Clinical trial NCT03942042
Conditions: Generalized Pustular Psoriasis Erythrodermic Psoriasis
Keywords: Generalized Pustular Psoriasis (GPP) Erythrodermic Psoriasis (EP) Japan
Sponsor: Eli Lilly and Company
Start date: 2019-07-05; Completion date: 2020-07-22
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The reason for this study is to see if the study drug ixekizumab is safe and effective in participants with generalized pustular psoriasis and erythrodermic psoriasis.

Detailed description:

Arms: arm 1: Induction Dosing Period:

Participants received 160 milligrams (mg) ixekizumab subcutaneously (SC) as 2 injections at Week 0 followed by 80 mg ixekizumab SC as 1 injection at Week 2, 4, 6, 8 and 10.

Maintenance Dosing Period:

Participants with Global Improvement Score (GIS) = 1 at Week 12 are responders who will complete the study.

Participants who are inadequate responders (GIS ≥2 at Week 12 and based on the investigators' discretion) will be administered 80 mg ixekizumab SC as 1 injection at Week 12, 14, 16, and 18 or until they achieve a GIS score of 1.
Interventions: intervention 1: Ixekizumab
Intervention descriptions: intervention 1: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I1F-JE-RHCV 
 
A Multicenter, Open-Label, Post Marketing Clinical Trial to Evaluate the Efficacy And Safety 
Of Ixekizumab in Patients With Generalized Pustular Psoriasis and Erythrodermic Psoriasis 
 
NCT03942042 
 
Approval Date: 01-Feb-2019 


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Protocol I1F-JE-RHCV
A Multicenter, Open-Label, Post Marketing Clinical Trial to 
Evaluate the Efficacy And Safety Of Ixekizumab in Patients 
With Generalized Pustular Psoriasis and Erythrodermic 
Psoriasis
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ixekizumab (LY2439821), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Ixekizumab (LY2439821)
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 01-Feb-2019 GMT


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Table of Contents
Section
Page
Protocol I1F-JE-RHCV A Multicenter, Open-Label, Post Marketing 
Clinical Trial to Evaluate the Efficacy And Safety Of Ixekizumab in 
Patients With Generalized Pustular Psoriasis and Erythrodermic 
Psoriasis..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................28
6.4.
Screen Failures.............................................................................................................28
7.
Treatments........................................................................................................................29
7.1.
Treatments Administered .............................................................................................29
7.1.1.
Packaging and Labelling ......................................................................................30
7.2.
Method of Treatment Assignment ................................................................................30
7.2.1.
Selection and Timing of Doses.............................................................................31
7.3.
Blinding .......................................................................................................................31
7.4.
Dosage Modification....................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.6.
Treatment Compliance .................................................................................................32
7.7.
Concomitant Therapy...................................................................................................32
8.
Discontinuation Criteria ....................................................................................................34


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8.1.
Discontinuation from Study Treatment.........................................................................34
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................34
8.1.2.
Discontinuation of Inadvertently Enrolled Patients...............................................35
8.2.
Discontinuation from the Study....................................................................................36
8.3.
Lost to Follow-Up........................................................................................................36
9.
Study Assessments and Procedures ...................................................................................37
9.1.
Efficacy Assessments...................................................................................................37
9.1.1.
Primary Efficacy Assessment:  Global Improvement Scores.................................37
9.1.2.
Secondary Efficacy Assessments..........................................................................37
9.1.2.1.
Psoriasis Area and Severity Index...................................................................37
9.1.2.2.
Static Physician Global Assessment................................................................37
9.1.2.3.
Scalp Psoriasis Severity Index ........................................................................38
9.1.2.4.
Percentage of Body Surface Area ...................................................................38
9.1.2.5.
Generalized Pustular Psoriasis Severity Index.................................................38
9.1.3.
Appropriateness of Assessments ..........................................................................38
9.2.
Adverse Events ............................................................................................................38
9.2.1.
Serious Adverse Events........................................................................................39
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................40
9.2.2.
Adverse Events of Special Interest .......................................................................41
9.2.3.
Complaint Handling.............................................................................................42
9.3.
Treatment of Overdose.................................................................................................42
9.4.
Safety...........................................................................................................................42
9.4.1.
Electrocardiograms ..............................................................................................42
9.4.2.
Vital Signs ...........................................................................................................42
9.4.3.
Laboratory Tests ..................................................................................................42
9.4.4.
Immunogenicity Assessments ..............................................................................43
9.4.5.
Other Safety Measures .........................................................................................43
9.4.5.1.
Physical Exam................................................................................................43
9.4.5.2.
Chest X-Ray and Tuberculosis Testing ...........................................................43
9.4.5.3.
Columbia-Suicide Severity Rating Scale.........................................................44
9.4.5.4.
Hepatitis B Screening .....................................................................................45
9.4.5.5.
Hepatitis C Screening .....................................................................................45
9.4.6.
Safety Monitoring ................................................................................................46
9.4.6.1.
Neutropenia....................................................................................................46
9.4.6.2.
Hepatic Safety Monitoring..............................................................................47
9.4.6.3.
Hypertension ..................................................................................................47
9.4.6.4.
Allergic Reactions and Hypersensitivity Events..............................................47
9.5.
Pharmacokinetics .........................................................................................................48


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9.6.
Pharmacodynamics ......................................................................................................48
9.7.
Whole Blood Samples for Pharmacogenetic Research..................................................48
9.8.
Biomarkers...................................................................................................................48
9.9.
Health Outcomes/Quality of Life Assessment ..............................................................48
9.9.1.
Itch Numeric Rating Scale....................................................................................49
9.9.2.
Dermatology Life Quality Index...........................................................................49
10.
Statistical Considerations ..................................................................................................50
10.1. Sample Size Determination ..........................................................................................50
10.2. Populations for Analyses..............................................................................................50
10.3. Statistical Analyses ......................................................................................................50
10.3.1.
General Statistical Considerations ........................................................................50
10.3.2.
Patients ................................................................................................................51
10.3.2.1.
Patient Disposition..........................................................................................51
10.3.2.2.
Patient Characteristics ....................................................................................51
10.3.2.3.
Concomitant Therapy .....................................................................................51
10.3.2.4.
Treatment Compliance....................................................................................51
10.3.3.
Efficacy Analyses ................................................................................................51
10.3.3.1.
Primary Analyses ...........................................................................................51
10.3.3.2.
Secondary Analyses........................................................................................52
10.3.4.
Safety Analyses....................................................................................................52
10.3.4.1.
Adverse Events...............................................................................................52
10.3.4.2.
Clinical Laboratory Tests................................................................................53
10.3.4.3.
Vital Signs, and Physical Findings and Other Safety 
Evaluations.....................................................................................................53
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................53
10.3.6.
Evaluation of Immunogenicity .............................................................................53
10.3.7.
Other Analyses.....................................................................................................53
10.3.7.1.
Health Outcomes/Quality of Life Assessment.................................................53
10.3.7.2.
Subgroup Analyses.........................................................................................53
10.3.8.
Interim Analyses..................................................................................................53
11.
References ........................................................................................................................54
12.
Appendices .......................................................................................................................56


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List of Tables
Table
Page
Table RHCV.1.
Schedule of Activities....................................................................................12
Table RHCV.2.
Objectives and Endpoints...............................................................................18
Table RHCV.3.
Treatment Periods..........................................................................................30


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List of Figures
Figure
Page
Figure RHCV.1. Illustration of study design for Clinical Protocol I1F-JE-RHCV.....................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................57
Appendix 2.
Clinical Laboratory Tests...............................................................................62
Appendix 3.
Study Governance Considerations..................................................................64
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................69
Appendix 5.
Tests for Allergic Reactions and Hypersensitivity Events...............................70
Appendix 6.
List of Excluded Medications and Procedures................................................71


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1. Synopsis
Title of Study:
A Multicenter, Open-Label, Post Marketing Clinical Trial to Evaluate the Efficacy And Safety 
Of Ixekizumab in Patients With Generalized Pustular Psoriasis (GPP) and Erythrodermic 
Psoriasis (EP).
Rationale: 
This study is being conducted to fulfil a regulatory commitment to the Pharmaceuticals and 
Medical Devices Agency (PMDA) to evaluate the efficacy and safety of ixekizumab when dosed 
every 2 weeks (Q2W) beyond Week 12 in patients with GPP and EP.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To assess the efficacy of ixekizumab 
Q2W beyond Week 12 in patients with 
generalized pustular psoriasis (GPP) 
and erythrodermic psoriasis (EP)

Number of patients who improve their Global 
Improvement Score (GIS) at least 1 point from 
Week12 through Week 20 and with ≤2 of GIS
Secondary
The following endpoints will be assessed at each scheduled 
visit after Week 12:

To assess the efficacy of ixekizumab 
Q2W beyond Week 12 in patients with 
GPP and EP

To assess the health outcomes of 
ixekizumab Q2W beyond Week 12 in 
patients with GPP and EP

To evaluate the potential development 
of anti-ixekizumab antibodies of 
ixekizumab Q2W beyond Week 12 in 
patients with GPP and EP

Number of patients with each GIS grade 
(1: Resolved, 2: Improved, 3: Unchanged, 
4: Worsened)

Number of patients who achieve sPGA (0, 1) and 
sPGA (0)

Number of patients who achieve PASI 75, PASI 90, 
and PASI 100 from baseline

Change from baseline, and percent improvement 
from baseline in PASI

Change from baseline in PSSI in patients with scalp 
involvement at baseline, and percent of BSA 
involvement of Psoriasis

Change from baseline in DLQI total score and 
domains, and Itch NRS score

Number of patients who achieve DLQI (0, 1) and 
DLQI (0) 

Number of patients who achieve Itch NRS ≥4 point 
reduction from baseline for patients who had 
baseline Itch NRS ≥4

Number of patients who develop treatment-emergent 
anti-ixekizumab antibody (TE-ADA) and 
neutralizing anti-ixekizumab antibody (NAb)
GPP ONLY

Change from baseline on assessment of Generalized 
Pustular Psoriasis Severity Index at Week 12 and 
Week 20/ETV.


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Note:  Global improvement scores will be assessed in the four grades by comparing the psoriatic findings: 
(1) resolved, (2) improved, (3) unchanged, and (4) worsened. The global improvement score is assessed based 
on the comparison of the psoriatic findings, sPGA, PASI score, and other evaluations with those at the baseline.
Abbreviations:  BSA = body surface area; DLQI = Dermatology Life Quality Index; EP = erythrodermic psoriasis;
GIS = Global Improvement Score; GPP = generalized pustular psoriasis; NAb = neutralizing anti-ixekizumab 
antibody; NRS = Numeric Rating Scale; PASI = Psoriasis Area and Severity Index; PASI 75 = at least a 75%
improvement from baseline in PASI score; PASI 90 = at least a 90% improvement from baseline in PASI score; 
PASI 100 = a 100% improvement from baseline in PASI score; PSSI = Psoriasis Scalp Severity Index; 
Q2W = every 2 weeks; sPGA = static Physician Global Assessment; TE-ADA = treatment-emergent anti-drug 
antibody.


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Summary of Study Design:  
Study I1F-JE-RHCV is a multicenter, open-label, post marketing clinical trial to evaluate the 
efficacy and safety of ixekizumab Q2W beyond Week 12 until Week 20 in patients with GPP 
and EP.
Treatment Arms and Duration:  
Study I1F-JE-RHCV consists of 3 periods: a screening period of up to 30 days, a 12-week 
Induction Dosing Period, and an 8-week Maintenance Dosing period.  All eligible patients will 
be administered 160 mg ixekizumab as 2 SC injections at Week 0 (baseline; Visit 2) followed by 
80 mg as 1 injection at Week 2, 4, 6, 8 and 10.  Patients who are inadequate responders (Global 
Improvement Score [GIS] ≥2 at Week 12 and based on the investigators’ discretion) will be 
administered 80 mg as 1 injection at Week 12, 14, 16, and 18 or until they achieve a GIS score 
of 1.
Number of Patients:
A total of 12 patients will be enrolled so that at least 5 patients with EP and 5 patients with GPP 
who are inadequate responders (GIS ≥2 at Week 12 and based on the investigators’ discretion) 
will continue to use ixekizumab beyond Week 12. Additional enrollment may occur and sample 
size may be increased, if no GPP or EP patients enter into Period 3 (Maintenance Dosing Period) 
of the study.
Statistical Analysis:
Primary analysis of efficacy, health outcome and safety measures will be conducted based on 
patients who continued ixekizumab 80 mg Q2W beyond Week 12 by disease type (ie, GPP and 
EP separately).
Baseline is defined as the last available value before the first dose in Period 2; in most cases, it 
will be the value recorded at Week 0 (Visit 2).
As this is a single arm study with very small sample size, no statistical inference will be 
performed.
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.


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2. Schedule of Activities


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Table RHCV.1.
Schedule of Activities
Procedure
Screening
Period
(Period 1)
Treatment Period - Induction
(Period 2)
Treatment Period - Maintenance
(Period 3)
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ETV
Study Week
-
0
2
4
8
12
14
16
18
20
Visit Intervals
-30d to 
-7d
0
14
± 2d
28
± 4d
56
± 4d
84
± 2d
98
± 2d
112
± 2d
126
± 2d
140
± 2d
NA
Informed consent
X
Complete medical history
X
Demographya
X
Full physical examinationb
X
Height
X
Weight
X
X
X
X
Habitsc
X
X
X
Chest X-rayd
Xd
Xe
Xe
Body temperature
X
X
X
X
X
Inclusion and exclusion criteriaf
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Vital sign (BP and pulse)
X
Xg
X
X
X
X
X
X
X
X
X
Genetic information
(Mutation of IL-36 RN)
X
Adverse event (AE/SAE/AESI) 
review
X
X
X
X
X
X
X
X
X
X
X
Administer IP
Xgh
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
X
X
X
IP compliance
X
X
X
X
X
X
X
X
X
X
Dispense Study Drug 
Administration Logi
X
X
X
X
X
X
X
X


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Procedure
Screening
Period
(Period 1)
Treatment Period - Induction
(Period 2)
Treatment Period - Maintenance
(Period 3)
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ETV
Study Week
-
0
2
4
8
12
14
16
18
20
Visit Intervals
-30d to 
-7d
0
14
± 2d
28
± 4d
56
± 4d
84
± 2d
98
± 2d
112
± 2d
126
± 2d
140
± 2d
NA
Collect, review, & enter data from 
Study Drug Administration Log
X
X
X
X
X
X
X
X
X
X
Global Improvement Scores
X
X
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
X
X
X
X
X
X
PSSIj
X
X
X
X
X
X
X
X
X
X
Itch NRS
X
X
X
X
X
X
X
X
X
X
DLQI
X
X
X
X
X
X
X
X
C-SSRS Baseline
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
X
Self-Harm Supplement Form and 
Self-Harm Follow-Up Formk
X
X
X
X
X
X
X
X
X
X
X
GPP Severity Indexl
X
X
X
X
X
Administer PPD/QuantiFERON 
Gold/T-SPOTm
X
12-lead ECGn
X
FSHo
X
HIV/HBV/HCVp
X
HBV DNAq
X
X
X
X
X
X
X
Serum pregnancy test (Women of 
childbearing potential [WCBP] 
only)r
X


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Procedure
Screening
Period
(Period 1)
Treatment Period - Induction
(Period 2)
Treatment Period - Maintenance
(Period 3)
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ETV
Study Week
-
0
2
4
8
12
14
16
18
20
Visit Intervals
-30d to 
-7d
0
14
± 2d
28
± 4d
56
± 4d
84
± 2d
98
± 2d
112
± 2d
126
± 2d
140
± 2d
NA
Urine pregnancy test (WCBP only)r
X
X
X
Clinical chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
hsCRP
X
X
X
X
Beta-D-glucans
X
KL-6t
X
Immunogenicity testingu
X
X
X
X
LY2439821 serum concentrationuv
X
X
X
Pharmacogenetic sample (genetic 
sample/DNA)
X
Abbreviations: AE = adverse event; AESI = adverse event of special interest; BP = blood pressure; BSA = body surface area; C-SSRS = Columbia- Suicide 
Severity Rating Scale; d = days; DLQI = Dermatology Life Quality Index; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ETV = early termination 
visit; FSH = follicular stimulating hormone; GPP = generalized pustular psoriasis; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; 
HBV = hepatitis B virus; HCV = hepatitis C virus;  HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; 
IL-36 RN = interleukin 36 receptor antagonist; IP = investigational product; KL-6 = Kerbs von Lungren 6 antigen; NA = not applicable; NRS = numeric 
rating scale; PASI = Psoriasis Area and Severity Index; PCP = pneumocystis pneumonia; PPD = purified protein derivative; Ps = psoriasis; PSSI = Psoriasis 
Scalp Severity Index; SAE = serious adverse event; SC = subcutaneous; sPGA = static Physician's Global Assessment; TB = tuberculosis; V = study visit.
a
Demographics includes recording of year of birth, gender, and race.
b
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be performed at screening.  All physical examinations throughout 
the study should include a symptom-directed physical, as well as examination of heart, lungs, abdomen, and visual examination of the skin.
c
Habits include recording of caffeine, alcohol, and tobacco consumption.
d
A chest X-ray will be taken at screening unless one has been obtained within the past 6 months (provided the X-ray and/or report are available for review).


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e
To be performed if more than 12 weeks have elapsed since the previous study X-ray was obtained.  This X-ray may be performed within 12 weeks if 
medically indicated.
f
Patients who test positive for latent TB at screening may be rescreened following appropriate treatment as described in Section 9.4.5.2. Additionally, patients 
who do not qualify at screening under Exclusion Criteria [10] (active or recent infection) may be rescreened as described in Section 6.2.
g
At baseline (Week 0), BP and pulse should be measured prior to administration of the investigational product and again approximately 1 hour 
postadministration.
h
All patients will receive 2 SC doses of investigational product at Week 0.
i
Patients will record information in the Study Drug Administration Log, including the date, time, and location of administration of investigational product (for 
treatment compliance), and who administered.
j
To be collected for the patient with scalp Ps at baseline.
k
A Self-Harm Follow-Up Form is to be completed only during visits for which there is at least 1 discrete self-harm event identified on the Self-Harm 
Supplement Form.
l
To be collected for patients who have confirmed pustular Ps at Screening (Visit 1) and Baseline (Visit 2).
m See Section 9.4.5.2 for detailed description of QuantiFERON Gold TB, T-SPOT.TB, and PPD testing.  PPD test is performed at Visit 1, and patients will 
return approximately 48 and 72 hours after Visit 1 to have their PPD test read.
n
ECGs should be performed prior to injection of investigational product and collection of blood sample, as applicable.  ECGs are locally performed.
o
FSH test performed for women ≥40 and <60 years of age who have had a cessation of menses for at least 12 months to confirm non-childbearing potential 
(≥40 mIU/mL).
p
All patients will be tested for HBV at screening. Patients who are HBcAb+ and/or HBsAb+ at screening will have serum HBV DNA obtained by the central 
lab.  Patients that are found to be HBV DNA positive (detectable) and/or HBsAg+ positive at screening will be excluded from the trial.
q
If patient is HBcAb+ and/or HBsAb+, HBV DNA needs to be confirmed negative at screening and at least once every month in Periods 2 and 3.  (See Section
9.4.5.4).  
r
To be performed for females of childbearing potential only.  Urine pregnancy tests are locally performed. 
s
Beta-D-glucan is required at screening and if an investigator believes it is warranted at subsequent visits, a beta-D-glucan test may be included in the work-up 
panel at any time during the study and may be done locally.  If the beta-D-glucan test is positive, PCP needs to be ruled out.  If PCP is ruled out and the 
investigator deems the patient fit to continue, the patient may continue in the study.  If a patient has a confirmed diagnosis of PCP during the study, the patient 
must discontinue the study.
t
KL-6 is required at screening, and if an investigator believes it is warranted at subsequent visits, a KL-6 test may be included in the work-up panel at any time 
during the study and may be done locally.
u
Additional blood samples will be collected (as specified in Appendix 5) when possible for any patients who experience a potential serious
allergic/hypersensitivity reaction during the study as judged by the investigator.
v
LY2439821 serum concentration will be analyzed to help facilitate the interpretation of immunogenicity data.


