW study; (ii) have been 
treated with ixekizumab for at least 18 months; and (iii) have mSASSS data at 
both Week 0 in the originating study and Week 56 in RHBY.
Long-Term Ixekizumab
Treatment Efficacy Population
All patients who are randomized to ixekizumab 80 mg Q2W or ixekizumab 
80 mg Q4W at Week 0 of the originating studies and consistently received 
ixekizumab in RHBY.
Flare Population
All patients in Group B who experience a flare after randomization at Week 24 
and who receive ixekizumab retreatment after flare in Period 2 and Periods 2 
and 3 combined (exploratory analyses).
Follow-Up Period Population
All patients who receive at least 1 dose of study treatment at any time during 
Study RHBY and enter the Post-Treatment Follow-Up Period (Period 4).  
Patients will be analyzed according to the treatment they were taking before 
entering Period 4.

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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
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 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.  Complete details of the planned analyses will be documented in the 
statistical analysis plan (SAP).
10.3.1.1. General Considerations for Analyses during the Combined Periods 1, 2, 
and 3
Combined Periods 1, 2, and 3 start at the first injection of ixekizumab 80 Q2W or ixekizumab 
80 mg Q4W in Study RHBY and ends on the date of Week 104 (Group A: Visit 14/Group B: 
Visit 519) or at early termination visit (ETV) prior to Week 104.
10.3.1.1.1.Lead-In Period Safety Population
Safety data collected in Combined Periods 1, 2 and 3 will be summarized for the Lead-In Period 
Safety Population by combined ixekizumab treatment group and each of the ixekizumab dose
groups without inferential statistics.
10.3.1.1.2.Long-Term Ixekizumab Treatment Efficacy Population
The long-term treatment effect in both categorical and continuous variables will be summarized 
by treatment group at each scheduled visit including Week 24, Week 64, and Week 104, and will 
also be summarized graphically using the response rate for categorical variables and mean for 
continuous variables by group at each scheduled visit in the Combined Periods 1, 2, and 3.
10.3.1.2. General Considerations for Analyses during Period 2 (Extension Period, 
Including Blinded, Randomized Withdrawal–Retreatment)
10.3.1.2.1.Randomized Withdrawal ITT Population
For patients who are randomized in Period 2, comparisons between combined ixekizumab 
treatments versus placebo, as well as each ixekizumab dose treatment to placebo, will be 
performed for all analyses in Study Period 2.  For efficacy, and health outcomes, baseline is 
defined as the last available value before the first dose of study treatment in Period 2 from the 
originating study and in most cases will be the value recorded at Week 0 (from the originating 
study). For safety analysis, baseline is defined as the last available value before the first dose at 
the start of Period 2 in Study RHBY.

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Endpoint for Study Period 2 is defined as the last visit in Period 2 (Week 64; Group A: Visit 
10/Group B: Visit 515).  Change from baseline will be calculated as the visit value of interest 
minus the baseline value.
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 regions, and originating study in the model.  The odds ratio and 95% 
confidence intervals (CIs) will be reported; treatment difference and 95% CIs will also be 
reported.  Secondary analysis will be conducted using a Fisher’s exact test.
The Kaplan-Meier product limit method will be used to estimate the survival curves for 
time-to-flare for the patients who are randomized to the randomized withdrawal–retreatment
period. Treatment comparisons will be performed using the stratified log-rank test with 
treatment, geographic region, and originating study in the model.
The analysis for all continuous efficacy and health outcome variables, change from baseline to 
endpoint analysis, will be made using analysis of covariance (ANCOVA) with treatment, 
baseline value, geographic region, and originating study in the model.  Missing data will be 
imputed using modified baseline observation carried forward (mBOCF).  Type III sums of 
squares for the least-squares (LS) means will be used for the statistical comparison; the 95% CI
will also be reported.
Fisher's exact test will be used for all AEs, baseline, discontinuation, and other categorical safety 
data.  Continuous vital signs and laboratory values will be analyzed by an ANCOVA with 
treatment and baseline values in the model.
For patients who are randomized and subsequently experience a flare in Period 2, efficacy, health 
outcomes, and safety data collected between time of flare and the end of Period 2 will be 
summarized for ixekizumab 80 mg Q2W or ixekizumab Q4W without inferential statistics.
10.3.1.2.2.Flare Population
For the Flare Population, Period 2 starts at the time of first injection of the retreatment  of 
ixekizumab 80 mg Q2W or 80 mg Q4W following the flare and ends on the date of Week 64 
prior to injection of study treatment (Visit 515) or the ETV before the date of Week 64.
Summary statistics will be provided based on the Flare Population within 16 weeks after the 
ixekizumab retreatment for patients who have 16 weeks of post-retreatment follow-up.  No 
inferential statistics will be provided.  The Kaplan–Meier estimates of the proportion of patients 
who first regain response on the variables of interest will be carried out at each post-retreatment  
interval (4 weeks, 8 weeks, etc.) up to 40 weeks.  If a patient has not regained response or 
discontinues the study by Week 64, the patient will be censored at the date of their last visit 
during Period 2.
10.3.1.3. General Considerations for Analyses at Week 56 for the 2-Year 
Radiographic Progression in Spine Assessments
Assessment of 2-year radiographic progression in the spine from baseline in Studies RHBV and 
RHBW to Week 56 (Group A: Visit 9/Group B: Visit 513) in Study RHBY will be evaluated by 

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comparing the radiographic progression of the Ixekizumab Structure Population to the Historical 
Control Population.
Important patient characteristics, such as age at baseline, baseline syndesmophytes, baseline 
CRP, age at onset, sex, smoking history and duration of disease, will be compared between the 
Ixekizumab Structure Population and the Historical Control Population.  The primary analysis 
will be ANCOVA to compare the 2-year radiographic progression in spine measured by change 
in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS).  The ANCOVA model will 
include population and baseline mSASSS score.
Fisher’s exact test will be used to compare the proportion of nonprogressors measured by change 
in Total mSASSS <2 and by mSASSS=0, the proportion of progressors measured by change in 
Total mSASSS ≥0, and the proportion of patients with no new syndesmophytes.
10.3.1.4. General Considerations for Analyses during the Post-Treatment 
Follow-Up (Period 4)
For the safety analyses during Period 4, baseline is defined as the last nonmissing assessment 
prior to entering Period 4, that is, on or prior to Week 104 (Group A: Visit 14/Group B: Visit 
519), or ETV.  Safety data collected will be summarized using descriptive statistics.
10.3.1.5. Missing Data Imputation
In accordance with precedent set with other Phase 3 AS trials (van der Heijde et al. 2006; Inman 
et al. 2008), the following methods for imputation of missing data will be used:
10.3.1.5.1.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 at any specified analysis time point.  All
nonresponders at any specified time point as well as all patients who discontinue study treatment
before the specified analysis time point, for any reason, will be defined as a nonresponder for the
NRI analysis. Patients without at least 1 observation on study treatment will also be defined as a
nonresponder for the NRI analysis.  The NRI may be applied at any time point specified for 
analysis.
10.3.1.5.2.Modified Nonresponder Imputation for Clinical Response
Analysis of categorical efficacy and health outcome variables for long-term ixekizumab 
treatment analysis will be assessed using a modified nonresponder imputation (mNRI) method.  
Patients will be considered as nonresponders if they discontinue study drug due to a flare, an AE,
or lack of efficacy. For patients discontinuing study drug for any other reason, the data will be
imputed using multiple imputation method (as described in Section 10.3.1.5.4). Patients without 
at least 1 observation will also be defined as nonresponders for the mNRI analysis.
10.3.1.5.3.Modified Baseline Observation Carried Forward
The primary analyses for all continuous efficacy and health outcome variables will be based on 
an mBOCF approach. For patients discontinuing study drug due to an AE, the baseline (from the 

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originating study) observation will be carried forward to the corresponding primary endpoint for 
evaluation. For patients discontinuing study drug for any other reason, the last nonmissing 
observation before discontinuation will be carried forward to the corresponding primary endpoint 
for evaluation with the following exception; for patients who experience a flare in Period 2 and 
are retreated with ixekizumab 80 mg Q2W or Q4W, the last nonmissing observations prior to the 
ixekizumab re-treatment 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.
10.3.1.5.4.Multiple Imputation
Analysis of continuous efficacy and health outcome variables for long-term ixekizumab 
treatment analysis will be assessed using multiple imputation method.  In the multiple imputation
analyses, missing data will be imputed so as to estimate what observations would have been if 
the patient had not discontinued.  Specifically, multiple imputation is the partial imputation of 
nonmonotone missing data using Markov chain Monte Carlo method with the simple imputation 
model, followed by a sequential regression imputation with the baseline score.
10.3.1.6. Adjustment for Multiple Comparisons
The primary outcome of proportion of patients who do not experience a flare will be tested for 
ixekizumab versus placebo at a 2-sided α=0.05. The comparison of major secondary objectives 
(Section 4) 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.
10.3.2. Treatment Group Comparability
10.3.2.1. 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 for each treatment period.  Reasons for discontinuation 
from the study will be summarized.  The reason for discontinuation during Period 2 for the 
Randomized Withdrawal ITT Population will be tested between treatment groups using Fisher’s 
exact test.
10.3.2.2. Patient Characteristics
Patient characteristics and baseline clinical measures will be summarized.  Baseline 
characteristics will include gender, age, age category, weight, race, geographic region, 
originating study, abnormal/normal CRP.  Baseline clinical measurements may include 
BASDAI, BASFI, BASMI, chest expansion, Fatigue NRS, Patient Global NRS, total back pain, 
spinal pain at night, spinal pain, inflammation, MASES, enthesitis SPARCC, TJC, and SJC.

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Treatment group comparisons in Period 2 will be conducted using Fisher’s exact test for 
categorical data and an analysis of variance with treatment as a factor for continuous data.
10.3.2.3. Concomitant Therapy
Previous and concomitant medications will be summarized and will be presented by WHO 
Anatomic Therapeutic Class Level 4 and WHO preferred term.  Concomitant DMARDs, 
concomitant corticosteroids, and concomitant NSAIDs will also be summarized.  Treatment 
group comparisons in Period 2 will be conducted using Fisher’s exact test.
10.3.2.4. Treatment Compliance
Treatment compliance with investigational product will be summarized.  A patient will be 
considered overall compliant for each study 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 (i.e., 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 using Fisher’s exact test.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis, the proportion of patients in the combined ixekizumab treatment group 
who do not experience a flare during Period 2 compared with placebo, will be based on the 
Randomized Withdrawal ITT Population.
Treatment comparison between combined ixekizumab treatment group and placebo in the 
proportion of patients who do not experience a flare during Period 2 will be analyzed using the 
logistic regression model defined in Section 10.3.1.2.  Missing data will be imputed using the 
NRI method described in Section 10.3.1.5.1.
10.3.3.2. Major Secondary Analyses
The major secondary analysis for the time to flare will be based on the Randomized Withdrawal 
ITT Population.  Time to flare will be calculated in weeks as follows:
Date of flare −Date of First Dose in Period 2 + 1
7
The date of flare is the time point when the patient qualifies for retreatment.  If the date of the 
first dose is missing, the date of randomization will be used.  Patients who complete Period 2 
without a flare will be censored at the date of completion (i.e., the date of the last scheduled visit 
in the period).  Patients without a date of completion or discontinuation for Period 2 and who did 
not experience a flare will be censored at the latest nonmissing date out of the following dates:  
date of last dose and date of last attended visit in Period 2 (scheduled or unscheduled).
Treatment comparisons between ixekizumab and placebo in time to flare for the Randomized 
Withdrawal ITT Population will be analyzed using a stratified log-rank test with treatment, 
geographic region, and originating study in the model.  The Kaplan-Meier product limit method 

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will be used to estimate the survival curves for time to flare.  Time to flare will also be 
summarized graphically by treatment group using Kaplan-Meier techniques.
Treatment comparisons in the proportion of patients who do not experience a flare at Week 64 
(Group A: Visit 10/Group B: Visit 515) will be analyzed using the logistic regression model 
defined in Section 10.3.1.2.  Missing data will be imputed using NRI method described in 
Section 10.3.1.5.1.
The 2-year radiographic progression reflected by change from baseline of originating studies 
RHBV and RHBW to Week 56 of Study RHBY (Group A: Visit 9/Group B: Visit 513) will be 
measured by mSASSS score and summarized by treatment.  The comparison of the ixekizumab 
treatment group to the historical control will be analyzed by ANCOVA, with baseline score as 
covariate.  The historical control will be defined in the SAP.  Within-treatment changes from 
baseline along with 95% CI will be assessed by a paired t-test using the LS means.
10.3.3.3. Other Secondary Efficacy Analyses
There will be no adjustment for multiple comparisons.  Analyses will be conducted for the other 
secondary objectives defined in Section 4.
The secondary efficacy and health outcomes analysis for Period 2 will be based on the
Randomized Withdrawal ITT Population or the Flare Population.  Additional efficacy and health 
outcome analysis for combined Periods 1, 2, and 3 analyses will be based on the Long-Term 
Ixekizumab Treatment Efficacy Population.
10.3.3.3.1.Combined Periods 1, 2, and 3
The long-term treatment effect in both categorical and continuous variables will be summarized 
by treatment group at each scheduled visit including Week 24, Week 64, and Week 104.  
Missing data will be imputed using mNRI for categorical efficacy variables, described in 
Section 10.3.1.5.2, and mBOCF and multiple imputation for continuous efficacy variables, 
described in Sections 10.3.1.5.3 and 10.3.1.5.4, respectively.
10.3.3.3.2.Period 2 (Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment)
The other secondary analysis during Period 2 will be based on the Randomized Withdrawal ITT 
and Flare Populations.
For the Randomized Withdrawal ITT Population, all categorical efficacy variables and treatment 
group comparisons will be analyzed at each visit using the logistic regression model described in 
Section 10.3.1.2.1.  Missing data will be imputed using the NRI method described in 
Section 10.3.1.5.1.  All continuous efficacy variables and treatment group comparisons will be 
analyzed at each visit using the ANCOVA models as described in Section 10.3.1.2.1 when 
appropriate.  For the ANCOVA analysis, missing data will be imputed by the mBOCF as 
described in Section 10.3.1.5.3.
For the Flare Population who were retreated with ixekizumab following the flare, the following 
summaries will be provided:

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 8 9
L Y 2 4 3 9 8 2 1

T he pr o p orti o n of  p atie nts w h o re gai n s ustai ne d re missi on cri teria wit hi n 1 6 wee ks after 
i xe kiz u ma b retreat me nt will be s u m marize d b y t he origi nal  re-ra n d o mizat i on treat me nt 
gr o u p .

