Clinical trial NCT02993471
Conditions: Psoriasis
Sponsor: Eli Lilly and Company
Start date: 2016-12-22; Completion date: 2017-11-21
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is known as a "drug interaction study." The purpose is to learn about how ixekizumab may affect the blood levels of a mixture of commonly used drugs (caffeine, omeprazole, warfarin, dextromethorphan, and midazolam) that are metabolized by cytochrome P450. Each participant will complete two study periods. Participants will take the mixture of commonly used drugs (plus vitamin K) by mouth on 3 occasions (prior to treatment with ixekizumab and after 1 and 12 weeks of treatment with ixekizumab). The study will last about 17 weeks, including follow-up. Screening must be completed prior to study start.

Detailed description:

Arms: arm 1: Drug cocktail (caffeine, warfarin \[plus vitamin K\], omeprazole, dextromethorphan, and midazolam) administered orally once in Period 1 (day 1). arm 2: Drug cocktail (caffeine, warfarin \[plus vitamin K\], omeprazole, dextromethorphan, and midazolam) administered orally twice in Period 2 (day 8 and day 85). Ixekizumab administered subcutaneously (SC) on multiple occasions in Period 2.
Interventions: intervention 1: Drug Cocktail intervention 2: Ixekizumab
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
Protocol I1F-MC-RHBU(a) 
 
 
Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of Cytochrome P450 Substrates 
in Patients with Moderate-to-Severe Plaque Psoriasis 
 
 
NCT02993471 
 
 
Approval Date: 08-Dec-2016 


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 1
Ixekizumab (LY2439821)
Protocol I1F-MC-RHBU(a)
Evaluation of the Effect of Ixekizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in 
Patients with Moderate-to-Severe Plaque Psoriasis
Confidential Information
The information contained in this protocol 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 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 and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 25 August 2016
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 08-Dec-2016 GMT


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 2
Ixekizumab (LY2439821)
Table of Contents
Evaluation of the Effect of Ixekizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in 
Patients with Moderate-to-Severe Plaque Psoriasis
Section
Page
Protocol I1F-MC-RHBU(a) Evaluation of the Effect of Ixekizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in Patients with 
Moderate-to-Severe Plaque Psoriasis...................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................19
3.1.
Study Rationale............................................................................................................19
3.2.
Background..................................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................25
5.3.
End of Study Definition ...............................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................28
6.3.
Lifestyle and/or Dietary Requirements .........................................................................33
6.3.1.
Meals and Dietary Restrictions.............................................................................33
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................33
6.3.3.
Activity................................................................................................................33
6.4.
Screen Failures.............................................................................................................33
7.
Treatment..........................................................................................................................35
7.1.
Treatment Administered...............................................................................................35
7.1.1.
Packaging and Labeling .......................................................................................36
7.2.
Method of Treatment Assignment ................................................................................36
7.2.1.
Selection and Timing of Doses.............................................................................36
7.3.
Blinding .......................................................................................................................37


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
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Ixekizumab (LY2439821)
7.4.
Dose Modification........................................................................................................37
7.5.
Preparation/Handling/Storage/Accountability...............................................................37
7.6.
Treatment Compliance .................................................................................................37
7.7.
Concomitant Therapy...................................................................................................37
7.8.
Treatment after the End of the Study............................................................................38
8.
Discontinuation Criteria ....................................................................................................39
8.1.
Discontinuation from Study Treatment.........................................................................39
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................40
8.2.
Discontinuation from the Study....................................................................................40
8.3.
Patients Lost to Follow-up............................................................................................41
9.
Study Assessments and Procedures ...................................................................................42
9.1.
Efficacy Assessments...................................................................................................42
9.2.
Adverse Events ............................................................................................................42
9.2.1.
Serious Adverse Events........................................................................................43
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................44
9.2.2.
Complaint Handling.............................................................................................44
9.3.
Treatment of Overdose.................................................................................................44
9.4.
Safety...........................................................................................................................44
9.4.1.
Laboratory Tests ..................................................................................................44
9.4.2.
Vital Signs ...........................................................................................................44
9.4.3.
Electrocardiograms ..............................................................................................45
9.4.4.
Quick Inventory of Depressive Symptomatology-Self Report 
(16-Items) ............................................................................................................45
9.4.5.
Columbia-Suicide Severity Scale .........................................................................46
9.4.6.
Safety Monitoring ................................................................................................46
9.4.7.
Inflammatory Bowel Diseases Assessments .........................................................47
9.4.8.
Immunogenicity Assessments ..............................................................................47
9.5.
Pharmacokinetics .........................................................................................................47
9.5.1.
Bioanalysis...........................................................................................................48
9.6.
Pharmacodynamics ......................................................................................................48
9.7.
Genetics .......................................................................................................................48
9.8.
Biomarkers...................................................................................................................49
9.9.
Health Economics ........................................................................................................49
10.
Statistical Considerations and Data Analysis.....................................................................50
10.1. Sample Size Determination ..........................................................................................50
10.2. Populations for Analyses..............................................................................................51
10.2.1.
Study Participant Disposition ...............................................................................51
10.2.2.
Study Participant Characteristics ..........................................................................51


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 4
Ixekizumab (LY2439821)
10.3. Statistical Analyses ......................................................................................................51
10.3.1.
Pharmacokinetic Analyses....................................................................................51
10.3.1.1.
Pharmacokinetic Parameter Estimation...........................................................51
10.3.1.2.
Pharmacokinetic Statistical Inference .............................................................52
10.3.2.
Immunogenicity Analyses....................................................................................52
10.3.3.
Exploratory Analyses...........................................................................................52
10.3.4.
Safety Analyses....................................................................................................53
10.3.4.1.
Clinical Evaluation of Safety..........................................................................53
10.3.4.2.
Statistical Evaluation of Safety.......................................................................53
10.3.5.
Interim Analyses..................................................................................................53
11.
References ........................................................................................................................54


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 5
Ixekizumab (LY2439821)
List of Tables
Table
Page
Table RHBU.1.
Objectives and Endpoints .......................................................................21


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 6
Ixekizumab (LY2439821)
List of Figures
Figure
Page
Figure RHBU.1.
Illustration of study design for I1F-MC-RHBU.......................................24


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 7
Ixekizumab (LY2439821)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................56
Appendix 2.
Clinical Laboratory Tests........................................................................60
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................62
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............65
Appendix 5.
Blood Sampling Summary......................................................................66
Appendix 6.
Protocol Amendment I1F-MC-RHBU(a) Summary 
Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of 
Cytochrome P450 Substrates in Patients with Moderate-to-Severe 
Plaque Psoriasis......................................................................................67


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 8
Ixekizumab (LY2439821)
1. Protocol Synopsis
Title of Study:  
Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of Cytochrome P450 Substrates in Patients with 
Moderate-to-Severe Plaque Psoriasis
Rationale:  
Psoriasis is a chronic inflammatory skin disease in which elevated levels of proinflammatory cytokines are 
observed.  Elevated proinflammatory cytokines can lead to disease-drug interactions by reducing the expression and 
activity of some cytochrome P450 (CYP) enzymes, thereby theoretically altering the systemic exposure of CYP 
substrates.  Thus, treatment of psoriasis with biological products that reduce inflammation could theoretically reduce 
elevations in cytokines and in turn affect CYP activity.  It is currently unknown if treatment with a biologic agent 
affecting the interleukin (IL)-17 pathway has the potential to influence CYP activity as has been seen with anti-IL-6 
or anti-Tumor Necrosis Factor agents.
In vitro assays demonstrated that IL-17 inhibition by ixekizumab had little or no influence on mRNA CYP 
expression; however, while the use of in vitro assays to predict risk of clinical drug-drug interactions (DDI) is well 
established for small molecule chemical entities, the utility of in vitro assays to predict clinical DDI with biologic 
agents has been inconsistent and thus not yet routinely accepted by global regulatory agencies in lieu of clinical 
studies for biologic agents that may affect cytokines.  This study therefore seeks to evaluate the effect of single and 
multiple doses of ixekizumab on the single–dose pharmacokinetics (PK) of CYP3A, CYP2C9, CYP2D6, CYP2C19, 
and CYP1A2 substrates midazolam, warfarin, dextromethorphan, omeprazole, and caffeine, respectively, in patients 
with moderate-to-severe psoriasis.  
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To assess the effects of single and multiple doses of 
ixekizumab on the PK of a drug cocktail of CYP 
substrates in patients with moderate-to-severe 
psoriasis.
Ratio of geometric least squares means between each 
CYP substrate administered alone and in combination 
with ixekizumab for maximum observed drug 
concentration (Cmax) and area under the concentration 
versus time curve from zero to infinity (AUC[0-∞]) of 
parent drug.
Secondary
To evaluate the tolerability of ixekizumab in patients 
with moderate-to-severe psoriasis.
Incidence of treatment-emergent adverse events 
(TEAEs).  


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 9
Ixekizumab (LY2439821)
Summary of Study Design:  
This is a 2-period, fixed-sequence, open-label, multi-center, Phase 1 study to assess the effects of single and multiple 
doses of ixekizumab on the PK of a drug cocktail of CYP substrates (midazolam, warfarin, dextromethorphan, 
omeprazole, and caffeine) in patients with moderate-to-severe psoriasis.  
Patients will be admitted to the clinical research unit (CRU) on Day -1 of Period 1 and receive the drug cocktail on 
the morning of Day 1.  Patients will reside at the CRU until Day 2 and may be discharged from the CRU following 
collection of the 24 hour PK samples, at the discretion of the investigator.  Patients will return to the CRU as 
outpatients for collection of PK samples and safety assessments, as applicable, on Day 3 (48 hours post-drug 
cocktail dose), Day 4 (72 hours post-drug cocktail dose), and Day 5 (96 hours post-drug cocktail dose).
Patients will attend the CRU as outpatients on Day 1 of Period 2 (3 to 7 days after Day 5 of Period 1) and receive a 
160-mg dose of ixekizumab (administered as two 80-mg subcutaneous [SC] injections).
Patients will be admitted to the CRU on Day 7 (±2 days) of Period 2 and receive the drug cocktail on the following 
morning (Day 8; Week 1).  Patients will reside at the CRU until Day 9 and may be discharged from the CRU 
following collection of the 24 hour PK samples, at the discretion of the investigator.  Patients will return to the CRU 
as outpatients for collection of PK samples and safety assessments, as applicable, on Day 10 (48 hours post-drug 
cocktail dose), Day 11 (72 hours post-drug cocktail dose), and Day 12 (96 hours post-drug cocktail dose).
Patients will receive single 80-mg doses of ixekizumab on Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), 
Day 57 (Week 8), and Day 71 (Week 10) of Period 2.  Patients will be admitted to the CRU on Day 84 (±2 days) 
and receive 80 mg ixekizumab and the drug cocktail on the following morning (Day 85; Week 12).  Patients will 
reside at the CRU until Day 86 and may be discharged from the CRU following collection of the 24 hour PK 
samples, at the discretion of the investigator.  Patients will return to the CRU as outpatients for collection of 
additional drug cocktail PK samples and safety assessments, as applicable, on Day 87 (48 hours post-drug cocktail 
dose), Day 88 (72 hours post-drug cocktail dose), and Day 89 (96 hours post-drug cocktail dose).  Patients will 
attend a follow-up visit on Day 113 (±4 days; Week 16).  
Safety will be monitored throughout the study by recording of adverse events (AEs), clinical laboratory parameters, 
vital signs, physical examination, Quick Inventory of Depressive Symptomatology-Self Report (16 items)
(QIDS-SR16), Columbia-Suicide Severity Rating Scale (C-SSRS) and Lilly Self-Harm Supplement responses, and 
electrocardiograms (ECGs).  
Treatment Arms and Duration:  
In Period 1, patients will receive a single oral dose of drug cocktail (with single oral doses of 1 mg midazolam, 
10 mg warfarin [+ 10 mg vitamin K], 30 mg dextromethorphan, 20 mg omeprazole, and 100 mg caffeine) on Day 1
and PK sampling will be conducted up to 96 hours post-drug cocktail dose (Day 5).
In Period 2, patients will receive a 160-mg SC dose of ixekizumab (administered as 2 x 80-mg SC injections) on 
Day 1, followed by 80-mg SC doses every 2 weeks from Day 15 (Week 2) through Day 85 (Week 12).  On Day 8 
and Day 85, patients will receive a single oral dose of drug cocktail and PK sampling will be conducted up to 
96 hours post-drug cocktail dose (Days 12 and 89).  
Patients will attend a follow-up visit at Week 16.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 10
Ixekizumab (LY2439821)
Number of Patients:  
Approximately 30 patients will be enrolled with the assumption that 21 patients complete the study.  
Statistical Analysis:
Pharmacokinetic parameter estimates for midazolam and 1-hydroxymidazolam, S-warfarin, dextromethorphan and 
dextrorphan, omeprazole and 5-hydroxyomeprazole, and caffeine and paraxanthine will be calculated by standard 
noncompartmental methods of analysis.
Pharmacokinetic parameter estimates will be evaluated to delineate the effects of drug interaction.  Midazolam, 
warfarin, dextromethorphan, omeprazole, and caffeine administered in the absence of ixekizumab will represent the 
reference treatments and will be analyzed separately. Each drug administered with ixekizumab will represent the 
test treatments and will be analyzed separately. Data for each drug will also be analyzed separately after single or 
multiple doses of ixekizumab.  For the primary analysis, log-transformed Cmax and AUC(0-∞) estimates will be 
evaluated in a linear mixed-effects analysis of variance model with a fixed effect for treatment and a random effect 
for patient.  The treatment differences will be back-transformed to present ratios of geometric least squares means 
and the corresponding 90% confidence intervals (CIs).  
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and C-SSRS scores.  
The parameters will be listed, and summarized using standard descriptive statistics.  