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3. Introduction
3.1.
Study Rationale
Psoriasis (Ps) is a common chronic skin disorder with an estimated prevalence of 1.0% in Japan 
(Tang et al. 2014). The pathogenesis of psoriasis has undergone many paradigm shifts during 
the past 3 decades.  Psoriasis is no longer considered fundamentally a skin disease, but rather a 
chronic inflammatory process resulting from a dysfunctional immune system (Kim and Krueger 
2015).  For patients with psoriasis, the protective elements of the skin (corneocytes, 
keratinocytes, chemokines, and immunocytes, such as T cells and dendritic antigen-presenting 
cells [DiMeglio et al. 2011; Bergboer et al. 2012]) become disrupted, resulting in dysfunctional 
feedback loops and vicious cycles leading to development of life-long, thick, scaly, well-
demarcated plaques (DiMeglio et al. 2014). Psoriasis includes several phenotypes often 
separated into the following classifications; plaque Ps, guttate Ps, pustular Ps, and erythrodermic 
Ps (EP).  Psoriatic arthritis (PsA) may coexist in up to 30% of patients with Ps.  The most 
common type of psoriasis is plaque Ps (psoriasis vulgaris), and clinical features include sharply 
demarcated, scaly erythematous plaques that are often associated with itching, pain, and cracking 
of the skin. These lesions most typically affect the elbows, knees, scalp, lumbar area, umbilical 
area, and gluteal cleft.  Approximately 1/4 to 1/3 of plaque Ps patients have moderate-to-severe 
Ps, corresponding to involvement of over 5% of their body surface area (BSA) (Dubin et al. 
2003; Menter and Griffiths 2007). Disease of this extent is physically and/or socially debilitating 
to a degree comparable with other chronic medical conditions (Rapp et al. 1999).
Generalized pustular Ps (GPP) and EP are relatively rare but more severe variants of Ps.  
Generalized pustular Ps is characterized by multiple sterile pustules all over the body and may be
accompanied by systemic symptoms including fever, chills, severe itching, dehydration, rapid
pulse rate, exhaustion, anemia, weight loss, and muscle weakness. Erythrodermic Ps is a
particular inflammatory type of Ps that can affect the whole body. The reddening and shedding
of the skin are often accompanied by severe itching and pain, heart rate increase, fluid loss, and
fluctuating body temperature. Both Ps subtypes can sometimes be life-threatening without
adequate treatment.  Patients with these severe subtypes are known to experience frequent 
relapses (Rosenbach et al. 2010), and require systemic treatment.  However the treatment options 
are further limited and there are significant unmet needs for effective treatments for patients with 
GPP and EP.
Study I1F-JE-RHCV (RHCV) is a multicenter, open-label, post marketing clinical trial designed 
to assess the efficacy and safety of ixekizumab through Week 20 when administered Q2W 
beyond Week 12 in patients with GPP and EP.  This study is being conducted by Eli Lilly Japan 
to fulfil a regulatory commitment to the PMDA to evaluate the efficacy and safety of Q2W 
dosing in patients with GP and EPP.
3.2.
Background
Ixekizumab (LY2439821, Taltz®) is a humanized immunoglobulin G subclass 4 (IgG4)
monoclonal antibody (MAb) that binds with high affinity and specificity to interleukin (IL)-17A,


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a proinflammatory cytokine.  Ixekizumab does not bind to ligands IL-17B, IL-17C, IL-17D, IL-
17E, or IL-17F.  
Phase 3 clinical studies show that ixekizumab is efficacious and has an acceptable safety profile
for the treatment of adult patients with moderate-to-severe Ps and for adult patients with active
PsA. Ixekizumab was approved in Japan for the treatment of Ps, PsA, EP, and GPP at an initial 
dose of ixekizumab 160 mg followed by ixekizumab 80 mg administered Q2W from Week 2 
through Week 12, and thereafter 80 mg Q4W. In August 2018, a new dosage and administration 
was approved in Japan to support 80mg Q2W continued dosing beyond Week 12 for patients 
with Ps, PsA, EP and GPP who have an inadequate response at Week 12. However, clinical 
studies consisting of the main data package in this new approval did not include the data from 
patients with EP and GPP who underwent treatment of ixekizumab 80 mg Q2W over 12 weeks.
Therefore, the PMDA agreed that Eli Lilly Japan would conduct a study to evaluate the use of 
ixekizumab Q2W dosing beyond Week 12 in patients with EP and GPP in order to provide 
support for consistent dosing guidelines for the treatment of all indications (ie, Ps, PsA, EP, and 
GPP) with ixekizumab.
3.3.
Benefit/Risk Assessment
Continued 80 mg Q2W dosing of ixekizumab was shown to be more efficacious over 52 weeks 
of treatment compared with continuous Q4W dosing in moderate-to-severe plaque psoriasis 
patients (Langley et al. 2018).  Clinically meaningful benefit from continued Q2W dosing 
beyond Week 12 was prominent in moderate-to-severe plaque psoriasis patients who had 
inadequate response at Week 12.  Although there are no data available for efficacy of 
ixekizumab Q2W dosing beyond 12 weeks in EP and GPP patients, the long term efficacy data 
in plaque psoriasis patients are suggestive of the incremental efficacy of ixekizumab with 
continued Q2W dosing in EP and GPP patients who have an inadequate response at Week 12,
over the initially approved dosing regimen.
Safety profiles in plaque psoriasis patients who received ixekizumab Q2W over 52 weeks were 
comparable to those in Q4W treatment groups, with no unexpected safety signals observed.  
Meanwhile, no serious adverse events (SAEs) or adverse events (AEs) leading to treatment 
discontinuation were reported from EP and GPP patients who received ixekizumab via the 
initially approved dosing regimen. Also, overall safety profiles were comparable between EP 
and GPP patients and psoriasis patients.
Given the expected clinical benefit, potential risks derived from continued Q2W dosing may be 
acceptable in EP and GPP patients.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of ixekizumab are to be found in the Investigator’s Brochure (IB).


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4.
Objectives and Endpoints
Table RHCV.2 shows the objectives and endpoints of the study.
Table RHCV.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the efficacy of ixekizumab Q2W 
beyond Week 12 in patients with generalized 
pustular psoriasis (GPP) and erythrodermic 
psoriasis (EP)

Number of patients who improved Global 
Improvement Score (GIS) at least 1 point from 
Week 12 through Week 20 and with ≤2 of GIS
Objectives and Endpoints
Objectives
Endpoints
Secondary

To assess the efficacy of ixekizumab Q2W 
beyond Week 12 in patients with GPP and EP

To assess the health outcomes of ixekizumab 
Q2W beyond Week 12 in patients with GPP 
and EP

To evaluate the potential development of 
anti-ixekizumab antibodies of ixekizumab 
Q2W beyond Week 12 in patients with GPP 
and EP
The following endpoints will be assessed at each 
scheduled visit after Week 12:

Number of patients with each GIS grade 
(1: Resolved, 2: Improved, 3: Unchanged,
4: Worsened)

Number of patients who achieved sPGA (0, 1) 
and sPGA (0)

Number of patients who achieved PASI 75, 
PASI 90, and PASI 100 from baseline

Change from baseline, and percent 
improvement from baseline in PASI

Change from baseline in PSSI in patients with 
scalp involvement at baseline, and percent of 
BSA involvement of Psoriasis

Change from baseline in DLQI total score and 
domains, and Itch NRS score

Number of patients who achieved DLQI (0, 1) 
and DLQI (0) 

Number of patients who achieved Itch NRS 
≥4 point reduction from baseline for patients 
who had baseline Itch NRS ≥4

Number of patients who developed 
treatment-emergent anti-ixekizumab antibody 
(TE-ADA) and neutralizing anti-ixekizumab 
antibody (NAb)
GPP ONLY

Change from baseline on assessment of 
Generalized Pustular Psoriasis Severity Index 
at Week 12 and Week 20/ETV.
Note:  Global improvement scores will be assessed in the four grades by comparing the psoriatic findings: (1) 
resolved, (2) improved, (3) unchanged, and (4) worsened. The global improvement score is assessed based on 
the comparison of the psoriatic findings, sPGA, PASI score, and other evaluations with those at the baseline.


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Abbreviations:  BSA = body surface area; DLQI = Dermatology Life Quality Index; EP = erythrodermic psoriasis; 
GIS = Global Improvement Score; GPP = generalized pustular psoriasis; NAb = neutralizing anti-ixekizumab 
antibody; NRS = Numeric Rating Scale; PASI = Psoriasis Area and Severity Index; PASI 75 = at least a 75%
improvement from baseline in PASI score; PASI 90 = at least a 90% improvement from baseline in PASI score ; 
PASI 100 = a 100% improvement from baseline in PASI score; PSSI = Psoriasis Scalp Severity Index; 
Q2W = every 2 weeks; sPGA = static Physician Global Assessment; TE-ADA = treatment-emergent anti-drug 
antibody. 


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5. Study Design
5.1.
Overall Design
Study I1F-JE-RHCV is a multicenter, open-label, post marketing clinical trial to evaluate the 
efficacy and safety of ixekizumab Q2W beyond Week 12 until Week 20 in patients with GPP 
and EP.
The study consists of 3 periods:

Period 1: Screening Period (Visit 1) lasting from 7 to 30 days prior to Period 2 (baseline; 
Week 0; Visit 2)
Study investigator(s) will review patient history and screening test results to determine if the 
patient meets all inclusion and none of the exclusion criteria to qualify for participation in 
the study.

Period 2: Induction Dosing Period from Week 0 (Visit 2) to Week 12 (Visit 6)
All eligible patients will be administered 160 mg ixekizumab as 2 SC injections at Week 0 
(baseline; Visit 2) followed by 80 mg as 1 injection at Week 2, 4, 6, 8 and 10.

Period 3: Maintenance Dosing Period from Week 12 to Week 20
Responders (GIS = 1 at Week 12) will complete the study.
Inadequate responders (GIS ≥2 at Week 12 and based on investigators’ discretion) will 
continue to use ixekizumab 80 mg Q2W during Period 3.  If patients show a therapeutic 
response (GIS = 1) with 80 mg Q2W after Week 12, the patient will complete the study.  
Patients who complete the study before Week 20 will have an early termination visit (ETV)
instead of the original scheduled visit. 
Patients discontinuing from the study treatment who have received at least 1 dose of 
investigational product will continue to the ETV.
Ixekizumab will not be made available after conclusion of the study to patients.
Study governance considerations are described in detail in Appendix 3.
Figure RHCV.1 illustrates the study design.  


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Figure RHCV.1.
Illustration of study design for Clinical Protocol I1F-JE-RHCV.
5.2.
Number of Participants
A total of 12 patients will be enrolled so that at least 5 patients with EP and 5 patients with GPP 
who are inadequate responders (GIS ≥2 at Week 12 and based on the investigators’ discretion),
will continue to use ixekizumab beyond Week 12.  Additional enrollment may occur and sample 
size may be increased, if no GPP or EP patients enter into Period 3 (Maintenance Dosing Period) 
of the study.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This is an open-label, single-arm study to primarily assess the efficacy of ixekizumab Q2W 
beyond Week 12 in patients with EP and GPP.  The absence of a placebo arm is consistent with 
other studies evaluating efficacy and safety of investigational drugs in these severe forms of Ps.  
In addition, placebo-controlled studies are not ethical for patients with EP and GPP. 
The Induction Dosing Period (Period 2) is based on the dosage and administration which was 
approved via initial regulatory review.  This will be followed by the Maintenance Dosing Period 
(Period 3), if patients do not show a therapeutic response (GIS ≥2 at Week 12 and based on the 
investigators’ discretion).


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5.5.
Justification for Dose
The dosing schedule for Study RHCV was selected based on the initially approved dosage and 
administration of ixekizumab, and is designed to evaluate the response of patients with EP and 
GPP at Week 12 following the administration of ixekizumab at a starting dose of 160 mg 
followed by 80 mg Q2W up to Week 12.  Thereafter, according to the newly approved schedule, 
patients with an inadequate response will receive a dose of ixekizumab 80 mg Q2W up to and 
including Week 18, or until they achieve a GIS score of 1. 


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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
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Type of Patient and Disease Characteristics
[1]
Present with GPP or EP based on an investigator-confirmed diagnosis and 
meet the associated criteria
[1a] GPP:

Meet the criteria for GPP set by Ministry of Health, Labour and Welfare 
(MHLW) at screening (Visit 1) and baseline (Week 0; Visit 2) regardless 
of IL-36 mutation status. 
[1b] EP:

Diagnosed to have BSA ≥80% involvement (with inflammatory erythema) 
at screening (Visit 1) and baseline (Week 0; Visit 2).
[2]
Candidates for phototherapy and/or systemic therapy
Patient Characteristics
[3]
Are at least 20 years of age at the time of screening
[3a] male patients:
agree to use a reliable method of birth control* during the study 
[3b] female patients:
Are women of childbearing potential who test negative for pregnancy and 
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.
-or-
Are women of non-childbearing potential, defined as:
Women who have had surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation);
-or-
Women who are ≥60 years of age;
-or-


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Women ≥40 and <60 years of age who have had a cessation of menses for 
≥12 months and a follicle-stimulating hormone test confirming 
nonchildbearing potential (≥40 mIU/mL).
* Each of the following is considered as highly effective method of birth control:

oral contraceptives

condom with spermicide

intrauterine device

vasectomized male (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate).  For female 
patients in the study, the vasectomized male partner should be the sole 
partner for that patient.
Informed Consent
[4]
Have given written informed consent approved by Eli Lilly Japan or its 
designee and the Investigational Review Board/Ethical Review Board 
(IRB/ERB) governing the site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Medical Conditions
[5]
Have any other skin conditions that would affect interpretation of the results 
(including, but not limited to, scleroderma, eczema, drug-induced psoriasis, 
guttate psoriasis, parapsoriasis, or cutaneous manifestations of other 
autoimmune diseases such as systemic lupus erythematosus).
[6]
Have a known allergy or hypersensitivity to any biologic therapy that would 
pose an unacceptable risk to the patient if participating in this study.
[7]
Had a serious infection (for example, pneumonia, cellulitis), have been 
hospitalized, or have received IV antibiotics for an infection, within 12 weeks 
prior to baseline (Week 0; Visit 2), or had a serious bone or joint infection 
within 24 weeks prior to baseline, or have ever had an infection of an artificial 
joint, or are immunocompromised to an extent such that participation in the 
study would pose an unacceptable risk to the patient.
[8]
Have or had an infection typical of an immunocompromised host, and/or that 
occurs with increased incidence in an immunocompromised host (including, 
but not limited to, pneumocystis pneumonia (PCP), histoplasmosis, or 
coccidioidomycosis); or have a known immunodeficiency.  Additionally, 
patients with a positive beta-D-glucan test at screening and a confirmed 
diagnosis of PCP will be excluded.


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[9]
Have or had a herpes zoster or any other clinically apparent varicella-zoster 
virus infection within 4 weeks of baseline (Week 0; Visit 2).
[10] Have any other active or recent infection within 4 weeks of baseline (Week 0; 
Visit 2) that, in the opinion of the investigator, would pose an unacceptable 
risk to the patients if participating in the study; these patients may be 
rescreened 4 or more weeks after documented resolution of symptoms.
[11] Have evidence or suspicion of active or latent tuberculosis (TB).
[12] Are positive for human immunodeficiency virus serology (HIV; positive for 
human immunodeficiency virus antibody [HIVAb]).
[13] Have hepatitis B or test positive for hepatitis B virus (HBV) at screening, 
defined as:

Positive for hepatitis B surface antigen (HBsAg+)
OR

Positive for hepatitis B core antibody (HBcAb+) in conjunction with 
positive confirmatory HBV for HBV deoxyribonucleic acid (DNA) 
test
OR

Positive for hepatitis B surface antibody (HBsAb+) and positive 
confirmatory for HBV DNA.
Note: Patients who are HBcAb+ and/or HBsAb+ and HBV DNA negative may be 
enrolled in the study.  Patients who meet these criteria at screening will be 
monitored during the study as detailed in protocol Section 9.4.5.4.
[14] Have hepatitis C or test positive for hepatitis C virus (HCV) at screening, 
defined as: positive result for hepatitis C antibody and positive confirmatory
HCV ribonucleic acid (RNA) test (see protocol Section 9.4.5.5).  Patients in 
sustained virologic response after HCV therapy, and patients who have 
spontaneously cleared HCV infection (see protocol Section 9.4.5.5) can be 
included in this study.
[15] Have clinical laboratory test results at screening that are outside the normal 
reference range for the population and are considered clinically significant, 
and/or have any of the following specific abnormalities:
[15a] Neutrophil count <1500 cells/μL
[15b] Lymphocyte count <500 cells/μL
[15c] Platelet count <100,000 cells/μL
[15d] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5 times the upper limit of normal (ULN)
[15e] Total white blood cell (WBC) count <3000 cells/μL


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[15f] Hemoglobin <10.0 g/dL (100.0 g/L)
[15g] Serum creatinine >2.0 mg/dL
[15h] Serum albumin <2.5 g/dL
(Note: The AST and ALT may be repeated once within a week if the initial 
response exceeds this limit, and the repeat value may be accepted if it meets this 
criterion.)
[16] Have received systemic nonbiologic Ps therapy or have received phototherapy 
at the day of baseline (however, see exception below).

Oral corticosteroids will be permitted, if average daily doses are not 
greater than 10 mg/day of prednisone or its equivalent.

All topical treatment will be permitted.

Methotrexate or oral retinoids will be permitted before and during the 
study if doses are not greater than that of baseline.

Cyclosporine and Apremilast will be permitted, if daily doses are not 
greater than that of baseline
[17] Presence of significant uncontrolled neuropsychiatric disorder, have recent 
history (within 30 days prior to screening [Visit 1] and any time between 
screening [Visit 1] and baseline [Visit 2]) of a suicide attempt; or have 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 are clinically judged by the investigator 
to be at risk for suicide.  
[18] Have had any major surgery within 8 weeks of baseline (Week 0; Visit 2) or 
will require major surgery during the study that, in the opinion of the 
investigator in consultation with Lilly, would pose an unacceptable risk to the 
patient.
[19] Have current or a history of lymphoproliferative disease, or signs or 
symptoms of lymphoproliferative disease within 5 years of baseline (Week 0; 
Visit 2); or have active or history of malignant disease within 5 years of 
baseline (Week 0, Visit 2), except for basal cell carcinoma, squamous cell 
carcinoma, skin Bowen’s disease, or actinic keratoses that have been treated 
with no evidence of recurrence in the past 12 weeks, or carcinoma in situ of 
the cervix, or non-invasive malignant colon polyps that have been removed.
(Note:  patients with history of malignancy with no evidence of recurrence or active 
disease within 5 years of baseline may participate in the study).
[20] Have had fluid overload, myocardial infarction, or new onset ischemic heart 
disease (e.g., unstable angina), uncompensated heart failure, or in the opinion 
of the investigator other serious cardiac disease within 12 weeks of baseline 
(Week 0; Visit 2).


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[21] Have current or a history of inflammatory bowel disease (IBD) (ulcerative 
colitis and Crohn’s disease), or signs or symptoms of IBD at screening 
(Visit 1) that, in the opinion of the investigator, pose an unacceptable risk to 
the patient if participating in the study.
Prior/Concomitant Therapy
[22] Cannot avoid excessive sun exposure or use of tanning booths for at least 
4 weeks prior to baseline (Week 0; Visit 2) and during the study.
[23] Concurrent use of any biologic agent during this clinical study.
[24] Have previously received ixekizumab treatment.
[25] Have previously completed or withdrawn from this study.
[26] Had a live vaccination within 12 weeks prior to baseline (Week 0; Visit 2), 
intend to have a live vaccination during the course of the study or within 
12 months of completing treatment in this study, or have participated in a 
vaccine clinical study within 12 weeks prior to baseline.  Investigators should 
review the vaccination status of their patients and follow Japan guidelines for 
adult vaccination with nonlive vaccines intended to prevent infectious disease 
prior to therapy.
(Note: Killed/inactive or subunit vaccines are expected to be safe; however, 
their efficacy with ixekizumab treatment is unknown.)
[27] Had a vaccination with Bacillus Calmette-Guerin (BCG) within 12 months 
prior to baseline (Week 0; Visit 2) or intend to have this vaccination with 
BCG during the course of the study, or within 12 months of completing 
treatment in this study.
Prior/Concurrent Clinical Trial Experience
[28] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[29] Have participated in any other clinical study during this clinical study.
Other Exclusions
[30] Have any other condition that precludes the patient from following and 
completing the protocol, in the opinion of the investigator.  Investigators 
should read and follow especially warning, contraindications, and precautions 
section of most recent Japan ixekizumab package insert (Taltz Subcutaneous 
Injection 80 mg syringe).
[31] Have donated more than 400 ml of blood (for patients weighing ≥50 kg) or 
200 ml of blood (for patients weighing <50 kg) or plasmapheresis/platelet 
apheresis within 30 days prior to study entry, or plan to donate blood during 
the study.


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[32] Are women who are lactating or breastfeeding.
[33] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[34] Are Lilly employees or its designee or are employees of third-party
organizations (TPOs) involved in the 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) maybe 
rescreened.  Individuals may be rescreened up to 3 times.  The interval between rescreenings 
should be at least 1 week.  Each time rescreening is performed the individual must sign a new 
informed consent form (ICF) and will be assigned a new identification number.  Patients who 
have had previous screening TB tests as per protocol within 3 months of their rescreening date of 
consent do not need to repeat these procedures but may do so at the discretion of the investigator.
Individuals may be rescreened as follows:

Patients who test positive for latent TB at screening may be rescreened following 
appropriate treatment as described in Section 9.4.5.2.

Patients who do not qualify at screening under Exclusion Criteria [10] (active or recent 
infection) may be rescreened as described in Section 6.2.


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7. Treatments
7.1.
Treatments Administered
The investigator (or his/her designee) is responsible for explaining the correct use of the 
investigational agent(s) to the patient and/or patient’s caregiver, verifying that instructions are 
followed properly, maintaining accurate records of investigational product dispensing and 
collection, and returning all unused medication to Lilly or its designee at the end of the study.  
Further instructions regarding administration of the investigational product are provided below in 
this section.
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.
The Induction Dosing Period (Period 2) begins at Week 0 (baseline; Visit 2) when patients 
receive a starting dose of 160 mg ixekizumab as 2 SC injections.  For the remaining doses, 80 
mg is administered Q2W.  All doses are administered as SC injections.
Administration of Investigational Product
Training: For training purposes, the proper procedures for administration of the investigational 
product and administration of the initial injection will be performed by the investigator or his/her 
designee at Week 0 (Visit 2) and the second injection of investigational product can be self-
administered by the patient under the supervision of the investigator at Week 0 (Visit 2).  Study 
drug must be administered under the supervision of the investigator until the investigator judges 
the patient sufficiently competent to perform the self-injections independently.  After this time, 
patients will be allowed to self-inject alone.
Administration: All subsequent injections can be administered by the patient.  If a patient is 
unable to perform the injection, the investigator or a caregiver, may inject the investigational 
product.  In this case, the caregiver will also be trained to inject the study drug under supervision 
of the investigator until the investigator judges the caregiver sufficiently competent to inject.  
A dose of investigational product will consist of 1 SC injection of ixekizumab (except Week 0).  
Possible injection sites include the abdomen, thigh, and upper arm.  The injection site should not 
be in a psoriatic lesion and should be rotated to another area for subsequent doses.
Syringes should be at room temperature prior to injection (refer to Manual Syringe Directions for 
Use provided by the sponsor).
Throughout their participation in the study, enrolled patients will record information in a Study 
Drug Administration Log, including the date, time, injection site, and location of patient at time 
of administration of investigational product (for treatment compliance), who administered the 
investigational product, and the reason if investigational product was not fully administered in a 
Study Drug Administration Log.  As needed, patients may use the log to record other 
information about the injection.  At each visit, the investigator will review the log to confirm 
whether the self-injections were successfully performed.