T he pr o p orti o n of patie nts wi t h A S A S 2 0 as well as t he pr o p orti o n of  patient s wi t h
A S A S 4 0 wit hi n 1 6 wee ks after i xe kiz u ma b retreat me nt will be s u m marize d b y t he 
ori gi nal  r e-ra n d omizat i on treat m e nt gr o u p .
1 0. 3. 4. S af et y A n al y s e s
S af et y will be assesse d b y s u m marizi n g a n d a nal yzi n g A Es i ncl u di n g a dj u dicate d 
cere br ocar di o vasc ular e ve nts , I B D e ve nts, lab orat or y  a nal yt es i n clu di n g ne utr o p hil c o u nts , 
QI D S -S R 1 6, C -S S R S, a n d vital si g ns.  T he d urati o n of treat me nt e x p os ure will als o be 
s u m marize d.
Pri mar y safet y a nal yses will be base d o n t he R a n d o mize d W ith dra wal S afet y P o p ul at i on i n 
P eri o d 2.
F or c o m bi ne d P erio ds 1, 2, a n d 3, safet y data will be s u m marize d f or t he Lea d- I n Perio d Safet y 
P o p ul at i on.
F or Peri o d 2, safet y data will be s u m marize d f or t he Ra n d o mize d Wit h dra wal Safet y P o p ul at i on .  
Treat me nt gr o u p c o m paris o ns will be perf or me d o n cate g orical safet y data usi n g Fis her’s e xact 
test as descri be d i n Secti o n 1 0. 3. 1. 2. 1 ; c o nti n u o us safety data will be a nal yze d b y a n A N C O V A 
m o d el .
F or Peri o d 4 safety data will be s u m mari ze d acc or di n g t o t he treat me nt patie nts were o n pri or t o 
e nteri n g Peri o d 4.
T he cate g orical safet y meas ures will be s u m marize d wit h i nci de nce rates.  T he mea n c ha n ge of 
t he c o nti n u o us safet y me as ures will be s u m marize d b y visits.
F urt her details will be descri be d i n t he S A P.
1 0. 3. 5. P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
Bl o o d sa m pl es f or deter mi nat i on of i xe kiz u ma b c o nce ntrati o ns will be c o llecte d a n d ma y be 
a nal yze d usi n g gra p hical met h o ds t o ai d i n i nter pretatio n of  t he i m m u n o ge nicity data.
A d dit i onal e x plor at or y  a nal yses of t he data ma y be c o n d ucte d if dee me d a p pr o priate.
1 0. 3. 6. Ot h er A n al y s e s
1 0. 3. 6. 1. H e alt h O ut c o m e s
T here will be n o a dj ust me nt  for m ul tiple c o m paris o ns.  A nal yses will be c o n d ucte d f or t he ot her 
sec o n dar y he alt h o ut c o mes o bject i ves as defi ne d i n Secti o n
C CI
 4.

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Period 2 (Extension Period, Including Blinded, Randomized Withdrawal–Retreatment):
Unless otherwise specified, the other secondary analyses during Period 2 will be based on the 
Randomized Withdrawal ITT Population.
Treatment comparisons in the proportion of patients achieving a categorical response at specified 
time points will be analyzed using the logistic regression model defined in Section 10.3.1.2.1. 
Missing data will be imputed using the NRI method described in Section 10.3.1.5.1.
For all continuous health outcomes variables, treatment group comparisons will be analyzed 
using the ANCOVA model defined in Section 10.3.1.2.1; missing data will be imputed by the 
mBOCF method as described in Section 10.3.1.5.3.
Combined Periods 1, 2, and 3:
Data collected in combined Periods 1, 2, and 3 will be summarized for the Long-Term 
Ixekizumab Treatment Efficacy Population.  The within-treatment group comparisons may be 
conducted as appropriate.
10.3.6.2. Subgroup Analyses
Subgroup analyses will be conducted for time to flare and the proportion of patients who 
experienced a flare for the Randomized Withdrawal ITT Population.
Subgroup analyses may be conducted based on gender, age category, race, geographic region, 
population (radiographic and nonradiographic axSpA), origination study, and CRP status at the 
time of randomization in Period 2.  Additional subgroups may be described in the SAP.
The Kaplan-Meier product limit method will be used to estimate the survival curves or time to 
flare.  Analyses will be performed using a log-rank test with treatment, subgroup, and the 
interaction of treatment-by-subgroup included as factors in the model.
For the proportion of patients who experience a flare, a logistic regression model will be used 
with treatment, subgroup, and the interaction of treatment-by-subgroup included as factors. 
Missing data will be imputed using NRI.
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, regardless of whether 
the interaction is statistically significant.
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.
10.3.6.3. Immunogenicity
The analyses of anti-drug antibody (ADA) effects will be conducted on all evaluable patients 
within the defined Randomized Withdrawal Safety Population.  Evaluable patients will be 
defined as either: a) patients with an evaluable baseline sample and at least 1 evaluable 
postbaseline sample (i.e., sample after administration of study drug); or b) patients with no 
evaluable baseline sample whose evaluable postbaseline samples were all ADA negative.

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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 
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 efficacy responses will be evaluated, as appropriate.
Assessment of immunogenicity with respect to safety will include comparison of patients who 
experience treatment-emergent adverse event (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.
10.3.7. Interim Analyses
The study will have approximately 1 interim database lock and 1 final database lock. The 
interim database lock will occur and the analysis will be performed at the time when all patients 
have completed through Week 64 or have discontinued at or prior to Week 64.  At this time, 
study team members will become unblinded; however, investigators, patients, and site personnel 
will remain blinded to study treatment until final database lock. The interim database lock will 
include all data collected by the cutoff date, including the data from the Long-Term Extended 
Treatment Period (Period 3), and follow-up data from patients that have begun the Post-
Treatment Follow-Up Period (Period 4).  The analyses from the Week 64 database lock will be 
treated as a primary analysis because all primary and major secondary study objectives will be 
assessed at this time.  The final database lock, unblinding, and analysis will occur when all 
patients have completed or discontinued the study.
Additional analyses and snapshots of study data may be performed during Period 3 or after 
completion of Period 4 to fulfill the need for regulatory interactions or publication purposes.
Unblinding details are specified in the blinding/unblinding plan.

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11.
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12.
Appendices

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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
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BCG
Bacillus Calmette- Guérin
bDMARD
biological disease modifying antirheumatic drug
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.

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Term
Definition
BP
blood pressure
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
High sensitivity 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
FSH
follicle stimulating hormone
GCP
good clinical practice
HBV
hepatitis B virus
HLA
human leukocyte antigen 
IB
Investigator’s Brochure

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Term
Definition
IBD
Inflammatory bowel disease (e.g., Crohn’s disease and Ulcerative Colitis)
ICF
informed consent form
ICFD
International Classification of Functioning Disability and Health
ICH
International Council for 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
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 (i.e., 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
LS
least-squares
MAb
monoclonal antibody
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
mBOCF
modified baseline observation carried forward
MI
myocardial infarction
MOA
mechanism of action
mNRI
modified nonresponder imputation

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Term
Definition
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
NSAID
nonsteroidal anti-inflammatory drug
PK/PD
pharmacokinetics/pharmacodynamics
PPD
Purified protein derivative
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
Ps
psoriasis
PsA
psoriatic arthritis
PT
prothrombin time
Q2W
every 2weeks 
Q4W
every 4 weeks
QIDS-SR 16
Quick Inventory of Depressive Symptomatology-Self-Report 16
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 joint

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Term
Definition
SJC
swollen joint count
SpA
Spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
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 
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.
Clinical Laboratory Tests

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Clinical Laboratory Tests to Be Performed by Sponsor-Designated Laboratory
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 clearanceb
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
HBV DNAf
Follicle-stimulating hormone (FSH)e
High sensitivity C-reactive protein (CRP)
Ixekizumab serum concentration (pharmacokinetic)
Urine pregnancy testd (assayed by clinical study site)
Partial thromboplastin time (PTT)
TB test (e.g., PPD, QuantiFERON®-TB Gold, 
T-SPOT®)g
Prothrombin time/international normalized ratio
Exploratory storage samples (serum, urine, plasma, and
RNA)
Immunogenicity testing (anti-ixekizumab Ab)
Abbreviations:  Ab = antibody; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; PPD = purified protein 
derivative; RNA = messenger ribonucleic acid; SGOT = serum glutamic oxaloacetic transaminase; SGPT = 
serum glutamic pyruvic transaminase; TB = tuberculosis.
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.
d
Urine pregnancy test performed locally for women of childbearing potential.
e
For female patients ≥40 and <60 years of age who cease menstruation for at least 12 months during study 
participation, an FSH test may be performed to confirm nonchildbearing potential (FSH ≥40 mIU/mL).  FSH test 

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will be performed centrally.
f
HBV DNA monitoring will be performed as indicated in the Schedule of Activities for patients positive for 
hepatitis B core antibody at the screening visit of the originating study (RHBV, RHBW, or RHBX) and who 
required HBV DNA monitoring during the originating study (RHBV, RHBW, or RHBX).  If the result of the 
HBV DNA testing is positive, the patient is to be discontinued from the study and is to receive appropriate 
follow-up medical care (refer to Section 9.4.10.2 for further information regarding the timing of discontinuation).
g
See Section 9.4.6:  In countries where the QuantiFERON®-TB Gold test or T-SPOT® test is available, it may be 
used instead of the PPD TB test.  The QuantiFERON®-TB Gold test and the T-SPOT® test will be performed 
locally.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
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 informed 
consent form (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.
Appendix 3.1.2.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for 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 Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent form

relevant curricula vitae
Appendix 3.1.3.
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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Appendix 3.1.4.
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.
Appendix 3.1.5.
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.
Appendix 3.1.6.
Final Report Signature
The clinical study report (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.
Appendix 3.2.
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.
Appendix 3.2.1.
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.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
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.
Appendix 3.3.2.
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 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality

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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 Lilly medical.
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 normalized 
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.
Protocol Amendment I1F-MC-RHBY(a) 
Summary:  A Multicenter, Long-Term Extension Study of 
104 Weeks, Including a Double-Blind, 
Placebo-Controlled 40-Week Randomized 
Withdrawal-Retreatment Period, to Evaluate the 
Maintenance of Treatment Effect of Ixekizumab 
(LY2439821) in Patients with Axial Spondyloarthritis
Overview
Protocol I1F-MC-RHBY, A Multicenter, Long-Term Extension Study of 104 Weeks, Including a 
Double-Blind, Placebo-Controlled 40-Week Randomized Withdrawal–Retreatment Period, to 
Evaluate the Maintenance of Treatment Effect of Ixekizumab (LY2439821) in Patients with 
Axial Spondyloarthritis, has been amended.  The new protocol is indicated by amendment (a) 
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:

In the original protocol, patients participating in the randomized withdrawal–retreatment 
period (Group B) were unblinded to study treatment once the Week 64 datalock had been 
completed.  In Protocol RHBY Amendment (a), patients in Group B will be blinded until 
the completion of the study or time of flare.  Changing the time of unblinding for patients 
in Group B will help to eliminate bias from participants and retain patients who are on 
placebo; therefore, it will facilitate the assessment of the proportion of patients who 
experience a flare after Week 64.  Revisions were made to Section 7.3 (Blinding), 
Section 10.3.7 (Interim Analyses), and Table RHBY.2.

Section 10 (Statistical Considerations) was revised, as follows:
o
The Ixekizumab Structure Population definition was added to Table RHBY.5 to 
align with the structure objective.
o
To assess the long-term efficacy of ixekizumab treatment, an analysis of 
Combined Periods 1, 2, and 3 was added.  Therefore, the Long-Term Ixekizumab 
Treatment Efficacy Population was defined in Table RHBY.5.  The analysis 
methods were updated to include the handling of missing data (i.e., mNRI and 
MI).  Due to the inclusion of the assessment of Combined Periods 1, 2, and 3, it 
was determined that the analysis of Period 1 only and Combined Periods 2 and 3 
was longer needed.
o
The last observation carried forward method for handling missing data was 
removed; other methods for missing data are included and considered more 
appropriate for the analysis.