I1F-MC-RHBU(a) Clinical Pharmacology Protocol 
Page 11
Ixekizumab (LY2439821)
2. Schedule of Activities


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 12
Ixekizumab (LY2439821)
Study Schedule Protocol I1F-MC-RHBU – Period 1
Screening
Baseline
Procedure
D -29 to -2
D -1
D 1
D 2
D 3
D 4
D 5
Informed Consent
X
Medical History
X
Review of AEs
X
Review Concomitant 
Medications
X
TB Testa
X
Chest X-ray
Xf
Height
X
Weight
X
X
Patient Admission to CRU
X
Patient Discharge from CRU
Xg
Outpatient Visit
X
X
X
X
Urine Drug Screen
X
X
Ethanol Breath Test
X
X
Vital Signs (Supine and 
Standing Blood Pressure and 
Pulse Rate and Body 
Temperature)
X
X
X
Clinical Laboratory Testsb
X
X
X
X
Pregnancy Testc
X
X
Physical Examination/ Medical 
Assessmentd
X
X
X
12-Lead ECG
X
X
X
QIDS-SR16
X
C-SSRS and Self-Harm 
Supplement
X
X
X
PASI
X
X
sPGA
X
X
% BSA Assessment
X
X
Drug Cocktail Administration
X


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 13
Ixekizumab (LY2439821)
Screening
Baseline
Procedure
D -29 to -2
D -1
D 1
D 2
D 3
D 4
D 5
Midazolam and 
1-hydroxymidazolam PK 
Samplee
Predose, 0.5, 1, 2, 3, 4, 6, 
8, 12 h
24 h
Warfarin PK Samplee
Predose, 1, 2, 4, 6, 8, 
10 h
24 h
48 h
72 h
96 h
Dextromethorphan and 
Dextrorphan PK Samplee
Predose, 1, 2, 4, 6, 8, 
10 h
24 h
48 h
72 h
Omeprazole and 
5-hydroxyomeprazole PK 
Samplee
Predose, 0.5, 1, 2, 3, 4, 6, 
8, 12 h
24 h
48 h
Caffeine and Paraxanthine PK 
Samplee
Predose, 0.5, 1, 2, 3, 4, 6, 
8, 12 h
24 h
48 h
Pharmacogenetic Sample
X
Abbreviations:  AE = adverse event; BSA = body surface area; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; 
ECG = electrocardiogram; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; PPD = purified protein derivative; QIDS-SR16 = Quick Inventory 
of Depressive Symptomatology-Self Report (16 items); sPGA = static Physicians Global Assessment; TB = tuberculosis; W = Week.  
a
TB test(s) include PPD, QuantiFERON®-TB Gold, and T-SPOT®.
b
Screening samples tested at a local laboratory, all other clinical laboratory test samples tested at a central laboratory.  Additional samples for coagulation 
parameters (Appendix 2) may be collected and tested at a local laboratory at the discretion of the investigator.  
c
Females only.  Serum pregnancy test to be performed at screening.  Serum or urine pregnancy test may be performed locally at all other times, at the 
discretion of the investigator.
d
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be performed at screening.  All medical assessments throughout 
the study should include a symptom directed physical as well as examination of heart, lungs, abdomen, and visual examination of the skin.
e
Sample times are relative to administration of the drug cocktail. The PK sample collection times are nominal; actual times should be recorded.  Separate 
blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, warfarin, dextromethorphan, and midazolam).
f
A chest X-ray will be taken at screening unless one has been obtained within the last 6 months (provided the x-ray and/or report are available for review).
g
Patients may be discharged after collection of the 24 hour PK sample, at the discretion of the investigator.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 14
Ixekizumab (LY2439821)
Study Schedule Protocol I1F-MC-RHBU – Period 2
W 0
Check-in 
for W 1
W 1
W 2
W 4
W 6
W 8
W 10
D 1e
D 7g
±2d
D 8g
D 9g
D 10g
D 11g
D 12g
D 15
±2d
D 29
±2d
D 43
±2d
D 57
±2d
D 71
±2d
Procedure
Patient Admission to 
CRU
X
Patient Discharge from 
CRU
Xh
Outpatient Visit
X
X
X
X
X
X
X
X
X
Review of AEs
X
Review Concomitant 
Medications
X
Urine Drug Screen
X
Ethanol breath test
X
Vital Signs (Supine 
and Standing Blood 
Pressure and Pulse 
Rate and Body 
Temperature)
Predosef
X
X
Predosef
Predosef
Predosef
Predosef
Predosef
Clinical Laboratory 
Testsa
Predosef
X
X
X
Predosef
Pregnancy Testb
Predosef
Medical Assessmentc
X
12-Lead ECG
Predosef
QIDS-SR16 
X
C-SSRS and 
Self-Harm Supplement
Predosef
X
X
Predosef
Predosef
Predosef
Predosef
Predosef
PASI
Predosef
X
X
X
sPGA
Predosef
X
X
X
% BSA Assessment
Predosef
X
X
X
Inflammatory 
Biomarker Sample
Predosef
X
Predosef
Predosef
Ixekizumab 
160 mg
80 mg
80 mg
80 mg
80 mg
80 mg


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 15
Ixekizumab (LY2439821)
W 0
Check-in 
for W 1
W 1
W 2
W 4
W 6
W 8
W 10
D 1e
D 7g
±2d
D 8g
D 9g
D 10g
D 11g
D 12g
D 15
±2d
D 29
±2d
D 43
±2d
D 57
±2d
D 71
±2d
Procedure
Administration
Drug Cocktail 
Administration
X
Ixekizumab PK 
Sample
Predosef
X
Predosef
Predosef
Predosef
Midazolam and 
1-hydroxymidazolam
PK Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8,12 h
24 h
Warfarin PK Sampled
Predose, 1, 
2, 4, 6, 8, 
10 h
24 h
48 h
72 h
96 h
Dextromethorphan and 
Dextrorphan PK 
Sampled
Predose, 1, 
2, 4,6, 8, 
10 h
24 h
48 h
72 h
Omeprazole and 
5-hydroxyomeprazole
PK Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24 h
48 h
Caffeine and 
Paraxanthine PK 
Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24 h
48 h
Ixekizumab 
Immunogenicity 
Sample
Predosef
X
Predosef
Predosef
Predosef
Abbreviations:  AE = adverse event; BSA = body surface area; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; 
ECG = electrocardiogram; ED = early discontinuation; PASI = Psoriasis Area Severity Index; PK = pharmacokinetics; QIDS-SR16 = Quick Inventory of 
Depressive Symptomatology-Self Report (16 items); sPGA = static Physicians Global Assessment; W = Week.
a
All clinical laboratory test samples tested at a central laboratory.  Additional samples for coagulation parameters (Appendix 2) may be collected and tested at 
a local laboratory at the discretion of the investigator.  


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 16
Ixekizumab (LY2439821)
b
Females only.  Serum or urine pregnancy test may be performed locally, at the discretion of the investigator.  
c
All medical assessments throughout the study should include a symptom directed physical as well as examination of heart, lungs, abdomen, and visual 
examination of the skin.
d
Sample times are relative to administration of the drug cocktail.  The PK sample collection times are nominal; actual times should be recorded.  Separate 
blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, warfarin, dextromethorphan, and midazolam).  
e
Day 1 of Period 2 will be 3 to 7 days after Day 5 of Period 1.  
f
Time is relative to that day’s ixekizumab dose.
g
Drug cocktail administration and drug cocktail PK sampling days must run consecutively from admission to CRU (on Day 5 to Day 9).
h
Patients may be discharged after collection of the 24 hour PK sample, at the discretion of the investigator.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 17
Ixekizumab (LY2439821)
Study Schedule Protocol I1F-MC-RHBU –Period 2 continued
Check-in for 
W 12
W 12
Follow-up/ED
D 84f
±2d
D 85f
D 86f
D 87f
D 88f
D 89f
W 16
Procedure
D 113
±4d
Patient Admission to CRU
X
Patient Discharge from CRU
Xg
Outpatient Visit
X
Review of AEs
X
Review Concomitant 
Medications
X
Urine Drug Screen
X
Ethanol breath test
X
Vital Signs (Supine and 
Standing Blood Pressure and 
Pulse Rate and Body 
Temperature)
X
X
X
Clinical Laboratory Testsa
X
X
X
X
Pregnancy Testb
X
Medical Assessmentc
X
X
12-lead ECG
X
C-SSRS and Self-Harm 
Supplement
X
X
X
PASI
Predosee
sPGA
Predosee
% BSA Assessment
Predosee
Inflammatory Biomarker 
Sample
Predosee
Ixekizumab Administration
80 mg
Drug Cocktail Administration
X
Ixekizumab PK Sample
Predosee
X


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
Page 18
Ixekizumab (LY2439821)
Check-in for 
W 12
W 12
Follow-up/ED
D 84f
±2d
D 85f
D 86f
D 87f
D 88f
D 89f
W 16
Procedure
D 113
±4d
Midazolam and 
1-hydroxymidazolam PK 
Sampled
Predose, 0.5, 1, 
2, 3, 4, 6, 8,12 
h
24 h
Warfarin PK Sampled
Predose, 1, 2, 
4, 6, 8, 10 h
24 h
48 h
72 h
96 h
Dextromethorphan and 
Dextrorphan PK Sampled
Predose, 1, 2, 
4,6, 8, 10 h
24 h
48 h
72 h
Omeprazole and 
5-hydroxyomeprazole PK 
Sampled
Predose, 0.5, 1, 
2, 3, 4, 6, 8, 
12 h
24 h
48 h
Caffeine and Paraxanthine PK 
Sampled
Predose, 0.5, 1, 
2, 3, 4, 6, 8, 
12 h
24 h
48 h
Ixekizumab Immunogenicity 
Sample
Predosee
X
Abbreviations:  AE = adverse event; BSA = body surface area; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; 
ECG = electrocardiogram; ED = early discontinuation; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; QIDS-SR16 = Quick Inventory of 
Depressive Symptomatology-Self Report (16 items); sPGA = static Physicians Global Assessment; W = Week.  
a
All clinical laboratory test samples tested at a central laboratory.  Additional samples for coagulation parameters (Appendix 2) may be collected and tested at 
a local laboratory at the discretion of the investigator.  
b
Females only.  Serum or urine pregnancy test may be performed locally, at the discretion of the investigator.  
c
All medical assessments throughout the study should include a symptom directed physical as well as examination of heart, lungs, abdomen, and visual 
examination of the skin.
d
Sample times are relative to administration of the drug cocktail.  The PK sample collection times are nominal; actual times should be recorded.  Separate 
blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, warfarin, dextromethorphan, and midazolam).
e
Time is relative to that day’s ixekizumab dose.
f
Drug cocktail administration and drug cocktail PK sampling days must run consecutively from admission to CRU (on Day 82 to Day 86).
g
Patients may be discharged after collection of the 24 hour PK sample, at the discretion of the investigator.


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Ixekizumab (LY2439821)
3. Introduction
3.1.
Study Rationale
Psoriasis is a chronic inflammatory skin disease in which elevated levels of proinflammatory 
cytokines are observed.  Elevated proinflammatory cytokines can lead to disease-drug 
interactions by reducing the expression and activity of some cytochrome P450 (CYP) enzymes, 
thereby theoretically altering the systemic exposure of CYP substrates (Wang et al. 2014).  Thus, 
treatment of psoriasis with biological products that reduce inflammation could theoretically
reduce elevations in cytokines and in turn affect CYP activity.  It is currently unknown if 
treatment with a biologic agent affecting the interleukin (IL)-17 pathway has the potential to 
influence CYP activity as has been seen with anti-IL-6 or anti-Tumor Necrosis Factor agents.
In vitro assays demonstrated that IL-17 inhibition by ixekizumab had little or no influence on 
mRNA CYP expression; however, while the use of in vitro assays to predict risk of clinical 
drug-drug interactions (DDI) is well established for small molecule chemical entities, the utility 
of in vitro assays to predict clinical DDI with biologic agents has been inconsistent, and thus not 
yet routinely accepted by global regulatory agencies in lieu of clinical studies for biologic agents 
that may affect cytokines. This study therefore seeks to evaluate the effect of single and multiple 
doses of ixekizumab on the pharmacokinetics (PK) of CYP3A, CYP2C9, CYP2D6, CYP2C19, 
and CYP1A2 substrates midazolam, warfarin, dextromethorphan, omeprazole, and caffeine, 
respectively, in patients with moderate-to-severe psoriasis.  
3.2.
Background
Ixekizumab (LY2439821) is an immunoglobulin subclass 4 (IgG4) monoclonal antibody that 
binds with affinity (<3 pM) and specificity to IL-17A, a proinflammatory cytokine.  Elevated 
levels of IL-17A have been implicated in the pathogenesis of a variety of autoimmune diseases, 
including psoriasis.  
Ixekizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who 
are candidates for systemic therapy or phototherapy and is administered by subcutaneous (SC) 
injection.  The recommended dose is 160 mg (two 80-mg injections) at Week 0, followed by 
80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks thereafter.  
In psoriasis patients, the mean (geometric coefficient of variation [CV%]) half-life was 13 days 
(40%) as determined from a population PK analysis.  Following a single SC dose of 160 mg in 
subjects with plaque psoriasis, ixekizumab reached peak mean concentrations by approximately 
4 days postdose.  
3.3.
Benefit/Risk Assessment
As of the cut-off date for the current investigator’s brochure (IB), more than 4950 patients 
(4209 psoriasis patients, 532 rheumatoid arthritis patients, and 209 psoriatic arthritis patients) 
have received at least 1 dose of ixekizumab.  
There were 11 deaths among all ixekizumab-treated patients (8 among psoriasis patients), with 
none of these considered to be related to ixekizumab treatment.  In an integrated analysis of data 


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Ixekizumab (LY2439821)
from all psoriasis studies, a total of 411 ixekizumab-treated patients (9.8%) reported at least 
1 serious adverse event (SAE).  The individual SAE preferred terms with an incidence ≥0.2% 
included:  cellulitis (0.4%), fall (0.3%), myocardial infarction (0.3%), osteoarthritis (0.3%), acute 
myocardial infarction (0.2%), chronic obstructive pulmonary disease (0.2%), nephrolithiasis 
(0.2%), suicide attempt (0.2%), prostate cancer (0.2%), and coronary artery disease (0.2%).
The percentage of psoriasis patients reporting at least 1 treatment-emergent adverse event 
(TEAE) was greater for each ixekizumab treatment group than for that of the placebo group; 
46.8% of placebo-treated patients reported ≥1 TEAE, compared to 58.6% of patients treated with 
80 mg ixekizumab either once every 2 weeks or once every 4 weeks.  Individual TEAEs reported 
at a significantly greater frequency in ixekizumab-treated patients than in placebo-treated 
patients were injection site reaction, injection site erythema, nausea, and oropharyngeal pain.  
Most TEAEs were mild or moderate in severity.  Overall, severe TEAEs were similar across the 
ixekizumab and placebo-treated group.  
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated adverse events (AEs) of ixekizumab are to be found in the IB and the Package Insert.  
Information about the known and expected benefits, risks, SAEs, and reasonably anticipated AEs 
for each of the cocktail drugs are to be found in each drug’s respective Package Insert.  


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Ixekizumab (LY2439821)
4. Objectives and Endpoints
Table RHBU.1 shows the objectives and endpoints of the study.
Table RHBU.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effects of single and multiple doses 
ixekizumab on the pharmacokinetics (PK) of a drug 
cocktail of cytochrome P450 (CYP) substrates in 
patients with moderate-to-severe psoriasis.
Ratio of geometric least squares means between each 
CYP substrate administered alone and in combination 
with ixekizumab for maximum observed drug 
concentration (Cmax) and area under the concentration 
versus time curve from zero to infinity (AUC[0-∞]) of 
parent drug.
Secondary
To evaluate the tolerability of ixekizumab in patients 
with moderate-to-severe psoriasis.
Incidence of treatment-emergent adverse events 
(TEAEs).  
Exploratory

To explore the effects of ixekizumab on the PK 
of a drug cocktail of CYP substrates in the 
subgroups of patients with moderate-to-severe 
psoriasis who respond to ixekizumab treatment 
at Week 12 and those who do not respond.

To evaluate the effects of ixekizumab treatment 
over time on inflammatory biomarker 
concentrations in patients with 
moderate-to-severe psoriasis.