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Observation: Patients should remain under observation for at least 1 hour after dosing at Week 
0 (Visit 2) to monitor for safety.
Table RHCV.3.
Treatment Periods
Treatment Period
Weeks
Dose
Description
Induction Dosing Period 
(Period 2) and 
Maintenance Dosing 
Period (Period 3)
0 to 12
12 to 20
Ixekizumab 160 mg initially, 
followed by ixekizumab 
80 mg Q2W
A starting dose of 160 mg (Week 0) 
given as 2 SC injections followed by 
80 mg given as 1 SC injection Q2W 
(Weeks 2, 4, 6, 8, 10, 12, 14, 16 and 18)
Abbreviations:  Q2W = every 2 weeks; SC = subcutaneous.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law.
7.1.1. Packaging and Labelling
The ixekizumab solution for injection will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practices (cGMP).  Ixekizumab will be supplied as 
an injectable solution in 1-mL, single-dose, disposable manual prefilled syringes.  Each syringe 
of ixekizumab is designed to deliver ixekizumab 80 mg.  Syringes will be supplied in cartons, 
with the appropriate quantity of syringes specific to the planned dispensing schedule of the 
investigational product. 
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.  
Investigational products will be supplied by Lilly or its representative, in accordance with 
cGMP, and will be supplied with lot numbers and expiration dates. 
The investigational product should be stored at 2°C to 8°C in its original carton to protect from 
light.  Investigational product should not be frozen.  Sites will be required to monitor 
temperature of the on-site storage conditions of the syringes.
7.2.
Method of Treatment Assignment
Patients are assigned to treatment and will receive their assigned treatment as outlined in 
Section 7.1.


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7.2.1. Selection and Timing of Doses
Investigational product should 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 18, the missed dose should be administered within 4 days of the scheduled day. Dates 
of subsequent study visits should not be modified according to this delay.  
The actual time of all dose administrations will be recorded in the patient’s case report form 
(CRF). 
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
Dose adjustments are not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
Detailed instructions regarding supplies and preparation and handling of investigational products 
will be provided by the sponsor.
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.  
All investigational products will be stored, inventoried, reconciled, or destroyed according to 
applicable regulations.
The investigational product should be stored at 2°C to 8°C in its original carton to protect from 
light.  Investigational product should not be frozen.  Sites will be required to monitor 
temperature of the on-site storage conditions of the syringes.


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7.6.
Treatment Compliance
Every attempt will be made to select patients who have the ability to understand and comply with
instructions. The investigator is responsible for discussing methods to ensure high treatment
compliance with the patient before administration of study treatment.
Throughout their participation in the study, enrolled patients will record information in a Study 
Drug Administration Log, including the date, time, injection site, and location of patient at time 
of administration of investigational product (for treatment compliance), who administered the 
investigational product, and the reason if investigational product was not fully administered.  As 
needed, patients may use the log to record other information about the injection.  At each visit, 
the investigator will review the log to confirm whether the self-injections were successfully 
performed.
Patient compliance with study drug administration will be assessed at each visit.  Compliance 
will be assessed by direct questioning, and counting returned syringes.  Deviation(s) from the 
prescribed dosage regimen should be recorded in the CRF.
7.7.
Concomitant Therapy
The list of excluded medications and procedures is provided in Appendix 6.
The following medications will not be permitted during the course of the study (from obtaining 
written Informed Consent to study completion):

Ps therapy as described in the inclusion/exclusion criteria (Sections 6.1 and 6.2) with the 
exceptions described below.

Any biologic therapy specified in Section 6.2

Concomitant medications as described in the inclusion/exclusion criteria (Sections 
6.1 and 6.2)

Live vaccines

Phototherapy.
The following medications will be permitted during the course of the study:

Vaccine: Use of nonlive seasonal vaccinations and/or emergency vaccination (such as 
rabies or tetanus vaccinations) is allowed.

Methotrexate and oral retinoids will be permitted before and during the study if the 
patient has been using such medication before starting the study and if doses are not 
greater than that of baseline. 

Oral corticosteroids will be permitted before and during the study, if the patient has been 
using such medication before starting the study and if average daily doses are not greater 
than 10 mg/day of prednisone or its equivalent. 


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
Cyclosporine will be permitted, if the patient has been using such medication before 
starting the study and if daily doses are not greater than that of baseline. 

Topical steroids: topical steroids (all classes) will be permitted.

Granulocyte-monocyte adsorption apheresis (GMA): use of GMA is allowed.

Other Concomitant Therapies: topical treatments will be permitted.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Patient Decision
o
the patient requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality. A patient who is
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via CRF.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:

ALT or AST >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

In addition, a patient who meets any one of the following criteria should be 
discontinued from the investigational product and conduct ETV, and 
discontinue from the study:

Absolute neutrophil (segmented) counts (see safety monitoring for neutropenia; 
Section 9.4.6.1):
o
<500 cells/μL
o
≥500 and <1000 cells/μL (based on 2 test results; the second test 
performed within 1 week from knowledge of the initial result).
o
≥1000 and <1500 cells/μL (based on 3 test results as specified in 
Section 9.4.6.1) - AND - an infection that is not fully resolved.

Total WBC count <2000 cells/μL (<2.00 x 103/μL).

Lymphocyte count <500 cells/μL (<0.50 x 103/μL).

Platelet count <50,000 cells/μL (<50 x 103/μL).


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
The patient experiences a severe AE, an SAE, or a clinically significant change in 
a laboratory value occurs that, in the opinion of the investigator, merits the 
discontinuation of the investigational product.

Clinically significant systemic hypersensitivity event following administration of 
investigational product that does not respond to symptomatic medication or 
results in clinical sequelae.

The patient becomes pregnant.

The patient develops a malignancy (Note: patients may be allowed to continue if 
they develop no more than 2 non-melanoma skin cancers during the study).

The patient has a change in disease phenotype at any time.

It is recommended that the patient be assessed by an appropriately trained 
professional to assist in deciding whether the patient is to be discontinued from 
study treatment if:
o
The patient 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 C-SSRS),
-OR-
The patient develops suicide-related behaviors as recorded on the C-SSRS, 
then it is recommended that the patient be assessed by a psychiatrist or 
appropriately trained professional to assist in deciding whether the patient 
is to be discontinued from the study.
o
The patient develops active TB or HIV/ acquired immunodeficiency 
syndrome (AIDS) during the study.
o
The patient becomes HBV (DNA) or HCV RNA positive.  The patient 
should be referred to a specialist physician (see Sections 9.4.5.4 and
9.4.5.5).

Discontinuation due to Allergic Reactions or Hypersensitivity Events

The investigator, after consultation with the sponsor-designated medical monitor, 
determines that a clinically significant hypersensitivity reaction has occurred.  A 
clinically significant systemic hypersensitivity reaction is one that occurs after 
administration of the investigational intervention (for example, drug-related 
symptomatic bronchospasm, allergy-related edema/angioedema, or hypotension) 
and requires parenteral medication, does not respond to symptomatic medication, 
results in clinical sequelae, or is an anaphylactic reaction.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 


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study treatment.  If the investigator and the sponsor clinical research physician (CRP) agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP to allow the inadvertently enrolled patient to continue in the study with or without 
treatment with investigational product. Safety follow up is as outlined in Section 2 (Schedule of 
Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
patient will be discontinued from the study in the following circumstances:

enrollment in any other clinical study 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 good clinical 
practice (GCP)

investigator decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of the 
new agent

patient decision
o
the patient or the patient’s designee, for example, parents or legal guardian
requests to be withdrawn from the study.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
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
9.1.1. Primary Efficacy Assessment:  Global Improvement Scores
Global improvement scores will be assessed in the 4 grades by comparing the psoriatic findings: 
(1) resolved, (2) improved, (3) unchanged, or (4) worsened. The global improvement score is 
assessed based on the comparison of the psoriatic findings, Static Physician Global Assessment 
(sPGA), Psoriasis Area and Severity Index (PASI) score, and other evaluations with those at the 
baseline.
9.1.2. Secondary Efficacy Assessments
The following secondary and exploratory efficacy measures will be assessed in this study:

Psoriasis Area and Severity Index (PASI)

Static Physician Global Assessment (sPGA)

Scalp Psoriasis Severity Index (PSSI)

Percentage of Body Surface Area (BSA)

GPP Severity Index
9.1.2.1.
Psoriasis Area and Severity Index
The PASI combines an assessment of the extent of body surface involvement in 4 anatomical 
regions (head, trunk, arms, and legs) and the severity of desquamation (scaling), erythema, and 
plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 (no Ps) to 
72 (the most severe disease) (Fredriksson and Pettersson 1978).  The PASI has been the most 
frequently used endpoint and measure of Ps severity in clinical trials (EMEA 2004 [WWW]; 
Menter et al. 2008).
9.1.2.2.
Static Physician Global Assessment
The sPGA is the physician's determination of the patient's Ps lesions overall at a given time point.  
The sPGA is recommended as an endpoint to use efficacy in the treatment of Ps (EMEA 2004 
[WWW]).  Overall lesions are categorized by descriptions for induration, erythema, and scaling.  
For analysis of responses, the patient's Ps is assessed as clear (0), minimal (1), mild (2), 
moderate (3), severe (4), or very severe (5).


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9.1.2.3.
Scalp Psoriasis Severity Index
If the patient has scalp Ps at baseline, the PSSI will be used.  The PSSI is a composite score 
derived from the sum scores for erythema, induration, and desquamation multiplied by a score 
for the extent of the scalp area involved (range 0 to 72).
9.1.2.4.
Percentage of Body Surface Area
The investigator will evaluate the percentage involvement of Ps on each patient’s BSA on a 
continuous scale from 0% (no involvement) to 100% (full involvement), in which 1% 
corresponds to the size of the patient’s hand (including the palm, fingers and thumb) (National 
Psoriasis Foundation 2009 [WWW]).
9.1.2.5.
Generalized Pustular Psoriasis Severity Index
The GPP Severity Index will be evaluated only for patients with pustular Ps at screening and at 
baseline.  This is a composite score derived from the sum of scores for assessment of dermal 
symptoms, systemic symptoms, and laboratory findings (range, 0 to 17).

Assessment of Dermal Symptoms
Assessment of dermal symptoms, according to the Japanese Dermatological Association 
GPP revised criteria (2010) (Iwatsuki et al. 2010 [WWW]) will be evaluated only for 
patients with pustular Ps at screening and at baseline.  Skin symptoms will be assessed by 
the score with the area of erythema (on a 0 to 3 scale), area of confluent pustules (on a 0
to 3 scale), and are of skin edema (on a 0 to 3 scale).  The total score will be assessed
(range, 0 to 9).

Systemic symptoms and laboratory findings
Systemic symptoms and laboratory findings, according to the Japanese Dermatological 
Association GPP revised criteria (2010) (Iwatsuki et al. 2010 [WWW]) will be evaluated 
only for patients with pustular Ps at screening and at baseline.  It will be assessed by the 
score with fever (on a 0 to 2 scale), WBC (on a 0 to -2 scale), C-reactive protein (on a 0
to 2 scale) and Albumin (on a 0 to 2 scale).  The total score will be assessed (range, 0 to 
8).
9.1.3. Appropriateness of Assessments
All of the clinical and safety assessments in this study are standard, widely used, and generally 
recognized as reliable, accurate, and relevant.
9.2.
Adverse Events
investigator is 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 will record all relevant 
AE/SAE information in the CRF.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator must document his\her review of each laboratory safety report.


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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 ICF is signed, study site personnel will record via electronic data entry 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. The investigator should record 
his\her assessment of the potential relatedness of each AE to protocol procedure or
investigational product, via electronic data entry.
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.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device 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.
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.
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 (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect


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
important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.

when a condition related to the prefilled syringes necessitates medical or 
surgical intervention to preclude either permanent impairment of a body 
function or permanent damage to a body structure, the serious outcome of 
“required intervention” will be assigned.
All AEs occurring after signing the ICF are recorded in the electronic data entry and assessed for 
serious criteria.  The SAE reporting to the sponsor 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, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) 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. Patients with a serious hepatic AE should have additional data collected using the 
electronic data entry.
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 disposition 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
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or study 
procedure.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidances or national regulatory requirements in 
participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording and expedited reporting of 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 AEs 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:

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (ALT, AST, bilirubin, and alkaline 
phosphatase)

infection

injection-site reactions

allergic reactions/hypersensitivities

cerebrocardiovascular events

malignancies

inflammatory bowel disease

depression

interstitial lung disease (ILD).
If infections, injection-site reactions, or allergic/hypersensitivity reactions are reported, sites will 
provide details on these events 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.  A blood sample will be collected when possible for 
any patient who experiences an AE of allergic/hypersensitivity reactions during the study.
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, and peripheral arterial event and hospitalization for hypertension) will be collected,
and these events and any deaths will be adjudicated by an external Clinical Events Committee
(CEC) made up of a chairman, 2 cardiologists, and a neurologist.
Data on suspected IBD, as identified by events possibly indicative of ulcerative colitis and
Crohn’s disease, will be collected and the events will be adjudicated by an external CEC with
expertise in IBD.
The role of external CECs is to adjudicate defined clinical events in a blinded, consistent, and
unbiased manner throughout the course of a study. The purpose of the CEC for adjudication of
cerebrocardiovascular events and the CEC for adjudication of suspected IBD events is to ensure
that all reported events are evaluated uniformly by a single group.


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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.
A patient will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
9.3.
Treatment of Overdose
Refer to the Taltz IB and/or Product Label.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, electrocardiograms (ECGs) should be collected locally 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.  The qualified physician must document 
his/her review of the ECG at the time of screening. 
The ECG results will be stored at the site and would be made available to the sponsor as 
requested. The investigators are allowed to repeat the ECG collection.
9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Vital signs (BP and pulse) and body temperature will be measured (sitting) after resting for a 
minimum of 10 minutes at times indicated in the Schedule of Activities (Section 2).  At baseline 
(Week 0; Visit 2), BP and pulse should be measured prior to administration of the investigational 
product and again approximately 1 hour after administration.  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). 
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the clinical trial.  
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.


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9.4.4. Immunogenicity Assessments 
Samples for immunogenicity testing will be collected at time points indicated in the Schedule of 
Activities (Section 2).  Venous blood samples will be collected into tubes and used to determine 
antibody production against ixekizumab.  The actual date of each sampling will be recorded on 
the laboratory requisition.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of ixekizumab. Antibodies may be further characterized and/or evaluated for their ability to 
neutralize the activity of ixekizumab. Treatment-emergent immunogenicity is defined as any 
occurrence of a 4-fold or 2 dilution increase in titer over the pretreatment baseline titer.  In the 
case of a negative result at baseline, treatment-emergent immunogenicity is defined as an 
increase in titer to ≥1:10. Immunogenicity samples will also be analyzed for ixekizumab serum 
concentration to facilitate the interpretation of the immunogenicity data at Week 12 (Visit 6), 
Week 20 (Visit 10) and ETV. 
In the event of serious drug hypersensitivity reactions (such as generalized urticaria and/or 
anaphylaxis), additional samples will be collected as close to the onset of the event as possible 
and approximately 30 days following the event to evaluate antidrug antibodies (ADA), 
LY2439821 serum concentration, and additional exploratory biomarkers of hypersensitivity 
which could include tryptase, complement levels and cytokine measurements.
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to ixekizumab.  Any samples 
remaining after 15 years will be destroyed.
9.4.5. Other Safety Measures
9.4.5.1.
Physical Exam
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be 
performed at screening. This examination will determine whether the patient meets the criteria 
required to participate in the study and will also serve as a monitor for pre-existing conditions 
and as a baseline for treatment-emergent adverse event (TEAE) assessment. All physical 
examinations throughout the study should include a symptom-directed physical evaluation, as 
well as an examination of the heart, lungs, abdomen, and a visual examination of the skin. 
9.4.5.2.
Chest X-Ray and Tuberculosis Testing
A posterior-anterior view chest X-ray will be obtained, unless the X-ray or results from a chest 
X-ray obtained within 6 months prior to the study are available. The chest X-ray will be 
obtained locally. The chest X-ray or results will be reviewed by the investigator or designee to 
exclude patients with active TB infection. In the opinion of the investigator, if evaluating chest 
X-ray is medically necessary, the investigator may do so any time during the study.
In addition, patients will be locally tested at screening and at visits, as indicated on the Schedule
of Activities (Section 2) for evidence of active or latent TB indicated by a positive purified 
protein derivative (PPD) skin-test response (≥5 mm induration, between approximately 48 and 


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72 hours after test application, regardless of BCG vaccination history). If, in the judgment of the 
investigator, an interferon gamma release assay (QuantiFERON-TB Gold test) is preferred as an 
alternative to the PPD skin test for the evaluation of TB infection, it may be used instead of the 
PPD test (positive tests excluded) and would be read locally.  If an interferon gamma release 
assay (QuantiFERON-TB Gold test) is indeterminate, 1 retest is allowed. The same method 
should be used at the retest.  If the retest is indeterminate, then the patient is excluded from the 
study.  
Patients with documentation of a negative test result within 3 months prior to baseline (Week 0; 
Visit 2) do not need a TB screen at Visit 1. Documentation of this test result must include a 
record of the size of the induration response. A PPD test recorded as negative without 
documenting the size of induration will result in a retest.
However, patients with a PPD skin test ≥5 mm induration or a positive QuantiFERON-TB Gold
test at screening, but no other evidence of active TB, may be rescreened 1 time and may be 
enrolled without repeating the PPD or QuantiFERON-TB GOLD test if the following conditions 
are met:

after receiving at least 4 weeks of appropriate latent TB infection (LTBI) therapy,

having no evidence of hepatotoxicity (ALT/AST must remain ≤2 times ULN) upon 
retesting of serum ALT/AST prior to administration of investigational product.  Such 
patients must complete appropriate LTBI therapy during the course of the study in order 
to remain eligible, and

meeting all other Inclusion/Exclusion criteria for participation.
Patients who have a documented history of completing an appropriate TB treatment regimen 
with no history of re-exposure to TB since their treatment was completed and no evidence of 
active TB are eligible to participate in the study.  These patients should not undergo TB testing at 
screening or at later scheduled visits in the study, as per the Schedule of Activities (Section 2).
Patients who have had household contact with a person with active TB are excluded, unless 
appropriate and documented prophylaxis for TB was given.  
9.4.5.3.
Columbia-Suicide Severity Rating Scale
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and/or behavior during the assessment period. The scale includes suggested questions to solicit 
the type of information needed to determine if suicidal ideation and/or behavior occurred. The 
C-SSRS is administered by an appropriately trained healthcare professional with at least 1 year 
of patient care/clinical experience. The tool was developed by the National Institute of Mental 
Health trial group (TASA) 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 1-
question form that asks for the number of suicidal or nonsuicidal self-injurious behaviors the 
patient has experienced since the last assessment. For each unique event identified, a 
questionnaire (Self-Harm Follow-Up Form) which collects supplemental information on the self-


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injurious behavior is to be completed. The Self-Harm Supplement Form will be completed 
according to the Schedule of Activities (Section 2).
The non-leading AE collection should occur prior to the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS, but was not captured during the non-
leading AE collection, sites should not change the AE form. If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed.
9.4.5.4.
Hepatitis B Screening
Patients who test HBsAg, HBcAb+ in conjunction with positive confirmatory HBV DNA test, or 
have positive HBV DNA test, regardless of HBsAb status, at screening will be excluded.
If an enrolled patient is positive for HBsAb and/or HBcAb, and negative for HBV DNA, the 
HBV DNA needs to be checked at least once every month in Periods 2 and 3 (See Section 2).
In addition to the above, any enrolled patient who is HBcAb+ and/or HBsAb+ and who 
experiences an elevated ALT or AST level >3x ULN must undergo HBV DNA testing.  If the 
HBV DNA test is negative, the investigator should consult with the Lilly-designated medical 
monitor regarding further management of the patient.  
If the result of the HBV DNA testing is positive, the patient must be discontinued from the study 
and should receive appropriate follow-up medical care, including consideration for antiviral 
therapy. A specialist physician in the care of patients with hepatitis (for example, infectious 
disease or hepatologist subspecialists) should be consulted and potentially start antiviral therapy 
prior to discontinuation of any immunosuppressant therapy (including study drug). Timing of 
discontinuation from the study and of any immunosuppressant therapy (including study drug) 
needs to be based on the recommendations of the consulting specialist physician in conjunction 
with the investigator and medical guidelines/standard of care.
9.4.5.5.
Hepatitis C Screening
Patients who test positive for HCV antibody and have a positive confirmatory HCV RNA test at 
screening will be excluded.
Patients with a previous diagnosis of hepatitis C who have been treated with antiviral therapy 
and achieved a sustained virologic response may be eligible for inclusion in the study, provided 
they have no detectable RNA on the screening HCV RNA test for this protocol.  A sustained 
virologic response is defined as an undetectable HCV RNA level, 12 weeks after completion of a 
full, documented course of an approved antiviral therapy for HCV.  
Patients who have spontaneously cleared HCV infection, defined as (i) a positive HCV antibody 
test and (ii) a negative HCV RNA test, with no history of anti-HCV treatment, may be eligible 
for inclusion in the study, provided they have no detectable HCV RNA on screening for this 
study, and no detectable HCV RNA on the screening HCV RNA test for this protocol.  
Any patient with a history of HCV infection who develops elevated ALT >3x ULN will be tested 
for HCV RNA.


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Any patient diagnosed with hepatitis C during the study will be discontinued from the study and 
should receive appropriate follow-up medical care.
9.4.6. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Neutropenia
patient with neutrophil (segmented) counts <1500 cells/μL should be managed for neutropenia as 
follows:

<500 cells/μL, see Discontinuation Criteria (Section 8.1)

≥500 cells/μL and <1000 cells/μL, see Discontinuation Criteria (Section 8.1)

≥1000 cells/μL and <1500 cells/μL, and the patient has a concurrent infection that 
requires systemic anti-infective therapy (for example, antibiotic, antifungal agent, 
antiviral agent):
o
The dose of investigational product should be withheld, the patient should receive 
appropriate medical care, and a repeat test for neutrophil count should be performed 
within 4 weeks from knowledge of the initial report.  If the repeat neutrophil count 
has returned to ≥1500 cells/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/μL and <1500 cells/μL, 
investigational product should continue to be withheld and a repeat neutrophil count 
should again be performed within another 4 weeks.  If, after 2 repeat tests, the 
neutrophil count still remains ≥1000 cells/μL and <1500 cells/μL, and:
a. the infection has not fully resolved, the patient will be discontinued from the 
study.
b. 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.  Patients 
who discontinue the study continue to the ETV.