The remainder of the changes to the protocol were added to improve clarity.
o
The following changes were made to the Section 2 (Schedule of Activities 
[SOA]):

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 1 6
L Y 2 4 3 9 8 2 1

Assess me nt of Li near B A S MI, C hest e x pa nsi o n, Occi p ut – t o-wall dista nce, 
E nt hesit is, a n d TJ C/ SJ C was a d de d t o t he E T V s o t hat t he str uct ure data 
ca n be i nter prete d i n t he c o nte xt of ot her f u nct i onal o utc o mes.

Mi n or a d di tio ns t o F o ot n otes “h, ” “i,” “ k, ” a n d “p” were ma de f or 
c o nsiste nc y wit h t he m ai n b o d y of t he pr ot oc ol.

It was clarifie d t hat A Es i nitiati n g i n t he ori gi nati n g st u d y a n d are o n g oin g 
b y t he ti me t he patie nt c o m pletes i n t he ori gi nat i n g st u d y will be 
c o nsi dere d as pree xist i n g c o n diti on s i n St u d y R H B Y.

H o w a n d f or w h o m t o “E nter A S D A S ” was clarifie d.

T he c ollecti o n wi n d o w f or t he M RI at Visit
5 0 5 was cl arifie d.  A d ditio nal  
g ui da nce re gar di n g c o nc o mit a nt t hera p y for p ati e nts u n der g oi n g a n M RI is
pr o vi de d i n Sect i on 7. 7 ( C o nc o mita nt T hera p y).

T he x -r a y re q uire me nt at E T V was clarifie d.  I n a d diti on, t he a me n d me nt 
n ote d t hat x -r a ys are re q uire d o nl y for p ati e nts i niti all y e nr olle d i n St u di es 
R H B V or R H B W ; t his c ha n ge was ma de t o Secti o n 2 ( S O A), Secti o n 5. 4
( S cie ntific Rat i onale f or St u d y  D esig n), a n d Sect i on 9. 1. 2. 2. 1
( Ra dio gra p hic I m a gi n g of t he S pi ne).

F o ot n ote “o ” was a d de d t o Self -Har m  S u p ple me nt F or m o n Pa ge 3 of t he 
S O A.  T he f o ot n ote was e xcl u de d i n err or.

It was n ote d t hat H B V D N A m o nit ori n g is o nl y in di cate d f or patie nts 
p osi tive f or he patitis B c ore a nti b o d y at t he scree ni n g visit of t he 
ori gi nati n g st u d y  a n d w h o re q uire d H B V D N A m onit ori n g d uri n g t he 
ori gi nati n g st u d y; t his clarificat i on was als o ma de i n Secti o n 9. 4. 1 0. 2
( He patitis B M o nit ori n g) a n d A p pe n di x 2 ( Cli nical La b orat or y Tests).  
A d dit i onall y , Disc o nti n uati on Cri t erio n [ 1 3] was clarifie d t o disc uss t he 
ti mi n g of disc o nti n uati o n f or t h ose patie nts w h o were H B V D N A p ositi ve.
 
o
T he O bjecti ves a n d E n d p o i nts ( Secti o n 4 ) were re vise d f or clarity.   T here were n o 
c ha n ges (a d dit i ons a n d/ or delet i ons) t o t he o bject i ves a n d e n d p oi nts.  Sectio ns 1
( S y n o psis) a n d 9. 1. 1 ( Pri mar y Efficac y Assess me nts) were als o u p date d t o reflect 
these re visi o ns.
o
I n Secti o n 5. 1 ( O verall Desi g n), t he defi niti on of s ustai ne d re missi on was f ull y 
defi ne d f or furt her cl arit y a n d t o re d uce misi nter pretatio n.
o
I n Secti o n 5. 1 ( O verall Desi g n), t he defi nit i on of a flare was clarifie d t o i ncl u de 
P eri o d 2 a n d/ or Peri o d 3.
o
P ati e nts i n Gr o u p B w h o e x perie nce a flare after Wee k 6 4 ma y  ha ve t heir d ose 
escalate d t o i xe kiz u ma b 8 0 m g Q 2 W.  T h r o u g h o ut t he a me n d me nt , a d ditio nal 
clarit y is pr o vi de d o n t he re q uire me nts f or t he d ose escalati o n ( Secti o ns 1
[ S y n o psis], 5. 1 [O verall Desi g n ], 7. 1 [Treat me nts A d mi nistere d ], a n d 7. 4
C CI
[D o sa ge 
M o dificat i on] ).

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 1 7
L Y 2 4 3 9 8 2 1
o
Mi n or a d di tio ns a n d del et i ons were ma de t o Secti o ns 5. 2 [N u m ber of 
P arti cip a nts ], 5. 4 [Scie nt ific Rati onale f or St u d y  Desi g n], 7. 2 [ Met h o d of 
Treat me nt Assi g n me nt] , a n d 7. 7 [ C o nc o mita nt T hera p y] t o i m pr o ve clarity a n d 
re d uce re d u n da nc y.
o
I ncl usi on Cri t erio n [ 2] a n d E xcl usi o n Cri t eria [ 4] a n d [ 7] were re vise d f or clarit y.
o
Secti o n 6. 4 ( Scree n Fail ures) was u p date d t o pr o vi de m ore clarit y.
o
Ta ble R H B Y . 3 was a d de d t o e x plai n d osa ge m o dificat i on f or patie nts i n Gr o u p B 
w h o flare d uri n g Peri o d 2 a n d/ or Peri o d 3.
o
T he c o nc o mita nt treat me nt wit h N S AI Ds a n d a nal gesics, c D M A R Ds, a n d 
c ortic oster oids f or p atie nts i n Gr o u p B d uri n g Peri o d 3 were clarifie d (Ta ble 
R H B Y . 4).
o
I n Secti o n 9. 1. 1 ( Pri mar y Efficac y Assess me nts), t y p o gra p hical err ors i n t he 
A S D A S cr p f or mula were c orrecte d.
o
A d dit i onal detail t o pr o vi de clarit y was i ncl u de d i n Secti o n 9. 4. 6 ( T u berc ul osis 
Testi n g).  T he t y p e of  T B test was clarifie d i n  A p pe n di x 2 ( Cli nical La b orat or y  
Tests).
 
 
o
T he f o ot n otes i n Fi g ure R H B Y . 1 a n d Ta ble R H B Y . 2
C CI
were m o difie d acc or di n gl y 
wi t h t he c ha n ges ma de i n t his pr ot oc ol a me n d me nt.

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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.  Synopsis
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
the randomized withdrawal-retreatment 
periodPeriod 2

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during the randomized withdrawal-
retreatment periodPeriod 2
Objectives
Endpoints
Major Secondary

To compare the combined ixekizumab 
treatment group to historical control for 2-year
radiographic progression in spine in patients 
with active radiographic axSpA (rad axSpA)

Change in modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS) score

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg every 2 weeks (Q2W) treatment group 
or ixekizumab 80 mg every 4 weeks (Q4W) 
treatment group is superior to placebo in 
maintaining response after randomized 
withdrawal

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during the randomized withdrawal-
retreatment periodPeriod 2

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response after 
treatmentrandomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during the randomized 
withdrawal-retreatment periodPeriod 2

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg Q2W treatment group or ixekizumab 
80 mg Q4W treatment group is superior to 
placebo in maintaining response after 
treatmentrandomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during the randomized 
withdrawal-retreatment periodPeriod 2

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Objectives
Endpoints
Other Secondary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
the randomized withdrawal-retreatment 
periodPeriod 2

The proportion of patients in the randomized
withdrawal population with Assessment of 
Spondyloarthritis International Society
(ASAS)20, ASAS40, ASAS 5/6, ASAS partial 
remission, clinically-important improvement 
(change of Ankylosing Spondylitis Disease 
Activity Score [ASDAS] ≥1.1 units), major 
improvement (change of ASDAS ≥2.0 units), 
and inactive disease (ASDAS <1.3) during the 
randomized withdrawal-treatment 
periodPeriod 2

Change from baseline of originating study in 
the individual components of the ASAS criteria

Change from baseline of originating study in 
Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI)

Proportion of patients with Bath Ankylosing 
Spondylitis Disease Activity Index 50 
(BASDAI50) response

Change from baseline of originating study in 
ASDAS

Change from baseline of originating study in 
the measure of high sensitivity C-reactive 
protein (CRP)

Change from baseline of originating study in 
Bath Ankylosing Spondylitis Functional Index 
(BASFI)

Change from baseline of originating study in 
the measures of spinal mobility 
o
Bath Ankylosing Spondylitis 
Metrology Index (BASMI) (linear), 
and BASMI individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline of originating study in 
Maastricht Ankylosing Spondylitis Enthesitis 
Score (MASES) and Spondyloarthritis 
Research Consortium of Canada Score 
(SPARCC)

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

Change from baseline of originating study in 

I1F-MC-RHBY(a) Clinical Protocol
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LY2439821
Objectives
Endpoints
the following health outcomes measures
o
Fatigue numeric rating scale (NRS)  
score
o
Quick Inventory of Depressive 
Symptomatology Self-Report-16 
(QIDS-SR16)
o
SF-36 (both physical and mental 
component scores)
o
Assessments of Spondyloarthritis 
international Society Health Index 
(ASAS-HI)
o
European Quality of Life – 5 
Dimensions 5 Level (EQ-5D-5L)
o
Work Productivity Activity 
Impairment-Spondyloarthritis 
(WPAI-SpA)
o
Jenkins Sleep Evaluation 
Questionnaire (JSEQ)

To assess the efficacy of retreatment with 
ixekizumab following a flare in the randomized 
withdrawal-treatment periodduring Period 2

Proportion of patients who regain ASDAS <1.3 
within 16 weeks after ixekizumab retreatment

Proportion of patients who regain ASDAS <2.1 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve/maintain an 
ASAS20, ASAS40, ASAS5/6, ASAS partial 
remission, ASDAS major improvement, and 
ASDAS clinically important improvement
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve an ASAS20, 
ASAS40, ASAS5/6, ASAS partial remission, 
ASDAS major improvement, ASDAS clinically 
important improvement, and ASDAS-inactive 
disease through Week 64

To determine whether the long-term treatment effect 
of 80 mg ixekizumab Q2W and 80 mg ixekizumab 
Q4W is maintained through Week 104

The proportion of patients with ASAS20, 
ASAS40, ASAS 5/6, ASAS partial remission, 
clinically important improvement (change of 
ASDAS ≥1.1 units), major improvement
(change of ASDAS ≥2.0 units), and inactive 
disease (ASDAS <1.3)

Change from baseline of originating study in 
the individual components of the ASAS criteria

Change from baseline of originating study in 
BASDAI

Proportion of patients with BASDAI50
response

Change from baseline of originating study in 
ASDAS

Change from baseline of originating study in 

I1F-MC-RHBY(a) Clinical Protocol
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LY2439821
Objectives
Endpoints
the measure of CRP

Change from baseline of originating study in 
BASFI

Change from baseline of originating study in 
the measures of spinal mobility
o
BASMI (linear), and BASMI 
individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline of originating study in 
MASES and SPARCC

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

Proportion of patients with change in mSASSS 
score <2 from baseline of originating study  to
Week 56 in RHBY

Proportion of patients with no new 
syndesmophyte formation from baseline of
originating study to Week 56 in RHBY

Change from baseline of originating study in 
the following health outcomes measures
o
Fatigue NRS score
o
QIDS SR16 
o
SF-36 (both physical and mental 
component scores) 
o
ASAS-HI
o
EQ-5D-5L
o
WPAI-SpA 
o
JSEQ

To evaluate the development of 
anti-ixekizumab antibodies and its impact on 
the efficacy of ixekizumab

Efficacy response rates listed below at 
Weeks 5664 and 104 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

I1F-MC-RHBY(a) Clinical Protocol
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Treatment Arms and Duration:

During the Long-Term Extension Period (Period 3; 40 weeks),
o
(Group B):  Patients in Group B will continue the same treatment that they were receiving at the 
end of Period 2.  However, if a patient experiences a flare and meets criteria for retreatment, the 
patient will be retreated with the ixekizumab treatment regimen (ixekizumab 80 mg Q2W or 
ixekizumab 80 mg Q4W) that he or she was receiving prior to withdrawal to evaluate whether the 
patient can regain his or her original response.  During the Long-Term Extension Period, patients 
in Group B receiving ixekizumab 80 mg Q4W may also have their dose escalated to ixekizumab 
80 mg Q2W if the investigator determines that the patient may benefit from an increase in 
frequency of dosing to achieve adequate disease control.  Escalation to ixekizumab 80 mg Q2W 
may occur only after the patient has been retreated upon flare with the ixekizumab treatment 
regimen received during Period 1 (ixekizumab 80 mg Q4W) for at least 12 weeks.
Statistical Analysis:
The analysis for all continuous efficacy and health outcome variables will be made using analysis of covariance 
(ANCOVA) with treatment, baseline value, geographic region, and originating study in the model. Missing data 
will be imputed using last observation carried forward (LOCF) or modified baseline observation carried forward 
(mBOCF).  Type III sums of squares for the least-squares (LS) means will be used for the statistical comparison; the 
95% CI will also be reported.