To determine the PK of metabolites and 
metabolite to parent ratios where appropriate.

Ratio of geometric least squares means between 
each CYP substrate administered alone and in 
combination with ixekizumab for Cmax and 
AUC(0-∞) of parent drug in responders and 
nonresponders.

Change from baseline in inflammatory biomarker 
concentrations over time during 12 weeks of 
ixekizumab treatment.

Cmax and AUC(0-∞) of CYP substrate metabolites, 
where appropriate, and metabolite to parent ratios.


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Ixekizumab (LY2439821)
5. Study Design
5.1.
Overall Design
This is a 2-period, fixed-sequence, open-label, multi-center, Phase 1 study to assess the effects of 
single and multiple doses of ixekizumab on the PK of a drug cocktail of CYP substrates 
(midazolam, warfarin, dextromethorphan, omeprazole, and caffeine) in patients with 
moderate-to-severe psoriasis.  
Patients will be admitted to the clinical research unit (CRU) on Day -1 of Period 1 and receive 
the drug cocktail, with single oral doses of 1 mg midazolam, 10 mg warfarin (+ 10 mg 
vitamin K), 30 mg dextromethorphan, 20 mg omeprazole, and 100 mg caffeine on the morning 
of Day 1.  Patients will reside at the CRU until Day 2 and may be discharged from the CRU 
following collection of the 24 hour PK samples, at the discretion of the investigator.  Patients 
will return to the CRU as outpatients for collection of PK samples and safety assessments, as 
applicable, on Day 3 (48 hours post-drug cocktail dose), Day 4 (72 hours post-drug cocktail 
dose), and Day 5 (96 hours post-drug cocktail dose).
Patients will attend the CRU as outpatients on Day 1 of Period 2 (3 to 7 days after Day 5 of 
Period 1) and receive a 160-mg dose of ixekizumab (administered as two 80-mg SC injections). 
Patients will be admitted to the CRU on Day 7 (±2 days) of Period 2 and receive the drug 
cocktail on the following morning (Day 8; Week 1).  Patients will reside at the CRU until Day 9
and may be discharged from the CRU following collection of the 24 hour PK samples, at the 
discretion of the investigator.  Patients will return to the CRU as outpatients for collection of PK 
samples and safety assessments, as applicable, on Day 10 (48 hours post-drug cocktail dose), 
Day 11 (72 hours post-drug cocktail dose), and Day 12 (96 hours post-drug cocktail dose).
Patients will receive single 80-mg doses of ixekizumab on Day 15 (Week 2), Day 29 (Week 4), 
Day 43 (Week 6), Day 57 (Week 8), and Day 71 (Week 10) of Period 2.  Patients will be 
admitted to the CRU on Day 84 (±2 days) and receive 80 mg ixekizumab and the drug cocktail 
on the following morning (Day 85; Week 12).  Patients will reside at the CRU until Day 86 and 
may be discharged from the CRU following collection of the 24 hour PK samples, at the 
discretion of the investigator.  Patients will return to the CRU as outpatients for collection of 
additional drug cocktail PK samples and safety assessments, as applicable, on Day 87 (48 hours 
post-drug cocktail dose), Day 88 (72 hours post-drug cocktail dose), and Day 89 (96 hours 
post-drug cocktail dose).  
Blood sampling for assessment of inflammatory biomarkers (IL-1β, IL-6, IL-19, and Tumor 
Necrosis Factor ) and ixekizumab PK and immunogenicity will be conducted at prespecified 
visits. Concentrations of IL-17A will not be measured as it complexes with ixekizumab, and
therefore correlates with the PK of ixekizumab.  Interleukin-17A drives production of IL-19 in 
keratinocytes of psoriatic skin. C-reactive protein will also be used as an inflammatory 
biomarker and is collected as part of the clinical laboratory testing. Efficacy will be evaluated 
using static Physicians Global Assessment (sPGA), Psoriasis Area Severity Index (PASI), and 
percentage of body surface area (BSA) assessments at prespecified visits.  


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Ixekizumab (LY2439821)
All patients will attend a follow-up visit on Day 113 (±4 days; Week 16).  
Safety will be monitored throughout the study by recording of AEs, clinical laboratory 
parameters, vital signs, physical examination, Quick Inventory of Depressive 
Symptomatology-Self Report (16 items) (QIDS-SR16), Columbia-Suicide Severity Rating Scale 
(C-SSRS) and Lilly Self-Harm Supplement responses, and electrocardiograms (ECGs).  
Figure RHBU.1 illustrates the study design.


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Ixekizumab (LY2439821)
Screening 
Day -36 to 
Day -9
-1
Day
1
2
Inpatient period
3
4
5
160 mg ixekizumab administration
80 mg ixekizumab administration
Drug cocktail 
administration
Drug Cocktail PK sampling
Period 1
X  Ixekizumab immunogenicity and PK samples 
□   PASI, sPGA, and % BSA assessment and Inflammatory biomarker samples
15 ±2
29 ±2
43 ±2
57 ±2
71 ±2
84 ±2
85
86
87
88
Drug Cocktail PK sampling
Drug cocktail 
administration
X
X
X
89
113 ±4
X
□ 
□ 
□ 
Follow-up 
1
7
Drug Cocktail PK sampling
Drug cocktail 
administration
X
X
□ 
8
9
10
11
12
Period 2
□ 
Abbreviations:  BSA = body surface area; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; sPGA= static Physicians Global Assessment.
Figure RHBU.1.
Illustration of study design for I1F-MC-RHBU.


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Ixekizumab (LY2439821)
5.2.
Number of Participants
Approximately 30 patients will be enrolled with the assumption that 21 patients complete 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 study.  Blinding is not necessary because the primary endpoint is PK and 
thus not vulnerable to patient or investigator bias.  The fixed-sequence design is used due to the 
long half-life of ixekizumab.  
This study will be conducted in patients with moderate-to-severe plaque psoriasis as this is the 
patient population for whom ixekizumab treatment is indicated; conducting the study in this 
population allows the assessment of the effect of ixekizumab on CYP enzymes expressed at 
clinically relevant levels.
Regulatory agencies recommend conducting a clinical drug interaction study using a drug 
cocktail approach when interactions with multiple CYPs are investigated (European Medicines 
Agency [EMA] Guideline 2012; Food and Drug Administration [FDA] 2012, PMDA Draft 
Guideline 2013).  Drugs used in such a cocktail should be selective for the specific CYP 
enzymes, should not interact with each other, and ultimately should be safe when administered.  
One such drug cocktail is a modified 5+1 Cooperstown cocktail which includes midazolam 
(CYP3A), warfarin (CYP2C9), dextromethorphan (CYP2D6), omeprazole (CYP2C19), caffeine 
(CYP1A2), and vitamin K (to counter the anticoagulant effect of warfarin), and has been 
administered in previous studies (Goh et al 2010; Ma et al 2006).  The drug cocktail will be 
administered prior to initiation of ixekizumab dosing and again on Day 8 (Week 1) of Period 2, 
to assess the effect of a single dose of ixekizumab, and on Day 85 (Week 12) of Period 2, when
steady-state concentrations of ixekizumab should be achieved.  The total required blood volume 
of 650 mL is considered acceptable given that blood samples are taken during the course of the 
study which has a minimum duration of approximately 17 weeks.  
5.5.
Justification for Dose
Drug cocktail containing 1 mg midazolam, 10 mg warfarin (+ 10 mg vitamin K), 30 mg 
dextromethorphan, 20 mg omeprazole, and 100 mg caffeine has been chosen as these are 
clinically relevant doses considered safe to administer and have been used concomitantly in 
previous clinical studies.  
The 1 mg oral dose of midazolam used for this study is lower than the 5 mg oral dose that has 
been used in some published cocktail studies.  Use of 1 mg benefits patient safety since this dose 
does not result in conscious sedation yet still provides sufficient exposure to midazolam to assess 
midazolam PK.


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Ixekizumab (LY2439821)
The dosing regimen for ixekizumab is consistent with that recommended in the United States 
Package Insert.  


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Ixekizumab (LY2439821)
6. Study Population
Eligibility of patients for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, QIDS-SR16, C-SSRS, clinical laboratory tests, and 
ECG.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Patients who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
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 for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
Males or females.
[1a] Male patients:
agree to use a reliable method of contraception and not donate sperm for the 
duration of the study
[1b] Female patients:
Women not of child-bearing potential may participate, and include those who are:
a) Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal 
ligation), congenital anomaly such as Müllerian agenesis; or
b) Postmenopausal – postmenopausal is defined as women with an intact uterus who 
have not taken hormones or oral contraceptives within 1 year, who have had either 
cessation of menses for at least 1 year, or 6 to 12 months of spontaneous amenorrhea 
with follicle-stimulating hormone consistent with menopause (>40 mIU).
Women of child-bearing potential may participate, and include those who test 
negative for pregnancy prior to initiation of treatment based on a serum pregnancy 
test and agree to use a reliable method of contraception during the study and until 
3 months after the last dose of ixekizumab received in the study.
[2] Are 18 years or older at the time of screening.
[3] Have a body mass index (BMI) of 18.5 to 40.0 kg/m2, inclusive, at screening.
[4] Have venous access sufficient to allow for blood sampling as per the protocol.


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Ixekizumab (LY2439821)
[5] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[6] Have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.
[7] Present with chronic plaque psoriasis based on a confirmed diagnosis of 
chronic psoriasis vulgaris for at least 6 months prior to screening.
[8]
Have ≥10% BSA involvement at screening and first admission to the CRU.
[9] Have both an sPGA score of ≥3 and PASI score ≥12 at screening and first 
admission to the CRU.
[10] Are a candidate for phototherapy and/or systemic therapy.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[11] 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.
[12] Are employees of Lilly or Covance.
[13] Are currently enrolled in, or discontinued from a clinical trial involving an 
investigational product or nonapproved use of a drug or device, within the 
last 4 weeks or a period of at least of 5 half-lives of the last administration of 
the drug, whichever is longer, or are concurrently enrolled in any other type 
of medical research judged not to be scientifically or medically compatible 
with this study.
[14] Have ECG abnormalities that are considered clinically significant and would 
pose an unacceptable risk to the patient if participating in the study.
[15] Have allergy to rubber or latex.
[16] Have any other condition that precludes the patient from following and 
completing the protocol, in the opinion of the investigator.
[17] Have donated more than 500 mL of blood within the last 4 weeks, or intend 
to donate blood during the course of the study.
[18] Are women who are lactating.
[19] Are unwilling to comply with the dietary requirements/restrictions during the 
study:  (i) consume only the meals provided during the inpatient visits, and 
(ii) refrain from consuming grapefruit, Seville oranges, star fruit, pomelos, or 
products containing these fruits, for at least 14 days prior to the first 
administration of the drug cocktail through the end of Week 12 assessments.  


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Ixekizumab (LY2439821)
[20] Are currently or have been smokers or users of tobacco or nicotine 
replacement products within 1 month prior to first admission to the CRU.
[21] Intend to consume caffeine- or xanthine-containing food or beverages from 5 days 
prior to each administration of the drug cocktail and until collection of the 48 hour 
drug cocktail PK samples in each period.
[22] Have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption for at least 24 hours prior to each visit 
to the CRU, and while resident in the CRU (1 unit = 12 oz or 360 mL of beer; 
5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
[23] Require treatment with inhibitors of CYP3A, CYP2C9, CYP2D6, CYP2C19, or 
CYP1A2, with inducers of CYP3A or CYP1A2, or with rifampin (inducer of 
multiple CYPs) within 14 days prior to the first administration of the drug cocktail 
through the end of Week 12 assessments.  
[24] Require treatment with substrates of CYP3A, CYP2C9, CYP2D6, CYP2C19, or 
CYP1A2 with narrow therapeutic indices within 14 days prior to the first 
administration of the drug cocktail through the end of Week 12 assessments, at the 
discretion of the investigator and by agreement with the Lilly clinical research 
physician (CRP), or clinical pharmacologist (CP), or designee.
[25] Require ongoing treatment with midazolam, warfarin, dextromethorphan, 
omeprazole, or caffeine, or require treatment with a drug contraindicated with 
midazolam, warfarin, dextromethorphan, omeprazole, or caffeine (per the prescribing 
label and Package Insert for each drug) within 14 days prior to the first 
administration of the drug cocktail through the end of Week 12 assessments.  
[26] Have pustular, erythrodermic, and/or guttate forms of psoriasis.
[27] Have a history of drug-induced psoriasis.
[28] Have received systemic nonbiologic psoriasis therapy (including, but not 
limited to, oral psoralen and ultraviolet A [PUVA] light therapy; 
cyclosporine; corticosteroids; methotrexate; oral retinoids; mycophenolate 
mofetil; thioguanine; hydroxyurea; sirolimus; azathioprine; fumaric acid 
derivatives; or 1, 25 dihydroxy vitamin D3 and analogues), or phototherapy 
(including either oral and topical PUVA light therapy, ultraviolet B, or 
self-treatment with tanning beds or therapeutic sunbathing) within 4 weeks 
prior to first admission to the CRU
-or-


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Ixekizumab (LY2439821)
Had topical prescription psoriasis treatment (including, but not limited to, 
corticosteroids, anthralin, calcipotriene, topical vitamin D derivatives, 
retinoids, tazarotene, and emollients) within the previous 14 days prior to first 
admission to the CRU.  Exceptions:  Class 6 (mild, such as desonide) or 
Class 7 (least potent, such as hydrocortisone) topical steroids will be 
permitted for use limited to the face, axilla, and/or genitalia.
[29] Cannot avoid excessive sun exposure or use of tanning booths for at least 
4 weeks prior to first admission to the CRU and during the study.
[30] Have concurrent use or have received any of the following biologic agents 
within the last year:  human growth hormone (hGH), interferons,  rituximab, 
efalizumab, tocilizumab or other agents that target interleukin-6, interferons, 
basiliximab or other agents that target IL-2, muromonab or other agents that 
target CD3, canakinumab or other agents that target IL-1, or Cimzia 
(certolizumab pegol); or have concurrent use or have received any of the 
following biologic agents with the following washout periods:  alefacept, or
any agents that target Tumor Necrosis Factor (such as Remicade 
[infliximab], Humira [adalimumab], or Enbrel [etanercept]), (<60 days),
ustekinumab or other agents that target IL-12 or IL-23, (<8 months),  
Simponi (golimumab) (<90 days); or any other biologic agent <5 half-lives 
prior to first admission to the CRU.
[31] Have ever received natalizumab or other agents that target alpha-4-integrin.
[32] Have previously completed or withdrawn from this study, or have 
participated in any other study with ixekizumab or other IL-17 antagonists 
such as secukinumab or brodalumab, or have been prescribed ixekizumab or 
secukinumab.
[33] Have a known allergy or hypersensitivity to any component of the drug 
cocktail that would pose an unacceptable risk to the patient if participating in 
this study.
[34] Had a live vaccination within 12 weeks prior to first admission to the CRU, 
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 first admission to the CRU.  
Investigators should review the vaccination status of their patients and follow 
the local guidelines for adult vaccination with nonlive vaccines intended to 
prevent infectious disease prior to therapy.
(Note:  Killed/inactive or subunit vaccines are expected to be safe)
[35] Had a vaccination with Bacillus Calmette-Guérin (BCG) within 12 months 
prior to first admission to the CRU, or intend to have a vaccination with BCG 
during the course of the study, or within 12 months of completing treatment 
in this study.