≥1000 cells/μL and <1500 cells/μL, and the patient has no concurrent infection that 
requires systemic anti-infective therapy (for example, antibiotic, antifungal agent, 
antiviral agent):
o
Dosing may continue, and a repeat neutrophil count should be performed 4 to 
8 weeks from knowledge of the initial report.  Testing may be at a regularly 
scheduled visit or at an unscheduled visit, as necessary. 
Repeat testing should be performed at 4- to 8-week intervals until the neutrophil count has 
returned to ≥1500 cells/μL. If the patient has 3 or more post-baseline neutrophil counts of 
≥1000 cells/μL and <1500 cells/μL, no value of <1000 cells/μL, and no post-baseline infection 
requiring systemic anti-infective therapy, the patient may continue or resume further evaluation 
at scheduled visits, as deemed appropriate by the investigator.


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If a patient without initial concurrent infection develops an infection that requires systemic 
anti-infective therapy, then the patient should be managed as indicated above for patients with
concurrent infection.
9.4.6.2.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.  
Hepatic Safety Data Collection
Additional safety data should be collected via the electronic case report form (CRF) if 1 or more 
of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE
See Section 9.4.5.4 with regards to hepatitis B monitoring.
9.4.6.3.
Hypertension
Patients who experience changes in BP (systolic BP at ≥160 mm Hg plus ≥20 mm Hg increase 
from baseline [Week 0; Visit 2]; and/or diastolic BP at ≥100 mm Hg plus ≥10 mm Hg increase 
from baseline) on 2 consecutive visits should 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 an anti-hypertensive agent.
9.4.6.4.
Allergic Reactions and Hypersensitivity Events
All biologic 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)

Dyspnea

Urticarial (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Hypotension

Anaphylactic reaction


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Participants with clinical manifestations of systemic allergic/hypersensitivity reactions should be 
treated per local standard of care.  Additional data describing each symptom should be provided
to the sponsor in the CRF. 
In case of anaphylaxis or generalized urticaria, additional blood samples should be collected as 
close as possible to the onset of the event (see Section 9.4.4 Immunogenicity Assessments). 
Follow-up samples should be obtained at the next regularly scheduled visit or 4 weeks after the 
event, whichever is later.  The lab results are provided to the sponsor via the central laboratory.  
9.5.
Pharmacokinetics
Not applicable
9.6.
Pharmacodynamics
Not applicable
9.7.
Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to ixekizumab and to 
investigate genetic variants thought to play a role in GPP and EP.  Assessment of variable 
response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient/number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  Samples will be retained at 
a facility selected by Eli Lilly Japan or its designee for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ERBs/IRBs impose 
shorter time limits. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section. 
9.8.
Biomarkers
Not applicable
9.9.
Health Outcomes/Quality of Life Assessment 
The following health outcomes measures that will be assessed in this study:

Itch Numeric Rating Scale (NRS)

Dermatology Life Quality Index (DLQI)


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9.9.1. Itch Numeric Rating Scale
The Itch NRS is a patient-administered, 11-point horizontal scale anchored at 0 and 10, with 0 
representing “no itch” and 10 representing “worst itch imaginable.” Overall severity of a 
patient's itching from Ps is indicated by circling the number that best describes the worst level of 
itching in the past 24 hours.
9.9.2. Dermatology Life Quality Index
The DLQI is a simple, patient-administered, 10-question, validated, quality-of-life questionnaire 
that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and 
school, personal relationships, and treatment.  Response categories include “not at all”, “a little”, 
“a lot”, and “very much”, with corresponding scores of 0, 1, 2, and 3, respectively, and 
unanswered (“not relevant”) responses scored as “0.” Totals range from 0 to 30 (the higher the 
score, the more quality of life is impaired) and a 5-point change from baseline is considered 
clinically relevant (Basra et al. 2008).


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10. Statistical Considerations
10.1. Sample Size Determination
A total of 12 patients will be enrolled so that at least 5 patients with EP and 5 patients with GPP 
who are inadequate responders (GIS ≥2 at Week 12 and based on investigators’ discretion) will 
continue to use ixekizumab beyond Week 12.  Additional enrollment may occur and the sample 
size may be increased, if no GPP or EP patients enter into Period 3 (Maintenance Dosing Period) 
of the study.
The sample size is based on the following:

In the I1F-JE-RHAT (RHAT) study, 5 GPP and 8 EP patients were enrolled.  One GPP 
patient achieved GIS = 1 (resolved) at Week 12 and the other 4 GPP patients achieved 
GIS = 2 (improved).  One EP patient achieved GIS = 1 at Week 12 and 7 EP patients 
achieved GIS = 2.  Although the sample size is very small, based on the result of RHAT 
study, it is assumed that approximately 5 patients at maximum may not achieve GIS = 1 
at Week 12 and may continue ixekizumab Q2W beyond Week 12 based on the 
investigators’ discretion.

The sample size is determined based on the feasibility in Japan.  The prevalence rate of 
these patients is very low in Japan and it is also difficult to conduct a placebo-controlled 
study for these severe conditions (Umezawa et al. 2003, Rosenbach et al. 2010).
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Efficacy, health outcomes and safety analyses for Period 2 will be conducted on the largest 
analysis set (Full Analysis Set [FAS]), defined as the set of patients with GPP and EP separately 
who receive at least 1 dose of study treatment in Period 2 (FAS Population).
Efficacy, health outcomes and safety analyses for Period 3 will be conducted based on patients 
with GPP and EP separately who receive at least 1 dose of study treatment in Period 3 
(Maintenance Dosing Period Population).
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly Japan.
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 (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
Primary analysis of efficacy, health outcome, and safety measures will be conducted based on 
patients who continued ixekizumab 80 mg Q2W beyond Week 12 by disease type (ie, GPP and 


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EP separately) on the Maintenance Dosing Period Population.  Secondary analyses of efficacy, 
health outcome, and safety measures will be conducted for Period 2 on the FAS Population and 
Period 3 on the Maintenance Dosing Period Population, respectively.
Baseline for efficacy, health outcomes, and safety analyses in Period 2 is defined as the last 
available value before first dose in Period 2; in most cases, it will be the value recorded at Week 
0 (Visit 2).  For the efficacy and health outcomes analyses in Period 3, baseline is defined as the 
last available value before the first dose in Period 2 and, in most cases, will be the value recorded 
at Week 0 (Visit 2). Unless otherwise specified, for the safety analyses during Period 3, baseline 
is defined as the last available value before the first dose of ixekizumab in Period 3. In most 
cases, this will be the measure recorded at Week 12 (Visit 6).
As this is a single arm study with very small sample size, no statistical inference will be 
performed.
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.
10.3.2. Patients
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. 
10.3.2.2. Patient Characteristics
Patient characteristics and baseline clinical measures will be summarized. Baseline 
characteristics will include gender, age, height, weight, baseline disease severity, duration of 
disease, previous systemic therapy, and previous biologic therapy. Baseline clinical and health 
outcome measurements will include PASI, sPGA, BSA, PSSI, Itch NRS, DLQI, C-SSRS, and 
GPP severity index.
10.3.2.3. Concomitant Therapy 
Previous and concomitant medications will be summarized and presented by World Health 
Organization Anatomical Therapeutic Class (WHOATC) and generic name.
10.3.2.4. Treatment Compliance
Treatment compliance with study drug will be summarized for patients who enter Periods 2 and 
3 (Induction Dosing Period and Maintenance Dosing Period), respectively.  Overall compliance 
with therapy is defined to be missing no more than 20% of the expected doses and not missing 2 
consecutive doses, and does not overdose (that is, take more injections at the same time point 
than specified in the protocol).  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis is to assess the efficacy of ixekizumab 80 mg Q2W beyond Week 12 in 
patients with GPP and EP separately, as measured by the number of patients who improved their 


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GIS from baseline by at least 1 point from Week 12 through Week 20 and with ≤2 of GIS on the 
Maintenance Dosing Period Population.
10.3.3.2. Secondary Analyses
Secondary analyses of the efficacy measures will be summarized for Period 2 on the FAS 
Population and Period 3 on the Maintenance Dosing Period Population, respectively by the 
following endpoints:

Number of patients with each GIS grade (1: Resolved, 2: Improved, 3: Unchanged, 
4: Worsened)

Number of patients who achieve sPGA (0, 1) and sPGA (0)

Number of patients who achieve PASI 75, PASI 90, and PASI 100 from baseline

Change from baseline, and percent improvement from baseline in PASI

Change from baseline in PSSI in patients with scalp involvement at baseline, and percent 
of BSA involvement of Ps.
GPP ONLY

Change from baseline on assessment of GPP which includes assessment of dermal 
symptoms, whole body findings, and laboratory findings for GPP.
10.3.4. Safety Analyses
Safety will be assessed by AEs, laboratory analytes including neutrophil counts, vital signs, 
weight, and C-SSRS.  Overall AEs will be summarized with frequencies.  Other safety measures
including the detailed AEs will be reviewed by listings.  Summaries of overall AEs will be 
created for Period 2 on the FAS Population and for Period 3 on the Maintenance Dosing Period 
Population, respectively.
10.3.4.1. Adverse Events
Adverse events are classified based upon the Medical Dictionary for Regulatory Activities 
(MedDRA).  A TEAE is defined as an event that first occurred or worsened in severity after 
baseline and on or prior to the date of the last visit within the treatment period.  Both the 
date/time of the event onset and the date/time of the first study drug injection are considered 
when determining TEAEs.  Treatment-emergent adverse events will be assigned to the treatment 
period in which they first occurred or worsened.
An overall summary of AEs will be provided for each of the treatment periods, including the 
number of patients who experienced TEAEs, TEAEs by maximum severity, deaths, SAEs, 
TEAEs related to study drug, discontinuations from the treatment due to an AE, and treatment-
emergent AESIs.  By-patient listings of TEAEs, SAEs including deaths, AEs that lead to 
treatment discontinuation, and AESIs will be provided.
Adverse events of special interest will be identified by a standardized MedDRA query (SMQ) or 
a Lilly defined MedDRA preferred term listing.


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10.3.4.2. Clinical Laboratory Tests
By-patient listings of laboratory measurements will be provided.
10.3.4.3. Vital Signs, and Physical Findings and Other Safety Evaluations
By-patient listings of vital signs, weight, and C-SSRS will be provided.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable
10.3.6. Evaluation of Immunogenicity 
The frequency of patients with preexisting ADA and with TE ADA+ to ixekizumab will be 
tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater 
than the minimum required dilution if no ADAs were detected at baseline (treatment-induced 
ADA) or those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were 
detected at baseline (treatment-boosted ADA).  For the TE ADA+ patients the distribution of 
maximum titers will be described.  The frequency of neutralizing antibodies will also be
tabulated in TE ADA+ patients.
10.3.7. Other Analyses
10.3.7.1. Health Outcomes/Quality of Life Assessment
Health Outcomes will be evaluated in this study utilizing the Itch Numeric Rating Scale (NRS)
and the DLQI. The following endpoints will be summarized using descriptive statistics 
described for continuous or categorical data in Section 10.3.1 for Period 2 on the FAS Population 
and Period 3 on the Maintenance Dosing Period Population, respectively:

Change from baseline in DLQI total score and domains, and Itch NRS score

Number of patients who achieve DLQI (0, 1) and DLQI (0)

Number of patients who achieve Itch NRS ≥4 point reduction from baseline for patients 
who had baseline Itch NRS ≥4
10.3.7.2. Subgroup Analyses 
Not applicable
10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.


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11.
References
Basra MKA, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 
1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol. 
2008;159(5):997-1035.
Bergboer JGM, Zeeuwen PLJM, Schalkwijk J. Genetics of psoriasis: evidence for epistatic 
interaction between skin barrier abnormalities and immune deviation. J Invest Dermatol. 
2012;132(10):2320-2331.
Di Meglio P, Perera GK, Nestle FO. The multitasking organ: recent insights into skin immune 
function. Immunity. 2011;35(6):857-869.
Di Meglio P, Villanova F, Nestle FO. Psoriasis. Cold Spring Harb Perspect Med. 
2014;4(8):pii:a015354.
Dubin DB, Tanner W, Ellis R. Biologics for psoriasis. Nat Rev Drug Discov. 2003;2(11):855-
856.
[EMEA] European Medicines Agency. Committee for medicinal products for human use 
(CHMP). Guideline on clinical investigation of medicinal products indicated for the treatment 
of psoriasis. Available at: https://www.ema.europa.eu/documents/scientific-
guideline/guideline-clinical-investigation-medicinal-products-indicated-treatment-
psoriasis_en.pdf. Accessed November 16, 2018.
Fredriksson T, Pettersson U. Severe psoriasis—oral therapy with a new retinoid. Dermatologica.
1978;157(4):238-244.
Iwatsuki K, Terui T, Ozawa A, Komiyane M, Umezawa Y, Torii H, Nakanishi G, Hara H,
Mabuchi T, Aoyama Y, Kitajima Y. Practice Guidelines 2010 for generalized pustular
psoriasis (GPP): Treatment guidelines incorporating TNFα inhibitor [Japanese].
http://www.nanbyou.or.jp/pdf2/088_l.pdf. Accessed November 16, 2018.
Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin. 2015;33(1):13-23.
Langley RG, Papp K, Gooderham M, Zhang L, Mallinckrodt C, Agada N, Blauvelt A, Foley P, 
Polzer P; of the IXORA-P Investigators. Efficacy and safety of continuous every-2-week 
dosing of ixekizumab over 52 weeks in patients with moderate-to-severe plaque psoriasis in a 
randomized phase III trial (IXORA-P). Br J Dermatol. 2018;178(6):1315-1323.
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 
2007;445(7130):866-873.
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, Lebwohl M, 
Koo JY, Elmets CA, Korman NJ, Beutner KR, Bhushan R. Guidelines of care for the 
management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and 
guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 
2008;58(5):826-850.
Menter A, Griffiths CE. Current and future management of psoriasis. Lancet. 
2007;370(9583):272-284.
Rapp SR, Feldman SR, Exum ML, Fleisher AB Jr., Reboussin DM. Psoriasis causes as much 
disability as other medical diseases. J Am Acad Dermatol. 1999;41(3 Pt 1):401-407.


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Rosenbach M, Hsu S, Korman NJ, Lebwohl MG, Young M, Bebo BF Jr, Van Voorhees AS; 
National Psoriasis Foundation Medical Board. Treatment of erythrodermic psoriasis: from the 
medical board of the National Psoriasis Foundation. J Am Acad Dermatol. 2010;62(4):655-
662.
Tang B, Annunziata K, DiBonaventura M. Burden of psoriasis in developing and developed 
countries [abstract]. In: International Society for Pharmacoeconomics and Outcomes Research 
19th annual international meeting research abstracts. May 31-Jun 4, 2014. Montreal, Canada. 
Value Health. 2014;17(3): A289. Abstract PSS35.
Umezawa Y, Ozawa A, Kawasima T, Shimizu H, Terui T, Tagami H, Ikeda S, Ogawa H,
Kawada A, Tezuka T, Igarashi A, Harada S. Therapeutic guidelines for the treatment of
generalized pustular psoriasis (GPP) based on a proposed classification of disease severity. 
Arch Dermatol Res. 2003;295 Suppl 1:S43-S54.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
Ab
antibody
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 event of special interest
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
BP
blood pressure
BSA
body surface area
CEC
Clinical Events Committee
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practices
CIOMS
Council for International Organizations of Medical Sciences
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.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.


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CSR
clinical study report
C-SSRS
Columbia- Suicide Severity Rating Scale
DLQI
Dermatology Life Quality Index (Dermatology-specific quality of life)
DNA
deoxyribonucleic acid
ECG
electrocardiogram
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EP
erythrodermic psoriasis
ERB
Ethics Review Board
ETV
early termination visit
FAS
Full Analysis Set
FSH
follicle stimulating hormone
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GIS
Global Improvement Score
GMA
granulocyte-monocyte adsorption apheresis
GPP
generalized pustular psoriasis
HBcAb
hepatitis B core antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
hsCRP
high sensitivity C-reactive protein
IB
Investigator’s Brochure
IBD
inflammatory bowel disease


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ICF
informed consent form
ICH
International Council for Harmonisation
IgG
immunoglobulin G
ILD
interstitial lung disease
IL
interleukin
IL-36 RN
interleukin 36 receptor antagonist
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
INR
International Normalized Ratio
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.
IP
investigational product
IRB
Investigational Review Board
Itch NRS
Itch Numeric Rating Scale
MAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Affairs
MHLW
Ministry of Health, Labour and Welfare
NAb
neutralizing antibody
NRS
numeric rating system
PASI
Psoriasis Area and Severity Index
PASI 75
at least a 75% improvement from baseline in PASI score
PASI 90
at least a 90% improvement from baseline in PASI score
PASI 100
a 100% improvement from baseline in PASI score
PCP
pneumocystis pneumonia


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PMDA
Pharmaceuticals and Medical Devices Agency
PPD
purified protein derivative
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
Ps
psoriasis
PsA
psoriatic arthritis
PSSI
Psoriasis Scalp Severity Index
Q2W
every 2 weeks
Q4W
every 4 weeks
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
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. 
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SMQ
standardized MedDRA query
SOA
Schedule of Activities
sPGA
static Physician Global Assessment
SUSAR
suspected unexpected serious adverse reactions
TASA
Treatment of Adolescent Suicide Attempters
TB
tuberculosis
TBL
total bilirubin
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TPO
third-party organization
ULN
upper limit of normal


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WBC
white blood cell
WCBP
women of childbearing potential
WHOATC
World Health Organization Anatomical Therapeutic Class


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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Testsa
Hematologyb
Clinical Chemistryb
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin concentration
Phosphorus
Leukocytes (WBC)
Total bilirubin
Platelets
Direct bilirubin
Absolute Counts of:
Alanine aminotransferase (ALT/SGPT)
Neutrophils, segmented
Aspartate aminotransferase AST/SGOT)
Neutrophils, juvenile
Blood urea nitrogen (BUN)
Lymphocytes
Uric acid
Monocytes
Creatinine
Eosinophils
Calcium
Basophils
Albumin
Gamma-glutamyl transferase (GGT)
Urinalysis (dipstick)b
Total protein
Color
Specific Gravity
Other Tests
pH
Human immunodeficiency virus antibody (HIV)
Protein
Hepatitis B virus DNAc
Glucose
Hepatitis B Surface antigen (HBsAg)
Ketones
Hepatitis B Core antibody (HBcAb)
Bilirubin
Hepatitis C antibody 
Urobilinogen
Hepatitis E antibodyd
Blood
High Sensitivity C-reactive protein (CRP)
Nitrite
Purified Protein Derivative (PPD)e
Urine Creatinine
Leukocyte esterase
Pregnancy test (serum and urine)f
Follicle-stimulating hormone (FSH)g
LY2439821 serum concentrationh
Immunogenicity testing (anti-ixekizumab Ab)h
Beta-D-Glucani
KL-6j
Abbreviations:  Ab = antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CRP = C-reactive protein; DNA = deoxyribonucleic acid; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyl transferase; HbsAg = hepatitis B surface antigen; HBcAb = hepatitis B core antibody; 
HIV = human immunodeficiency virus; RBC = red blood cells; PPD = purified protein derivative; 
SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white 
blood cells.


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a
Assayed by Lilly-designated laboratory.
b
Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the discretion of 
the investigator, as needed.
c
If patient is HBcAb+ and/or HBsAB+, HBV DNA needs to be confirmed negative at screening and at least once 
every month in Periods 2 and 3.
d
Hepatitis E antibody is not a part of routine screening for this study; however, it may be required during the study
for hepatic follow-up.
e
See section 9.4.5.2:  The QuantiFERON-TB Gold/T-SPOT.TB test may be used instead of the PPD TB test, and 
is performed locally.
f
To be performed for females of childbearing potential only. Urine pregnancy tests are locally performed as 
scheduled in the SOA (Section 2). Necessary equipment may be provided centrally if needed.  
g
FSH test performed for women ≥40 and <60 years of age who have had a cessation of menses for at least
12 months to confirm non-childbearing potential (≥40mIU/mL)
h
Immunogenicity samples will also be analyzed for ixekizumab serum concentration to facilitate in the 
interpretation of the immunogenicity data at Week 12 (visit 6), Week 20 (Visit 10) and ETV.  In addition, a 
blood sample will be collected, when possible for any patient who experiences a potential systemic 
allergic/hypersensitivity reaction during the study as judged by the investigator. 
i
Beta-D-glucan is required at a screening and if an investigator believes it is warranted at subsequent visits, a 
beta-D-glucan test may be included in the work-up panel at any time during the study and may be done locally.
If the beta-D-glucan test is positive, PCP needs to be ruled out. If PCP is ruled out and the investigator deems 
the patient fit to continue, the patient may continue in the study. If a patient has a confirmed diagnosis PCP 
during the study, the patient must discontinue the study. 
j
KL-6 is required at screening, and if an investigator believes it is warranted at subsequent visits, a KL-6 test may 
be included in the work-up panel at any time during the study and may be done 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 nature of the study, the potential risks 
and benefits of participating in the study, and that their participation is voluntary.

ensuring 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 study.

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative 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 protocol and related amendments and addenda, current IB and updates during 
the course of the study

informed consent form 

other relevant documents (for example, curricula vitae, advertisements).


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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the

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 will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in dermatology or other relevant specialties with appropriate 
experience with diagnosis and treatment of patients with psoriasis will participate as 
investigators in this clinical trial.
Appendix 3.1.6.
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 3.1.7.
Final Report Signature
The investigator will sign the final clinical study report (CSR) for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The 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


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
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.
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 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.
Case report form data will be encoded and stored in a clinical trial database.  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 data 
warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
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 Eli Lilly Japan, 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 Eli Lilly Japan judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 3.4.
Publication Policy
The publication policy for Study I1F-JE-RHCV is described in the letters of agreement between 
the sponsor and the investigators and institutions.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 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.
Tests for Allergic Reactions and 
Hypersensitivity Events
Selected tests may be obtained in the event of anaphylaxis or generalized urticaria.
Hypersensitivity Testsa
Anti-LY2439821 antibodies (immunogenicity)
Tryptase
LY243821 serum concentration
N-methylhistamine
Drug Specific IgEb
Basophil Activation Testb
Complements
Cytokine Panel
Abbreviations:  IgE = Immunoglobulin E.
a
Assayed by Lilly-designated laboratory.
b
Basophil Activation test will be performed if a drug specific IgE assay is unavailable.