I1F-MC-RHBY(a) Clinical Protocol
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Section 2. Schedule of Activities
Schedule of Activities, Protocol I1F-MC-RHBY (changes/additions)
Page 1
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment (Period 2)
Long-Term Extension 
Period (Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518
V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Enter ASDASl
X
X
X
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl

I1F-MC-RHBY(a) Clinical Protocol
Page 124
LY2439821
Schedule of Activities, Protocol I1F-MC-RHBY (changes/additions)
Page 2
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment (Period 2)
Long-Term Extension 
Period (Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518
V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Clinical Efficacy/Health Outcomes
MRI of spine plus 
SIJm
Xm
x-ray—spinen
X
Xn
Linear BASMI
X
X
X
X
X
X
X
X
X
Chest expansion
X
X
X
X
X
X
X
X
X
Occiput to wall 
distance
X
X
X
X
X
X
X
X
X
Enthesitis 
(MASES and 
SPARCC)
X
X
X
X
X
X
X
X
X
Assessment of 
TJC/SJC (46/44)
X
X
X
X
X
X
X
X
X

I1F-MC-RHBY(a) Clinical Protocol
Page 125
LY2439821
Schedule of Activities, Protocol I1F-MC-RHBY (changes/additions)
Page 3
Lead-In Period
(Period 1)
Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment (Period 2)
Long-Term Extension 
Period (Period 3)
ETV
Visit No
(Group A)c
V1a
V2
V3
V4
V5c
-
V6
-
V7
-
V8
-
V9
-
V10
V11
V12
V13
V14
ETV
Visit No
(Group B)c
V505c V506 V507 V508 V509 V510 V511 V512 V513 V514 V515 V516 V517 V518 V519
Study Week
W0
W8
W16
W20
W24
W28
W32
W36
W40
W44
W48 W52 W56 W60
W64
W76
W88 W100 W104
Study Day
b
56 
± 5d
112
± 5d
140
± 5d
168
± 5d
196
± 5d
224
± 5d
252
± 5d
280
± 5d
308
± 5d
336
± 5d
364
± 5d
392
± 5d
420
± 5d
448
± 5d
532
± 5d
616
± 5d
700
± 5d
728
± 5d
Self-Harm
Supplement 
Formo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 2 6
L Y 2 4 3 9 8 2 1
Sc he d ule of Acti vities , Pr ot oc ol I 1 F-M C -R H B Y (c h a n ges/ a d diti o ns)
P a ge 4
Le a d -I n Peri o d
( Peri o d 1)
E xte nsi o n Peri o d, I ncl u di n g Bli n de d, R a n d o mize d 
Wit h dr a w al – Retre at me nt ( Peri o d 2)
L o n g -Ter m E xte nsi o n 
Peri o d ( Peri o d 3)
E T V
Visit N o
( Gr o u p A)c
V 1 a
V 2  
V 3  
V 4
V 5 c
-
V 6
-
V 7
-
V 8
-
V 9
-
V 1 0
V 1 1
V 1 2
V 1 3
V 1 4
E T V
Visit N o
( Gr o u p B)c
V 5 0 5 c V 5 0 6
V 5 0 7
V 5 0 8
V 5 0 9
V 5 1 0 V 5 1 1 V 5 1 2 V 5 1 3 V 5 1 4
V 5 1 5
V 5 1 6
V 5 1 7
V 5 1 8
V 5 1 9
St u d y Wee k
W 0  
W 8
W 1 6
W 2 0
W 2 4
W 2 8
W 3 2  
W 3 6
W 4 0
W 4 4
W 4 8
W 5 2
W 5 6
W 6 0
W 6 4
W 7 6
W 8 8
W 1 0 0
W 1 0 4
St u d y D a y
b
5 6 
± 5 d
1 1 2
± 5 d
1 4 0
± 5 d
1 6 8
± 5 d
1 9 6
± 5 d
2 2 4
± 5 d
2 5 2
± 5 d
2 8 0
± 5 d
3 0 8
± 5 d
3 3 6
± 5 d
3 6 4
± 5 d
3 9 2
± 5 d
4 2 0
± 5 d
4 4 8
± 5 d
5 3 2
± 5 d
6 1 6
± 5 d
7 0 0
± 5 d
7 2 8
± 5 d
Ur i nal ysis  
X
X
X
X
X  
X
A b bre viati o ns:  A S D A S = A n k yl osi n g S p o n d ylitis Disease Acti vit y Sc ore; B A S MI = Bat h A n k yl osi n g S p o n d ylitis Metr ol o g y I n de x; C R P = hi g h se nsiti vit y C -
reacti ve pr otei n; d = da ys; D N A = de o x yri b o n ucleic aci d; E T V = earl y ter mi nati o n visit; H B V = he patitis B v ir us; I W R S = i nteracti ve we b-res p o nse s yste m; 
M A S E S = Maastric ht A n k yl osi n g S p o n d ylitis E nt hesitis Sc ore;
M RI = ma g netic res o na nce i ma gi n g; R N A = ri b o n ucleic aci d; SIJ = sacr oiliac j oi nts; SJ C = 
s w olle n j oi nt c o u nt; S P A R C C = S p o n d yl oart hritis Researc h C o ns orti u m of Ca na da; TJ C = te n der j oi nt c o u nt; V = st u d y visit; W = st u d y wee k.
a
F or m ost patie nts, t he fi nal visit of t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) will c oi nci de wit h Visit 1 ( Wee k 0) of St u d y R H B Y.  I n t hese cases, a n y 
assess me nts/ pr oce d ures (i ncl u di n g la b orat or y tests) c o n d ucte d d uri n g t he patie nt’s fi nal visit i n t he ori gi nati n g st u d y s h o ul d n ot be re peate d f or Visit 1 
( Wee k 0) of St u d y R H B Y.  I n cases w here e ntr y i nt o St u d y R H B Y is dela ye d be y o n d Wee k 5 2 of t he ori gi nati n g st u d y, assess me n ts/ pr oce d ures (i ncl u di n g 
la b orat or y tests) i n dicate d f or Visit 1 ( Wee k 0) of St u d y R H B Y t hat are n ot c o n d ucte d d uri n g t he last visit ( Visit 8 0 1 or Visit 8 0 2) of t he ori gi nati n g st u d y 
will be perf or me d as i n dicate d i n t he Sc he d ule of Acti vities.
b
F or m ost patie nts, t he fi nal visit of t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) will c oi nci de wit h Visit 1 ( Wee k 0) of St u d y R H B Y.  H o we ver, i n 
partic ular circ u msta nces, t he d urati o n bet wee n t he fi nal visit of t he ori gi nati n g st u d y a n d Visit 1 ( Wee k 0) of St u d y R H B Y ma y be e xte n de d after c o ns ultati o n 
wit h t he s p o ns or.  T heref ore, t here is n o s pecifie d visit wi n d o w f or Visit 1 ( Wee k 0) of St u d y R H B Y.
c
C CI
Patie nts will be assi g ne d t o Gr o u p A or Gr o u p B at Visit 5/ Visit 5 0 5 ( Wee k 2 4).

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 2 7
L Y 2 4 3 9 8 2 1
h
If patie nts are n ot eli gi ble t o e nter St u d y R H B Y at Wee k 5 2 i n t he ori gi nati n g st u d y (e. g. , d ue t o u nres ol ve d safet y c o ncer ns), t he n e ntr y i nt o St u d y R H B Y 
m a y  be dela ye d be y o n d Wee k 5 2 of t he ori gi nati n g st u d y.  See Secti o n  6. 1 .
i
Patie nts w h o ha ve ac hie ve d a state of s ustai ne d re missi o n ( Gr o u p B) will partici pate i n ra n d o mize d wit h dra wal – retreat me nt a n d will be ra n d o mize d t o t heir 
treat me nt assi g n me nt at Wee k 2 4.  See Secti o n  5. 1 .
j
E val uati o n i ncl u des b ot h hist orical e ve nts as well as pree xisti n g c o n diti o ns w hic h are assesse d after baseli ne t o deter mi ne a n y  treat me nt-e mer ge nt w orse ni n g 
of pree xisti n g c o n diti o ns.   A Es t hat i nitiate d i n t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) a n d are o n g oi n g b y t he ti me t he patie nt c o m pletes 
partici pati o n i n t he ori gi nati n g st u d y will be c o nsi dere d as pree xisti n g c o n diti o ns i n St u d y R H B Y.
k
Patie nts nee d t o be as ke d a b o ut prese nce of e ye s y m pt o ms; if e ye s y m pt o ms are prese nt t he n a n e ye e xa mi nati o n is re q uire d.   See Secti o n  9. 4. 5.
l
Sites will e nter i nt o I W R S t he partial A S D A S sc ore pr o vi de d b y t he SI T E pr o ta blet E P X T M we bsite a n d t he ce ntral la b orat ory C R P val ue fr o m t he ce ntral 
la b orat or y res ults fr o m t his visit, as s o o n as a vaila ble i nt o I W R S as a p pr o priate.  After Visit 5/ Visit 5 0 5 , t he partial A S D A S sc ore a n d C R P val ue will be 
e ntere d i nt o I W R S o nl y f or patie nts partici pati n g i n t he ra n d o mize d wit h dra wal – retreat me nt ( Gr o u p B).  O n ce a patie nt e x perie nces a flare (see Secti o n 5. 1 ), 
t he partial A S D A S sc ore a n d C R P val ue is n o l o n ger e ntere d i nt o I W R S.
m
A n M RI of t he s pi ne pl us SIJ will be perf or me d at Wee k 2 4 (1 0 da ys) f or patie nts partici pati n g i n ra n d o mize d wit h dra wal – retreat me nt ( Gr o u p B).  If t he 
M RI was n ot c o m plete d wit hi n t he pr ot oc ol -defi ne d wi n d o w, please c o ntact Lill y me dical f or a d diti o nal g ui da nce.   See Secti o n 7. 7 f or a d diti o nal gui da nce 
re gar di n g c o nc o mita nt t hera p y f or patie nts u n der g oi n g a n M RI.
n
Cer vical a n d l u m bar s pi ne o nl y .  A n  x-r a y is o nl y nee de d f or patie nts i nitiall y e nr olle d i n St u dies R H B V or R H B W.  If t he patie nt’s E T V occ urs pr i or t o 
Visit 9/ Visit 5 1 3 ( Wee k 5 6), t he n a n x -ra y will nee d t o be perf or me d at t he E T V.  If t he patie nt’s E T V occ urs after Visit 9/ Visit 5 1 3 ( Wee k 5 6), a n x -r a y will 
o nl y be re q uire d at E T V if a n x-ra y was n ot c ollecte d at Wee k 5 6.
o
A Self -Har m F oll o w - Up F or m m ust be c o m plete d f or eac h discrete e ve nt i de ntifie d o n t he Self -Har m S u p ple me nt F or m.
p
T B testi n g re q uire d o nl y base d o n cli nical assess me nt of T B ris k (s y m pt o ms/si g ns/ k n o w n or s us pecte d T B e x p os ure) , as deter mi ne d b y t he pri nci pal 
i n vesti gat or, a n d acc or di n g t o l ocal re g ulati o ns a n d/ or l ocal sta n dar d of care ( Secti o n 9. 4. 6) .
q
H B V D N A m o nit ori n g will be perf or me d as i n dicate d i n t he Sc he d ule of Acti vities f or patie nts p ositi ve f or he patitis B c ore a nti b o d y at t he scree ni n g visit of 
t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) a n d w h o re q uire d H B V D N A m o nit ori n g d uri n g t he ori gi nati n g st u d y ( R H B V, R H B W, or R H B X) .  If t he 
res ult of t he H B V D N A testi n g is p ositi ve, t he patie nt is t o be disc o nti n ue d fr o m t he st u d y a n d is t o recei ve a p pr o priate f oll o w-u p me dical care (refer t o 
Secti o n 9. 4. 1 0. 2
C CI
f or f urt her i nf or mati o n re gar di n g t he ti mi n g of disc o nti n uati o n).
t
W here c ollecti o n is all o we d b y l ocal re g ulati o ns.  All sa m ples ( ur i ne, ser u m, plas ma, R N A, a n d w h ole bl o o d) will be c ollecte d at t he desi g nate d sc he d ule d 
visit s.