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Ixekizumab (LY2439821)
[36] Had any major surgery within 8 weeks prior to first admission to the CRU, or 
will require such during the study that, in the opinion of the investigator in 
consultation with Lilly or its designee, would pose an unacceptable risk to the 
patient.
[37] Have current or a history of lymphoproliferative disease; or signs or 
symptoms of lymphoproliferative disease; or have active or history of 
malignant disease.
(Note:  Patients with successfully treated basal-cell carcinoma [no more 
than 3], squamous-cell carcinoma of the skin, or cervical carcinoma in situ, 
with no evidence of recurrence within the 5 years prior to first admission to 
the CRU may participate in the study.)
[38] Have presence of significant uncontrolled cerebrocardiovascular disorder (for 
example, myocardial infarction [MI], unstable angina, moderate-to-severe 
[New York Heart Association Class III/IV] heart failure, or cerebrovascular 
accident), respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, 
neurologic or neuropsychiatric disorders, or abnormal laboratory values at 
screening that, in the opinion of the investigator, pose an unacceptable risk to 
the patient if participating in the study or of interfering with the interpretation 
of data.
[39] Have a history of uncompensated heart failure, fluid overload, or MI, or 
evidence of new-onset ischemic heart disease or other serious cardiac disease, 
within 12 weeks prior to first admission to the CRU.
[40] Presence of significant uncontrolled neuropsychiatric disorder; have a recent 
history of a suicide attempt (30 days within screening visit and any time 
between screening visit and baseline); or have a score of 3 on Item 12 
(Thoughts of Death or Suicide) of the QIDS-SR16 at screening, or are 
clinically judged by the investigator to be at risk for suicide.
[41] Had a serious infection (for example, pneumonia, cellulitis), have been 
hospitalized, or have received intravenous antibiotics for an infection, within 
12 weeks prior to first admission to the CRU, or had a serious bone or joint 
infection within 24 weeks prior to first admission to the CRU, 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.
[42] 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 jirovecii pneumonia, histoplasmosis, or 
coccidioidomycosis); or have a known immunodeficiency.
[43] Have or had a herpes zoster or any other clinically apparent varicella-zoster 
virus infection within 12 weeks of first admission to the CRU.


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Ixekizumab (LY2439821)
[44] Have any other active or recent infection within 4 weeks of first admission to 
the CRU that, in the opinion of the investigator, would pose an unacceptable 
risk to the patient if participating in the study; these patients may be 
rescreened (1 time) ≥4 weeks after documented resolution of symptoms.
[45] Have a body temperature ≥38 °C (100.5 °F) at first admission to the CRU; 
these patients may be rescreened (1 time) ≥4 weeks after documented 
resolution of elevated temperature.
[46] Show evidence of active or latent tuberculosis (TB), as documented by 
medical history and physical examination, chest x-rays (posterior anterior and 
lateral), and TB testing:  lack of TB will be demonstrated by either a negative 
purified protein derivative (PPD) test (defined as a skin induration <5 mm at 
48 to 72 hours, regardless of BCG or other vaccination history) or a negative 
(not indeterminate) QuantiFERON-TB Gold test or T-SPOT.  The choice to 
perform a PPD, QuantiFERON-TB Gold test, or T-SPOT will be made by the 
investigator according to local licensing and standard of care.  The 
QuantiFERON-TB Gold test can only be used in countries where it is 
licensed, and the use of this test is dependent on previous treatment(s).  This 
test may not be suitable if previous treatment(s) produce significant 
immunosuppression.
Patients who test positive for latent TB at screening may be rescreened 
following appropriate treatment (see Section 6.4).  
[47] Have uncontrolled arterial hypertension characterized by a systolic blood 
pressure (BP) >160 mm Hg or diastolic BP >100 mm Hg.
(Note:  Determined by 2 consecutive elevated readings.  If an initial BP 
reading exceeds this limit, the BP may be repeated once after the patient has 
rested sitting for ≥10 minutes.  If the repeat value is less than the criterion 
limits, the second value may be accepted.)
[48] Show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[49] Show evidence of hepatitis B and/or positive hepatitis B surface antigen or 
positive hepatitis B core antibody (HBcAb+).
[50] Show evidence of hepatitis C and/or positive hepatitis C antibody.
[51] 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:
[51a] Neutrophil count <1500 cells/µL.
[51b] Lymphocyte count <500 cells/µL.
[51c] Platelet count <100,000 cells/µL.


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[51d] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5 times the upper limit of normal (ULN).
[51e] Total white blood cell count <3000 cells/µL.
[51f] Hemoglobin <8.5 g/dL (85 g/L) for male patients and <8.0 g/dL (80 g/L) for 
female patients.
[51g] Serum creatinine >2.0 mg/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 used to assess 
eligibility.  Other laboratory tests should not be repeated unless there is a 
technical error or clinical reason to believe a result may be erroneous.).
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Patients will be provided with standard meals while resident in the CRU.  Patients should not 
consume food from 1 hour before until 1 hour after each administration of drug cocktail.  
Patients must refrain from consuming grapefruit, Seville oranges, star fruit, pomelos, or products 
containing these fruits, within 14 days prior to first administration of the drug cocktail until the 
last drug cocktail PK sample is collected.  
6.3.2. Caffeine, Alcohol, and Tobacco
No caffeine- or xanthine-containing food or beverages will be allowed within 5 days of each 
administration of the drug cocktail (Day 1 of Period 1, Day 8, and Day 85 of Period 2) and until 
collection of the 48 hour drug cocktail PK samples for each administration.
No alcohol will be allowed from at least 24 hours prior to each CRU visit or while resident in the 
CRU.  
Patients will not be permitted to use tobacco products from 1 month prior to first admission to 
the CRU until collection of the last drug cocktail PK samples in Period 2.  
6.3.3. Activity
Patients will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to each CRU visit or while 
resident in the CRU.  
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened unless they failed due to having latent TB and have received appropriate treatment, an 
active or recent infection within 4 weeks of the first admission to the CRU, or a body 


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temperature ≥38 °C (100.5 °F) at first admission to the CRU.  These individuals may be 
rescreened once.  Rescreenings should occur at least 4 weeks after documented resolution of 
symptoms.  Each time rescreening is performed, the individual must sign a new informed 
consent form (ICF) and will be assigned a new identification number.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of the PK of oral doses of midazolam, warfarin, 
dextromethorphan, omeprazole, and caffeine when administered alone to that when administered 
following single and multiple doses of ixekizumab.  
The timing of administration of study treatments will be consistent with the Schedule of 
Activities (Section 2).  Administration of drug cocktail and ixekizumab up to Day 85 (Week 12) 
will be conducted by qualified staff at the CRU.  
Ixekizumab
Each injection of ixekizumab should be administered according to the instructions for use.  
The 160-mg dose of ixekizumab will be administered on Day 1 of Period 2 as two 1.0-mL SC 
injections; 80 mg of ixekizumab per injection.  
The 80-mg dose of ixekizumab will be administered on Day 15 (Week 2), Day 29 (Week 4), 
Day 43 (Week 6), Day 57 (Week 8), Day 71 (Week 10), and Day 85 (Week 12) in Period 2, as 
one 1.0-mL SC injection.
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 the subsequent dose.
Drug cocktail
The drug cocktail will contain midazolam, warfarin (plus vitamin K), dextromethorphan, 
omeprazole, and caffeine.  Each study site will source cocktail drugs, and will ensure that the 
same package lot is used for each cocktail drug in each of the 2 periods for an individual patient.  
Administration of each cocktail drug will be according to the respective instructions for use.  
The following doses of cocktail drugs will be coadministered orally with approximately 240 mL 
of room temperature water, in a sitting position.  
If a patient experiences clinically significant changes in coagulation parameters after receiving 
the second dose of drug cocktail, the patient may be administered the third dose of drug cocktail 
without warfarin.
Midazolam
A 1-mg oral dose of commercially available midazolam syrup.
Warfarin
A 10-mg oral dose of commercially available warfarin, plus a 10-mg oral dose of commercially 
available vitamin K.
Dextromethorphan
A 30-mg oral dose of commercially available dextromethorphan.


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Omeprazole
A 20-mg oral dose of commercially available omeprazole.  
Caffeine
A 100-mg (caffeine base) oral dose administered as a commercially available caffeine citrate 
solution (for example, if each mL of commercially available caffeine citrate solution contains 
10 mg caffeine base then the dose would be 10 mL of caffeine citrate solution).
All study treatments
The investigator or designee is responsible for:

explaining the correct use of the investigational products to the site personnel,

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.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  
7.1.1. Packaging and Labeling
Ixekizumab will be supplied by the sponsor or its designee in accordance with current Good 
Manufacturing Practices (cGMP), labeled according to the country’s regulatory requirements, 
and supplied with lot numbers, expiry dates, and certificates of analysis, as applicable.  
Ixekizumab will be supplied as injectable solution in 1-mL, single-dose, prefilled, disposable,
manual syringes with study-specific labels.  Each syringe of ixekizumab is designed to deliver 
ixekizumab 80 mg.  Syringes will be supplied in cartons, with the appropriate quantity of 
syringes specific to the planned dispensing schedule of the investigational product.
Commercially available midazolam, warfarin, vitamin K, dextromethorphan, omeprazole, and 
caffeine will be used in the drug cocktail.  
All investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations.
7.2.
Method of Treatment Assignment
This study is not subject to randomization.
7.2.1. Selection and Timing of Doses
The selected dosing regimen for ixekizumab is that recommended for the treatment of adults 
with moderate-to-severe plaque psoriasis.


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Doses of cocktail drugs are clinically relevant and considered safe to administer.  In Period 2, the 
drug cocktail will be administered on Day 8, to assess the effect of a single dose of ixekizumab, 
and Day 85 (Week 12), at which time steady-state concentrations of ixekizumab should be
achieved.  
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the patient’s electronic case report form (eCRF).
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose reductions or adjustments will not be allowed during this study.  
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive investigational product and only authorized 
site staff may supply or administer study treatment while the patient is attending the CRU.  All 
study treatments should be stored in an 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.
Ixekizumab is to be stored at 2°C to 8°C (36°F to 46°F) in its original carton to protect from 
light.  Ixekizumab must not be frozen or shaken.  Sites will be required to monitor temperature of 
the on-site storage conditions of the investigational product.
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).
7.6.
Treatment Compliance
Investigational products will be administered at the clinical site and documentation of treatment 
administration will occur at the site.  
7.7.
Concomitant Therapy
Treatment with midazolam, warfarin, dextromethorphan, omeprazole, or caffeine will not be 
allowed during the study.  
Drugs that are known inhibitors of CYP3A, CYP2C9, CYP2D6, CYP2C19, or CYP1A2, 
inducers of CYP3A or CYP1A2, or rifampin (inducer of multiple CYPs) will not be allowed 
within 14 days prior to the first administration of the drug cocktail through the end of the 
Week 12 assessments.  
Drugs that are known substrates of CYP3A, CYP2C9, CYP2D6, CYP2C19, or CYP1A2, with 
narrow therapeutic indices, will not be allowed within 14 days prior to the first administration of 


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the drug cocktail through the end of the Week 12 assessments, at the discretion of the 
investigator, and by agreement with the Lilly CRP or designee.
Drugs that are contraindicated with midazolam, warfarin, dextromethorphan, omeprazole, or 
caffeine (per the prescribing label and Package Insert for each drug) will not be allowed within 
14 days prior to the first administration of the drug cocktail through the end of the Week 12
assessments.  
Patients should not receive systemic nonbiologic psoriasis therapy (including, but not 
limited to, oral PUVA light therapy; cyclosporine; corticosteroids; methotrexate; oral 
retinoids; mycophenolate mofetil; thioguanine; hydroxyurea; sirolimus; azathioprine; 
fumaric acid derivatives; or 1, 25 dihydroxy vitamin D3 and analogues) or phototherapy 
(including either oral and topical PUVA light therapy, ultraviolet B, or self-treatment 
with tanning beds or therapeutic sunbathing) within 4 weeks prior to first admission to 
the CRU and during the study.  
Patients should not receive topical prescription psoriasis treatment (including, but not 
limited to, corticosteroids, anthralin, calcipotriene, topical vitamin D derivatives, 
retinoids, tazarotene, and emollients) within the previous 14 days prior to first admission 
to the CRU or during the study.  Class 6 (mild, such as desonide) or Class 7 (least potent, 
such as hydrocortisone) topical steroids will be permitted for use limited to the face, 
axilla, and/or genitalia.
The following drugs will not be allowed within 1 year of screening or during the study:  hGH, 
interferons, rituximab, efalizumab, tocilizumab or other agents that target IL-6, interferons, 
basiliximab or other agents that target IL-2, muromonab or other agents that target CD3, 
canakinumab or other agents that target IL-1, or Cimzia (certolizumab pegol).  
The following drugs will not be allowed without the following washout before screening:  
alefacept, any agents that target Tumor Necrosis Factor (such as Remicade [infliximab], 
Humira [adalimumab], or Enbrel [etanercept]) (<60 days), ustekinumab or other agents that 
target IL-12 or IL-23, (<8 months), Simponi (golimumab) (<90 days); or any other biologic 
agent <5 half-lives prior to first admission to the CRU.
The investigator may approve administration of acetaminophen at doses not to exceed a total of 
2 g in any 24-hour period, without consultation with Lilly. The investigator should consult with 
Lilly if a total dose >2 g in a 24-hour period is desired; however, the maximum total dose cannot 
exceed 3 g in any 24-hour period.
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.  If the need for concomitant medication arises, 
inclusion or continuation of the patient may be at the discretion of the investigator after 
consultation with a Lilly CP or CRP.  Any additional medication used during the course of the 
study must be documented.
7.8.
Treatment after the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
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:

Alanine aminotransferase or AST >5× ULN.

ALT or AST >3× ULN along with one of the following criteria:
o
sustained for more than 2 weeks or
o
total bilirubin level (TBL) >2× ULN or
o
prothrombin time >1.5× ULN or
o
the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3× ULN.

ALP>2.5× ULN and TBL >2× ULN.

ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
In addition, patients will be discontinued from the investigational product in the following 
circumstances:

The patient becomes pregnant.

Neutrophil (segmented) counts:
o
<500 cells/µL.
o
≥500 and <1000 cells/µL (based on 2 test results; the second test performed 
within 1 week of knowledge of the initial result).
o
≥1000 and <1500 cells/µL and the patient has a concurrent infection that requires 
systemic anti-infective therapy.  

Total white blood cell count <2000 cells/µL.

Lymphocyte count <200 cells/µL.