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Appendix 6.
List of Excluded Medications and 
Procedures
Excluded Medications
IV antibiotics for an infection within 12 weeks prior to baseline
Systemic nonbiologic psoriasis therapy with the exception of:

oral corticosteroids, if average daily doses are not greater than 10 mg/day of prednisone or its equivalent.

all topical treatment 

methotrexate or oral retinoids administered before and during the study if doses are not greater than that 
of baseline.

cyclosporine and Apremilast if daily doses are not greater than that of baseline

Granulocyte-monocyte adsorption apheresis (GMA):  use of GMA is allowed.
Concurrent use of any biologic agent
Previous treatment with ixekizumab
Live vaccination within 12 weeks prior to baseline (Week 0; Visit 2), or

intend to have a live vaccination during the course of the study or within 12 months of completing 
treatment in this study, or

have participated in a vaccine clinical study within 12 weeks prior to baseline.
Vaccination with Bacillus Calmette-Guerin (BCG) within 12 months prior to baseline (Week 0; Visit 2), or 

intend to have this vaccination with BCG during the course of the study, or 

within 12 months of completing treatment in this study.
Excluded Procedures
Have received phototherapy at the day of baseline (Week 0; Visit 2) and during the course of the study.
Have donated more than 400 ml of blood (for patients weighing ≥50 kg), or 

200 ml of blood (for patients weighing <50 kg), or 

plasmapheresis/platelet apheresis within 30 days prior to study entry, or plan to donate blood during the 
study.
Excessive sun exposure or use of tanning booths for at least 4 weeks prior to baseline (Week 0;  Visit 2) and 
during the study.


Leo Document ID = e6d41fb9-3470-4c34-a272-74b8ebb854cf
Approver: 
Approval Date & Time: 01-Feb-2019 03:01:24 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Feb-2019 03:32:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Feb-2019 11:25:36 GMT
Signature meaning: Approved
PPD
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan: I1F-JE-RHCV 
A Multicenter, Open-Label, Post Marketing Clinical Trial to Evaluate the Efficacy And Safety 
Of Ixekizumab in Patients With Generalized Pustular Psoriasis and Erythrodermic Psoriasis 
NCT03942042 
Approval Date: 12-Aug-2020


I1F-JE-RHCV Statistical Analysis Plan Version 2
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1.
Statistical Analysis Plan:
I1F-JE-RHCV:  A Multicenter, Open-Label, Post Marketing 
Clinical Trial to Evaluate the Efficacy And Safety Of 
Ixekizumab in Patients With Generalized Pustular 
Psoriasis and Erythrodermic Psoriasis
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Ixekizumab (LY2439821) Generalized Pustular Psoriasis and Erythrodermic 
Psoriasis
Study I1F-JE-RHCV is a multicenter, open-label, post marketing clinical trial to evaluate the 
efficacy and safety of ixekizumab Q2W beyond Week 12 until Week 20 in patients with 
Generalized Pustular Psoriasis and Erythrodermic Psoriasis.  
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Protocol I1F-JE-RHCV
Phase 4
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 12-Aug-2020 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I1F-JE-RHCV:  A Multicenter, Open-
Label, Post Marketing Clinical Trial to Evaluate the Efficacy And 
Safety Of Ixekizumab in Patients With Generalized Pustular 
Psoriasis and Erythrodermic Psoriasis .................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................9
5.3.
Method of Assignment to Treatment ..............................................................................9
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Considerations ................................................................................................10
6.2.
Adjustments for Covariates ..........................................................................................10
6.3.
Handling of Dropouts or Missing Data.........................................................................10
6.3.1.
Nonresponder Imputation (NRI)...........................................................................11
6.3.2.
Last Observation Carried Forward (LOCF) ..........................................................11
6.4.
Multicenter Studies ......................................................................................................11
6.5.
Multiple Comparisons/Multiplicity...............................................................................11
6.6.
Use of an “Efficacy Subset” of Patients........................................................................11
6.7.
Patient Disposition .......................................................................................................11
6.8.
Patient Characteristics ..................................................................................................12
6.8.1.
Demographics and Baseline Characteristics..........................................................12
6.8.2.
Historical Illness and Preexisting Conditions........................................................15
6.9.
Treatment Compliance .................................................................................................15
6.10. Previous and Concomitant Therapy..............................................................................16
6.10.1.
Previous Therapy .................................................................................................16
6.10.2.
Concomitant Therapy...........................................................................................17
6.11. Efficacy Analyses ........................................................................................................17
6.11.1.
Primary Outcome and Methodology.....................................................................24
6.11.2.
Additional Analyses of the Primary Outcome.......................................................24
6.11.3.
Other Secondary Efficacy Analyses .....................................................................24
6.12. Health Outcomes/Quality-of-Life Analyses..................................................................24
6.13. Safety Analyses............................................................................................................27
6.13.1.
Extent of Exposure...............................................................................................27


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6.13.2.
Adverse Events ....................................................................................................28
6.13.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................29
6.13.3.1.
Special Safety Topics including Adverse Events of 
Special Interest ...............................................................................................29
6.13.4.
Clinical Laboratory Evaluation.............................................................................37
6.13.4.1.
Hepatic Tests..................................................................................................37
6.13.4.2.
Leukocytes (WBC) and Platelets ....................................................................37
6.13.5.
Vital Signs and Other Physical Findings...............................................................38
6.13.6.
Electrocardiograms ..............................................................................................38
6.13.7.
Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................38
6.14. Immunogenicity...........................................................................................................39
6.14.1.
Definitions and Terms..........................................................................................39
6.14.1.1.
Sample Category Definitions ..........................................................................39
6.14.1.2.
Patient Category Definitions...........................................................................41
6.14.1.3.
Definitions for Clinical Interpretation of Assay Results ..................................42
6.14.2.
Immunogenicity Analyses....................................................................................44
6.14.2.1.
Analyses of Characteristics of ADA Immune Response..................................45
6.15. Subgroup Analyses.......................................................................................................45
6.16. Protocol Deviations......................................................................................................45
6.17. Interim Analyses and Data Monitoring.........................................................................45
6.18. Annual Report Analyses...............................................................................................45
6.19. Clinical Trial Registry Analyses...................................................................................46
7.
References ........................................................................................................................47


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Table of Contents
Table
Page
Table RHCV.6.1.
Description and Derivation of Primary and Secondary Efficacy 
Measures ................................................................................................19
Table RHCV.6.2.
Description and Derivation of Health Outcomes Measures .....................25
Table RHCV.6.3.
Definitions and Derivations of Special Safety Topics including 
Adverse Events of Special Interest..........................................................31


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Table of Contents
Figure
Page
Figure RHCV.5.1.
Illustration of study design for Clinical Protocol I1F-JE-RHCV................9
Figure RHCV.6.1.
Sample definitions..................................................................................41
Figure RHCV.6.2.
Patient categories (evaluable/unevaluable) based on sample 
status at baseline and post-baseline.........................................................42
Figure RHCV.6.3.
Relationship of terms for clinical interpretation of assay results 
for evaluable patients..............................................................................43
Figure RHCV.6.4.
Flow chart of ADA assessment with clinical interpretation of 
the various result possibilities.................................................................44


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to first patient visit.
SAP Version 2 was approved prior to the final analysis.  The overall changes incorporated in
Version 2 are as follows:
1)
Section of protocol deviation was updated to refer to the latest version of Trial Issue 
Management Plan (TIMP).
2)
Race and race subcategory were added to the section of demographics and baseline 
characteristics.
3)
Section of historical illnesses and preexisting conditions was added.
4)
Summary of treatment compliance as continuous variable was added to the section of 
treatment compliance.
5)
Wording was slightly updated to clarify the definition of primary analysis of the primary 
endpoint in the section of primary outcome and methodology.
6)
Minor grammatical or formatting changes were made.


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4.
Study Objectives
Objectives
Endpoints
Primary

To assess the efficacy of ixekizumab Q2W 
beyond Week 12 in patients with generalized 
pustular psoriasis (GPP) and erythrodermic 
psoriasis (EP)

Number of patients who improved Global 
Improvement Score (GIS) at least 1 point from 
Week 12 through Week 20 and with ≤2 of GIS
Secondary

To assess the efficacy of ixekizumab Q2W 
beyond Week 12 in patients with GPP and EP

To assess the health outcomes of ixekizumab 
Q2W beyond Week 12 in patients with GPP 
and EP

To evaluate the potential development of 
anti-ixekizumab antibodies of ixekizumab
Q2W beyond Week 12 in patients with GPP 
and EP
The following endpoints will be assessed at each 
scheduled visit after Week 12:

Number of patients with each GIS grade 
(1: Resolved, 2: Improved, 3: Unchanged, 
4: Worsened)

Number of patients who achieved sPGA (0, 1) 
and sPGA (0)

Number of patients who achieved PASI 75, 
PASI 90, and PASI 100 from baseline

Change from baseline, and percent 
improvement from baseline in PASI

Change from baseline in PSSI in patients with 
scalp involvement at baseline, and percent of 
BSA involvement of Psoriasis

Change from baseline in DLQI total score and 
domains, and Itch NRS score

Number of patients who achieved DLQI (0, 1) 
and DLQI (0) 

Number of patients who achieved Itch NRS 
≥4 point reduction from baseline for patients 
who had baseline Itch NRS ≥4

Number of patients who developed 
treatment-emergent anti-ixekizumab antibody 
(TE-ADA) and neutralizing anti-ixekizumab 
antibody (NAb)
GPP ONLY

Change from baseline on assessment of 
Generalized Pustular Psoriasis Severity Index 
at Week 12 and Week 20/ETV.
Note:  Global improvement scores will be assessed in the four grades by comparing the psoriatic findings: (1) 
resolved, (2) improved, (3) unchanged, and (4) worsened. The global improvement score is assessed based on 
the comparison of the psoriatic findings, sPGA, PASI score, and other evaluations with those at the baseline.
Abbreviations:  BSA = body surface area; DLQI = Dermatology Life Quality Index; EP = erythrodermic psoriasis; 
GIS = Global Improvement Score; GPP = generalized pustular psoriasis; NAb = neutralizing anti-ixekizumab 
antibody; NRS = Numeric Rating Scale; PASI = Psoriasis Area and Severity Index; PASI 75 = at least a 75%
improvement from baseline in PASI score; PASI 90 = at least a 90% improvement from baseline in PASI score ; 
PASI 100 = a 100% improvement from baseline in PASI score; PSSI = Psoriasis Scalp Severity Index; 
Q2W = every 2 weeks; sPGA = static Physician Global Assessment; TE-ADA = treatment-emergent anti-drug 
antibody.


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5.
Study Design
5.1.
Summary of Study Design
Study I1F-JE-RHCV is a multicenter, open-label, post marketing clinical trial to evaluate the 
efficacy and safety of ixekizumab Q2W beyond Week 12 until Week 20 in patients with GPP 
and EP.
The study consists of 3 periods:

Period 1:  Screening Period (Visit 1) lasting from 7 to 30 days prior to Period 2 (baseline; 
Week 0; Visit 2)
Study investigator(s) will review patient history and screening test results to determine if the 
patient meets all inclusion and none of the exclusion criteria to qualify for participation in 
the study.

Period 2: Induction Dosing Period from Week 0 (Visit 2) to Week 12 (Visit 6)
All eligible patients will be administered 160 mg ixekizumab as 2 SC injections at Week 0 
(baseline; Visit 2) followed by 80 mg as 1 injection at Week 2, 4, 6, 8 and 10.

Period 3: Maintenance Dosing Period from Week 12 to Week 20
Responders (GIS = 1 at Week 12) will complete the study.
Inadequate responders (GIS ≥2 at Week 12 and based on investigators’ discretion) will 
continue to use ixekizumab 80 mg Q2W during Period 3.  If patients show a therapeutic 
response (GIS = 1) with 80 mg Q2W after Week 12, the patient will complete the study.  
Patients who complete the study before Week 20 will have an early termination visit (ETV) 
instead of the original scheduled visit. 
Figure RHCV.5.1 illustrates the study design.


I1F-JE-RHCV Statistical Analysis Plan Version 2
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LY2439821
Figure RHCV.5.1.
Illustration of study design for Clinical Protocol I1F-JE-RHCV.
5.2.
Determination of Sample Size
A total of 12 patients will be enrolled so that at least 5 patients with EP and 5 patients with GPP
who are inadequate responders (GIS ≥2 at Week 12 and based on investigators’ discretion) will 
continue to use ixekizumab beyond Week 12.  Additional enrollment may occur and the sample 
size may be increased, if no GPP or EP patients enter into Period 3 (Maintenance Dosing Period) 
of the study.
The sample size is based on the following:

In the I1F-JE-RHAT (RHAT) study, 5 GPP and 8 EP patients were enrolled.  One GPP 
patient achieved GIS = 1 (resolved) at Week 12 and the other 4 GPP patients achieved 
GIS = 2 (improved).  One EP patient achieved GIS = 1 at Week 12 and 7 EP patients 
achieved GIS = 2.  Although the sample size is very small, based on the result of RHAT 
study, it is assumed that approximately 5 patients at maximum may not achieve GIS = 1 
at Week 12 and may continue ixekizumab Q2W beyond Week 12 based on the 
investigators’ discretion.

The sample size is determined based on the feasibility in Japan.  The prevalence rate of 
these patients is very low in Japan and it is also difficult to conduct a placebo-controlled 
study for these severe conditions (Umezawa et al. 2003, Rosenbach et al. 2010).
5.3.
Method of Assignment to Treatment
Patients are assigned to treatment and will receive their assigned treatment as outlined in the 
protocol Section 7.1.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly Japan.
Efficacy, health outcomes and safety analyses for Period 2 will be conducted on the largest 
analysis set (Full Analysis Set [FAS]), defined as the set of patients with GPP and EP separately 
who receive at least 1 dose of study treatment in Period 2 (FAS Population).  Efficacy, health 
outcomes and safety analyses for Combined Periods 2 and 3 will be conducted based on patients 
with GPP and EP separately who receive at least 1 dose of study treatment in Period 3 
(Maintenance Dosing Period Population) although the protocol stated that these analyses wll be 
conducted only for Period 3 on the Maintenance Dosing Period Population.
Baseline for efficacy, health outcomes, and safety analyses in Period 2 and Combined Periods 2 
and 3 is defined as the last available value before the first dose in Period 2; in most cases, it will 
be the value recorded at Week 0 (Visit 2).
Change from baseline will be calculated as the value at the visit of interest minus the baseline 
value.  If all baseline values are missing for a particular variable, then the change from baseline 
and the percent improvement from baseline will not be calculated.
In the analysis of adverse events for Period 2 and Combined Periods 2 and 3, all pre-existing
conditions recorded at Visit 1 and any on-study adverse events recorded prior to the first dose in 
Period 2 will be used as baseline events.
As this is a single arm study with very small sample size, no statistical inference will be 
performed.
Continuous data will be summarized in terms of the mean, standard deviation (SD), minimum,
maximum, median, and number of observations.  The minimum and maximum will be reported 
to the same number of decimal places as the raw data recorded in the database.  The mean and 
median will be reported to 1 more decimal place than the raw data recorded in the database.  The 
SD will be reported to 2 more decimal places than the raw data recorded in the database.  In 
general, the maximum number of decimal places reported shall be 4 for any summary statistics.  
Categorical data will be summarized as frequency counts.
The statistical analyses will be performed using SAS® Version 9.4 or higher.
6.2.
Adjustments for Covariates
No statistical adjustments for covariates will be made as statistical inference will not be 
performed in this single arm study with very small sample size.
6.3.
Handling of Dropouts or Missing Data
The methods for imputation of missing data to be used in this study are in accordance with the 
precedent set in other Phase 3 psoriasis trials (Leonardi et al. 2008; Papp et al. 2008) and 
ixekizumab Phase 3 studies.


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6.3.1. Nonresponder Imputation (NRI)
Categorical binary efficacy and health outcomes variables will be summarized using a 
nonresponder imputation (NRI) method.  Patients will be considered a nonresponder if they do 
not meet the clinical response criteria or have missing clinical response data at the scheduled
time point.  All patients who discontinue study treatment at any time prior to the scheduled visit 
for any reason will be defined as nonresponders regardless of study continuation without study 
treatment at the visit.  Enrolled patients without at least 1 post-baseline observation will also be 
defined as nonresponders.
6.3.2. Last Observation Carried Forward (LOCF)
Continuous efficacy and health outcomes variables will be summarized using a last observation 
carried forward (LOCF) method. For patients discontinuing study treatment for any reason, the 
last non-missing post-baseline observation before the missing data will be carried forward to the 
corresponding time point for evaluation. Enrolled patients without at least 1 post-baseline 
observation will not be included for evaluation.
6.4.
Multicenter Studies
This study will be conducted in multiple investigators at multiple sites. However, since all sites 
will have small numbers of subjects, center differences will not be explored.
6.5.
Multiple Comparisons/Multiplicity
No statistical multiple comparisons will be made in this single arm study with very small sample 
size. 
6.6.
Use of an “Efficacy Subset” of Patients
An efficacy subset will not be used in this study because of very small sample size.
6.7.
Patient Disposition
The following patient disposition summaries will be provided for patients with GPP and EP
separately and total:

Number of patients:
o
failed in screening, by primary reason for screen failure
o
enrolled (defined as patients who have been assigned to a treatment) at Week 0
(Visit 2)
o
completing Period 2 (Week 12, Visit 6)
o
discontinuing the study in Period 2, by primary reason for study discontinuation
o
completing Period 3 including patients who complete the study because of GIS = 
1 prior to Week 20 (Visit 10)
o
discontinuing the study in Period 3, by primary reason for study discontinuation
(Analysis population: All Entered Patients)

Number of patients:
o
completing the study treatment in Period 2
o
discontinuing the study treatment in Period 2, by primary reason for treatment
discontinuation


I 1 F-J E - R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 2
L Y 2 4 3 9 8 2 1
(A nal ysis p o p ulat i on: F A S P o p ul at i on)

N u m ber of  patie nts:
o
c o mplet i n g t he st u d y treat me nt i n Peri o d 3
o
di sc o nti n ui n g t he st u d y treat me nt i n P eri o d 3 , b y pri mar y  reas o n f or treat me nt 
di sc o nti n uati on 
(A nal ysis p o p ulat i on: Mai nte na nce D osi n g Peri o d P o p ulat i on )
A b y- pat ient  listi n g will be pr o vi de d t o i ncl u de t he f oll owi n g i nf or mati on ( A nal ysis p o p ul at i on:  
All E ntere d Patie nts ):

P ati e nt dis p osit i on d uri n g tr e at me nt peri o ds , i ncl u di n g t he date of  e nr oll me nt at Visit 2, 
t he date of  first a n d last d ose, t he date of st u d y c o mplet i on or stu d y disc o nti n uat i on , t he 
pri mar y  reas o n f or st u d y disc o nti n uati o n if a p plica ble, a n d t he n u m ber of  da ys i n 
treat me nt p erio ds .  T he n u m ber of da ys i n tr e at me nt perio ds will be calc ulate d as: date of 
treat me nt disc o nt i n uati on ( or treat me nt c o m p leti on) - date of  first d ose i n P erio d 2 + 1 .  
F or patie nts w h o di sc o nti n ue d ue t o l ost t o f oll o w-u p, t he date of  disc o nt i n uati on 
ca pt ure d i n t he Dis p ositi o n Eve nt: L ost t o F oll o w  Up electr o nic case re p ort f or m (e C R F)
pa ge will be use d f or t hi s calc ulati on.
6. 8.
P ati e nt C h ar a ct eri sti c s
6. 8. 1.
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s
T he f o ll owi n g d e m o gra p hic varia bles a n d baseli ne c haracterist ics will  be s u m marize d
descri pt i vel y f or pati e nts wit h G P P a n d E P se paratel y a n d t otal (A nal ysis p o p ul at i on: F A S 
P o p ul at i on):

A ge at t he ti me of i nf or me d c o nse nt (i n years) : It will be calc ulate d usi n g a n i m p ute d date 
of  birt h of  Jul y 1 st i n t he year of  birt h c ollecte d i n t he De m o gr a p hics
e C R F pa ge as 
f oll ows:
   (     ) =
                   −             ℎ
3 6 5 .2 5

A ge gr o u p :  < 6 5 y ears, ≥6 5 years t o < 7 5 years, ≥7 5 years

Ge n der

Race

Race s u bcate g or y: Ja pa nese, ot her (if “ N o” is selecte d f or t he “ Race Asia n” 
c ollecte d i n t he De m o gr a p hics e C R F pa ge )

H ei g ht (c m )

Wei g ht ( k g)

Wei g ht cate g or y :  < 8 0 k g, ≥8 0 k g a n d < 1 0 0 k g, ≥1 0 0 k g

B o d y  mass i n de x ( B MI) ( k g/ m 2): It will be calc ulate d as f oll ows :
  (  /  2 ) =
   ℎ (  )
(   ℎ ( )) 2


I 1 F-J E - R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 3
L Y 2 4 3 9 8 2 1

Alc o h o l use:  ne ver, c urre nt, f or mer

Caffei ne use:  ne ver, c urre nt, f or mer

T o bacc o use:  ne ver, c urre nt, f or mer

Pre vi o us s yste mic t hera p y:  ne ver use d, n o n- bi o l ogic o nl y, bi o l ogic o nl y , biol o gic 
a n d n o n-bi o l ogic.  
o
N o n -bi o l ogics are defi ne d as:  met h otre xate, c y clos p ori ne, reti n o i ds, 
c ortic oster oids, f u maric aci d deri vati ves, a pre milast, ot her n o n- bi o l ogics, a n d 
ps oral e n a n d ultra viol et A ( P U V A)
o
Bi ol o gi cs are defi ne d as:  efaliz u ma b, uste ki n u ma b, i nfli xi ma b, eta nerce pt, 
aleface pt, a dali m u ma b, g oli m u ma b, cert oliz u ma b pe g ol, sec u ki n u ma b, 
br o dal u ma b, or ot her bi o l ogi cs

Pre vi o us n o n- bi o l ogic s yste mic t hera p y:  ne ver use d, e ver use d

Pre vi o us bi o l ogic t hera p y : ne ver use d, e ver u se d

Pre vi o us p h ot ot hera p y  ( ultra viol et B [ U V B] or P U V A):  ne ver use d, e ver use d

Pre vi o us I L -1 7 t hera p y (sec u ki n u ma b or br o dal u ma b):  ne ver use d, e ver use d

A ge at G P P or E P d ia gn osi s (in years)

D urati o n si nce G P P or E P dia g n osis (i n years) :  It will be cal c ulate d usi n g t he 
date of G P P or E P dia g n osis as f o ll ows:
                        (     )
=
                   −                  3 6 5 .2 5
I n case of partial date of  G P P or E P dia g n osis, t he f oll owi n g i m p utati o n r ules will 
be utilize d :

If b ot h m o nt h a n d da y  are missi n g, i m p ute J ul y 1.