I1F-MC-RHBY(a) Clinical Protocol
Page 128
LY2439821
Section 4.  Objectives and Endpoints
Table RHBY.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
the randomized withdrawal-retreatment 
periodPeriod 2

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during the randomized withdrawal-
retreatment periodPeriod 2
Objectives and Endpoints
Objectives
Endpoints
Major Secondary

To compare the combined ixekizumab 
treatment group to historical control for 2-year 
radiographic progression in spine in patients 
with active radiographic axSpA (rad-axSpA)

Change in modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS score)

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg every 2 weeks (Q2W) treatment group 
or ixekizumab 80 mg every 4 weeks (Q4W) 
treatment group is superior to placebo in 
maintaining response after randomized 
withdrawal

The proportion of patients in the randomized
withdrawal population who do not experience a 
flare during the randomized withdrawal-
retreatmentPeriod 2

To evaluate in patients having achieved a state 
of sustained remission whether the combined
ixekizumab treatment group is superior to the 
placebo group in maintaining response after 
treatmentrandomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during the randomized 
withdrawal-retreatment periodPeriod 2

To evaluate in patients having achieved a state 
of sustained remission whether the ixekizumab 
80 mg Q2W treatment group or ixekizumab 80 
mg Q4W treatment group is superior to placebo 
in maintaining response after 
treatmentrandomized withdrawal

Time to flare for patients in the randomized 
withdrawal population during the randomized 
withdrawal-retreatment periodPeriod 2

I1F-MC-RHBY(a) Clinical Protocol
Page 129
LY2439821
Objectives
Endpoints
Other Secondary

To evaluate in patients having achieved a state 
of sustained remission whether the combined 
ixekizumab treatment group is superior to the 
placebo group in maintaining response during 
the randomized withdrawal-retreatment 
periodPeriod 2

The proportion of patients in the randomized 
withdrawal population with Assessment of 
Spondyloarthritis International Society 
(ASAS)20, ASAS40, ASAS 5/6, ASAS partial 
remission, clinically important improvement 
(change of Ankylosing Spondylitis Disease 
Activity Score [ASDAS] ≥1.1 units), major 
improvement (change of ASDAS ≥2.0 units),
and inactive disease (ASDAS <1.3) during the 
randomized withdrawal-retreatment 
periodPeriod 2

Change from baseline of originating study in 
the individual components of the ASAS criteria

Change from baseline of originating study in 
Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI)

Proportion of patients with Bath Ankylosing 
Spondylitis Disease Activity Index 50 
(BASDAI50) response

Change from baseline of originating study in 
(ASDAS)

Change from baseline of originating study in 
the measure of high sensitivity C-reactive 
protein (CRP)

Change from baseline of originating study in 
Bath Ankylosing Spondylitis Functional Index 
(BASFI)

Change from baseline of originating study in 
the measures of spinal mobility:
o
Bath Ankylosing Spondylitis 
Metrology Index (BASMI) (linear), 
and BASMI individual components
o
Chest expansion
o
Change from baseline in occiput to 
wall distance

Change from baseline of originating study in 
Maastricht Ankylosing Spondylitis Enthesitis 
Score (MASES) and Spondyloarthritis 
Research Consortium of Canada Score 
(SPARCC)

The incidence and severity of peripheral 
arthritis by tender and swollen joint counts of 
46/44 joints

The incidence rate of anterior uveitis or uveitis 
flares

Change from baseline of originating study in 
the following health outcomes measures:

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Objectives
Endpoints
o
Fatigue numeric rating scale (NRS) 
score
o
Quick Inventory of Depressive 
Symptomatology Self-Report-16 
(QIDS-SR16)
o
SF-36 (both physical and mental 
component scores)
o
Assessments of Spondyloarthritis 
international Society Health Index 
(ASAS-HI)
o
European Quality of Life -
5 Dimensions 5 Level (EQ-5D-5L)
o
Work Productivity Activity 
Impairment-Spondyloarthritis 
(WPAI-SpA)
o
Jenkins Sleep Evaluation 
Questionnaire (JSEQ)

To assess the efficacy of retreatment with 
ixekizumab following a flare in the randomized 
withdrawal-retreatment periodduring Period 2

Proportion of patients who regain ASDAS <1.3 
within 16 weeks after ixekizumab retreatment

Proportion of patients who regain ASDAS <2.1 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve/maintain an 
ASAS20, ASAS40, ASAS5/6, ASAS partial 
remission, ASDAS major improvement, and 
ASDAS clinically important improvement 
within 16 weeks after ixekizumab retreatment

Proportion of patients who achieve an ASAS20, 
ASAS40, ASAS5/6, ASAS partial remission, 
ASDAS major improvement, ASDAS clinically 
important improvement, and ASDAS-inactive 
disease through Week 64

To determine whether the long-term treatment
effect of 80 mg ixekizumab Q2W and 80 mg 
ixekizumab Q4W is maintained through 
Week 104

The proportion of patients with ASAS20, 
ASAS40, ASAS 5/6, ASAS partial remission, 
clinically important improvement (change of 
ASDAS ≥1.1 units), major improvement
(change of ASDAS ≥2.0 units), and inactive 
disease (ASDAS <1.3)

Change from baseline of originating study in 
the individual components of the ASAS criteria

Change from baseline of originating study in 
BASDAI

Proportion of patients with BASDAI50
response

Change from baseline of originating study in 
ASDAS

Change from baseline of originating study in 
the measure of CRP

Change from baseline of originating study in 

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 3 1
L Y 2 4 3 9 8 2 1
O bjecti ves
E n d p oi nts
B A S FI

C ha n ge f r om baseli ne of ori gi nati n g st u d y i n 
t he meas ures of s pi nal m o bilit y:
o
B A S MI (li near), a n d B A S MI 
i n di vi d ual c o m p o ne nts
o
C hest e x pa nsi o n
o
C ha n ge f r om baseli ne i n occi p ut t o 
wall dista nce

C ha n ge f r om baseli ne of ori gi nati n g st u d y i n 
M A S E S a n d S P A R C C

T he i nci de nce a n d se verit y of peri p heral 
art hritis b y te n der a n d s w olle n j oi nt c o u nts of 
4 6/ 4 4 j oi nts

T he i nci de nce rate of a nteri or u veitis or u veitis 
flares

Pr o p orti o n of patie nts wit h c ha n ge i n m S A S S S 
scor e < 2 fr o m baseli ne of ori gi nati n g st u d y t o 
Wee k 5 6 i n R H B Y

Pr o p orti o n of patie nts wit h n o ne w 
s yn des m o p h y te f or mati o n fr o m baseli ne of 
or i gi nati n g st u d y t o Wee k 5 6 i n R H B Y

C ha n ge f r om baseli ne of ori gi nati n g st u d y i n 
t he f oll o wi n g healt h o utc o mes meas ures :
o
Fati g ue N R S sc ore
o
QI D S S R 1 6
o
S F -3 6 ( b ot h p h ysical a n d me ntal 
c o m p o ne nt sc ores)
o
A S A S -HI
o
E Q - 5 D- 5 L
o
W P AI -S p A
o
J S E Q

T o e val uate t he de vel o p me nt of 
a nti -i xe kiz u ma b a nti b o dies a n d its i m pact o n 
t he efficac y of i xe kiz u ma b

Efficac y res p o nse rates liste d bel o w at 
Wee k s 5 6 6 4 a n d 1 0 4 b y treat me nt-e mer ge nt 
a nti -dr u g a nti b o d y ( T E -A D A ) stat us a n d b y 
ne utralizi n g a nti -dr u g a nti b o d y ( N A b ) stat us:
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 4 0
o
Pr o p orti o n of patie nts ac hie vi n g A S A S 2 0
o
Pr o p orti o n of patie nts ac hie vi n g A S D A S
i nacti ve disease
C CI

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 3 2
L Y 2 4 3 9 8 2 1
S e cti o n 5. 1. O v er all D e si g n
St u d y  R H B Y will e val uate t he s ustai na bilit y of cli nical be nefits, safet y,  a n d t olera bilit y of 
i xe kiz u ma b treat me nt as well as t he i m pact of i xe kiz u ma b o n str uct ural pr o gressi o n i n pat ient s 
wi t h a x S p A. I n a d diti on, ma i nte na nce of res p o nse after treat me nt wit h dra wal will be e val uate d 
i n t h ose patie nts ha vi n g ac hie ve d a state of s ustai ne d re missi on, defi ne d as o ne of t he f o ll owi n g :

A n k yl osi n g S p o n d ylit is Disease Acti vity Sc ore ( A S D A S) < 1. 3 at Wee k s 1 6 a n d 2 0 .,
O R

A S D A S < 1. 3 at Wee k 1 6 or Wee k 2 0, a n d A S D A S < 2. 1 at t he ot her visit. Wee k
2 0,
O R

A S D A S < 2. 1 at Wee k 1 6 a n d A S D A S < 1. 3 at Wee k 2 0.
C CI

I1F-MC-RHBY(a) Clinical Protocol
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Abbreviations:  Q2W = once every 2 weeks; Q4W = once every 4 weeks; W = week.
a
Patients in Group A will continue to receive the same ixekizumab dose regimen that they were receiving at Week 24 during 
Periods 2 and 3during Period 1.
b
Only patients having achieved a state of sustained remission (Group B) are eligible for participation in the randomized 
withdrawal–retreatment period.
c
Patients who experience a flare will be retreated with the ixekizumab treatment regimen that they were receiving prior to 
withdrawal.
d
After the 64-week database lock for Study RHBYAs of Week 64, patients receiving ixekizumab 80 mg Q4W during Period 3 
may have their dose escalated to ixekizumab 80 mg Q2W if the investigator determines that the patient may benefit from an 
increase in frequency of dosing to achieve adequate disease control.  However, for patients in Group B, escalation to 
ixekizumab 80 mg Q2W may occur only after the patient has been retreated upon flare with the ixekizumab treatment 
regimen received during Period 1 (ixekizumab 80 mg Q4W) for at least 12 weeks.
e
For patients who were receiving ixekizumab in the originating study, the dose in the 24-week Lead-In Period (Period 1) will 
be based on the current dosing in the originating study.  For patients in Study RHBX who were on placebo, patients will
receive ixekizumab 80 mg Q4W.
Figure RHBY.1.
Illustration of study design for Clinical Protocol I1F-MC-RHBY.

I1F-MC-RHBY(a) Clinical Protocol
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Extension Period, Including Blinded, Randomized Withdrawal–Retreatment (Period 2):
Eligibility criteria for participation in randomized withdrawal are described belowdefined as one 
of the following:

ASDAS <1.3 at Weeks 16 and 20.,
OR

ASDAS <1.3 at Week 16 or Week 20, and ASDAS <2.1 at the other visit.Week 20,
OR

ASDAS <2.1 at Week 16 and ASDAS <1.3 at Week 20.
Patients who DO NOT meet entry criteria for participation in the 40-week double-blind,
placebo-controlled, randomized withdrawal–retreatment period (i.e., patients who have not 
achieved a state of sustained remission) will continue to receive uninterrupted ixekizumab 
therapy and are referred to as Group A.
A flare is defined as follows:

ASDAS ≥2.1 at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2 and/or 
Period 3.
Long-Term Extension Period (Period 3):
Group B: Patients in Group B will continue the same treatment that they were receiving at the 
end of Period 2.  However, if a patient experiences a flare, the patient will be retreated with the 
ixekizumab treatment regimen (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W) that he or 
she was receiving prior to withdrawal to evaluate whether the patient can regain his or her 
original response.  A flare is defined as follows:

ASDAS≥2.1 at 2 consecutive visits, or ASDAS>3.5 at any visit during Period 3.
During Period 3, patients in Group B receiving ixekizumab 80 mg Q4W may also have their 
dose escalated to ixekizumab 80 mg Q2W if the investigator determines that the patient may 
benefit from an increase in frequency of dosing to achieve adequate disease control.  Escalation 
to ixekizumab 80 mg Q2W may occur only after the patient has been retreated upon flare with 
the ixekizumab treatment received during Period 1 (ixekizumab 80 mg Q4W) for at least 
12 weeks.
Section 5.2.  Number of Participants
It is estimated that approximately 750 patients will enter the long-term extension study (RHBY) 
after completion of studies RHBV, RHBW, or RHBX.  This sample size is estimated based on 
the 1-year retention rates from ixekizumab Ps studies and from 1 secukinumab rad-axSpA study 
(Baeten et al. 2015), which had a retention rate of approximately 85%.

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Section 5.4. Scientific Rationale for Study Design
The length of the randomized withdrawal period is 10 months40 weeks and considered 
sufficiently long based on previous randomized withdrawal studies of TNF inhibitors in RA and 
axSpA (Haibel et al. 2008; Barkham et al. 2009; Haibel et al. 2010; Sieper et al. 2014; Smolen et 
al. 2014).  It is anticipated that the majority of patients who no longer receive active treatment 
will relapse within that time frame.
Patients who do not meet entry criteria for randomized-withdrawal by Week 24 (anticipated to be 
approximately 70% of the 750 patients) will continue to receive their active treatment regimen 
during the remainder of the study (Group A).  Patients receiving ixekizumab 80mg Q4W may 
have their dose escalated to ixekizumab 80 mg Q2W if the investigator determines that the 
patient may benefit from an increase in frequency of dosing to achieve adequate disease control.  
Patients who have their dose escalated will continue on ixekizumab 80 mg Q2W for the 
remainder of Period 3.
A repeat x-ray of the cervical and lumbar spine will be taken at Week 56 in Study RHBY 
(approximately 2 years after baseline of the originating study) to evaluate the potential effect of 
ixekizumab treatment on structural progression.  The x-ray at Week 56 is only needed for 
patients initially enrolled in Studies RHBV or RHBW (see Schedule of Activities, Section 2).  
As structural progression in axSpA is slow, a 2-year time interval between consecutive x-rays is 
appropriate for such evaluation in patients with radiographic axSpA and avoids radiographic 
overexposure for patients.
Section 6.1.  Inclusion Criteria
[2.]
Must agree to use a reliable method of birth control.

If athe patient is male, the patient, the patient must 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 athe patient is female patient, patient isand is a woman of childbearing 
potential who tests negative for pregnancy, the patient must 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 birth control include, but are not 
limited to, condoms with spermicide, male sterilization, oral 
contraceptives, contraceptive patch, injectable or implantable 
contraceptives, intrauterine device, vaginal ring, or diaphragm with 
contraceptive gel.