Platelet count <50,000 cells/µL.
Patients will be evaluated for discontinuation if a suicide-related thought or behavior is identified 
at any time during the study, or if during the study a patient gives:
•
a "yes" answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the "Suicidal Ideation" portion of the C-SSRS; or 
•
a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the "Suicidal Ideation" portion of the C-SSRS; or 


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•
a "yes" answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the "Suicidal Behavior" 
portion of the C-SSRS.  
It is recommended that the patient also be assessed by a psychiatrist or appropriately trained 
professional to assist the investigator in deciding whether the patient should be discontinued 
from the study.
In addition, patients will also be evaluated for discontinuation if they have self-injurious 
behavior that would be classified as non-suicidal self-injurious behavior.  It is recommended that 
a patient be assessed by a psychiatrist or appropriately trained professional to assist the 
investigator in deciding whether the patient should be discontinued from the study.
Patients who discontinue the investigational product early will have early discontinuation 
procedures performed as shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the Sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled patient to continue in the study with or without continued treatment with 
investigational product.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and 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 requests to be withdrawn from the study
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).


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8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
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, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in 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.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
Efficacy will be evaluated using sPGA, PASI, and percentage of BSA assessments (see 
Section 9.6) according to the Schedule of Activities (Section 2).  
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
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.
After the ICF is signed, study site personnel will record, via eCRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, 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 or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

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

events considered significant by the investigator based upon appropriate medical 
judgment
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  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.
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.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting begins 
after the patient has signed informed consent and has received investigational product.  However, 
if an SAE occurs after signing informed consent, but prior to receiving investigational product, 
AND is considered reasonably possibly related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from and/or completed the study (the patient summary eCRF 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.  
Pregnancy (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.


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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 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 recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products used in clinical trials in order to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of ixekizumab is any dose above that assigned.  
Doses of up to 180 mg have been administered SC in clinical trials without dose-limiting 
toxicity.  Overdoses up to 240 mg SC have been reported without any SAEs.  In the event of 
overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse 
reactions and appropriate symptomatic treatment be instituted immediately.  
Refer to the Package Insert of each cocktail drug for information on treatment of overdose.  
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
9.4.2. Vital Signs
For each patient, vital sign measurements (standing and supine BP and pulse rate, and body 
temperature) should be conducted according to the Schedule of Activities (Section 2).
Blood pressure and pulse rate should be measured standing and after at least 5 minutes supine.
Additional vital signs may be assessed as clinically indicated as well as at the scheduled times.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If orthostatic measurements are required, patients should be supine 
for at least 5 minutes and stand for at least 3 minutes.  If the patient feels unable to stand, supine 
vital signs only will be recorded.  
Additional scheduled vital signs may be added during each study period if warranted and agreed 
upon between the sponsor and investigator.


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9.4.3. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational product, should be reported to Lilly, or its 
designee, as an AE via eCRF.  
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood for 
safety or PK tests.  Patients must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician or qualified designee assigned by 
the investigator at the site as soon after the time of ECG collection as possible, and ideally while 
the patient is still present, to determine whether the patient meets entry criteria at the relevant
visit(s) and for immediate patient management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QT 
corrected for heart rate interval from baseline) after enrollment, the investigator will determine if 
the patient can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in patient management is needed, and must document his/her review 
of the ECG printed at the time of collection.  Any new clinically relevant finding should be 
reported as an AE.
9.4.4. Quick Inventory of Depressive Symptomatology-Self Report 
(16-Items)
The QIDS-SR16 is a self-administered, 16-item instrument intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association’s 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (APA 1994).  
A patient is asked to consider each statement as it relates to the way they have felt for the past 
7 days.  There is a 4-point scale for each item ranging from 0 to 3.  The 16 items corresponding 
to 9 depression domains are summed to give a single score ranging from 0 to 27, with higher 
scores denoting greater symptom severity.  The domains assessed by the instrument include:  
(1) sad mood, (2) concentration, (3) self-criticism, (4) suicidal ideation, (5) interest, 
(6) energy/fatigue, (7) sleep disturbance (initial, middle, and late insomnia or hypersomnia), 
(8) decrease/increase in appetite/weight, and (9) psychomotor agitation/retardation.  Additional 
information and the QIDS-SR16 questions can be found at the University of Pittsburgh 
IDS/QIDS internet page (http://www.ids-qids.org).


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9.4.5. Columbia-Suicide Severity Scale
Any occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the 
Schedule of Activities (Section 2) using the C-SSRS. 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 (NIMH) trial 
group (TASA) for the purpose of being a counterpart to the Columbia Classification Algorithm 
of Suicide Assessment (C CASA) categorization of suicidal events.  
The nonleading 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 
nonleading 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.
Terms captured by the use of the C-SSRS can be mapped to C CASA (Posner et al. 2007) to 
facilitate future pooling of data.  
The first time the scale is administered in this study, the C-SSRS “Baseline” version will be used, 
and the findings will constitute the baseline assessment. The C-SSRS “Since Last Visit” scale 
will be used for all subsequent assessments. If a suicide-related thought or behavior is identified 
at any time during the study, a thorough evaluation will be performed by a study physician, and 
appropriate medical care will be provided. It is recommended that a patient be assessed by a 
psychiatrist or appropriately trained professional to assist in deciding whether the patient should 
be discontinued from study treatment (Section 8.1).  A patient does not necessarily have to be 
discontinued if they have self-injurious behavior that would be classified as non-suicidal 
self-injurious behavior.  Of course, if this situation arises, it is recommended that the patient be 
referred to a psychiatrist or appropriately trained professional.
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have 
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.
9.4.6. Safety Monitoring
The Lilly CP or CRP/clinical research scientist will monitor safety data throughout the course of 
the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
research physician will consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical research scientist when appropriate, and periodically 
review:

trends in safety data


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
laboratory analytes 

AEs 
If a study patient experiences elevated ALT ≥3× ULN, ALP ≥2× ULN, or elevated TBL
≥2× ULN, clinical and laboratory monitoring should be initiated by the investigator.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test
abnormalities.  To ensure patient safety and compliance with regulatory guidance, the 
investigator is to consult with the Lilly designated CRP regarding collection of specific 
recommended clinical information and follow-up laboratory tests (Appendix 4).
9.4.7. Inflammatory Bowel Diseases Assessments
Data on suspected inflammatory bowel disease, 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 Clinical Events Committee (CEC) made up of gastroenterologists with expertise in 
inflammatory bowel disease. The role of the CEC is to adjudicate defined clinical events, in a 
blinded, consistent, and unbiased manner throughout the course of a study.  The importance of 
the CEC is to ensure that all events that have been reported are evaluated uniformly by a single 
group.
9.4.8. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected to determine antibody production 
against ixekizumab.  Additional samples may be collected if there is a possibility that an AE is 
immunologically mediated.  
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies in 
the presence of ixekizumab.  Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of ixekizumab.  Immunogenicity samples may also be analyzed 
for ixekizumab serum concentration to facilitate in the interpretation of the immunogenicity data.
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.  
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), separate venous blood 
samples of approximately 2 mL each will be collected to determine the plasma concentrations of 
midazolam and its metabolite 1-hydroxymidazolam, S-warfarin, dextromethorphan and its 
metabolite dextrorphan, omeprazole and its metabolite 5-hydroxyomeprazole, and caffeine and 
its metabolite paraxanthine.  Samples of approximately 3 mL will be collected to determine the 
serum concentrations of ixekizumab.  Instructions for the collection and handling of blood 
samples will be provided by the sponsor.  The actual date and time (24-hour clock time) of each 
sampling will be recorded.


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9.5.1. Bioanalysis
Samples will be analyzed at a laboratory designated by the sponsor.  Plasma concentrations of 
each analyte in the drug cocktail will be assayed using a validated method.  Serum 
concentrations of ixekizumab will be measured using a validated enzyme-linked immunosorbent 
assay method.  
Bioanalytical samples collected to measure drug concentrations will be retained for a maximum 
of 1 year following last patient visit for the study.  
9.6.
Pharmacodynamics
The PASI, sPGA, and percent BSA are considered pharmacodynamic measures of disease 
activity in this study.
The PASI is the most commonly used primary endpoint and measure of psoriasis severity in 
clinical trials (EMA 2004; Menter et al. 2008).  The PASI combines assessments of the extent of 
BSA involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of 
desquamation, erythema, and plaque induration/infiltration (thickness) in each region, yielding 
an overall score of 0 for no psoriasis to 72 for severe disease (Fredriksson and Pettersson 1978).  
The static Physician Global Assessment (sPGA) is the physician’s global assessment of the 
patient’s psoriasis (Ps) lesions evaluated 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).
Percent BSA will be evaluated as the percent involvement of psoriasis on each patient’s BSA on 
a continuous scale from 0% (no involvement) to 100% (full involvement), where 1% 
corresponds to the size of the patient’s hand (including the palm, fingers, and thumb) (National 
Psoriasis Foundation 2009).
Data will be collected at the times shown in the Schedule of Activities (Section 2).
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, 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 psoriasis.  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 investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/institutional review boards impose shorter time limits, 
for the study at a facility selected by Lilly or its designee.  This retention period enables use of 


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new technologies, response to regulatory questions, and investigation of variable response that 
may not be observed until later in the development of ixekizumab.  
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, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
Whole blood samples for non-pharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for measurement of the inflammatory biomarkers, IL-1β, IL-6, IL-19, and 
Tumor Necrosis Factor .  C-reactive protein is collected as part of the clinical laboratory testing 
panel and may also be used as an exploratory biomarker.  Samples may also be used for research 
on the drug target, disease process, variable response to ixekizumab, pathways associated with 
psoriasis, mechanism of action of ixekizumab, and/or research method, or for validating 
diagnostic tools or assay(s) related to psoriasis.  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 
investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, at a facility selected by Lilly 
or its designee.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1.
Sample Size Determination
Approximately 30 patients will be enrolled with the assumption that 21 complete the study.  
Midazolam
For midazolam AUC and Cmax, the intrasubject variability (CV) was estimated to be 16.1% and 
26.4%, respectively (derived from a previous study).  Based on this assumption, 21 patients will 
provide a precision of 0.1 and 0.17 on a log-scale for AUC and Cmax, respectively.  This would 
result in a 90% probability that the half-width of the 90% CI of the ratio of the geometric means 
for AUC and Cmax is no larger than 9.8% and 15.3%, respectively.  .  
Warfarin
For S-warfarin AUC and Cmax, the intrasubject variability (CV) was estimated to be 7% and 8%, 
respectively (Steinijans et al. 1995).  Based on these estimates, 21 patients will provide a 
precision of 0.045 and 0.049 on a log-scale for AUC and Cmax, respectively.  This would result 
in a 90% probability that the half-width of the 90% CI of the ratio of the geometric means for
AUC and Cmax is no larger than 4.4% and 4.8%, respectively.  
Dextromethorphan
For dextromethorphan AUC and Cmax, the intrasubject variability (CV) was estimated to be 
33.5% and 32.1%, respectively (derived from a previous study).  Based on these estimates, 
21 patients will provide a precision of 0.206 and 0.197 on a log-scale for AUC and Cmax, 
respectively.  This would result in a 90% probability that the half-width of the 90% CI of the 
ratio of the geometric means for AUC and Cmax is no larger than 18.6% and 17.9%, respectively.  
Omeprazole
For omeprazole AUC and Cmax, the intrasubject variability (CV) was estimated to be 21.8% and 
29.8%, respectively (Public Assessment Report 1 Omeprazole “Copyfarm” Omeprazole).  Based 
on these assumptions, 21 patients will provide a precision of 0.135 and 0.184 on a log-scale for
AUC and Cmax, respectively.  This would result in a 90% probability that the half-width of the 
90% CI of the ratio of the geometric means for AUC and Cmax is no larger than 12.6% and 
16.8%, respectively.  
Caffeine
For caffeine AUC and Cmax, the intrasubject variability (CV) was estimated to be 21.0% 
(Blanchard and Sawers 1983) and 23.4% (Turpault et al. 2009), respectively.  Based on these 
estimates, 21 patients will provide a precision of 0.13 and 0.148 on a log-scale for AUC and 
Cmax, respectively.  This would result in a 90% probability that the half-width of the 90% CI of 
the ratio of the geometric means is no larger than 12.2% and 13.8%, respectively.  


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10.2.
Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study.  
10.2.2. Study Participant Characteristics
The patient’s age, sex, race, weight, height, BMI, and other demographic characteristics will be 
recorded.  Baseline disease severity (PASI and sPGA score, and percentage of BSA), age of 
psoriasis onset, and previous psoriasis therapy type will also be recorded and reported.
Patient characteristics will be summarized.  The summaries will include descriptive statistics 
(mean, standard deviation, sample size, minimum, maximum, lower and upper quartiles) for the 
continuous parameters, and frequencies and percentages for the remaining categorical 
parameters.  
10.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  For drug cocktail PK, the 
full analysis set includes all data from all patients receiving at least one dose of drug cocktail, 
with evaluable PK data, according to the treatment the patients actually received.  For 
ixekizumab PK, the full analysis set includes all data from all patients receiving at least one dose 
of ixekizumab with evaluable PK data.  
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements. Pharmacodynamic and biomarker analyses will be conducted for all 
patients receiving at least one dose of ixekizumab with at least one postbaseline measurement in
Period 2.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Pharmacokinetic Analyses
10.3.1.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for midazolam and 1-hydroxymidazolam, S-warfarin, 
dextromethorphan and dextrorphan, omeprazole and 5-hydroxyomeprazole, and caffeine and 
paraxanthine will be calculated by standard noncompartmental methods of analysis.
For ixekizumab, sparse sampling is conducted to obtain concentrations over the time course of 
the study which will be summarized using descriptive statistics.  
For midazolam and 1-hydroxymidazolam, S-warfarin, dextromethorphan and dextrorphan, 
omeprazole and 5-hydroxyomeprazole, and caffeine and paraxanthine, the primary parameters 


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for analysis will be Cmax and area under the concentration versus time curve from zero to infinity 
(AUC[0-∞]).  Other noncompartmental parameters such as time of maximum observed drug 
concentration (tmax), area under the concentration versus time curve from time zero to the last 
time point with a measurable concentration (AUC[0-tlast]), half-life associated with the terminal 
rate constant in noncompartmental analysis (t1/2), apparent clearance, and apparent volume of 
distribution may be reported.  
Exploratory analyses of the metabolite to parent ratios may be conducted.
10.3.1.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates of cocktail drugs will be evaluated to delineate the effects 
of drug interaction.  Midazolam, warfarin, dextromethorphan, omeprazole, and caffeine 
administered in the absence of ixekizumab will represent the reference treatments and will be 
analyzed separately.  Each drug administered with ixekizumab will represent the test treatments
and will be analyzed separately. Data for each drug will also be analyzed separately after single 
or multiple doses of ixekizumab.  For the primary analysis, log-transformed Cmax and AUC(0-∞) 
estimates will be evaluated in a linear mixed-effects analysis of variance model with a fixed 
effect for treatment and a random effect for patient.  The treatment differences will be 
back-transformed to present ratios of geometric least squares means and the corresponding 90% 
CIs. 
The AUC(0-tlast) will be analyzed using the same method described above.
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CI, and p-values will be calculated.  
10.3.2. Immunogenicity Analyses
Immunogenicity data will be listed for individual patients and the frequency of antibody
detection will be reported at each time point.  
10.3.3. Exploratory Analyses
The same model used for the primary analysis will be applied to the subgroups of responders to 
ixekizumab and nonresponders at Week 12.  The treatment differences for each subgroup will be 
back-transformed to present ratios of geometric least squares means and the corresponding 90% 
CIs.  
A responder to ixekizumab will be defined as a patient with a sPGA equal to 0 or 1 at Week 12.  
A nonresponder will be defined as a patient with sPGA >1 at Week 12.
Change from baseline in percentage of BSA, percent change from baseline in PASI scores, sPGA 
(0,1) response, and PASI 75 response will be calculated at each time point and summarized using 
descriptive statistics.  