If m o nt h is missi n g a n d da y is n ot missi n g, i m p ute J ul y 1 .

If o nl y  da y is missi n g, i m p ute 1 5.

Ps ori asis v ul garis:  y es, n o

Ps ori at ic art hritis:  yes, n o

Baseli ne s P G A as c o nt i n u o us varia ble

Baseli ne s P G A cate g or y :  0, 1, 2, 3, 4, 5

Baseli ne P A SI sc ore

S calp ps ori asis:  yes, n o

Baseli ne P S SI sc ore

Baseli ne B S A ( %)


I 1 F-J E - R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 4
L Y 2 4 3 9 8 2 1

Baseli ne Itc h N R S sc ore

Baseli ne D L QI t otal  s c or e

Di a g n osis of G P P ( G P P o nl y): ac ute G P P , ot her

T y pe of G P P ( G P P o nl y): G P P wit h prece di n g ps oriasis v ul garis, ot her: If start 
date of ps oriasis v ul garis is pri or t o dia g n osis date of G P P, it will be classifie d 
i nto G P P wi t h prece di n g ps oriasis v ul garis. Ot her wise, it will be classifie d i nt o 
ot her.  If start date of ps oriasis v ul garis a n d/ or dia g n osis date of G P P are missi n g 
or parti al, t hes e dates will be c o m pare d as far as p ossi ble.  If t here is clear 
e vi de nce t o s u g gest t hat t he ps ori asis v ul garis starte d pri or t o t he dia g n osis of 
G P P , t he patie nt will be ass u me d t o be G P P wi t h prece di n g ps oriasis v ul garis.

M utati o n of  I L-3 6 R N ( G P P o nl y): c o m p o u n d heter oz yg o us, heter oz y g o us, 
h o m o z yg o us, n o m ut ati o n , ot her, u n k n o w n

Baseli ne a ssess me nt of der mal s y m pt o ms t ot al sc ore ( G P P o nl y): It will be 
assesse d b y t he sc ore wit h t he area of er yt he ma ( o n a 0 t o 3 scale), area of 
c o nfl ue nt p ust ules ( o n a 0 t o 3 scal e), a n d are of s ki n e de ma ( o n a 0 t o 3 scale)
(see ta ble belo w) .  T he t otal sc ore will be calc ulate d (ra n ge , 0 t o 9).
Assess me nt of der mal s y m pt o ms ( 0 - 9 p oi nts)
Se vere
M o derate
Mil d
N o ne
Area of er y t he ma*
3 
2 
1 
0
Area of er y t he ma wit h p ust ules * *
3 
2 
1 
0
Area of e de ma * *
3 
2 
1 
0
*% a g ai nst b o d y s urface area ( Se vere : > 7 5 %, M o derate : < 7 5 % > 2 5 %, Mil d : < 2 5 %)
* *% a g ai nst b o d y s urface area ( Se vere : > 5 0 %, M o d er at e : < 5 0 % > 1 0 %, Mil d : < 1 0 %)

Baseli ne s yste mic s y m pt o m s a n d la b orat or y fi n di n gs t otal sc ore ( G P P o nl y): It 
will be assesse d b y  t he sc ore wit h b o d y  t e mperat ure ( o n a 0 t o 2 scal e), le uc oc yt es
( o n a 0 t o - 2 scale), C-reacti ve pr otei n ( o n a 0 t o 2 scale) a n d ser u m al bu mi n ( o n a 
0 t o 2 scale) (see ta ble bel o w).  T he t otal sc ore will be calc ulate d (ra n ge, 0 t o 8) .
S y ste mic s y m pt o ms a n d la b orat or y fi n di n gs ( 0 - 8 p oi nts)
S c or e
2
1
0
B o d y  t e mperat ure ( ℃)
≥3 8. 5
3 7 ≤, < 3 8. 5 
< 3 7
Le uc oc y t es (/μ L)
≥1 5, 0 0 0
1 0, 0 0 0 ≤, < 1 5, 0 0 0
< 1 0, 0 0 0
C- reacti ve pr otei n ( mg/ dl)
≥7. 0
0. 3 ≤, < 7. 0
< 0. 3
S er u m al b u mi n ( g/ dl)
< 3. 0
3. 0 ≤, < 3. 8
≥3. 8

Baseli ne G P P se veri t y in de x t otal sc ore ( G P P o nl y): It will be calc ulate d b y t he 
s u m of assess me nt of der mal s y m pt o ms t otal sc ore a n d s yste mic s y m pt o ms a n d 
la b orat or y fi n di n gs t otal sc ore (ra n ge, 0 t o 1 7).


I 1 F-J E -R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 5
L Y 2 4 3 9 8 2 1

Baseli ne G P P se veri t y: mil d, mo derate, se vere ( G P P o nl y): It will be defi ne d as 
mil d ( 0 – 6 p oi nts), m o derate ( 7 – 1 0 p oi nts), a n d se vere ( 1 1 – 1 7 p oi nts) fr o m 
G P P se verit y i n de x t otal s c or e.

Baseli ne C o l um bia -S ui ci de Se verit y Rati n g Scale ( C-S S R S) i n lifeti me: Cate g or y  
1 – Wis h t o be Dea d , Cate g or y  2 – N o n- s pecific Acti ve S uici dal T h o u g hts, 
Cate g or y  3 – Act i ve S uici dal I deati on wi t h A n y Met h o ds ( N ot Pla n) wit ho ut 
I nte nt t o Act, Cate g or y 4 – Acti ve S uici dal I deati o n wit h S o me I nte nt t o Act, 
wi t ho ut S pecific Pl a n, Cate g or y  5 – Acti ve S uici dal I deat i on wi t h S pecific Pla n 
a n d I nte nt , Cate g or y  6 – Pre parat or y Acts or Be ha vi or , Cate g or y 7 – A b o rte d 
At t e mpt , Cate g or y 8 – I nterr u pte d Atte m pt, Cate g or y  9 – Act ual Atte m pt ( n o n -
fatal), a n d Self -i nj urio us be ha vi or wi t ho ut s ui ci dal int e nt .
A b y -pat ient  listi n g of  d e mo gra p hic a n d baseli ne c haracterist ics will be pr o vi de d (A nal ysis 
p o p ul at i on: F A S P o p ul at i on).
6. 8. 2.
Hi st ori c al Ill n e s s a n d Pr e e xi sti n g C o n diti o n s
Hi st orical ill nesses a n d pree xist i n g c o n diti ons will be classifie d usi n g t he latest versi o n of t he 
Me dical Dict i onar y f or Re g ul at or y Acti vities ( Me d D R A).  
Hi st orical ill ness/c o n dit i on is defi ned as t he c o n di tio n /e ve nt rec or de d o n t he Pre-E xi sti n g 
C o n di tio ns a n d Me dical  Hist or y e C R F pa ge or o n t he Pres pecifie d Me dical Hist or y e C R F pa ge 
wi t h a n e n d date prior t o t he date of i nf or me d c o nse nt.  
Pree xist i n g c o n diti on is defi ne d as t he c o n diti on/e ve n t rec or de d o n t he Pre-E xi sti n g C o n diti ons 
a n d Me dical Hist or y e C R F pa ge or o n t he Pres pecifie d Me dical Hist or y e C R F pa ge wit h a start 
date pri or t o t he date of i nf or me d c o nse nt, a n d n o e n d date (t hat is, t he e ve nt is o n g o i n g) or a n 
e n d date o n or after t he date of i nf or me d c o nse nt.  N otice if a pree xist i n g c o n diti on w orse ns i n 
se verit y o n or after t he date of i nf or me d c o nse nt, it will be rec or de d as a n A E o n A d verse E ve nts 
e C R F pa ge fr o m t he date of w orse ni n g o n war ds.  
B y -pat ient  listi n gs of hist orical ill nesses a n d pree xisti n g c o n diti ons will be pr o vi de d , res pecti vel y
( A nal ysis p o p ulati on: F A S P o p ulat i on) .  
6. 9.
Tr e at m e nt C o m pli a n c e
T hr o u g h o ut treat me nt peri o ds, e nr olle d pati e nts will rec or d i nf or matio n i n a St u d y  Dr u g 
A d mi nistrati o n L o g (ca pt ure d i n t he Ex p os ure as C ollecte d e C R F pa ge), i ncl u di n g t he date, ti me, 
a n d a nat o mical l o cat i on of a d mi nistrati o n of i n vesti gat i onal pr o d uct, pac ka ge n u m ber, w h o 
a d mi nistere d t he i n vest i gati onal pr o d uct, a n d t he reas o n if t he i n vest i gati onal pr o d uct was n ot 
f ull y a d mi nistere d.
Treat me nt c o m plia nce f or eac h pat ient  will be calc ulate d as:
                 (%) =
1 0 0  ×                                                          

I1F-JE-RHCV Statistical Analysis Plan Version 2
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LY2439821

For patients who complete Period 2, the number of injections prescribed (that is, 
expected) during Period 2 will be equal to 7 (2 injections at Week 0 and 1 injection every 
2 weeks from Week 2 to Week 10).  

For patients who discontinue during Period 2, the number of injections prescribed during 
Period 2 can be derived from the IWRS study drug dispense dataset.

For patients who complete Period 3, the number of injections prescribed (that is, 
expected) during Period 3 will be equal to 4 (1 injection every 2 weeks from Week 12 to 
Week 18).  

For patients who discontinue during Period 3 or who complete study treatment because of 
GIS = 1 (i.e., Responder) before Week 18 , the number of injections prescribed during 
Period 3 can be derived from the IWRS study drug dispense dataset.  

The total number of injections administered will be derived using the response to the 
question “Was dose administered?” on the Exposure as Collected eCRF page.
A patient will be considered overall compliant with study treatment if he/she misses no more 
than 20% of the expected doses, does not miss 2 consecutive doses (all injections at an injection 
week are counted as 1 dose), and does not over-dose (that is, take more injections at the same 
time point than specified in the protocol).  
The treatment compliance (continuous variable) and the number of patients that are compliant 
and non-compliant (categorical variable) will be summarized for patients with GPP and EP
separately and total for Period 2 and for Combined Periods 2 and 3, respectively (Analysis 
population: FAS Population for Period 2, Maintenance Dosing Period Population for Combined 
Periods 2 and 3).
By-patient listings of study drug dispensed (including lot number and package number) and 
study treatment administration and compliance will be provided (Analysis population: FAS 
Population).
6.10. Previous and Concomitant Therapy
Medication/therapy will be classified into anatomical therapeutic chemical (ATC) drug classes 
using the latest version of the World Health Organization (WHO) drug dictionary.
A by-patient listing of previous and concomitant therapy, and a by-patient listing of previous 
psoriasis therapy will be provided (Analysis population: FAS Population).
6.10.1. Previous Therapy
Previous therapy is defined as the therapy that starts and ends prior to the date of first dose of 
study treatment in Period 2. If therapy start and/or end dates are missing or partial, the dates will 
be compared as far as possible with the date of first dose of study treatment in Period 2. If there 
is clear evidence to suggest that the therapy stopped prior to the first dose of study treatment in 
Period 2, the therapy will be assumed to be previous only.
The number of patients with the followings will be presented for patients with GPP and EP
separately and total (Analysis population: FAS Population):


I1F-JE-RHCV Statistical Analysis Plan Version 2
Page 17
LY2439821

Previous therapy (captured in the Prior Therapy: Indication eCRF page and Concomitant 
Therapy eCRF page) by WHO ATC Level 4 and WHO drug generic name

Previous psoriasis therapy (captured in the Prior Therapy: Indication eCRF page) by type 
(topical prescription therapy, topical non-prescription therapy, non-biologic systemic 
agent, biologic agent, non-biologic non-systemic agent, phototherapy) and therapy.  The 
previous biologic agent will be further classified as TNF-α inhibitor (including
infliximab, etanercept, adalimumab, golimumab, certolizumab pegol), interleukin (IL) 
12/23 inhibitor (including ustekinumab), IL-17 inhibitor (including secukinumab and 
brodalumab), and other (including efalizumab, alefacept, or other biological agent).

Reason for discontinuation of previous psoriasis therapy (captured in the Prior Therapy: 
Indication eCRF page) by type and therapy.
6.10.2. Concomitant Therapy
Concomitant therapy for Period 2 is defined as the therapy that starts before, on, or after the first 
day of study treatment of Period 2 and before the last visit date of Period 2, and continues into 
Period 2, that is, either no end date (the therapy is ongoing) or an end date on or after the first 
day of study treatment of Period 2.  Concomitant therapy will belong to Period 2 if the therapy 
starts and ends on the exact same day as the first day of study treatment of Period 2.  
Concomitant therapy for Period 3 is defined as the therapy that starts before, on, or after the last 
visit date of Period 2 and continues into Period 3, that is, either no end date (the therapy is 
ongoing) or an end date after the last visit date of Period 2.  Concomitant therapy will belong to 
Period 3 if the therapy starts and ends on the exact same day as the last visit date of Period 2.
If a partial medication start date is present, the following imputation rules will be utilized in the 
analysis: 

If either month or month and day are missing, then use January 1.

If only day is missing, impute the first day of the month.

If there is any doubt, the medication will be flagged as concomitant.
The number of patients with the following will be presented for patients with GPP and EP
separately and total for Period 2 and for Period 3, respectively (Analysis population: FAS 
Population for Period 2, Maintenance Dosing Period Population for Period 3):

Concomitant therapy (captured in the Concomitant Therapy eCRF page) by WHO ATC
Level 4 and WHO drug generic name.  
6.11. Efficacy Analyses
Table RHCV.6.1 includes the description and derivation of the primary and secondary efficacy 
measures.
Summaries of efficacy measures will be provided in patients with GPP and EP separately for 
Period 2 and for Combined Periods 2 and 3, respectively (Analysis population: FAS Population 
for Period 2, Maintenance Dosing Period Population for Combined Periods 2 and 3).


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By-patient listings of each efficacy measure will be provided (Analysis population: FAS 
Population).


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Table RHCV.6.1.
Description and Derivation of Primary and Secondary Efficacy Measures
Measure
Description
Variable
Derivation / Comment
Imputation Approach if 
with Missing 
Components
GIS
Global Improvement Score (GIS): will be 
assessed in the 4 grades by comparing the 
psoriatic findings: (1) resolved, (2) 
improved, (3) unchanged, or (4) worsened. 
The GIS is assessed based on the 
comparison of the psoriatic findings, sPGA, 
PASI score, and other evaluations with 
those at the baseline.
GIS
Range from 1 to 4: resolved (1), improved (2), 
unchanged (3), or worsened (4)
Single item, missing if 
missing
sPGA
Static Physician Global Assessment 
(sPGA): the physician’s global assessment 
of the patient’s psoriasis lesions at a given 
time point (European Medicines Agency 
[EMA] 2004 [WWW]).  Plaques are 
assessed for induration, erythema, and 
scaling, and an overall rating of psoriasis 
severity is given using the anchors of clear 
(0), minimal (1), mild (2), moderate (3), 
severe (4), or very severe (5).  
sPGA score
Range from 0 to 5: clear (0), minimal (1), mild (2), 
moderate (3), severe (4), or very severe (5).  
Single item, missing if 
missing
sPGA (0,1)
An sPGA assessed as either 0 or 1, which 
represents a clinically meaningful response of 
minimal plaque severity or complete resolution of 
psoriasis.  
Missing if sPGA is 
missing
sPGA (0)
An sPGA assessed as 0, which represents a 
clinically important endpoint indicating complete 
resolution of psoriasis.  
Missing if sPGA is 
missing


I 1 F-J E - R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 2 0
L Y 2 4 3 9 8 2 1
Me as ure
Descri pti o n
V ari a ble
Deri v ati o n / C o m me nt
I m p ut ati o n A p pr o ac h if 
wit h Missi n g 
C o m p o ne nts
P A SI
Ps oriasis Area a n d Se verit y I n de x ( P A SI): 
c o m bi nes assess me nts of t he e xte nt of b o d y -
s urface i n v ol ve me nt i n 4 a nat o mical re gi o ns 
( hea d a n d nec k, tr u n k, ar ms, a n d le gs) a n d 
t he se verit y of scali n g ( S), re d ness ( R), a n d 
pla q ue i n d urati o n/i nfiltrati o n (t hic k ness, T) 
i n eac h re gi o n, yiel di n g a n o verall sc ore of 0 
f or n o ps oriasis t o 7 2 f or t he m ost se vere 
disease ( Fre dri kss o n a n d Petterss o n 1 9 7 8) .  
Se verit y  is rate d f or eac h i n de x ( R, S, T) o n 
a 0-4 scale ( 0 f or n o i n v ol ve me nt u p t o 4 f or 
ver y se vere i n v ol ve me nt):
0 = n o ne
1 = s li g ht
2 = m o derate
3 = se vere
4 = ver y se vere
T he b o d y is di vi de d i nt o f o ur a nat o mical 
re gi ons c o m prisi n g t he hea d ( h), u p per 
e xtre mit y ( u), tr u n k (t), a n d l o wer e xtre mit y
(l).  I n eac h of t hese areas, t he fracti o n of 
t otal b o d y s urface area affecte d is gr a de d o n 
a 0-6 scale ( 0 f or n o i n v ol ve me nt; u p t o 6 
f or 9 0 % - 1 0 0 % i n v ol ve me nt):   
0 = 0 % (clear)
1 = > 0 % t o < 1 0 %
2 = 1 0 % t o < 3 0 %
3 = 3 0 % t o < 5 0 %
4 = 5 0 % t o < 7 0 %
5 = 7 0 % t o < 9 0 %
6 = 9 0 % t o 1 0 0 %
P A SI sc ore
T he c o m p osite P A SI sc ore is calc ulate d b y 
m ulti pl yi n g t he s u m of t he i n di vi d ual -se verit y 
sc ores f or eac h area b y t he wei g hte d area-of -
i n v ol ve me nt sc ore f or t hat res pecti ve area, a n d t he n 
s u m mi n g t he f o ur res ulti n g q ua ntities as f oll o ws: 
P A SI = 0. 1( R h + T h + S h) Ah + 0. 2( R u + T u + S u) Au
+ 0. 3( R t + T t + S t) At + 0. 4( R l + T l + S l) Al
W here,
R h, Ru, Rt, Rl = re d ness sc ore of pla q ues o n t he 
hea d, u p per e xtre mit y, tr u n k, a n d l o wer 
e xtre mit y, sc ore d 0-4 res pecti vel y;
T h, Tu, Tt, Tl = t hic k ness sc ore of pla q ues o n t he 
hea d, u p per e xtre mit y, tr u n k, a n d l o wer 
e xtre mit y, sc ore d 0-4 res pecti vel y;
S h, Su, St, Sl = scali ness sc ore of pla q ues o n t he 
hea d, u p per e xtre mit y, tr u n k, a n d l o wer 
e xtre mit y, sc ore d 0-4 res pecti vel y; 
A h, A u, A t, A l = n u merical val ue tra nslati o n of 
% area of ps oriatic i n v ol ve me nt sc ore f or the 
hea d, 
u p per 
e xtre mit y, tr u n k, a n d 
l o wer 
e xtre mit y, res pecti vel y.
P A SI sc ores are treate d as a c o ntin u o us sc ore, wit h 
0. 1 i ncre me nts wit hi n t hese val ues .  
If a n y i n di vi d ual sc ore is 
missi n g, t he P A SI sc ore 
will n ot be calc ulate d, 
h e nce missi n g
P A SI c ha n ge 
fr o m 
baseli ne
Calc ulate d as :  obser ve d P A SI – b aseli ne P A SI
Missi n g if baseli ne or 
o bser ve d val ue is missi n g
P A SI 
p erce nt 
i m pr o ve me nt 
fr o m 
baseli ne
Calc ulate d as :  
If a patie nt has e x perie nce d a n i m pr o ve me nt, t his 
meas ure will be p ositi ve.  If a patie nt has 
e x perie nce d a w orse ni n g i n t he c o n diti o n, t his 
meas ure will be ne gati ve .  
Missi n g if baseli ne or 
o bser ve d val ue is missi n g
                          =
1 0 0 ×          −                  