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Section 6.2.  Exclusion Criteria
[4.]
Have significant uncontrolled cerebro-cardiovascular (e.g., myocardial 
infarction [MI], unstable angina, unstable arterial hypertension, severe heart 
failure, or cerebrovascular accident), respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematologic, neuropsychiatric disorders, or 
abnormal laboratory values that developed during a previous ixekizumab 
studythe originating ixekizumab study (RHBV, RHBW, or RHBX) that, in the 
opinion of the investigator, pose an unacceptable risk to the patient if 
investigational product continues to be administered.
[7.]
Had temporary investigational product interruption at any time during or at 
the final study visit of a previous ixekizumab studythe originating ixekizumab 
study (RHBV, RHBW, or RHBX) and, in the opinion of the investigator,
restarting ixekizumab poses an unacceptable risk for the patient’s participation 
in the study.
Section 6.4.  Screen Failures
Not applicable.Individuals who do not meet the criteria for participation in this study (screen 
failure) will not be rescreened.
Section 7.1.  Treatments Administered
During the Long-Term Extension Period, patients in Group B will continue the same treatment 
that they were receiving at the end of Period 2.  However, if a patient experiences a flare and 
meets criteria for retreatment (see Section 5.1), the patient will be retreated with the ixekizumab 
treatment regimen (ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W) that he or she was 
receiving prior to withdrawal to evaluate whether the patient can regain his or her original 
response.  DuringAs of Week 64 and during the Long-Term Extension Period, patients in Group 
B receiving ixekizumab 80 mg Q4W may also have their dose escalated to ixekizumab 80 mg 
Q2W after the 64-week database lock for Study RHBY, if the investigator determines that the 
patient may benefit from an increase in frequency of dosing to achieve adequate disease control. 
Escalation to ixekizumab 80 mg Q2W may occur only after the patient has been retreated upon 
flare with the ixekizumab treatment regimen received during Period 1 (ixekizumab 80 mg Q4W)
for at least 12 weeks (see Section 7.4).

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Table RHBY.2.
Summary of Treatment Regimens
Study RHBY
Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
RHBV or
RHBW
ixekizumab 80 
mg Q2W
ixekizumab 80 mg Q2W 
(open-label)
[Dose: 1 ixekizumab 80-mg 
Q2W injection (beginning at 
Week 0)]
Group A: open-label
ixekizumab 80 mg Q2W
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindedfa,d
ixekizumab 80 mg Q2W (blinded)c
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)a
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
ixekizumab 80 
mg Q4W
ixekizumab 80 mg Q4W 
(open-label)
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0)] 
Group A: open-labeldc
ixekizumab 80 mg Q4W
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24)] 
Group B: blindedfb,d
ixekizumab 80 mg Q4W (blinded)e
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24)]
or
placebo (blinded)b
[Dose: 1 placebo for ixekizumab injection Q4W (beginning at Week 24)]

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Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
RHBX
rescued to 
ixekizumab 80 
mg Q2W
ixekizumab 80 mg Q2W 
(open-label)
[Dose: 1 ixekizumab 80-mg
Q2W injection (beginning at 
Week 0)]
Group A: open-label
ixekizumab 80 mg Q2W
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindedfa,d
ixekizumab 80 mg Q2W (blinded)c
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)a
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
ixekizumab 80 
mg Q2W 
(blinded) 
ixekizumab 80 mg Q2W 
(blinded)ge
[Dose: 1 ixekizumab 80-mg 
Q2W injection (beginning at 
Week 0)]
Group A: blindedge
ixekizumab 80 mg Q2W  
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
Group B: blindedf, ga,d,e
ixekizumab 80 mg Q2W (blinded)
c
[Dose: 1 ixekizumab 80-mg Q2W injection (beginning at Week 24)]
or
placebo (blinded)a
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]

I1F-MC-RHBY(a) Clinical Protocol
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Originating 
Study
Treatment at 
End of 
Originating 
Study
Treatment During 
RHBY 
Period 1 
Treatment During 
RHBY 
Period 2 and Period 3
ixekizumab 80 
mg Q4W 
(blinded) 
ixekizumab 80 mg Q4W 
(blinded) ge
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0);  
and 1 placebo for ixekizumab 
injection Q4W (beginning at 
Week 2)]
Group A: blindedd, gc,e
ixekizumab 80 mg Q4W 
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24);  
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]
Group B: blindedf, gb,d,e
ixekizumab 80 mg Q4W (blinded)e
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]  
or
placebo (blinded)b
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]
placebo 
(blinded)
ixekizumab 80 mg Q4W 
(blinded)ge
[Dose: 1 ixekizumab 80-mg 
Q4W injection (beginning at 
Week 0); 
and 1 placebo for ixekizumab 
injection Q4W (beginning at 
Week 2)]
Group A: blindedd, gc,e
ixekizumab 80 mg Q4W 
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)]
Group B: blindedf, gb,d,e
ixekizumab 80 mg Q4W (blinded)e
[Dose: 1 ixekizumab 80-mg Q4W injection (beginning at Week 24); 
and 1 placebo for ixekizumab injection Q4W (beginning at Week 26)] 
or
placebo (blinded)b
[Dose: 1 placebo for ixekizumab injection Q2W (beginning at Week 24)]

I1F-MC-RHBY(a) Clinical Protocol
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Abbreviations:  Q2W = every 2 weeks; Q4W = every 4 weeks.
a
Patients who experience a flare and meet the criteria for retreatment during Period 2 or Period 3 will receive ixekizumab 80 mg Q2W.
b
Patients who experience a flare and meet the criteria for retreatment during Period 2 or Period 3 will receive ixekizumab 80 mg Q4W.  As of Week 64, 
patients in Group B may have their dose escalated to ixekizumab 80 mg Q2W only after the patient was retreated upon flare with ixekizumab 80 mg Q4W for 
at least 12 weeks (Section 7.4).
c
Patients who experience a flare and meet the criteria for retreatment will remain on their assigned dosing regimen of ixekizumab 80 mg Q2W.
dc After 64 weeks of treatmentAs of Week 64, patients in Group A receiving ixekizumab 80 mg Q4W may have their dose escalated to ixekizumab 80 mg Q2W 
in Period 3 if the investigator determines that the patient may benefit from an increase in frequency of dosing to achieve adequate disease control 
(Section 7.4).  Dose escalation may begin at the next scheduled visit or at an unscheduled visit prior to the next scheduled visit.
e
After the 64-week datalock for Study RHBY, patients in Group B receiving ixekizumab 80 mg Q4W may have their dose escalated to ixekizumab 80 mg 
Q2W in Period 3 if the investigator determines that the patient may benefit from an increase in frequency of dosing to achieve adequate disease control 
(Section 7.4).
fd All patients in Group B will remain on blinded study drug from Week 24 until the 64-week datalock for Study RHBY has been completedcompletion of the 
study or time of flare (Section 7.3). See Section 7.3.
ge For patients entering Study RHBY from Study RHBX who were receiving blinded treatment at the end of the originating study, patients will continue to 
receive blinded treatment in Study RHBY until the 52-week datalock for Study RHBX is achieved.

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Section 7.2.  Method of Treatment Assignment
TheDuring the Extension Period, the IWRS will be used to assign double-blind investigational 
product to each patient in Group B. Site personnel will confirm that they have located the 
correct investigational product package by entering a confirmation number found on the package 
into the IWRS.
During the Long-Term Extension Period (Period 3), patients will continue the same treatment 
that they were receiving at the end of Period 2.
Section 7.3.  Blinding
During the Extension Period (Period 2), including blinded, randomized withdrawal–retreatment, 
patients who do not meet entry criteria for participation in the randomized withdrawal–
retreatment period (Group A) will continue to receive ixekizumab 80 mg Q2W or ixekizumab 80 
mg Q4W.  Patients having achieved a state of sustained remission and do meet the criteria 
outlined in Section 5.1 (Group B) will participate in the double-blind, placebo-controlled, 
randomized withdrawal–retreatment period.  During the randomized withdrawal–retreatment 
period, patients in Group B, study site personnel, and study team will be blinded to study 
treatment randomization.  Patients participating in the randomized withdrawal–retreatment 
period will continue to receive blinded treatment until Week 64 datalock for Study RHBY has 
been completedthe completion of the study or time of flare.  Upon flare, patients will be retreated
with the ixekizumab treatment regimen assigned in Period 1 in an open-label fashion.  Patients 
who experience a flare and were originally from Study RHBX will not receive open-label 
treatment until the Week 52 datalock has occurred for Study RHBX.
During the Long-Term Extension Period (Period 3), patients from Group A will continue to 
receive ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W.  Patients from Group B will 
continue the same treatment they were receiving at the end of Period 2 (ixekizumab 80 mg Q2W, 
ixekizumab 80 mg Q4W, or placebo) in blinded fashion until the Week 64 datalock for the 
randomized withdrawal-retreatment period for Study RHBY has been completedcompletion of 
the study or time of flare.  Upon flare, patients will be retreated with the ixekizumab treatment 
regimen assigned in Period 1 in an open-label fashion.  As of Week 64, patients initially treated 
with ixekizumab 80 mg Q4W during Period 1 may have their dose escalated to ixekizumab 
80 mg Q2W, in an open-label fashion, only after the patient has experienced a flare and been 
subsequently retreated with ixekizumab 80 mg Q4W for at least 12 weeks.Patients may receive 
open-label treatment thereafter.
Patients who experience a flare and were originally from Study RHBX will not receive 
open-label treatment until the Week 52 datalock has occurred for Study RHBX.
During the Long-Term Extension Period (Period 3), patients from Group A will continue to 
receive ixekizumab 80 mg Q2W or ixekizumab 80 mg Q4W.  Patients from Group B will 
continue the same treatment they were receiving at the end of Period 2 (ixekizumab 80 mg Q2W, 
ixekizumab 80 mg Q4W, or placebo) in blinded fashion until Week 64 datalock for the 

I1F-MC-RHBY(a) Clinical Protocol
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randomized withdrawal-retreatment period for Study RHBY has been completed.  Patients may 
receive open-label treatment thereafter.
Section 7.4.  Dosage Modification
After 64 weeks of treatmentAs of Week 64, patients in Group A receiving ixekizumab 80 mg 
Q4W may have their dose escalated to ixekizumab 80 mg Q2W in Period 3 if the investigator 
determines that the patient may benefit from an increase in frequency of dosing to achieve 
adequate disease control.  Dose escalation may begin at the next scheduled visit or at an 
unscheduled visit prior to the next scheduled visit.
After the 64-week datalock for Study RHBYAs of Week 64, patients in Group B (Table 
RHBY.3):

who are receiving placebo will remain on placebo, and will be monitored per the 
Schedule of Activities (Section 2) for eligibility (i.e., flare) to be retreated with the 
ixekizumab treatment regimen they were receiving prior to withdrawal (ixekizumab 
80 mg Q2W or ixekizumab 80 mg Q4W).  After a minimum of 12 weeks on 
ixekizumab 80 mg Q4W, dosing may be escalated to 80 mg Q2W if the investigator 
determines that the patient may benefit from an increase in dosing to achieve 
adequate disease control.

who are receiving ixekizumab 80 mg Q4W may have their dose escalated to 
ixekizumab 80 mg Q2W in Period 3 if the investigator determines that the patient 
may benefit from an increase in dosing to achieve adequate disease control.  
Escalation to ixekizumab 80 mg Q2W may occur only after the patient has been 
retreated upon flare with the ixekizumab treatment regimen received during Period 1
(ixekizumab 80 mg Q4W) for at least 12 weeks.

who are receiving ixekizumab 80 mg Q2W will remain on this dose until completion 
of the study or early discontinuation.
Table RHBY.3.
Dosage Modification for Group B during Period 2 and Period 3
Period 1
(Open-Label)
Period 2
(Blinded)
Period 3
(Blinded)
If Flare during Period 2 or 3,
Retreat (Open-Label)
12 Weeks after Retreat, 
Escalate (Period 3)
(Open-Label)
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
ixekizumab
80 mg Q2W
N/A
placebo
placebo
ixekizumab
80 mg Q2W
N/A
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q2W
placebo
placebo
ixekizumab
80 mg Q4W
ixekizumab
80 mg Q2W
Abbreviations:  N/A = not applicable; Q2W = every 2 weeks; Q4W = every 4 weeks.

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Note:  Patients from Group B who experience a flare and meet criteria for retreatment during Period 2 or Period 3 
will be retreated with the ixekizumab treatment regimen received during Period 1 in an open-label fashion.  As of 
Week 64, patients initially treated with ixekizumab 80 mg Q4W during Period 1 may have their dose escalated to 
ixekizumab 80 mg Q2W, in an open-label fashion, only after the patient has experienced a flare and been 
subsequently retreated with ixekizumab 80 mg Q4W for at least 12 weeks.  Patients who experience a flare and 
were originally from Study RHBX will not receive open-label treatment until the Week 52 datalock has occurred 
for Study RHBX.
Section 7.7.  Concomitant Therapy
Patients participating inDuring the randomized withdrawal–retreatment period phase of Period 2, 
patients in Group B are requested to not have any changes to concomitant medications during the 
40-week observation period except for the defined retreatment medication or changes needing to 
be made for an AE or for safety reasons.
Patients undergoing an MRI at Week 24 (see Schedule of Activities, Section 2) may receive 
premedication of ≤30 mg of morphine or equivalent or other NSAIDs/cyclooxygenase-2
inhibitors, on the day of the MRI, for significant pain as judged by the investigator.  Patients with 
claustrophobia may receive premedication with benzodiazepine; the investigator should assess 
for potential interactions with other concomitant medication(s), such as opiates.