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10.3.4. Safety Analyses
10.3.4.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to study treatment will be distinguished from those reported as new or increased in severity 
during the study.  Each symptom will be classified by the most suitable term from the medical 
regulatory dictionary.
The number of investigational product-related SAEs will be reported.
10.3.4.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 
C-SSRS scores.  The parameters will be listed, and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.
10.3.5. Interim Analyses
No interim analysis is planned for this study.


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11.
References
[APA] American Psychiatric Association. Diagnostic and statistical manual of mental disorders 
4th ed. Washington DC; 1994.
Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. 
1983;24(1):93-98.
EMA CPMP/EWP/560/95/Rev. 1 Corr 2. Guideline on the investigation of drug interactions. 
2012.
EMA Committee for medicinal products for human use (CHMP). Guideline on clinical 
investigation of medicinal products indicated for the treatment of psoriasis. 
2004;CHMP/EWP/2454/02 corr. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
0 0003329.pdf. Accessed 08 April 2016.
FDA Center for Drug Evaluation and Research. Guidance for Industry – Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. 2012.
Fredriksson T, Pettersson U. Severe psoriasis-oral therapy with a new retinoid. Dermatologica.
1978;157(4):238-244.
Goh BC, Reddy NJ, Dandamudi UB, Laubscher KH, Peckham T, Hodge JP, Suttle AB, 
Arumugham T, Xu Y, Xu CF, Lager J, Dar MM, Lewis LD. An evaluation of the drug 
interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine 
kinase inhibitor, using a modified Cooperstown 5 + 1 cocktail in patients with advanced solid 
tumors. Clin Pharmacol Ther. 2010;88(5):652-659.
Ma JD, Nafziger AN, Villano SA, Gaedigk A, Bertino JS Jr. Maribavir pharmacokinetics and the 
effects of multiple –dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, 
CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase in healthy adults. Antimicrob 
Agents Chemother. 2006;50(4):1130-1135.
Menter A, Gottlieb A, Feldman SR, VanVoorhees AS, Leonardi CL, Gordon KB, Lebwohl M, 
Koo JYM, 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.
National Psoriasis Foundation. The Psoriasis and Psoriatic Arthritis Pocket Guide. Portland, OR.
2009.
Pharmaceuticals Medical Devices Agency (PMDA) Draft Guideline on Drug Interactions. 2013. 
Guideline on Drug Interactions.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-1043.


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Steinijans VW, Sauter R, Hauschke D, Diletti E, Schall R, Luus HG, Elze M, Blume H, Hoffman 
C, Franke G et al. Reference tables for the intrasubject coefficient of variation in 
bioequivalence studies. Int J Clin Pharmacol Ther. 1995;33(8):427-430. 
Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulenc X. 
Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. 
Br J Clin Pharmacol. 2009;68(6):928-935.
Wang J, Wang YM, Ahn HY. Biological products for the treatment of psoriasis: therapeutic 
targets, pharmacodynamics and disease-drug-drug interaction implications. AAPS J. 
2014;16(5):938-947.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
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 AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from zero to infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to the last time point with a 
measurable concentration
BCG
Bacillus Calmette-Guérin
BMI
body mass index
BP
blood pressure
BSA
body surface area
C CASA
Columbia Classification Algorithm of Suicide Assessment
CEC
Clinical Events Committee
CI
confidence interval
Cmax
maximum observed drug concentration
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 the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist


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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.
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interactions
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
hGH
human growth hormone
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IL
interleukin
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial 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.  
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.


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investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
MI
myocardial infarction
Non-
investigational 
product
A product that is not being tested or used as a reference in the clinical trial, but is provided 
to patients and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PASI
Psoriasis Area Severity Index
PPD
purified protein derivative
PK
pharmacokinetic
PUVA
psoralen and ultraviolet A
QIDS-SR16
Quick Inventory of Depressive Symptomatology-Self Report (16 items)
SAE
serious adverse event
SC
subcutaneous(ly)
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 trial.  
sPGA
Static Physicians Global Assessment
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
TB
tuberculosis
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  Any 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 
tmax
time of maximum observed drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Glucose random
Leukocytes (WBC)
Blood urea nitrogen (BUN)
Cell morphology
Uric acid 
Absolute counts of:
Total cholesterol 
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Platelets
Alanine aminotransferase (ALT)
Creatinine
Coagulation parametersa
Gamma-glutamyl transferase (GGT)
aPTT
High sensitivity C-reactive protein (hsCRP)
PT
INR
Additional testsa
Ethanol breath testing
Inflammatory biomarkersa,b
Urine drug screen
IL-1β
PPD/QuantiFERON-TB Gold/T-SPOTd
IL-6
Hepatitis B surface antigend
IL-19
Hepatitis B core antibody (HBcAb+)d
Tumor necrosis factor 
Hepatitis C antibodyd
HIVd
Urinalysisa
Pregnancy teste
Specific gravity
FSH (females, as appropriate)d
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Nitrite
Urine creatinine
Leukocyte esterase
Microscopic analysis of sedimentc
Abbreviations:  aPTT = activated partial thromboplastin time; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; IL = interleukin; INR = international normalized ratio; PPD = purified protein 
derivative; PT = prothrombin time; RBC = red blood cells; WBC = white blood cells.


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a
Results will be validated by local or central laboratory at the time of initial testing (screening tests, pregnancy 
tests and ethanol and drug screen performed locally, all other tests performed at central laboratory).
b
Samples obtained at time points detailed in the Schedule of Activities (Section 2).
c
Test only if dipstick result is abnormal.  
d
Performed at screening only.
e
Serum pregnancy test to be performed at screening.  Serum or urine pregnancy test may be performed at all other 
times, at the discretion of the investigator.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study.

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.
Ethical Review
The investigator or appropriate local representative must give assurance that the 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 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF 

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) 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 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
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.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
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.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or 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 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 the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.


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Ixekizumab (LY2439821)
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Ixekizumab (LY2439821)
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 Lilly or its designee CRP.
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
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Ixekizumab (LY2439821)
Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I1F-MC-RHBU Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
35
1
35
Clinical laboratory testsa
12
12
144
Pharmacokinetics:
Midazolam
Warfarin
Dextromethorphan
Omeprazole
Caffeine
Ixekizumab
2
2
2
2
2
3
30
33
30
33
33
7
60
66
60
66
66
21
Ixekizumab immunogenicity 
7.5
7
52.5
Inflammatory biomarkers
7
5
35
Blood discard for cannula patency
1
33
33
Pharmacogenetics
10
1
10
Total
648.5
Total for clinical purposes [rounded up to nearest 10 mL] 
650
a
Additional samples may be drawn if needed for safety purposes.


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Ixekizumab (LY2439821)
Appendix 6.
Protocol Amendment I1F-MC-RHBU(a) 
Summary
Evaluation of the Effect of Ixekizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in 
Patients with Moderate-to-Severe Plaque Psoriasis
Overview
Protocol I1F-MC-RHBU, Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of 
Cytochrome P450 Substrates in Patients with Moderate-to-Severe Plaque Psoriasis, has been 
amended.  The new protocol is indicated by Amendment (a) and will be used to conduct the 
study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

In Section 1, text in the “Treatment Arms and Duration” section a typographic error was 
correct to remove a minus sign and to indicate dose of drug cocktail occurs on Day 1.

In Section 1, confidence interval related text in the “Statistical Analysis” section was 
deleted based upon regulatory feedback.

In Section 2, the Schedule of Activities for Period 2 was updated to remove the ± 2d text 
from the D8, D9, D10, D11, and D12 columns; this change makes the schedule of 
activities consistent with footnote g.

In Section 6.1, inclusion criterion 1 was updated to indicate that the use of reliable 
methods of contraception for women of child-bearing potential participating in the study
will extend until 3 months after the last dose of ixekizumab received in the study and a 
typographic error was corrected.

In Section 9.6, text describing how lesions are categorized by the sPGA was updated to 
be consistent with other ixekizumab studies in patients with psoriasis.

In Section 10.1, a typographical error was corrected and text related to the confidence 
intervals was updated based upon regulatory feedback.  

In Section 10.3.1.2, text related to the confidence intervals for Cmax and AUC(0-∞) was 
deleted based upon regulatory feedback.

In Section 10.3.3, text was deleted in order to be consistent with the SAP.


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Ixekizumab (LY2439821)
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1. Protocol Synopsis
Treatment Arms and Duration:  
In Period 1, patients will receive a single oral dose of drug cocktail (with single oral doses of 1 mg midazolam, 
10 mg warfarin [+ 10 mg vitamin K], 30 mg dextromethorphan, 20 mg omeprazole, and 100 mg caffeine) on Day
minus 1 and PK sampling will be conducted up to 96 hours post-drug cocktail dose (Day 5).
Statistical Analysis:  
For each drug administered with ixekizumab, if the CIs for both Cmax and AUC(0-∞) of parent drug are contained 
within the 0.7 and 1.43 limits, a no drug-drug interaction will be declared for that drug and ixekizumab.
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and C-SSRS scores.  The 
parameters will be listed, and summarized using standard descriptive statistics.  


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Ixekizumab (LY2439821)
2.  Schedule of Activities
Study Schedule Protocol I1F-MC-RHBU – Period 2
W 0
Check-in 
for W 1
W 1
W 2
W 4
W 6
W 8
W 10
D 1e
D 7g
±2d
D 8g
±2d
D 9g
±2d
D 10g
±2d
D 11g
±2d
D 12g
±2d
D 15
±2d
D 29
±2d
D 43
±2d
D 57
±2d
D 71
±2d
Procedure
Patient Admission to 
CRU
X
Patient Discharge from 
CRU
Xh
Outpatient Visit
X
X
X
X
X
X
X
X
X
Review of AEs
X
Review Concomitant 
Medications
X
Urine Drug Screen
X
Ethanol breath test
X
Vital Signs (Supine 
and Standing Blood 
Pressure and Pulse 
Rate and Body 
Temperature)
Predosef
X
X
Predosef
Predosef
Predosef
Predosef
Predosef
Clinical Laboratory 
Testsa
Predosef
X
X
X
Predosef
Pregnancy Testb
Predosef
Medical Assessmentc
X
12-Lead ECG
Predosef
QIDS-SR16 
X
C-SSRS and 
Self-Harm Supplement
Predosef
X
X
Predosef
Predosef
Predosef
Predosef
Predosef
PASI
Predosef
X
X
X
sPGA
Predosef
X
X
X
% BSA Assessment
Predosef
X
X
X
Inflammatory 
Predosef
X
Predosef
Predosef


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Ixekizumab (LY2439821)
W 0
Check-in 
for W 1
W 1
W 2
W 4
W 6
W 8
W 10
D 1e
D 7g
±2d
D 8g
±2d
D 9g
±2d
D 10g
±2d
D 11g
±2d
D 12g
±2d
D 15
±2d
D 29
±2d
D 43
±2d
D 57
±2d
D 71
±2d
Procedure
Biomarker Sample
Ixekizumab 
Administration
160 mg
80 mg
80 mg
80 mg
80 mg
80 mg
Drug Cocktail 
Administration
X
Ixekizumab PK 
Sample
Predosef
X
Predosef
Predosef
Predosef
Midazolam and 
1-hydroxymidazolam
PK Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8,12 h
24 h
Warfarin PK Sampled
Predose, 1, 
2, 4, 6, 8, 
10 h
24 h
48 h
72 h
96 h
Dextromethorphan and 
Dextrorphan PK 
Sampled
Predose, 1, 
2, 4,6, 8, 
10 h
24 h
48 h
72 h
Omeprazole and 
5-hydroxyomeprazole
PK Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24 h
48 h
Caffeine and 
Paraxanthine PK 
Sampled
Predose, 
0.5, 1, 2, 3, 
4, 6, 8, 
12 h
24 h
48 h
Ixekizumab 
Immunogenicity 
Sample
Predosef
X
Predosef
Predosef
Predosef
Abbreviations:  AE = adverse event; BSA = body surface area; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; 
ECG = electrocardiogram; ED = early discontinuation; PASI = Psoriasis Area Severity Index; PK = pharmacokinetics; QIDS-SR16 = Quick Inventory of 
Depressive Symptomatology-Self Report (16 items); sPGA = static Physicians Global Assessment; W = Week.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
a
All clinical laboratory test samples tested at a central laboratory.  Additional samples for coagulation parameters (Appendix 2) may be collected and tested at 
a local laboratory at the discretion of the investigator.  
b
Females only.  Serum or urine pregnancy test may be performed locally, at the discretion of the investigator.  
c
All medical assessments throughout the study should include a symptom directed physical as well as examination of heart, lungs, abdomen, and visual 
examination of the skin.
d
Sample times are relative to administration of the drug cocktail.  The PK sample collection times are nominal; actual times should be recorded.  Separate 
blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, warfarin, dextromethorphan, and midazolam).  
e
Day 1 of Period 2 will be 3 to 7 days after Day 5 of Period 1.  
f
Time is relative to that day’s ixekizumab dose.
g
Drug cocktail administration and drug cocktail PK sampling days must run consecutively from admission to CRU (on Day 5 to Day 9).
h
Patients may be discharged after collection of the 24 hour PK sample, at the discretion of the investigator.