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Measure
Description
Variable
Derivation / Comment
Imputation Approach if 
with Missing 
Components
The various body regions are weighted to 
reflect their respective proportion of body 
surface area.  
PASI 75
A clinically meaningful response; at least a 75% 
improvement in PASI score from baseline
Missing if baseline or 
observed value is missing
PASI 90
Higher level of clearance; at least a 90% 
improvement in PASI score from baseline
Missing if baseline or 
observed value is missing
PASI 100
Complete resolution of Ps; a 100% improvement in 
PASI score from baseline
Missing if baseline or 
observed value is missing
BSA
Percentage of Body Surface Area (BSA): 
The investigator will evaluate the 
percentage involvement of psoriasis on each 
patient’s BSA on a continuous scale from 
0% (no involvement) to 100% (full 
involvement), in which 1% corresponds to 
the size of the patient’s hand (including the 
palm, fingers, and thumb) (National 
Psoriasis Foundation [NPF] 2009).
BSA
Collected as a single scale as part of Psoriasis Area 
and Severity Index eCRF page.  Range from 0% to 
100%.
Single item, missing if 
missing
BSA change 
from 
baseline
Calculated as:  observed BSA – baseline BSA 
Missing if baseline or 
observed value is missing
PSSI
Psoriasis Scalp Severity Index (PSSI): will 
be used if the patient has scalp psoriasis at 
baseline.  The scalp will be assessed for 
erythema (redness), induration (hardness), 
and desquamation (shedding of skin) and 
percentage of area affected as follows: 
Erythema, Induration and Desquamation:
0 = Absent
1 = Slight
2 = Moderate
3 = Severe
4 = Severest Possible
Percent of Scalp Involved:
0 = none
1 = <10%
2 = 10 – 29%
3 = 30 – 49%
PSSI score
The PSSI score is a composite score derived from 
the sum of the scores for erythema, induration and 
desquamation multiplied by the score for the extent 
of scalp area involved (percent of scalp involved).  
The range is 0 to 72.
If any individual score is 
missing, the PSSI score 
will not be calculated, 
hence missing.
PSSI score 
change from 
baseline
Calculated as: observed PSSI – baseline PSSI
Missing if baseline or 
observed value is missing


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Measure
Description
Variable
Derivation / Comment
Imputation Approach if 
with Missing 
Components
4 = 50 – 69%
5 = 70 – 89%
6 = 90 – 100%
GPP Severity 
Index
Generalized Pustular Psoriasis (GPP)
Severity Index: will be evaluated only for 
patients with pustular Ps at screening and at 
baseline according to the Japanese 
Dermatological Association GPP revised 
criteria (2010) (Iwatsuki et al. 2010 
[WWW]).  This is a composite score 
derived from the sum of scores for 
assessment of dermal symptoms, systemic 
symptoms, and laboratory findings (range, 0 
to 17).
Assessment 
of dermal 
symptoms
total score
Assessment of dermal symptoms will be assessed 
by the score with the area of erythema (on a 0 to 3 
scale), area of confluent pustules (on a 0 to 3 scale), 
and are of skin edema (on a 0 to 3 scale).  The total 
score will be calculated (range, 0 to 9).
If any individual score is 
missing, the total score 
will not be calculated, 
hence missing.
Systemic 
symptoms 
and 
laboratory 
findings total 
score
Systemic symptoms and laboratory findings will be 
assessed by the score with fever (on a 0 to 2 scale), 
WBC (on a 0 to 2 scale), C-reactive protein (on a 0
to 2 scale) and Albumin (on a 0 to 2 scale).  The 
total score will be calculated (range, 0 to 8).
If any individual score is 
missing, the total score 
will not be calculated, 
hence missing.
GPP severity 
index total 
score
GPP severity index total score will be calculated by 
the sum of assessment of dermal symptoms total 
score and systemic symptoms and laboratory 
findings total score (range, 0 to 17).
Missing if assessment of 
dermal symptoms total 
score or systemic 
symptoms and laboratory 
findings total score is 
missing
Assessment 
of dermal 
symptoms
total score 
change from 
baseline
Calculated as: observed total score – baseline total 
score
Missing if baseline or 
observed value is missing
Systemic 
symptoms 
and 
laboratory
findings total 
Calculated as: observed total score – baseline total 
score
Missing if baseline or 
observed value is missing


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Measure
Description
Variable
Derivation / Comment
Imputation Approach if 
with Missing 
Components
score change 
from 
baseline
GPP severity 
index total 
score change 
from 
baseline
Calculated as: observed total score – baseline total 
score
Missing if baseline or 
observed value is missing


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6.11.1. Primary Outcome and Methodology
The primary analysis is to assess the efficacy of ixekizumab 80 mg Q2W beyond Week 12 in 
patients with GPP and EP separately, by presenting the number of patients who decreased their 
GIS by at least 1 point from Week 12 through Week 20 and with ≤2 of GIS at any visit of Week 
14 (Visit 7), Week 16 (Visit 8), Week 18 (Visit 9), Week 20 (Visit 10), or ETV. (Analysis 
population: Maintenance Dosing Period Population).   
6.11.2. Additional Analyses of the Primary Outcome
As an additional analysis of the primary efficacy measure (i.e., GIS), the following endpoint will 
be summarized descriptively at each scheduled visit for Period 2 and for Combined Periods 2 
and 3, respectively (Analysis population: FAS Population for Period 2, Maintenance Dosing 
Period Population for Combined Periods 2 and 3):

Number of patients with each GIS grade (1: Resolved, 2: Improved, 3: Unchanged, 
4: Worsened).
6.11.3. Other Secondary Efficacy Analyses
For other efficacy measures, the following endpoints will be summarized descriptively at each 
scheduled visit for Period 2 and for Combined Periods 2 and 3, respectively (Analysis 
population: FAS Population for Period 2, Maintenance Dosing Period Population for Combined
Periods 2 and 3):

Number of patients who achieve sPGA (0, 1) and sPGA (0)

Number of patients who achieve PASI 75, PASI 90, and PASI 100 from baseline

Change from baseline, and percent improvement from baseline in PASI

Change from baseline in PSSI in patients with scalp involvement at baseline

Change from baseline in percent of BSA involvement of psoriasis.
GPP ONLY

Change from baseline in assessment of dermal symptoms total score

Change from baseline in systemic symptoms and laboratory findings total score

Change from baseline in GPP severity index total score.
6.12. Health Outcomes/Quality-of-Life Analyses
Table RHCV.6.2 includes the description and derivation of the health outcomes measures.
Summaries of health outcomes measures will be provided in patients with GPP and EP
separately for Period 2 and for Combined Periods 2 and 3, respectively (Analysis population: 
FAS Population for Period 2, Maintenance Dosing Period Population for Combined Periods 2 
and 3).
By-patient listings of each health outcome measure will be provided (Analysis population: FAS 
Population).


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Table RHCV.6.2.
Description and Derivation of Health Outcomes Measures
Measure
Description
Variable
Derivation / Comment
Imputation Approach if with 
Missing Components
Itch NRS
Itch Numeric Rating Scale (NRS): is a single-
item, patient-reported outcome (PRO) measure 
designed to capture information on the overall 
severity of a patient’s itching due to their 
psoriatic skin condition by having the patient 
circle the integer that best describes the worst 
level of itching in the past 24 hours on an 11-
point NRS anchored at 0 representing “no 
itching” and 10 representing “worst itch 
imaginable.” (Kimball et al. 2016)  
Itch NRS score
Range from 0 to 10.  
Single item, missing if missing
Itch NRS change 
from baseline
Calculated as:  observed Itch NRS –
baseline Itch NRS
Missing if baseline or observed 
value is missing
Itch NRS ≥4 point 
reduction from 
baseline
Reduced/decreased of ≥4 point from 
baseline
Missing if baseline or observed 
value is missing
DLQI
Dermatology Life Quality Index (DLQI): is a 
validated, dermatology-specific, patient-
reported measure that evaluates patient’s 
health-related QoL.  This questionnaire has 10 
items that are grouped in 6 domains, including
symptoms and feelings, daily activities, 
leisure, work and school, personal 
relationships, and treatment.  The recall period 
of this scale is over the “last week”.  Response 
categories and corresponding scores are:
Very much = 3
A lot = 2
A little = 1
Not at all = 0
Not relevant = 0
(Finlay and Khan 1994; Basra et al. 2008)
DLQI symptoms 
and feelings
domain
Sum of responses of questions #1 and #2:
#1.  How itchy, sore, painful or stinging 
has your skin been?
#2.  How embarrassed or self-conscious 
have you been because of your skin?
If one question in a domain is 
missing, that domain is missing.
DLQI daily 
activities domain
Sum of responses of questions #3 and #4:
#3.  How much has your skin interfered 
with you going shopping or looking after 
your home or yard?
#4.  How much has your skin influenced 
the clothes you wear?
If one question in a domain is 
missing, that domain is missing.
DLQI leisure
domain 
Sum of responses of questions #5 and #6:
#5.  How much has your skin affected 
any social or leisure activities?
#6.  How much has your skin made it 
difficult for you to do any sport?
If one question in a domain is 
missing, that domain is missing.
DLQI work and 
school domain
Sum of responses of questions question 
#7A and #7B:
#7A.  Has your skin prevented you from 
working or studying?
#7B.  If No: how much has your skin 
been a problem at work or studying?
If the answer to question #7A is 
missing, this domain is missing.  
If #7A is No, and #7B is 
missing, this domain is missing.


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Measure
Description
Variable
Derivation / Comment
Imputation Approach if with 
Missing Components
DLQI personal 
relationships
domain
Sum of responses of questions #8 and #9:
#8.  How much has your skin created 
problems with your partner or any of 
your close friends or relatives?
#9.  How much has your skin caused any 
sexual difficulties?
If one question in a domain is 
missing, that domain is missing.
DLQI treatment
Response of question #10:
#10.  How much of a problem has the 
treatment for your skin been, for example 
by making your home messy, or by 
taking up time?
If one question in a domain is 
missing, that domain is missing.
DLQI total score
A DLQI total score is calculated by 
summing all 10 question responses, and 
has a range of 0 to 30 (less to more 
impairment) (Finlay and Khan 1994; 
Basra et al. 2008).  
If two or more questions are 
missing, the total score is 
missing.  Note: #7B could be a 
valid missing while #7A is not 
“No.”  That is, #7 should be 
considered as one question.
DLQI (0,1)
A DLQI (0,1) response is defined as a 
post-baseline DLQI total score of 0 or 1.  
A DLQI total score of 0 to 1 is 
considered as having no effect on a 
patient’s HRQoL (Khilji et al. 2002; 
Hongbo et al. 2005).
Missing if DLQI total score is 
missing
DLQI (0)
A DLQI (0) response is defined as a post-
baseline DLQI total score of 0.
Missing if DLQI total score is 
missing
DLQI total score 
and domain 
scores change 
from baseline
Calculated as: observed DLQI (total 
score or domain scores) – baseline DLQI 
(total score or domain scores)
Missing if baseline or observed 
value is missing


I 1 F-J E - R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 2 7
L Y 2 4 3 9 8 2 1
F or healt h o utc o me s meas ures , t he f o ll owi n g e n d p oi nts will be s u m marize d descri pt i vel y at eac h 
sc he d ule d visit f or Peri o d 2 a n d f or C o m bi ne d Peri o d s 2 a n d 3, res pecti vel y (A nal ysis 
p o p ul at i on: F A S P o p ul at i on f or Perio d 2, Mai nte na nce D osi n g Peri o d P o p ulat i on f or Co m bi ne d
P eri o d s 2 a n d 3):

C ha n ge fr o m baseli ne i n Itc h N R S sc ore

N u m ber of patie nts w h o ac hie ve Itc h N R S ≥4 p oi nt re d ucti o n fr o m baseli ne f or patie nts 
w h o ha d baseli ne Itc h N R S ≥4

C ha n ge fr o m baseli ne i n D L QI t otal sc ore a n d d o mai ns (i.e., s y m pt o ms a n d feeli n gs, 
dail y  a cti vities, leis ure, w or k a n d sc h o ol , pers o nal relat i ons hi ps , a n d treat me nt )

N u m ber of patie nts w h o ac hie ve D L QI ( 0, 1) a n d D L QI ( 0) .
6. 1 3. S af et y A n al y s e s
S af et y will be assesse d b y A Es, la b orat or y  a nal ytes i ncl u di n g ne utr o p hil c o u nts, vital si g ns, 
w ei g ht, a n d C -S S R S.
O verall A Es a n d treat me nt-e mer ge nt a d verse e ve nt s (T E A Es ) will be s u m marize d wi t h 
fre q ue ncies.  T he d urati o n of  d osi n g e x p os ure will als o be s u m marize d.  Ot her safet y meas ures 
will be re vie we d b y  listi n gs.
S u m maries of  o verall A Es a n d T E A Es will be pr o vi de d i n patient s wit h G P P a n d E P se paratel y
a n d t otal f or Peri o d 2 a n d f or C o m bi ne d Peri o ds 2 a n d 3 , res pecti vel y (A nal ysis p o p ul at i on: F A S 
P o p ul at i on f or Perio d 2, Mai nte na nce D osi n g Peri o d P o p ulat i on f or C o m bi ne d Peri o ds 2 a n d 3).
6. 1 3. 1. E xt e nt of E x p o s ur e
E x p os ure t o st u d y  dr u g will be s u m marize d descri pti vel y f or P erio d 2 a n d f or Co m bi ne d P eri o ds 
2 a n d 3 , res pecti vel y (A nal ysis p o p ulat i on: F A S P o p ul at i on f or Perio d 2, Mai nte na nce D osi n g 
P eri o d P o p ul at i on f or C o m bi ne d Peri o ds 2 a n d 3).  
A b y- pat ient  listi n g of e x p os ure d urati o n wit h n u m ber of acti ve i njecti ons a n d t otal  d ose will be 
pr o vi d e d (A nal ysis p o p ulat i on: F A S P o p ulati o n ).  
T he d urati o n of  e x p os ure will be calc ulate d as:
                (    )
=           (  ℎ           ℎ     )              −                          + 1
T he n u m ber of pat ient s i n eac h of t he f oll owi n g cate g ori es will be i ncl u de d i n t he s u m maries:  

> 0, ≥7 da ys, ≥1 4 da y s, ≥3 0 da ys, ≥6 0 da ys, a n d ≥8 4 d a y s (P eri o d 2 ).  N ote t hat patie nts 
ma y be i ncl u de d i n m ore t ha n 1 cate g or y .  

> 0 t o < 7 da y s, ≥7 t o < 1 4 da y s, ≥1 4 t o < 3 0 da ys, ≥3 0 t o < 6 0 da y s, ≥6 0 t o < 8 4 da ys, ≥8 4
da ys ( Peri o d 2)

> 0, ≥7 da ys, ≥1 4 da y s, ≥3 0 da ys, ≥6 0 da ys, ≥9 0 da ys, ≥1 2 0 da ys, a n d ≥1 4 0 da ys
( C o m bi ne d Peri o ds 2 a n d 3) .  N ote t hat patie nts ma y be i ncl u de d i n m ore t ha n 1 cate g or y.  


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
>0 to <7 days, ≥7 to <14 days, ≥14 to <30 days, ≥30 to <60 days, ≥60 to <90 days, ≥90 to 
<120 days, ≥120 to <140 days, and ≥140 days (Combined Periods 2 and 3).
Total dose (in mg) is calculated by the number of active injections taken during the treatment 
period multiplied by a dose of 80 mg.
Total number of injections received will be derived using the response to the question “Was dose 
administered?” on the Exposure as Collected eCRF page and the actual dose description from 
IWRS study drug dispense dataset.
6.13.2. Adverse Events
Adverse events will be classified based upon the latest version of the MedDRA.  Adverse events 
will be recorded at every study visit.  Any condition starting on or after the date of informed 
consent will be considered an AE.  Any preexisting condition which worsens in severity on or 
after the date of informed consent will be considered and recorded as an AE on the Adverse 
Events (AE) eCRF page from the date of worsening onwards.  
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline and on or prior to the date of the last visit within the defined 
treatment period.  Both the date/time of the event and the date/time of the dose (that is, injection) 
are considered when determining TEAEs.  The TEAEs will be assigned to the study period to 
which it’s considered treatment-emergent:

The MedDRA lowest level term (LLT) will be used when classifying AEs as treatment-
emergent.  

The maximum severity recorded for each LLT prior to the first dose date/time in the 
treatment period will be used as the pre-treatment severity for that LLT.  If an event 
during the baseline period has missing severity, and the event persists during the 
treatment period, then it will be considered as treatment-emergent, regardless of the 
postbaseline level of severity.  Adverse events with a missing severity during the 
treatment period will be considered treatment-emergent.  

Adverse events with a particular LLT will be classified as treatment-emergent if they first 
start on or after the first dose date/time in the treatment period (i.e., a patient has no 
preexisting conditions with that LLT), or if the severity is greater than the pre-treatment 
severity for that LLT.  If a partial AE start date/time is present, the date/time will be 
compared as far as possible to the treatment start date/time in order to determine whether 
the event is treatment-emergent or not.  If there is any doubt, the event will be flagged as 
treatment-emergent.  
Overall AEs and TEAEs will be summarized for the following study periods and analysis 
populations:

Period 2 (Analysis population: FAS Population) 

Combined Periods 2 and 3 (Analysis population: Maintenance Dosing Period 
Population).


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The following summaries will be provided for Period 2 and for Combined Periods 2 and 3
(Analysis population: FAS Population for Period 2, Maintenance Dosing Period Population for 
Combined Periods 2 and 3):

An overall summary of AEs including the number of patients who experienced TEAE, 
TEAE by maximum severity, death, SAE, TEAE possibly related to study treatment, 
discontinuation from the treatment due to an AE (including death), and treatment-
emergent adverse events of special interest (AESIs)

TEAE by maximum severity, system organ class (SOC) and preferred term (PT).
In general, events will be ordered by decreasing frequency in the total patient group (i.e., 
combined GPP and EP) within SOC and PT for sorting.
A by-patient listing of all AEs will be provided (Analysis population: FAS Population).  
6.13.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
By-patient listings of deaths, SAEs, and AEs leading to treatment discontinuation will be 
provided (Analysis population: FAS Population).  
All deaths will be included, regardless of the investigator’s or the sponsor’s judgment about 
causality, including:

any deaths occurring during participation in the study in the database for which data are 
being presented 

any deaths occurring after a patient leaves (is discontinued from or completed) the study 
in the database for which data are being presented if the death is the result of a process 
initiated during the study, regardless of when it actually occurred.
An SAE is any AE that results in one of the following outcomes: death, life-threatening, initial or 
prolonged hospitalization, disability or permanent damage, congenital anomaly or birth defect, or 
any other serious/important medical events.
6.13.3.1. Special Safety Topics including Adverse Events of Special Interest
Safety information on special topics including AESIs will be provided.  
Table RHCV.6.3 provides the definitions and derivations of special safety topics including 
AESIs.
Potential AESIs will be identified by a standardized MedDRA query (SMQ) or a Lilly-defined 
MedDRA PT listing.  Preferred terms within an SMQ will be classified as broad and narrow.  In 
the Lilly-defined MedDRA PT listings, Lilly has provided the broad and narrow classification.  
The Lilly-defined broad terms are for a more sensitive search of potential events of interest and 
the Lilly-defined narrow terms are for a more specific search.


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In the event that the listing of terms or analysis changes for a special safety topic, it will be 
documented in the Program Safety Analysis Plan (PSAP) which will supersede this document; it 
will not warrant an amendment to the individual study SAP.
By-patient listings of each special safety topic will be provided (Analysis population: FAS 
Population).


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Table RHCV.6.3.
Definitions and Derivations of Special Safety Topics including Adverse Events of Special Interest
Special Safety 
Topic
Definition / Derivation
Summary / Listing
Hepatic
Hepatic AE will include events that are potentially drug-related hepatic disorders by using the 
MedDRA PTs contained in any of the following SMQ or sub-SMQ as defined in MedDRA:

Broad and narrow terms in the Liver related investigations, signs and symptoms (20000008)

Broad and narrow terms in the Cholestasis and jaundice of hepatic origin (20000009)

Broad and narrow terms in the Hepatitis, non-infectious (20000010) 

Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other liver damage 
(20000013) 

Narrow terms in the Liver-related coagulation and bleeding disturbances (20000015).
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (included in the same listing 
with cytopenia, depression and 
interstitial lung disease AESIs)
Cytopenias
Cytopenias are defined using the PTs from the following 2 sub-SMQs of the Haematopoietic cytopenias 
SMQ (20000027) as specified in MedDRA:  

Broad and narrow terms in the Haematopoietic leukopenia (20000030)

Broad and narrow terms in the Haematopoietic thrombocytopenia (20000031).
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (included in the same listing 
with hepatic, depression and 
interstitial lung disease AESIs)
Infections
Infections are events including all infections (defined using all the MedDRA PTs from the Infections 
and infestations SOC), serious infections, potential opportunistic infections, and infections resulting in
anti-infective medication administration (i.e. antibacterial, antivirals, antifungals, antiparasitic 
treatments).
Listing of patients experiencing a TEAE of infections will include the following additional information: 
types of infection, potential opportunistic infections (OIs) (Yes/No), anti-infective medications use (if 
treated) with medication start/end dates, indication for use, and route; minimum postbaseline value 
within each treatment period for leukocytes, platelets, lymphocytes, and absolute neutrophils.  Anti-
infective medications are defined in Appendix 5 of the PSAP Version 8.  The list of MedDRA terms 
used to identify infections that are predefined as potential OIs are found in Appendix 10 of the PSAP 
Version 8.
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (including information 
collected on Infection eCRF page)
Allergic 
Reactions/Hy-
persensitivities
Allergic reactions/hypersensitivity events will be categorized as either anaphylaxis or non-anaphylaxis 
events (these will refer to events that are not localized to the site of injection) and summarized 
separately.  
Allergic Reactions/Hypersensitivity Events, Anaphylaxis: Anaphylaxis has been broadly defined as “a 
serious allergic reaction that is rapid in onset and may cause death” (Sampson et al. 2006).
Overall summary:

Period 2

Combined Periods 2 and 3


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Special Safety 
Topic
Definition / Derivation
Summary / Listing
Identification of cases of potential anaphylaxis from the clinical trial data involves two criteria:
1)
designed to specifically identify cases (following Criterion 1) based on narrow terms from the 
MedDRA SMQ for anaphylactic reaction (20000021). Criterion 1 for anaphylaxis is defined by the 
presence of a TEAE based on the following MedDRA PTs from the anaphylactic reaction SMQ:

Anaphylactic reaction

Anaphylactic shock

Anaphylactoid reaction

Anaphylactoid shock

Kounis Syndrome

Type 1 hypersensitivity.
2)
to identify possible cases, following Criterion 2 as defined by Sampson et al. (2006). Criterion 2 
for anaphylaxis requires having TEAEs from two or more of four categories of AEs as described 
by Sampson et al. (2006). Occurrence of these events should be nearly coincident based on 
recording of events on the eCRF. All qualifying event must be within 1 day of study drug 
injection.  
The 4 categories to be considered in Criterion 2 are:

Category A:  Involvement of the skin-mucosal tissue

Category B:  Respiratory compromise

Category C:  Reduced blood pressure or associated symptoms

Category D:  Persistent gastrointestinal symptoms.
The specific MedDRA PTs covered by each of these Criterion 2 categories are shown in Appendix 
6 of the PSAP Version 8.
Criterion 2 anaphylactic TEAEs will be defined by the specific combination of categories as follows:

AB:  events based on meeting Category A and Category B (but no other category)

AC:  events based on meeting Category A and Category C (but no other category)

AD:  events based on meeting Category A and Category D (but no other category)

BC:  events based on meeting Category B and Category C (but no other category)

BD:  events based on meeting Category B and Category D (but no other category)

CD:  events based on meeting Category C and Category D (but no other category)

ABC:  events based on meeting Category A, Category B and Category C (but no other 
category)

ABD:  events based on meeting Category A, Category B and Category D (but no other 
category)

ACD:  events based on meeting Category A, Category C and Category D (but no other 


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Special Safety 
Topic
Definition / Derivation
Summary / Listing
category)

BCD:  events based on meeting Category B, Category C and Category D (but no other 
category)

ABCD:  events based on meeting each of the 4 Criterion 2 categories.
Overall summaries of treatment-emergent anaphylactic AEs will be provided for patients who meet 
either criteria.
Allergic Reactions/Hypersensitivity Events, Non-Anaphylaxis: TEAEs of allergic 
reaction/hypersensitivity categorized as non-anaphylaxis events are defined by the narrow terms within 
Hypersensitivity SMQ (20000214) excluding the PTs noted in Appendix 7 of the PSAP Version 8 and 
excluding the anaphylactic events as defined above. 
A by-patient listing will be provided for all patients experiencing TEAE of allergic 
reactions/hypersensitivities at any time, including status/criterion of anaphylaxis or non-anaphylaxis, 
and the associated information collected on Hypersensitivity, Anaphylactic, and Infusion Related 
Reactions eCRF page.
Listing:
TEAE (including information 
collected on Hypersensitivity, 
Anaphylactic, and Infusion Related 
Reactions eCRF page)
Injection Site 
Reactions
Injection site reaction is defined using the PTs from the MedDRA HLT of Injection site reactions as 
specified by MedDRA excluding the following 10 PTs:
1)
Embolia cutis medicamentosa
2)
Injection site joint discomfort
3)
Injection site joint effusion
4)
Injection site joint erythema
5)
Injection site joint infection
6)
Injection site joint inflammation
7)
Injection site joint movement impairment
8)
Injection site joint pain
9)
Injection site joint swelling
10) Injection site joint warmth.
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (including information 
collected on Injection Site Reaction
eCRF page)
Cerebro-
cardiovascular 
Events
Cerebro-cardiovascular events will be externally adjudicated by the Clinical Events Committee (CEC)
made up of a chairman, 2 cardiologists, and a neurologist. The CEC will adjudicate investigator-
reported events selected for adjudication and render an assessment as to whether the event represents a 
confirmed event (meeting the event definition with all necessary documentation), a non-event (does not 
meet the event definition and likely represents an alternative or nonevent diagnosis), or lacks sufficient 
documentation for confirmation of an event. Confirmed cerebro-cardiovascular events by CEC will be 
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE


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Special Safety 
Topic
Definition / Derivation
Summary / Listing
summarized overall. All events which qualify for CEC adjudication will be listed. The categories and 
subcategories of adjudicated events used for the listing will include the following:

Cardiovascular 
o
Death (Cardiovascular)
o
Cardiac Ischemic Event: Myocardial Infarction and Hospitalization for Unstable Angina
o
Serious Arrhythmia 
o
Hospitalization for Heart Failure
o
Hospitalization for Hypertension
o
Resuscitated Sudden Death 
o
Cardiogenic Shock
o
Coronary Revascularization.

Neurologic 
o
Cerebrovascular Event: Transient Ischemic Attack or Stroke (Hemorrhagic, Ischemic and 
Undetermined).

Peripheral Vascular Events
o
Peripheral Arterial Event
o
Peripheral Revascularization.
Listing of patients experiencing a cerebro-cardiovascular TEAE will include the following additional 
information: CEC assessment (confirmed event, no event, or insufficient documentation for event 
determination), categories/subcategories of adjudicated events, subtypes of stroke (Hemorrhagic Stroke, 
Ischemic Stroke, and Undetermined Stroke Type), major adverse cerebro-cardiovascular events
(MACE defined below; Yes/No), and subcategories of MACE (Vascular Death, Non-fatal myocardial 
infarction, and Non-fatal stroke).
Major Adverse 
Cerebro-
Cardiovascular 
Events 
(MACE)
MACE (requiring adjudication as defined above) is defined as:

Vascular Death (including cardiovascular and cerebro-vascular causes excluding hemorrhagic 
deaths outside of the central nervous system)

Non-fatal myocardial infarction 

Non-fatal stroke (subtypes:  hemorrhagic stroke, ischemic stroke, undetermined stroke type).
Where,

Vascular death should be captured as an Event on Adjudication - Death eCRF page with 
Adjudication Death Type = ‘Cardiovascular’.  

Non-fatal myocardial infarction should be captured as an Event on Adjudication - Cardiac 
Ischemic Event eCRF page with Type of Ischemic Event = “Myocardial Infarction” and the Event 
Listing:
TEAE (included in the same listing 
with cerebro-cardiovascular 
events)


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Special Safety 
Topic
Definition / Derivation
Summary / Listing
is NOT on Adjudication - Death eCRF page. 

Non-fatal strokes (ischemic, hemorrhagic) should be captured as an Event on Adjudication -
Cerebrovascular Event eCRF page with Stroke Cerebrovascular Event Subtype in one of the 
following categories:  hemorrhagic stroke, ischemic stroke, undetermined stroke type, and the 
Event is NOT on Adjudication - Death eCRF page.
Malignancies
Malignancy is defined using PTs from the Malignant or unspecified tumors SMQ as specified in 
MedDRA (SMQ: 20000091, which includes the sub-SMQs:  

20000194 [Malignant tumours], including sub-SMQs of 20000227 [Haematological malignant 
tumours] and 20000228 [Non-haematological malignant tumours]

20000195 [Tumours of unspecified malignancy], including sub-SMQs of 20000229 
[Haematological tumours of unspecified malignancy] and 20000230 [Non-haematological tumours 
of unspecified malignancy].
Events will be categorized as follows:

Nonmelanoma Skin Cancer (NMSC)
o
Basal Cell Carcinoma, PTs include: 

Basal cell carcinoma 

Basosquamous carcinoma

Basosquamous carcinoma of skin.
o
Squamous Cell Carcinoma, PTs include:

Squamous cell carcinoma of skin

Bowen’s disease

Lip squamous cell carcinoma

Skin squamous cell carcinoma metastatic

Keratoacanthoma.

Malignancies excluding NMSC: all PTs in the Malignant or unspecified tumors SMQ excluding 
the 8 defined NMSC PTs.
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE
Depressions
Depression is defined using the PTs from the Depression and suicide/self-injury SMQ as specified in 
MedDRA (SMQ: 20000035, which includes the sub-SMQs: 20000037 [Suicide/self-injury] and 
20000167 [Depression (excl suicide and self-injury)]).
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (included in the same listing 
with hepatic, cytopenia and 


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Special Safety 
Topic
Definition / Derivation
Summary / Listing
interstitial lung disease AESIs)
Inflammatory 
Bowel Disease 
(IBD)
IBD will be identified using the following subcategory and MedDRA PTs. The narrow terms are 
considered IBD and summarized overall.  IBD events will also be externally adjudicated by the CEC 
with expertise in IBD.
IBD (Narrow terms)

Inflammatory Bowel Disease: Inflammatory bowel disease

Crohn’s Disease: Crohn’s disease

Ulcerative Colitis: Acute haemorrhagic ulcerative colitis; Colitis ulcerative; Proctitis ulcerative.
Non-Specific Terms (Events That Can Occur with IBD (Broad Terms)): The PTs in this category are 
listed in Appendix 11 of the PSAP Version 8.
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (including adjudicated 
results)
Interstitial 
Lung Disease 
(ILD)
ILD is defined using the following terms:  

Broad and narrow terms in the Interstitial lung disease SMQ (20000042)

Additional 6 PTs from Eosinophilic pneumonia SMQ (20000157):  
o
Angiolymphoid hyperplasia with eosinophilia (Narrow)
o
Eosinophilic bronchitis (Narrow)
o
Hypereosinophilic syndrome (Narrow)
o
Loeffler’s syndrome (Narrow)
o
Pulmonary eosinophilia (Narrow)
o
Pulmonary vasculitis (Narrow).
Overall summary:

Period 2

Combined Periods 2 and 3
Listing:
TEAE (included in the same listing 
with hepatic, cytopenia and 
depression AESIs)
Abbreviations:  AE = adverse event; AESI = adverse event of special interest; eCRF = electronic case report form; HLT = high-level term; OI =opportunistic 
infection; PT = preferred term; SAE = serious adverse event; TEAE = treatment emergent adverse event.


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6.13.4. Clinical Laboratory Evaluation
Clinical laboratory assessments include hematology, serum chemistry, urinalysis, and safety-
related immune markers.
By-patient listings of all laboratory test values, and abnormal laboratory test results (criteria 
defined below) for parameters of special interest (hepatic, leukocytes and platelets) will be 
provided (Analysis population: FAS Population).  Both international system of unit (SI) and 
conventional unit will be listed when the SI and the conventional units are different.
6.13.4.1. Hepatic Tests
Categories in abnormal hepatic laboratory test results (including scheduled visits, unscheduled 
visits, and repeat measurements) using Performing Lab Reference Ranges are defined as:

Abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST): >1×upper 
limit of normal (ULN) to <3× ULN, ≥3× ULN to <5× ULN, ≥5× ULN to <10× ULN, ≥10× 
ULN to <20× ULN, and ≥20× ULN

Total bilirubin: >1× ULN to <1.5× ULN, ≥1.5× ULN to <2× ULN, and ≥2× ULN.

Alkaline phosphatase (ALP): >1× ULN to <1.5× ULN, and ≥1.5× ULN.
In addition, a by-patient listing of patients who meet any of the following criteria will be 
provided (Analysis population: FAS Population):

Elevated hepatic criteria: defined as maximum ALT ≥3× ULN and maximum total bilirubin 
≥2× ULN within the same study period

An ALT or AST ≥3× ULN

A total bilirubin ≥2× ULN

An ALP ≥1.5× ULN
The listing will include the following information: patient demographics, concomitant 
medications, ALT/AST/total bilirubin/ALP/ GGT by visit, treatment start and stop dates, and 
reason for treatment discontinuation.
6.13.4.2. Leukocytes (WBC) and Platelets
Categories in abnormal leukocytes (total leukocytes, neutrophils, and lymphocytes) and platelets 
laboratory test results (including scheduled visits, unscheduled visits, and repeat measurements) 
are defined as:

Leukocytes (total leukocytes): < lower limit of normal (LLN) to ≥3.0× 10^9/L (Grade 1), 
<3.0× 10^9/L to ≥2.0× 10^9/L (Grade 2), <2.0× 10^9/L to ≥1.0× 10^9/L (Grade 3), and 
<1.0× 10^9/L (Grade 4).

Neutrophils (absolute neutrophils): < LLN to ≥1.5× 10^9/L (Grade 1), <1.5× 10^9/L to 
≥1.0× 10^9/L (Grade 2), <1.0× 10^9/L to ≥0.5× 10^9/L (Grade 3), and <0.5× 10^9/L (Grade 


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4). Absolute neutrophils will be derived by adding segmented neutrophils and band 
neutrophils.

Lymphocytes: < LLN to ≥0.8× 10^9/L (Grade 1), <0.8× 10^9/L to ≥0.5× 10^9/L (Grade 2), 
<0.5× 10^9/L to ≥0.2× 10^9/L (Grade 3), and <0.2× 10^9/L (Grade 4)

Platelets: < LLN to ≥75.0 × 10^9/L (Grade 1), <75.0 × 10^9/L to ≥50.0 × 10^9/L (Grade 2), 
<50.0 × 10^9/L to ≥25.0 × 10^9/L (Grade 3), and <25.0 × 10^9/L (Grade 4).
The above LLNs are defined as:

Leukocytes: LLN = 4.0× 10^9/L

Neutrophils: LLN = 2.0× 10^9/L

Lymphocytes: LLN = 1.1× 10^9/L

Platelets: LLN = 150× 10^9/L
6.13.5. Vital Signs and Other Physical Findings
Vital signs and physical characteristics include systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), pulse (bpm), weight (kg), BMI (kg/m2), and body temperature (°C).
A by-patient listing of vital signs and physical characteristics (including scheduled visits, 
unscheduled visits, and repeat measurements) will be provided (Analysis population: FAS 
Population).
6.13.6. Electrocardiograms
As a 12-lead electrocardiogram (ECG) will be locally performed only at screening visit (Visit 1),
no ECG data analysis is planned in this study.
6.13.7. Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior.  Information on 
the C-SSRS scale can be found through the following link:  http://www.cssrs.columbia.edu.  
Specifically, the following outcomes are C-SSRS categories and have binary responses (yes/no).  
The categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the results.  
Category 1 – Wish to be Dead
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt


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Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide.
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-
related) and has a binary response (yes/no).  
Composite endpoints based on the above categories are defined below.

Suicidal ideation:  A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.

Suicidal behavior:  A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.

Suicidal ideation or behavior:  A “yes” answer at any time during treatment to any one 
of the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS.  
By-patient listings of C-SSRS and Self-Harm supplement and follow-up data will be provided 
(Analysis population: FAS Population).  Given that few or no suicidal ideation or behaviors are 
anticipated, C-SSRS will be listed by patient and visit.  Only patients that show suicidal 
ideation/behavior or self-injurious behavior without suicidal intent will be displayed (that is, if a 
patient’s answers are all ‘no’ for the C-SSRS, then that patient will not be displayed).  However, 
if a patient reported any suicidal ideation/ behavior or self-injurious behavior without suicidal 
intent at any time point then all their ideation and behavior will be displayed, even if not 
positive.  Note, missing data should not been imputed.  
The Self-Harm Supplement Form in the eCRF is a one-question form that is completed, at any 
visit, including baseline visit, that asks for the number of suicidal behaviors, possible suicidal 
behaviors or nonsuicidal self-injurious behaviors the patient has experienced since the last 
assessment.  For each unique event identified, a questionnaire (Self-Harm Follow-Up Form in 
the eCRF) which collects supplemental information on the self-injurious behavior is to be 
completed.  The Self-Harm data will be listed by patient and visit if number of events on Self-
Harm Supplement Form is not zero.
6.14. Immunogenicity
6.14.1. Definitions and Terms
The following sample- and patient-related definitions and parameters will be used to describe the 
immunogenicity data.  
6.14.1.1. Sample Category Definitions
Samples are classified into the following categories:

Unevaluable sample: Sample could not be tested for anti-drug antibody (ADA) due 
to sample loss, mishandling, or errors in collection, processing, storage, etc.  


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
Antidrug antibody (ADA) Positive sample: The presences of ADA is detected and 
confirmed.  The samples are reported as positive.  If the sample is positive, a titer 
value is reported.

Neutralizing anti-drug antibody (NAb) Positive sample: NAb are reported as 
detected.

ADA Negative sample: The presence of ADA is not detected and the assay drug 
tolerance level is not exceeded.

NAb Negative sample: The presence of NAb is not detected and the assay drug 
tolerance level is not exceeded.

Inconclusive sample: when ADA/NAb is not detected in a sample but drug is present 
in the same sample at a level that can cause interference in the ADA/NAb detection 
method, then the negative ADA/NAb result cannot be confirmed and the sample 
should be considered inconclusive.
o
Using the psoriasis disease-specific cut point, the upper limit of drug tolerance 
in the ADA assay is 480.5 µg/mL and the upper limit of drug tolerance in the 
NAb assay is 1100 ng/mL.  Confirmation of a negative ADA result is based 
on measured ixekizumab levels.  Ixekizumab concentration below the 
determined drug tolerance of the ADA/NAb assays allow for confirmation of 
negative ADA/NAb results.
Figure RHCV.6.1 illustrates the relationship of some of the above terms.


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Abbreviation:  ADA = anti-drug antibody.  
Figure RHCV.6.1.
Sample definitions.
6.14.1.2. Patient Category Definitions
The following categories are applied to patients based on the classification of their samples:

Unevaluable patient: a) a patient with no evaluable baseline sample and/or no 
evaluable post-baseline samples; b) a patient with an evaluable baseline sample 
but no evaluable post-baseline sample; c) a patient with no evaluable baseline 
sample, but whose evaluable post-baseline values are all ADA positive or a mix 
of positive and negative.  (Note: If all post-baseline samples are negative, the 
patient is considered ‘evaluable’ and will be classified as ADA-negative.)

Evaluable patient: a) Patient with an evaluable baseline sample and at least 1 
evaluable post-baseline sample (that is, sample after administration of study 
drug); b) patient with no evaluable baseline sample whose evaluable post-baseline
samples are all ADA negative.
Figure RHCV.6.2 illustrates the relationship of the above terms.


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Abbreviation:  ADA = anti-drug antibody.  
Figure RHCV.6.2.
Patient categories (evaluable/unevaluable) based on sample status 
at baseline and post-baseline.
6.14.1.3. Definitions for Clinical Interpretation of Assay Results

Baseline: For immunogenicity summaries, baseline is the last nonmissing 
observation on, or prior to, the date of the first injection of study treatment of 
ixekizumab (Week 0).  

Baseline ADA positive (preexisting antibody): ADA detected in a sample 
collected at baseline.

TE-ADA positive: a) a patient with a 4-fold (or 2 dilutions) increase over a 
positive baseline antibody titer; or b) for a negative baseline titer, a patient with 
an increase from the baseline to a level of 1:10.

Baseline ADA-negative: ADA is not detected in a sample collected at baseline.

TE-ADA inconclusive patient: A patient without a TE-ADA positive sample and 
with at least 1 sample for which drug levels may interfere with the ADA assay.  

TE-ADA negative patient: A patient who is evaluable for TE-ADA and is not 
either TE-ADA positive or TE-ADA inconclusive.  
Figure RHCV.6.3 illustrates the relationship of some of these terms.


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Abbreviation:  ADA = anti-drug antibody.  
Figure RHCV.6.3.
Relationship of terms for clinical interpretation of assay results for 
evaluable patients.
All ADA positive samples will be evaluated for NAb.  Definitions for NAb patient status will be 
defined as follows:

NAb-positive patient: A patient where a NAb positive result is detected for 
≥1 TE-ADA positive samples.

NAb-inconclusive patient: A patient without a NAb positive sample and with at 
least 1 sample for which drug levels may interfere with the NAb assay.  

NAb-negative patient: A patient who is evaluable for NAb and is not either NAb 
positive sample or NAb inconclusive.
A flow chart that reflects the connection between the analytical test results and the clinical 
interpretation based on the definitions is shown in Figure RHCV.6.4.  


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Abbreviation:  ADA = anti-drug antibody.  
Figure RHCV.6.4.
Flow chart of ADA assessment with clinical interpretation of the 
various result possibilities.
6.14.2. Immunogenicity Analyses
Immunogenicity evaluable patients will be grouped into TE-ADA status groups as follows:
TE-ADA Status Groups:

TE-ADA status (positive, negative, or inconclusive);

NAb status (positive, negative, or inconclusive) for TE-ADA positive patients; and

TE-ADA titer groups for TE-ADA positive patients:


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o
Low Titer: TE-ADA titer value (LOCF) <1:160;
o
Moderate Titer: TE-ADA titer value (LOCF) ≥1:160 and <1:1280; and 
o
High Titer: TE-ADA titer value (LOCF) ≥1:1280.  
6.14.2.1. Analyses of Characteristics of ADA Immune Response 
Overall ADA effects will be summarized on all evaluable patients within the following study 
periods and analysis populations:

Period 2 (Analysis population: FAS Population) 

Combined Periods 2 and 3 (Analysis population: Maintenance Dosing Period 
Population).
The overall frequency of patients will be summarized for the TE-ADA status groups.  Scheduled 
visits, unscheduled visits, and repeat measurements will be included.
A by-patient listing to include visit, sample date, injection date, ADA result, ADA titer value, 
TE-ADA result, NAb result, ixekizumab concentration, and GIS result will be provided
(Analysis population: FAS Population).
6.15. Subgroup Analyses
No subgroup analyses are planned for this study because of very small sample size.
6.16. Protocol Deviations
Protocol deviations will be identified throughout the study.  Important protocol deviations are 
defined as those violations from the protocol likely to have a significant impact on the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a 
subject’s rights, safety, or well-being.  
Important protocol deviations are identified in the TIMP.  Rerfer to the latest version of TIMP.  
The number of patients having important protocol deviations will be summarized within category 
and subcategory of deviations for Combined Periods 2 and 3 in patients with GPP and EP
separately and total (Analysis population: FAS Population).
A by-patient listing of important protocol deviations will be provided (Analysis population: FAS 
Population).
6.17. Interim Analyses and Data Monitoring
No interim analyses are planned for this study.
6.18. Annual Report Analyses
Summary table of treatment-emergent adverse events related to study treatment will be presented 
for Periodic Safety Report (PSR).  A by-patient listing will also be provided for re-examination.


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6.19. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by MedDRA 
preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients in every treatment group may not be included if a 5% threshold is 
chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.


I 1 F-J E -R H C V St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 4 7
L Y 2 4 3 9 8 2 1
7.
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2 0 0 8; 1 5 9( 5): 9 9 7 -1 0 3 5.
C ol u m bia U ni versit y Me dical Ce nter. C ol u m bia – S ui ci de Se verit y Rati n g Scale ( C-S S R S) we b 
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Leo Document ID = 9a3f3af5-4404-4c92-bfde-4bb6ff386273
Approver: 
Approval Date & Time: 12-Aug-2020 01:07:22 GMT
Signature meaning: Approved
PPD