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Table RHBY.4.
Concomitant Treatment with NSAIDs and Analgesics, Conventional DMARDs, and Corticosteroids
Study RHBY
Period 1
Period 2 
Period 3
NSAIDs and 
Analgesics
NSAIDs, including COX-2 inhibitors, 
will be allowed up to the maximum 
recommended doses for pain.  Patients 
are to be on stable dose during Period 1. 
Introduction of a new NSAID or dose 
adjustment to an existing NSAID is not 
permitted, unless required for safety 
reasons.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed and 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.  Patients are to be on stable 
dose during Period 1.  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.
Group A:
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 arthritis assessment.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed but 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.
Group B (participating in randomized
withdrawal): Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A and Group B:
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 arthritis assessment.
Short-acting analgesics with no anti-
inflammatory action (such as 
paracetamol) are permitted and may be 
administered ad hoc as needed but 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.
Opiate analgesic use is allowed but not 
to exceed >30 mg/day of morphine or its 
equivalent.
Group B (participating in randomized
withdrawal):  Same as Period 1 until they
flare.  Once they flare, same as patients 
in Group A during Period 3.

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Period 1
Period 2 
Period 3
Conventional 
DMARDs
Methotrexate (oral or parenteral up to 
25 mg/week), sulfasalazine (up to 
3 g/day), or hydroxychloroquine (up to 
400 mg/day) is allowed.
During Period 1, alteration of cDMARD 
dose or route, and/or introduction of a 
new cDMARD are not permitted, unless 
required for safety reasons.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs.  Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group A:  Methotrexate (oral or 
parenteral up to 25 mg/week), 
sulfasalazine (up to 3 g/day), or 
hydroxychloroquine (up to 400 mg/day) 
may be allowed, and adjustment of 
allowed cDMARDs (e.g., dose change, 
introduction, withdrawal of cDMARDs 
or replacement of a current cDMARD 
with the introduction of a new 
cDMARD) is permitted.  Not more than 
1 adjustment of cDMARDs at 1 time 
within 12 weeks is recommended.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs. Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A and Group B:
Methotrexate (oral or parenteral up to 
25 mg/week), sulfasalazine (up to 
3 g/day), or hydroxychloroquine (up to 
400 mg/day) may be allowed, and 
adjustment of allowed cDMARDs (e.g., 
dose change, introduction, withdrawal of 
cDMARDs or replacement of a current 
cDMARD with the introduction of a new 
cDMARD) is permitted.  Not more than 
1 adjustment of cDMARDs at 1 time 
within 12 weeks is recommended.  
Conventional DMARDs can only be 
used as single agents and not in 
combination with other cDMARDs. Any 
changes must be recorded in the eCRF.  
If, at any time, the investigator believes 
that side effects or laboratory 
abnormalities may be attributable to the 
cDMARD, the cDMARD dose is to be 
lowered or the medication stopped.
(Note:  For all study periods, the 
maximum allowed doses are 25 mg/week 
MTX, 400 mg/day hydroxychloroquine 
and 3 g/day sulfasalazine. Local 
standards of care are to be followed for 
concomitant administration of folic or 
folinic acid if MTX is taken, and for 
administration of other cDMARDs.)
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 3.

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Period 1
Period 2 
Period 3
Corticosteroids
Oral corticosteroids:  If on oral 
corticosteroids, the dose must not exceed 
10 mg/day of prednisone or its 
equivalent at any time during the study.
During Period 1, treatment alterations in 
oral corticosteroid dose are strongly 
discouraged.
Parenteral corticosteroids (intravenous, 
intramuscular):  Treatment with 
intravenous or intramuscular 
corticosteroids is not permitted.
Parenteral corticosteroids 
(intra-articular): Intra-articular injection 
of corticosteroid may be allowed on a 
limited basis: It is recommended that 
there be no more than 1 injection within 
any 1 year period.  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.
Group A:
Oral corticosteroids:
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 the 
study.
Parenteral corticosteroids (intravenous, 
intramuscular, intra-articular):
Treatment with parenteral corticosteroids 
is not recommended.  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.
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 2.
Group A and Group B:
Oral corticosteroids:
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 the 
study.
Parenteral corticosteroids (intravenous, 
intramuscular, intra-articular):
Treatment with parenteral corticosteroids 
is not recommended.  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.
Group B (participating in randomized
withdrawal):  Same as Period 1 until they 
flare.  Once they flare, same as patients 
in Group A during Period 3.
Abbreviations: cDMARD = conventional disease modifying antirheumatic drug; COX-2 = cyclooxygenase-2; eCRF = electronic case report form; 
MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; SJC = swollen joint count; TJC = tender joint count.

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Section 8.1.1.  Permanent Discontinuation from Study Treatment
[13] The patient becomes hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive.  
The patient is to be referred to a specialist physician.  Discussion of the timing of
discontinuation from study treatment and from the study is provided in Section 
9.4.10.2.
Section 9.1.1.  Primary Efficacy Assessments
As described in Section 10.3.3.1, the primary efficacy endpoint is the proportion of patients in 
the randomized withdrawal population who do not experience a flare (a flare is defined as 
ASDAS ≥2.1 at 2 consecutive visits, or ASDAS >3.5 at any visit during Period 2).  The ASDAS 
is a composite index to assess disease activity in axSpA (Machado et al. 2011a, 2011b; Zochling 
2011).  The parameters used for the ASDAS (with high sensitivity C-reactive protein [CRP] as 
acute phase reactant) are the following: 
1) Total back pain (BASDAI question 2)
2) Patient global assessment (Section 9.1.2.4)
3) Peripheral pain/swelling (BASDAI question 3)
4) Duration of morning stiffness (BASDAI question 6)
5) CRP in mg/L
The ASDAScrp is calculated with the following equation:  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).  (Note:  CRP is in mg/liter, the range of other 
variables is from 0 to 10; Ln represents the natural logarithm.)
Section 9.1.2.2.1. Radiographic Imaging of the Spine
At Week 56, a spinal x-ray, plain radiograph of the lateral views of cervical and lumbar spine, 
will be centrally read; the x-ray at Week 56 is only needed for patients initially enrolled in 
Studies RHBV or RHBW.  The data set will be scored by the modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS; Wanders 2004; Creemers 2005).
Section 9.4.6.  Tuberculosis Testing
Patients with a positive TB test and/or other evidence of active TB should be 
discontinued (Section 8.1.1).
In patients with a positive TB test indicating TB test conversion since prior testing (based on 
patient medical history), but no other evidence of active TB, study treatment should be withheld.  
These patients may continue in Study RHBY and resume study treatment without repeating TB 
testing if all of the following conditions are met:

a specialist in the care of patients with TB (e.g., infectious disease or pulmonary 
medicine subspecialists) is consulted and does not identify evidence of active TB, and the 
patient is assessed as having latent TB infection

a posterior-anterior view chest x-ray or results from a chest x-ray obtained within 30 days 
prior to the positive TB test does not indicate active TB infection

I1 F -M C -R H B Y( a) Cli ni c al Pr ot o c ol
P a g e 1 4 8
L Y 2 4 3 9 8 2 1

after recei vi n g at least t he i nit ial 4 wee ks of a p pr o pri ate late nt T B i nfect i on ( L T BI)
t hera p y wi t h no e vi de nce of he pat ot o xi cit y ( AL T/ A S T m ust re mai n ≤2 x U L N) u p o n 
retesti n g of ser u m A L T/ A S T

meet all ot her i ncl usi o n/e xcl usi o n cri t eria for partici pat i on
S uc h patie nts m ust c o m plete a p pr o priate L T BI t hera p y  in or der t o re mai n i n c o m p lia nce a n d
c o nti n ue t o partici pate i n t he st u d y.
If a p ositive T B test res ult is belie ve d t o re prese nt a false -p osi tive res ult base d o n t h or o u g h 
me dical assess me nt of t he patie nt, t he i n vest i gat or s h o ul d disc uss f urt her testi n g a n d 
ma na ge me nt wit h Lill y me dical .
S e c ti o n 9. 4. 1 0. 2.  H e p atiti s B M o nit ori n g
He pati tis B vi r us D N A m o ni t ori n g will be perf or me d as i n dicate d i n t he Sc he d ule of Acti vit ies 
( Sectio n 2 ) fo r patie nts p ositive f or he patitis B c ore a nt i b o d y at t he scree ni n g visit of t he 
ori gi nati n g st u d y  ( R H B V, R H B W, or R H B X) a n d w h o re q uire d H B V D N A m o nit ori n g d uri n g 
t he origi nat i n g st u d y ( R H B V, R H B W, or R H B X).
T a bl e R H B Y. 5.
M aj or P ati e nt P o p ul ati o n s f or St u d y R H B Y
P o p ul ati o n
Descri pti o n
Lea d -I n Peri o d Safet y 
P o p ulati o n
All patie nts w h o recei ve at least 1 d ose of i xe kiz u ma b i n Peri o d 1.
Ra n d o mize d Wit h dra wal 
I nte nt-t o-Treat (I T T) P o p ulati o n
All patie nts w h o are ra n d o mize d i n Peri o d 2 ( Gr o u p B), e ve n if t he patie nt d oes 
n ot recei ve t he c orrect treat me nt or d oes n ot f oll o w t he pr ot oc ol.  Patie nts will 
be a nal yze d acc or di n g t o t he treat me nt w hic h t he y were assi g ne d.
Ra n d o mize d Wit h dra wal Safet y 
P o p ulati o n
All patie nts i n Gr o u p B w h o recei ve at least 1 d ose of st u d y treat me nt after 
Peri o d 2 ra n d o mizati o n.  Patie nts will be a nal yze d acc or di n g t o t he treat me nt t o 
w h ic h t he y were assi g ne d.
N o nra n d o mize d p o p ulati o n
All patie nts i n Gr o u p A w h o were n ot ra n d o mize d i n Peri o d 2 a n d recei ve at 
least 1 d ose of i xe kiz u ma b i n Peri o d 2.
I xe kiz u ma b Str uct ure P o p ulati o n
All patie nts w h o i) are fr o m eit her R H B V or R H B W st u d y; ii) ha ve bee n treate d 
wit h i xe kiz u ma b f or at least 1 8 m o nt hs; a n d iii) ha ve m S A S S S data at b ot h 
Wee k 0 i n t he ori gi nati n g st u d y a n d Wee k 5 6 i n R H B Y.
L o n g -Ter m I xe kiz u ma b
Treat me nt Efficac y P o p ulati o n
All patie nts w h o are ra n d o mize d t o i xe kiz u ma b 8 0 m g Q 2 W or i xe kiz u ma b 8 0 
m g Q 4 W at Wee k 0 of t he ori gi nati n g st u dies a n d c o nsiste ntl y recei ve d 
i xe kiz u ma b i n R H B Y.
Flare P o p ulati o n
All patie nts i n Gr o u p B w h o e x perie nce a flare after Per i o d 2 ra n d o mizati o n at 
Wee k 2 4
a n d w h o recei ve at least 1 d ose of i xe kiz u ma b i n Peri o d 2 i xe kiz u ma b 
retreat me nt after flare i n Peri o d 2 a n d Peri o ds 2 a n d 3 c o m bi ne d (e x pl orat or y 
a nal yses).
C CI

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Population
Description
Follow-Up Period Population
All patients who receive at least 1 dose of study treatment at any time during 
Study RHBY and enter the Post-Treatment Follow-Up Period (Period 4).  
Patients will be analyzed according to the treatment they were taking before 
entering Period 4.
Section 10.3.1.1.  General Consideration for Analyses during Period 1 (Lead-in)the 
Combined Periods 1, 2, and 3
Unless otherwise specified, baseline will be defined as the last available value before the first 
injection of originating studies for efficacy analyses.  For safety analysis, baseline is defined as 
the last available value before the first dose of study treatment in RHBY.
Endpoint for Period 1 is defined as the last visit in Period 1 (Week 24; Group A: Visit 5/Group 
B: Visit 505).  Change from baseline will be calculated as the visit value of interest minus the 
baseline value.Efficacy, health outcome, and safety data collected in Period 1 will be 
summarized for each ixekizumab dose regimen without inferential statistics.
Combined Periods 1, 2, and 3 start at the first injection of ixekizumab 80 Q2W or ixekizumab 
80 mg Q4W in Study RHBY and ends on the date of Week 104 (Group A: Visit 14/Group B: 
Visit 519) or at early termination visit (ETV) prior to Week 104.
Section 10.3.1.1.1.  Lead-In Period Safety Population
Safety data collected in Combined Periods 1, 2 and 3 will be summarized for the Lead-In Period 
Safety Population by combined ixekizumab treatment group and each of the ixekizumab dose
groups without inferential statistics.