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
6.1.  Inclusion Criteria 
Women not of child-bearing potential may participate, and include those who are:
a)
Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal 
ligation), congenital anomaly such as Müllerian mullerian agenesis; or
Women of child-bearing potential may participate, and include those who test 
negative for pregnancy prior to initiation of treatment based on a serum pregnancy 
test and agree to use a reliable method of contraception during the study and until 
3 months after the last dose of ixekizumab received in the study.
9.6.  Pharmacodynamics 
The static Physician Global Assessment (sPGA) is the physician’s global assessment of the 
patient’s psoriasis (Ps) lesions evaluated 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  The sPGA is a physician’s 
assessment of the patient’s psoriasis lesions overall at a given time point.  The sPGA is 
recommended as an endpoint for assessing efficacy in the treatment of psoriasis (EMA 2004).  
Overall lesions are graded for induration, erythema, and scaling; and the sum of the 3 scores is 
divided by 3 to obtain a final sPGA score (range 0 to 5).  For the analysis of responder rates, the 
sPGA scores are rounded to the nearest whole number, and the patient’s psoriasis is assessed as
clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5).  
10.1.  Sample Size Determination
Approximamtely 30 patients will be enrolled with the assumption that 21 complete the study.  
For each of the following drugs, a lack of drug to drug interaction will be declared if the 90% 
confidence interval (CI) for the ratio of the least squares means for both area under the 
concentration versus time curve (AUC) and maximum observed drug concentration (Cmax) of 
parent drug are contained within the limits 0.7 and 1.43.
Midazolam
For midazolam AUC and Cmax, the intrasubject variability (CV) was estimated to be 16.1% and 
26.4%, respectively (derived from a previous study).  Based on this assumption, 21 patients will 
provide a precision of 0.1 and 0.17 on a log-scale for AUC and Cmax, respectively.  This would 
result in a 90% probability that the half-width of the 90% CI of the ratio of the geometric means 
for AUC and Cmax is no larger than 9.8% and 15.3%, respectively.    98% chance of declaring 
lack of drug interaction assuming a ratio equal to 1.05.  
Warfarin


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Ixekizumab (LY2439821)
For S-warfarin AUC and Cmax, the intrasubject variability (CV) was estimated to be 7% and 8%, 
respectively (Steinijans et al. 1995).  Based on these estimates, 21 patients will provide a 
precision of 0.045 and 0.049 on a log-scale for AUC and Cmax, respectively.  This would result 
in a 90% probability that the half-width of the 90% CI of the ratio of the geometric means for 
AUC and Cmax is no larger than 4.4% and 4.8%, respectively.greater than 99% chance of 
declaring lack of drug interaction assuming a ratio equal to 1.05.  
Dextromethorphan
For dextromethorphan AUC and Cmax, the intrasubject variability (CV) was estimated to be 
33.5% and 32.1%, respectively (derived from a previous study).  Based on these estimates, 
21 patients will provide a precision of 0.206 and 0.197 on a log-scale for AUC and Cmax, 
respectively.  This would result in a 90% probability that the half-width of the 90% CI of the 
ratio of the geometric means for AUC and Cmax is no larger than 18.6% and 17.9%, 
respectively..90% chance of declaring lack of drug interaction assuming a ratio equal to 1.05.  
Omeprazole
For omeprazole AUC and Cmax, the intrasubject variability (CV) was estimated to be 21.8% and 
29.8%, respectively (Public Assessment Report 1 Omeprazole “Copyfarm” Omeprazole).  Based 
on these assumptions, 21 patients will provide a precision of 0.135 and 0.184 on a log-scale for 
AUC and Cmax, respectively.  This would result in a 90% probability that the half-width of the 
90% CI of the ratio of the geometric means for AUC and Cmax is no larger than 12.6% and 
16.8%, respectively. a 95% chance of declaring lack of interaction assuming a ratio equal to 
1.05.  
Caffeine
For caffeine AUC and Cmax, the intrasubject variability (CV) was estimated to be 21.0% 
(Blanchard and Sawers 1983) and 23.4% (Turpault et al. 2009), respectively.  Based on these 
estimates, 21 patients will provide a precision of 0.13 and 0.148 on a log-scale for AUC and 
Cmax, respectively.  This would result in a 90% probability that the half-width of the 90% CI of 
the ratio of the geometric means is no larger than 12.2% and 13.8%, respectively. greater than 
99% chance of declaring lack of drug interaction assuming a ratio equal to 1.05.  
10.3.1.2 Pharmacokinetic Statistical Inference
For each drug administered with ixekizumab, if the CIs for both Cmax and AUC(0-∞) of parent 
drug are contained within the 0.7 and 1.43 limits, a no drug-drug interaction will be declared for 
that drug and ixekizumab.
10.3.3.  Exploratory Analyses
A repeated-measure mixed model will be used to summarize the changes over time in 
exploratory biomarkers after ixekizumab dosing in Period 2.  The model may include baseline, 


I1F-MC-RHBU(a) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
time, responder status (yes/no), and time*responder status interaction as fixed effects.  Patient 
will be included as a random effect.


Leo Document ID = b0aebef4-91f8-4e84-a152-0ebb784167c4
Approver: 
Approval Date & Time: 06-Dec-2016 21:29:12 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 08-Dec-2016 14:00:36 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I1F-MC-RHBU V3 
Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of Cytochrome P450 Substrates 
in Patients with Moderate-to-Severe Plaque Psoriasis 
NCT02993471 
Approval Date: 31-May-2017 


Final V3, 22 May 2017
             Page 1 of 24
STATISTICAL ANALYSIS PLAN
Evaluation of the Effect of Ixekizumab on the Pharmacokinetics of Cytochrome P450 
Substrates in Patients with Moderate-to-Severe Plaque Psoriasis
Statistical Analysis Plan Status:  Final V3
Statistical Analysis Plan Date:  22 May 2017
Study Drug: Ixekizumab (LY2439821)
Sponsor Reference:  I1F-MC-RHBU
Covance CRU Study: 1000071-8342913
Clinical Phase I
Approval Date: 31-May-2017 GMT


Final V3, 22 May 2017
             Page 2 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary objective .................................................................................................... 6
4.2
Secondary objective................................................................................................. 6
4.3
Exploratory objectives............................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ............................................................................... 10
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 11
9.
STATISTICAL METHODOLOGY ............................................................................. 12
9.1
General.................................................................................................................. 12
9.2
Demographics and Patient Disposition................................................................... 12
9.3
Pharmacokinetic Assessment................................................................................. 13
9.3.1
Pharmacokinetic Analysis............................................................................. 13
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 17
9.4
Pharmacodynamic Assessment .............................................................................. 18
9.4.1
Pharmacodynamic Analysis.......................................................................... 18
9.4.1.1 Static Physicians Global Assessment (sPGA) ............................................... 21
9.4.1.2 Psoriasis Area Severity Index (PASI) ........................................................... 21
9.4.1.3 Percentage of Body Surface Area (%BSA) Assessment ................................ 21
9.4.1.4
Exploratory biomarkers ............................................................................... 21
9.5
Safety and Tolerability Assessments...................................................................... 22
9.5.1
Adverse events ............................................................................................. 22
9.5.2
Concomitant medication............................................................................... 22
9.5.3
Clinical laboratory parameters...................................................................... 22
9.5.4
Vital signs .................................................................................................... 22
9.5.5
Electrocardiogram (ECG)............................................................................. 22
9.5.6
Immunogenicity ........................................................................................... 23
9.5.7
Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16). 23
9.5.8
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................... 23
9.5.9
Other assessments......................................................................................... 23
9.5.10
Safety and Tolerability Statistical Methodology............................................ 23


Final V3, 22 May 2017
             Page 3 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
10. INTERIM ANALYSES ............................................................................................... 23
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 23
12. REFERENCES ............................................................................................................ 23
13. DATA PRESENTATION ............................................................................................ 24
13.1 Derived Parameters ............................................................................................... 24
13.2 Missing Data ......................................................................................................... 24
13.3 Insufficient Data for Presentation .......................................................................... 24


Final V3, 22 May 2017
             Page 4 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from zero to infinity
%AUC(tlast-∞)
Fraction of AUC(0-∞) extrapolated
BQL
Below the quantifiable lower limit of the assay
BSA
Body surface area
Clast
Last measurable drug concentration
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CRU
Clinical Research Unit
CV
Coefficient of variation
CYP
cytochrome P450
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantitation
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio calculated as AUC(0-) metabolite/AUC(0-∞) 
parent
PASI
Psoriasis Area Severity Index


Final V3, 22 May 2017
             Page 5 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
PD
Pharmacodynamic
PK
Pharmacokinetic
QIDS-SR16
Quick Inventory of Depressive Symptomatology-Self Report
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
sPGA
static Physicians Global Assessment
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organisation


Final V3, 22 May 2017
             Page 6 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
25 August 2016 and Amendment [a] dated 08 December 2016).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned tables, figure 
and listings (TFLs) to be presented in the clinical study report (CSR) is provided in the 
accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical, PD and PK analyses of data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between Eli Lilly and Company and Covance Early Clinical (EC)
Biometrics. A limited amount of information concerning this study (e.g., objectives, study 
design) is given to help the reader’s interpretation. This SAP must be signed off prior to first 
patient administration for this study. When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary objective
To assess the effects of single and multiple doses of ixekizumab on the PK of a drug cocktail of 
cytochrome P450 (CYP) substrates in patients with moderate-to-severe psoriasis.
4.2
Secondary objective
To evaluate the tolerability of ixekizumab in patients with moderate-to-severe psoriasis.
4.3
Exploratory objectives

To explore the effects of ixekizumab on the PK of a drug cocktail of CYP substrates in 
the subgroups of patients with moderate-to-severe psoriasis who respond to ixekizumab 
treatment at Week 12 and those who do not respond.


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
To evaluate the effects of ixekizumab treatment over time on inflammatory biomarker
concentrations in patients with moderate-to-severe psoriasis.

To determine the PK of metabolites and metabolite to parent ratios where appropriate.
5. STUDY DESIGN
This is a 2-period, fixed-sequence, open-label, multi-center, Phase 1 study to assess the effects of 
single and multiple doses of ixekizumab on the PK of a drug cocktail of CYP substrates 
(midazolam, warfarin, dextromethorphan, omeprazole, and caffeine) in patients with 
moderate-to-severe psoriasis.
Patients will be admitted to the clinical research unit (CRU) on Day -1 of Period 1 and receive 
the drug cocktail, with single oral doses of 1 mg midazolam, 10 mg warfarin (+ 10 mg 
vitamin K), 30 mg dextromethorphan, 20 mg omeprazole, and 100 mg caffeine on the morning 
of Day 1.  Patients will reside at the CRU until Day 2 and may be discharged from the CRU 
following collection of the 24 hour PK samples, at the discretion of the investigator.  Patients 
will return to the CRU as outpatients for collection of PK samples and safety assessments, as 
applicable, on Day 3 (48 hours post-drug cocktail dose), Day 4 (72 hours post-drug cocktail 
dose), and Day 5 (96 hours post-drug cocktail dose).
Patients will attend the CRU as outpatients on Day 1 of Period 2 (3 to 7 days after Day 5 of 
Period 1) and receive a 160-mg dose of ixekizumab (administered as two 80-mg subcutaneous
[SC] injections).
Patients will be admitted to the CRU on Day 7 (±2 days) of Period 2 and receive the drug 
cocktail on the following morning (Day 8; Week 1). Patients will reside at the CRU until Day 9 
and may be discharged from the CRU following collection of the 24 hour PK samples, at the 
discretion of the investigator. Patients will return to the CRU as outpatients for collection of PK 
samples and safety assessments, as applicable, on Day 10 (48 hours post-drug cocktail dose), 
Day 11 (72 hours post-drug cocktail dose), and Day 12 (96 hours post-drug cocktail dose).
Patients will receive single 80-mg doses of ixekizumab on Day 15 (Week 2), Day 29 (Week 4), 
Day 43 (Week 6), Day 57 (Week 8), and Day 71 (Week 10) of Period 2. Patients will be 
admitted to the CRU on Day 84 (±2 days) and receive 80 mg ixekizumab and the drug cocktail 
on the following morning (Day 85; Week 12). Patients will reside at the CRU until Day 86 and 
may be discharged from the CRU following collection of the 24 hour PK samples, at the 
discretion of the investigator. Patients will return to the CRU as outpatients for collection of 
additional drug cocktail PK samples and safety assessments, as applicable, on Day 87 (48 hours 
post-drug cocktail dose), Day 88 (72 hours post-drug cocktail dose), and Day 89 (96 hours 
post-drug cocktail dose).
Blood sampling for assessment of inflammatory biomarkers (IL-1β, IL-6, IL-19, and Tumor 
Necrosis Factor α) and ixekizumab PK and immunogenicity will be conducted at prespecified 
visits. Concentrations of IL-17A will not be measured as it complexes with ixekizumab, and 
therefore correlates with the PK of ixekizumab. Interleukin-17A drives production of IL-19 in 
keratinocytes of psoriatic skin. C-reactive protein will also be used as an inflammatory 
biomarker and is collected as part of the clinical laboratory testing. Efficacy will be evaluated 


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using static Physicians Global Assessment (sPGA), Psoriasis Area Severity Index (PASI), and 
percentage of body surface area (BSA) assessments at prespecified visits.
All patients will attend a follow-up visit on Day 113 (±4 days; Week 16).
Figure RHBU.1 illustrates the study design.
Abbreviations:  BSA = body surface area; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; sPGA = 
static Physicians Global Assessment.
Figure RHBU.1. Illustration of Study Design for I1F-MC-RHBU
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the AE safety 
TFLs.
Study Treatment Name
Abbreviation
Treatment order 
in TFLs
1 mg midazolam + 10 mg warfarin (+ 10 mg 
vitamin K) + 30 mg dextromethorphan + 20 mg 
omeprazole + 100 mg caffeine
Drug cocktail (Period 1)
1
160 mg ixekizumab
160 mg ixekizumab
(Period 2)
2


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160 mg ixekizumab + 1 mg midazolam + 10 mg 
warfarin (+ 10 mg vitamin K) + 30 mg 
dextromethorphan + 20 mg omeprazole + 
100 mg caffeine
160 mg ixekizumab + 
Drug cocktail (Period 2)
3
80 mg ixekizumab Q2W
80 mg ixekizumab Q2W 
(Period 2)
4
80 mg ixekizumab Q2W + 1 mg midazolam + 10 
mg warfarin + 30 mg dextromethorphan + 20 mg 
omeprazole + 100 mg caffeine
80 mg ixekizumab Q2W 
+ Drug cocktail (Period 
2)
5
The following is a list of the study treatment abbreviations that will be used in the PK TFLs.
Study Treatment Name
Treatment 
order in TFLs
1 mg midazolam
1
160 mg ixekizumab + 1 mg midazolam
2
80 mg ixekizumab Q2W + 1 mg midazolam
3
10 mg warfarin
4
160 mg ixekizumab + 10 mg warfarin
5
80 mg ixekizumab Q2W + 10 mg warfarin
6
30 mg dextromethorphan
7
160 mg ixekizumab + 30 mg dextromethorphan
8


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80 mg ixekizumab Q2W + 30 mg 
dextromethorphan
9
20 mg omeprazole
10
160 mg ixekizumab + 20 mg omeprazole
11
80 mg ixekizumab Q2W + 20 mg omeprazole
12
100 mg caffeine
13
160 mg ixekizumab + 100 mg caffeine
14
80 mg ixekizumab Q2W + 100 mg caffeine
15
7. SAMPLE SIZE JUSTIFICATION
Approximately 30 patients will be enrolled with the assumption that 21 patients complete the 
study.
Midazolam
For midazolam AUC and Cmax, the intrasubject variability coefficient of variation (CV%) was 
estimated to be 16.1% and 26.4%, respectively (derived from a previous study).  Based on this 
assumption, 21 patients will provide a precision of 0.1 and 0.17 on a log-scale for AUC and Cmax, 
respectively.  This would result in a 90% probability that the half-width of the 90% confidence 
interval (CI) of the ratio of the geometric means for AUC and Cmax is no larger than 9.8% and 
15.3%, respectively.
Warfarin
For S-warfarin AUC and Cmax, the intrasubject variability CV% was estimated to be 7% and 8%, 
respectively (Steinijans et al. 1995).  Based on these estimates, 21 patients will provide a 
precision of 0.045 and 0.049 on a log-scale for AUC and Cmax, respectively.  This would result in 
a 90% probability that the half-width of the 90% CI of the ratio of the geometric means for AUC 
and Cmax is no larger than 4.4% and 4.8%, respectively.