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Section 10.3.1.1.2.  Long-Term Ixekizumab Treatment Efficacy Population
The long-term treatment effect in both categorical and continuous variables will be summarized 
by treatment group at each scheduled visit including Week 24, Week 64, and Week 104, and will 
also be summarized graphically using the response rate for categorical variables and mean for 
continuous variables by group at each scheduled visit in the Combined Periods 1, 2, and 3.
Section 10.3.1.2.  General Consideration for Analyses during Period 2 (Extension Period, 
Including Blinded, Randomized Withdrawal–Retreatment)
10.3.1.2.1  Randomized Withdrawal ITT Population
The analysis for all continuous efficacy and health outcome variables, change from baseline to 
endpoint analysis, will be made using analysis of covariance (ANCOVA) with treatment, 
baseline value, geographic region, and originating study in the model.  Missing data will be 
imputed using last observation carried forward (LOCF) or modified baseline observation carried 
forward (mBOCF).  Type III sums of squares for the least-squares (LS) means will be used for 
the statistical comparison; the 95% CI will also be reported.
10.3.1.2.2  Flare Population
For the Flare Population, Period 2 starts at the time of first injection of the retreatment  of 
ixekizumab 80 Q2W or 80 mg Q4W following the flare and ends on the date of Week 64 prior to 
injection of study treatment (Visit 515) or the ETV before the date of Week 64.
Summary statistics will be provided based on the Flare Population within 16 weeks after the 
ixekizumab retreatment for patients who have 16 weeks of post-retreatment follow-up.  No 
inferential statistics will be provided.  The Kaplan–Meier estimates of the proportion of patients 
who first regain response on the variables of interest will be carried out at each post-retreatment  
interval (4 weeks, 8 weeks, and etc.) up to 40 weeks.  If a patient has not regained response or 
discontinues the study by Week 64, the patient will be censored at the date of their last visit 
during Period 2.
Section 10.3.1.3.  General Consideration for Analyses during Period 3 (Long-Term 
Extension)at Week 56 for the 2-Year Radiographic Progression in Spine Assessments
Unless otherwise specified, Period 3 starts at the first injection of study treatment at Week 64 
(Group A: Visit 10/Group B: Visit 515) and ends on the date of Week 104 (Group A: Visit 
14/Group B: Visit 519) or the ETV (between Weeks 64 and 104).
For the efficacy and health outcomes analysis, baseline is defined as the last available value 
before the start of treatment in Period 1 from originating study and, in most cases, will be the 
value recorded at Week 0 (from the originating study).
For the safety analysis, baseline is defined as last available value before first dose at the start of 
the Long-Term Extension Period (Week 64; Group A: Visit 10/Group B: Visit 515). 
All efficacy and safety data collected will be summarized without inferential statistics.

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Assessment of 2-year radiographic progression in the spine from baseline in Studies RHBV and 
RHBW to Week 56 (Group A: Visit 9/Group B: Visit 513) in Study RHBY will be evaluated by 
comparing the radiographic progression of the Ixekizumab Structure Population to the Historical 
Control Population.
Important patient characteristics, such as age at baseline, baseline syndesmophytes, baseline 
CRP, age at onset, sex, smoking history and duration of disease, will be compared between the 
Ixekizumab Structure Population and the Historical Control Population.  The primary analysis 
will be ANCOVA to compare the 2-year radiographic progression in spine measured by change 
in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The ANCOVA model will 
include population and baseline mSASSS score.
Fisher’s exact test will be used to compare the proportion of non-progressors measured by 
change in Total mSASSS <2 and by mSASSS=0, the proportion of progressors measured by 
change in Total mSASSS ≥0, and the proportion of patients with no new syndesmophytes.
Section 10.3.1.4.  General Considerations for Analyses during Period 2 and 3 Combined
For patients who are participating in randomized withdrawal-retreatment in Period 2, efficacy, 
health outcomes, and safety data collected in Periods 2 and 3 combined will be summarized for 
ixekizumab 80 mg Q2W or ixekizumab Q4W without inferential statistics.
For efficacy, and health outcomes, baseline is defined as the last available value before the first 
dose of study medication in Period 2 from originating study and in most cases will be the value 
recorded at Week 0 (from the originating study).
For safety analysis, baseline is defined as the last available value before the first dose at the start 
of Period 2 in RHBY.
For patients who are not participating in randomized withdrawal-retreatment in Period 2, 
efficacy, health outcomes, and safety data collected in Periods 2 and 3 combined will be 
summarized for ixekizumab 80 mg Q2W or ixekizumab Q4W without inferential statistics.
Section 10.3.1.5.2.  Modified Nonresponder Imputation for Clinical Response
Analysis of categorical efficacy and health outcome variables for long-term ixekizumab 
treatment analysis will be assessed using a modified nonresponder imputation (mNRI) method.  
Patients will be considered as nonresponders if they discontinue study drug due to a flare, an AE,
or lack of efficacy. For patients discontinuing study drug for any other reason, the data will be 
imputed using multiple imputation method (as described in Section 10.3.1.5.4). Patients without 
at least 1 observation will also be defined as nonresponders for the mNRI analysis.
Section 10.3.1.5.4.  Last Observation Carried Forward
An LOCF analysis will be performed on selective continuous efficacy and health outcomes 
variables.  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.  

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Randomized patients without at least 1 postbaseline observation will not be included for 
evaluation.
Multiple Imputation
Analysis of continuous efficacy and health outcome variables for long-term ixekizumab 
treatment analysis will be assessed using multiple imputation method.  In the multiple imputation
analyses, missing data will be imputed so as to estimate what observations would have been if 
the patient had not discontinued.  Specifically, multiple imputation is the partial imputation of 
non-monotone missing data using Markov chain Monte Carlo method with the simple imputation 
model, followed by a sequential regression imputation with the baseline score.
Section 10.3.2.2.  Patient Characteristics
Patient characteristics and baseline clinical measures will be summarized for each treatment 
period.  Baseline characteristics will include gender, age, age category, weight, race, geographic 
region, originating study, abnormal/normal CRP.  Baseline clinical measurements may include 
BASDAI, BASFI, BASMI, chest expansion, Fatigue NRS, Patient Global NRS, total back pain, 
spinal pain at night, spinal pain, inflammation, MASES, enthesitis SPARCC, TJC, and SJC.
Section 10.3.2.3.  Concomitant Therapy
Previous and concomitant medications will be summarized for patients who enter each treatment 
period and will be presented by WHO Anatomic Therapeutic Class Level 4 and WHO preferred 
term.  Concomitant DMARDs, concomitant corticosteroids, and concomitant NSAIDs will also 
be summarized.  Treatment group comparisons in Period 2 will be conducted using Fisher’s 
exact test.
Section 10.3.2.4.  Treatment Compliance
Treatment compliance with investigational product will be summarized for patients who enter 
each treatment period.  A patient will be considered overall compliant for each study 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 (i.e., take more injections at the same time point than specified in the 
protocol).
Section 10.3.3.2.  Major Secondary Analyses
The 2-year radiographic progression reflected by change from baseline of originating studies 
RHBV and RHBW to Week 56 of Study RHBY (Group A: Visit 9/Group B: Visit 513) will be 
measured by mSASSS score and summarized by treatment.  The comparison of the ixekizumab 
treatment group to the historical control will be analyzed by ANCOVA, with baseline score as 
covariate.  The historical control will be defined in the SAP.  The historical control aims to 
include both the Outcome in AS International Study (OASIS cohort; van der Heijde et al. 2005) 
and the German SpA Inception Cohort (GESPIC; Reveille et al. 2012).  Within-treatment 
changes from baseline along with 95% CI will be assessed by a paired t-test using the LS means.

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Section 10.3.3.3.  Other Secondary Efficacy Analyses
The secondary efficacy and health outcomes analysis for Period 2 will be based on the
Randomized Withdrawal ITT Population or the Flare Population.  Additional efficacy and health 
outcome analysis for combined Period 2 and Period 3Periods 1, 2, and 3 analyses will be based 
on the nonrandomized population Long-Term Ixekizumab Treatment Efficacy Population.
Section 10.3.3.3.1.  Period 1 (Initial Lead-in treatment period)
The proportion of patients who achieve sustained remission during the initial lead-in treatment 
period will be summarized.
Combined Periods 1, 2, and 3
The long-term treatment effect in both categorical and continuous variables will be summarized 
by treatment group at each scheduled visit including Week 24, Week 64, and Week 104.  
Missing data will be imputed using mNRI for categorical efficacy variables, described in 
Section 10.3.1.5.2, and mBOCF and multiple imputation for continuous efficacy variables, 
described in Sections 10.3.1.5.3 and 10.3.1.5.4, respectively.
Section 10.3.3.3.2.  Period 2 (Extension Period, Including Blinded, Randomized 
Withdrawal–Retreatment)
For the Randomized Withdrawal ITT Population, all categorical efficacy variables and treatment 
group comparisons will be analyzed at each visit using the logistic regression model described in 
Section 10.3.1.2.1.  Missing data will be imputed using the NRI method described in 
Section 10.3.1.5.1.  All continuous efficacy variables and treatment group comparisons will be 
analyzed at each visit using the ANCOVA models as described in Section 10.3.1.2.1 when 
appropriate.  For the ANCOVA analysis, missing data will be imputed by the mBOCF and 
LOCF methods as described in Section 10.3.1.5.3 and Section 10.3.1.6.3, respectively.
Section 10.3.3.3.3.  Period 2 and 3 Combined
Data collected in these study periods for the nonrandomized population will be summarized.  
The within-treatment group comparisons will be conducted as appropriate.
Section 10.3.4.  Safety Analyses
For Period 1combined Periods 1, 2, and 3, safety data will be summarized for the Lead-In Period 
Safety Population.
For Period 3, the safety data will be summarized for the randomized withdrawal-retreatment 
safety population and no treatment group comparisons will be performed.  
For Periods 2 and 3 combined, the safety data will be summarized for the nonrandomized 
population and no treatment group comparisons will be performed.
Section 10.3.6.1.  Health Outcomes
Period 3 (Long-Term Extended Treatment Period):  

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Data collected in Period 3 will be summarized for the randomized withdrawal ITT population.  
The within-treatment group comparisons may be conducted as appropriate.  
Additional analyses of health outcomes measures will be specified in the SAP.
Period 2 and 3 Combined Periods 1, 2, and 3:
Data collected in combined Periods 1, 2, and 3 combined will be summarized for the 
nonrandomized populationLong-Term Ixekizumab Treatment Efficacy Population.  The within-
treatment group comparisons may be conducted as appropriate.
Section 10.3.7.  Interim Analysis
The study will have approximately 1 interim database lock and 1 final database lock. The 
interim database lock and the unblinding will occur and the analysis will be performed at the 
time when all patients have completed through Week 64 or have discontinued at or prior to 
Week 64.  At this time, study team members will become unblinded; however, investigators, 
patients, and site personnel will remain blinded to study treatment until final database lock.  The 
final database lock and the analysis will occur when all patients have completed or discontinued 
the study.  The interim database lock will include all data collected by the cutoff date, including 
the data from the Long-Term Extended Treatment Period (Period 3), and follow-up data from 
patients that have begun the Post-Treatment Follow-Up Period (Period 4).  The analyses from the 
Week 64 database lock will be treated as a primary analysis because all primary and major 
secondary study objectives will be assessed at this time.  The final database lock, unblinding, and 
analysis will occur when all patients have completed or discontinued the study.
Section 11.  References
van der Heijde D, Landewé R, van der Linden S. How should treatment effect on spinal 
radiographic progression in patients with ankylosing spondylitis be measured? Arthritis 
Rheum. 2005;52(7):1979-1985.
Appendix 1.  Abbreviations and Definitions
Term
Definition
LOCF
last observation carried forward
mNRI
modified nonresponder imputation
Appendix 2.  Clinical Laboratory Tests
Clinical Laboratory Tests to Be Performed by Sponsor-Designated Laboratory
Hematologya:
Serum Chemistrya:
Hemoglobin
   Sodium
Hematocrit
   Potassium
Erythrocyte count (RBC)
   Bicarbonate
Mean cell volume (MCV)
   Chloride
Mean cell hemoglobin concentration (MCHC)
   Phosphorus

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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 clearanceb
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
HBV DNAf
Follicle-stimulating hormone (FSH)e
High sensitivity C-reactive protein (CRP)
Ixekizumab serum concentration (pharmacokinetic)
Urine pregnancy testd (assayed by clinical study site)
Partial thromboplastin time (PTT)
TB test (e.g., PPD, QuantiFERON®-TB Gold, 
T-SPOT®)g
Prothrombin time/international normalized ratio
Exploratory storage samples (serum, urine, plasma, and
RNA)
Immunogenicity testing (anti-ixekizumab Ab)
Abbreviations:  Ab = antibody; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; PPD = Purifiedpurified
protein derivative; RNA = messenger ribonucleic acid; RBC = red blood cells; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; TB = tuberculosisWBC = 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.  
d
Urine pregnancy test performed locally for women of childbearing potential.
e
For female patients ≥40 and <60 years of age who cease menstruation for at least 12 months during study 
participation, an FSH test may be performed to confirm nonchildbearing potential (FSH ≥40 mIU/mL).  FSH test 
will be performed centrally. 
f
HBV DNA monitoring will be performed as indicated in the Schedule of Activities for patients positive for 
hepatitis B core antibody at the screening visit of the originating study (RHBV, RHBW, or RHBX) and who 
required HBV DNA monitoring during the originating study (RHBV, RHBW, or RHBX).  If the result of the 
HBV DNA testing is positive, the patient is to be discontinued from the study and is to receive appropriate 
follow-up medical care (refer to Section 9.4.10.2 for further information regarding the timing of discontinuation).

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g
See Section 9.4.6.  In countries where the QuantiFERON®-TB Gold test or T-SPOT® test is available, it may be 
used instead of the PPD TB test.  The QuantiFERON®-TB Gold test and the T-SPOT® test will be performed 
locally.

P P D
L e o  D o c u m e n t  I D  =  7 f 8 5 0 c 5 f - 4 a 3 e - 4 d 3 a - 8 9 8 a - a 5 7 e 8 4 8 6 d 3 a 8
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - J u n - 2 0 1 7  1 3 : 1 8 : 2 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - J u n - 2 0 1 7  1 4 : 0 0 : 0 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D