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Dextromethorphan
For dextromethorphan AUC and Cmax, the intrasubject variability CV% was estimated to be 
33.5% and 32.1%, respectively (derived from a previous study).  Based on these estimates, 21 
patients will provide a precision of 0.206 and 0.197 on a log-scale for AUC and Cmax, 
respectively.  This would result in a 90% probability that the half-width of the 90% CI of the 
ratio of the geometric means for AUC and Cmax is no larger than 18.6% and 17.9%, respectively.
Omeprazole
For omeprazole AUC and Cmax, the intrasubject variability CV% was estimated to be 21.8% and 
29.8%, respectively (Public Assessment Report 1 Omeprazole “Copyfarm” Omeprazole).  Based 
on these assumptions, 21 patients will provide a precision of 0.135 and 0.184 on a log-scale for 
AUC and Cmax, respectively.  This would result in a 90% probability that the half-width of the 
90% CI of the ratio of the geometric means for AUC and Cmax is no larger than 12.6% and 
16.8%, respectively.
Caffeine
For caffeine AUC and Cmax, the intrasubject variability CV% was estimated to be 21.0% 
(Blanchard and Sawers 1983) and 23.4% (Turpault et al. 2009), respectively.  Based on these 
estimates, 21 patients will provide a precision of 0.13 and 0.148 on a log-scale for AUC and 
Cmax, respectively.  This would result in a 90% probability that the half-width of the 90% CI of 
the ratio of the geometric means is no larger than 12.2% and 13.8%, respectively.
8. DEFINITION OF ANALYSIS POPULATIONS
PK analyses will be conducted on the full analysis set.  For drug cocktail PK, the full analysis set 
includes all data from all patients receiving at least one dose of drug cocktail, with evaluable PK 
data, according to the treatment the patients actually received.
For ixekizumab PK, the full analysis set includes all data from all patients receiving at least one 
dose of ixekizumab with evaluable PK data.
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.
PD (i.e. sPGA, PASI, percent BSA) and biomarker (e.g IL-1β, IL1-6, IL-19, tumor necrosis 
factor α, C-reactive protein) analyses will be conducted for all patients receiving at least one 
dose of ixekizumab with at least one postbaseline measurement in Period 2.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.


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9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. Continuous data (such as PASI, sPGA, and 
%BSA) will be summarized in terms of the number of observations, mean, SD, minimum, 
median, and maximum.  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 statistic.  For categorical data, 
frequency count and percentages will be presented. Percentages will be presented to 1 decimal 
place.  Percentages will not be presented for zero counts.  Data listings will be provided for all 
patients up to the point of withdrawal, with any patients excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
patients included in the relevant analysis population.
Change from baseline will be calculated as the value at the visit of interest minus the baseline 
value.  Baseline is defined as Day -1, Period 1, if this value is missing the screening value may 
be used.  If all baseline values are missing for a particular variable, then the change from 
baseline and the percentage improvement from baseline will not be calculated.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.
Age, sex, and race will be reported on all by-patient listings unless otherwise specified.  Sex will 
be abbreviated as follows:  female (F) and male (M).  Race will be abbreviated as follows:  
American Indian or Alaska Native (AI), Asian (AS), Black or African American (BL), Native 
Hawaiian or other Pacific Islander (NH), White (WH), and Multiple (MU).  
Data analysis will be performed using SAS® Version 9.3 or greater.
9.2
Demographics and Patient Disposition
Patient disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.  All 
other demographic variables will be listed.
Baseline disease severity (PASI and sPGA score, and percentage of BSA), age of psoriasis onset, 
and previous psoriasis therapy type will also be summarized and listed.


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9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Noncompartmental methods applied with a validated software program Phoenix WinNonlin 
(Pharsight Corporation, Version 6.4 or higher) to the plasma concentrations of midazolam and its 
metabolite 1-hydroxymidazolam, S-warfarin, dextromethorphan and its metabolite dextrorphan, 
omeprazole and its metabolite 5-hydroxyomeprazole, and caffeine and its metabolite 
paraxanthine, respectively, and will be used to determine the following PK parameters, when 
possible:
midazolam, S-warfarin, dextromethorphan, omeprazole and caffeine 
Parameter
Units
Definition
AUC(0-)
h*ng/mL
area under the concentration versus time curve from zero to 
infinity
%AUC(tlast-)
%
fraction of AUC(0-) extrapolated
AUC(0-tlast)
h*ng/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after extra-
vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration


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1-hydroxymidazolam, dextrorphan, 5-hydroxyomeprazole, paraxanthine
Parameter
Units
Definition
AUC(0-)
h*ng/mL
area under the concentration versus time curve from zero to 
infinity
%AUC(tlast-)
%
fraction of AUC(0-) extrapolated
AUC(0-tlast)
h*ng/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
MR
N/A
Metabolic ratio calculated as AUC(0-∞) metabolite/ AUC(0-∞) 
parent
Metabolic ratios will be corrected for the molecular weights of the parent and metabolite using the 
molecular weights.
Ixekizumab concentrations will be listed and summarized using descriptive summary statistics. 
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool:  
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantitation (LLOQ), with at 
least one of these concentrations following Cmax. AUC(0-) values where the percentage 
of the total area extrapolated is more than 20% will be flagged. Any AUC(0-) value 
excluded from summary statistics will be noted in the footnote of the summary table.


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
Half-life (t½) will be calculated, when appropriate, based on the apparent terminal log-
linear portion of the concentration-time curve. The start of the terminal elimination phase 
for each patient will be defined by visual inspection and generally will be the first point at 
which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a patient or from a 
subsequent dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) 
sampling times. 


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
The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will 
be used to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.

Concentrations excluded from the mean calculation will be documented in the 
final study report.

A concentration average will be plotted for a given sampling time only if 2/3 of 
the individual data at the time point have quantifiable measurements that are 
± 10%. An average concentration estimated with less than 2/3 but more than 
3 data points may be displayed on the mean concentration plot if determined to be 
appropriate and will be documented within the final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:


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a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values

Individual values excluded as outliers will be documented in the final report.  Approval 
of the final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
The PK parameter estimates of cocktail drugs will be evaluated to delineate the effects of drug 
interaction.  Midazolam, warfarin, dextromethorphan, omeprazole, and caffeine administered in 
the absence of ixekizumab (Period 1, Day 1) will represent the reference treatments and will be 
analyzed separately. Each drug administered with ixekizumab will represent the test treatments
(Period 2, Day 8 for single dosing and Period 2, Day 85 for multiple dosing). For the primary 
analysis, log-transformed Cmax and AUC(0-∞) estimates of the parent drugs only will be 
evaluated in a linear mixed-effects analysis of variance model with a fixed effect for treatment 
and a random effect for patient. The treatment differences will be back-transformed to present 
ratios of geometric least squares means and the corresponding 90% CIs.
Example SAS code:
proc mixed data=pk;
    by parameter;
    class patient treatment;
    model log_pk = treatment / residual ddfm=kr;
    random patient;
    lsmeans treatment / alpha=0.1 cl pdiff;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
run;
The AUC(0-tlast) will be analyzed using the same method described above.


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The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference 
based on the observed medians, 90% CI, and p-values will be calculated.
The same model used for the PK analysis will be applied to the subgroups of responders to 
ixekizumab and nonresponders at Week 12.  This will be based on patients that have a Week 12 
assessment.  The treatment differences for each subgroup will be back-transformed to present 
ratios of geometric least squares means and the corresponding 90% CIs.
A responder to ixekizumab will be defined as a patient with a sPGA equal to 0 or 1 at Week 12.  
A nonresponder will be defined as a patient with sPGA >1 at Week 12.
Additional exploratory analyses may be conducted if needed.
9.4
Pharmacodynamic Assessment
9.4.1
Pharmacodynamic Analysis
The sPGA, PASI, and percent BSA are considered PD (efficacy) measures of disease activity in 
this study. Table 9.1 includes the description and derivation of the efficacy outcomes.


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Table RHBU.9.1. Description and Derivation of Efficacy Outcomes (PD measures)
Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
with Missing 
Components
sPGA
Static Physician Global 
Assessment (sPGA): the 
physician’s global 
assessment of the 
patient’s psoriasis (Ps) 
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 (0) 
Score is clear (0)
Single item, 
missing if 
missing
SPGA (0,1)
Score is Clear or Minimal (0 or 1)
Single item, 
missing if 
missing
PASI
Psoriasis Area and 
Severity Index (PASI): 
combines assessments 
of the extent of body-
surface involvement in 4 
anatomical regions 
(head and neck, trunk, 
arms, and legs) and the 
severity of scaling (S), 
redness (R), and plaque 
induration/infiltration 
(thickness, T) in each 
region, yielding an 
overall score of 0 for no
psoriasis to 72 for the 
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 plaque Ps; a 
100% improvement in PASI score from 
baseline
Missing if 
baseline or 
observed 
value is 
missing


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
with Missing 
Components
most severe disease 
(Fredriksson and 
Pettersson 1978).  
Severity is rated for 
each index (R, S, T) on 
a 0-4 scale (0 for no 
involvement up to 4 for 
very severe 
involvement):
0 = none
1 = slight
2 = moderate
3 = severe
4 = very severe
The body is divided into 
four anatomical regions 
comprising the head (h), 
upper limb (u), trunk (t), 
and lower limb (l).  In 
each of these areas, the 
fraction of total body 
surface area affected is 
graded on a 0-6 scale (0 
for no involvement; up 
to 6 for 90% - 100% 
involvement):  
0 = 0% (clear)
1 = >0% to <10%
2 = 10% to <30%
3 = 30% to <50%
4 = 50% to <70%
5 = 70% to <90%
6 = 90% to 100%
The various body 
regions are weighted to 
reflect their respective 
proportion of body 
surface area.  
PASI total 
score
Sum the 3 scores for each body region to 
give a lesion score sum.
Multiple the lesion score sum by the area 
score, for each body region to give 4 
individual subtotals.
Multiply each of the subtotals by amount 
of body surface area represented by that 
region, i.e., x 0.1 for head, x 0.2 for 
upper body, x 0.3 for trunk, and x 0.4 for 
lower limbs.
Add together each of the scores for each 
body region to give the final PASI score.
Missing if 
baseline or 
observed 
value is 
missing
PASI change 
from baseline
Calculated as:  observed PASI – baseline
PASI
Missing if 
baseline or 
observed 
value is 
missing
PASI percent 
improvement 
from baseline
Calculated as:  
.......
=
100 ×


 



  
If a patient has experienced an 
improvement, this measure will be 
positive.  If a patient has experienced a 
worsening in the condition, this measure 
will be negative.  
Missing if 
baseline or 
observed 
value is 
missing
BSA
Percentage of Body 
Surface Area (BSA):  
The investigator will
BSA
Collected as a single scale as part of 
PASI electronic case report form (eCRF) 
page.  Range from 0% to 100%.
Single item, 
missing if 
missing


Final V3, 22 May 2017
             Page 21 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
with Missing 
Components
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 change 
from baseline
Calculated as:  observed BSA – baseline 
BSA 
Missing if 
baseline or 
observed 
value is 
missing
9.4.1.1
Static Physicians Global Assessment (sPGA)
The proportion of patients who achieve sPGA (0,1) and sPGA (0) will be summarized over time
using descriptive statistics.  A by-patient listing of sPGA scores and response rates will be 
provided.  The listing will include patient number, treatment, timepoint, sPGA score and the 
sPGA response.    
9.4.1.2
Psoriasis Area Severity Index (PASI)
The proportion of patients who achieve PASI 75 (at least a 75% improvement from baseline in 
PASI score), PASI 90 (at least a 90% improvement from baseline in PASI score) and PASI 100 
(a 100% improvement from baseline in PASI score) will be summarized over time using 
descriptive statistics.  In addition, the change from baseline and percent improvement from 
baseline will be summarized over time using descriptive statistics. A by-patient listing of PASI 
will be provided.  The listing will include patient number, treatment, timepoint, PASI total score, 
change from baseline, percent improvement and the PASI response.  
9.4.1.3
Percentage of Body Surface Area (%BSA) Assessment
The change from baseline in the %BSA will be summarized over time using descriptive 
statistics.  A by-patient listing of sPGA will be provided.  The listing will include patient 
number, treatment, timepoint, %BSA and change from baseline in the %BSA.    
9.4.1.4
Exploratory biomarkers
Concentration of the exploratory biomarkers, IL-1β, IL-6, IL-19, tumor necrosis factor α and C-
reactive protein, and their change from baseline will be summarized by treatment and listed.


Final V3, 22 May 2017
             Page 22 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the patient has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. AEs by day of onset will be presented.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of patients
experiencing an AE and the percentage of patients experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 19.1 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version
September 2016). Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All laboratory parameters will be reported in both conventional and SI units.
All clinical chemistry and hematology data will be summarized over time, and listed.  Baseline is 
defined as Day -1, Period 1. Urinalysis data will be listed. Additionally clinical chemistry, 
hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual patient data listings.
9.5.4 Vital signs
Vital signs data and change from baseline will be summarized over time and listed.  Baseline is 
defined as Day -1, Period 1.
9.5.5 Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented.


Final V3, 22 May 2017
             Page 23 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
9.5.6 Immunogenicity
Immunogenicity data will be summarized for treatment-emergent antidrug antibody (TE-ADA); 
definitions are documented in the ixekizumab program safety analysis plan (PSAP).
By-patient figures will also be provided which will include immunogenicity results, PK 
concentration and efficacy endpoints.  
A by-patient listing of immunogenicity data will be provided, to include patient, treatment, visit, 
TE-ADA status, NAb (neutralizing antibody) status, titer and PK concentration.  
Upon review of the data, additional analyses of immunogenicity data may be conducted.
9.5.7 Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16)
Data from the QIDS-SR16 questionnaire will be listed.
9.5.8 Columbia-Suicide Severity Rating Scale (C-SSRS)
Data from the C-SSRS will be listed.
9.5.9
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.5.10 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
The PASI 90% and PASI 100% response will be reported in addition to the PASI 75% response. 
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.


Final V3, 22 May 2017
             Page 24 of 24
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  1000071-8342913
Sponsor Reference I1F-MC-RHBU
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 6cdf6f38-7a3a-4daa-ba35-9a2611e578ef
Approver:
Approval Date & Time: 25-May-2017 08:33:45 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-May-2017 12:53:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-May-2017 07:09:36 GMT
Signature meaning: Approved
PPD
PPD
PPD