Clinical trial NCT03718884
Conditions: Psoriasis
Sponsor: Eli Lilly and Company
Start date: 2018-10-23; Completion date: 2019-10-28
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is known as a "drug interaction study." The purpose is to learn how commonly used drugs or substances (midazolam, warfarin, dextromethorphan, omeprazole, and caffeine) and their breakdown products get into the bloodstream after taking a "cocktail" (combination) of them before and after multiple doses of mirikizumab.

The study will last about 23 weeks for each participant. Screening must be completed within 4 weeks prior to study start.

Detailed description:

Arms: arm 1: Period 1:

Participants received a single dose of the following drug cocktail on Day 1: 1 mg midazolam, 10 mg warfarin, 10 mg vitamin K, 30 mg dextromethorphan, 20 mg omeprazole, 100 mg Caffeine administered orally arm 2: Period 2:

Participants received 250 mg mirikizumab subcutaneously (SC) once every 4 weeks (Q4W) for 16 weeks (Days 1 to Day 113)

Period 2:

Participants received the second dose of the drug cocktail: 1 mg midazolam, 10 mg warfarin, 10 mg vitamin K, 30 mg dextromethorphan, 20 mg omeprazole, 100 mg caffeine administered orally on Day 116.
Interventions: intervention 1: Drug Cocktail intervention 2: Mirikizumab
Intervention descriptions: intervention 1: Drug cocktail consists of caffeine, warfarin plus vitamin K, omeprazole, dextromethorphan, and midazolam, administered orally intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol I6T-MC-AMBP (a) 
 
Evaluation of the Effect of Mirikizumab on the Pharmacokinetics of Cytochrome P450 
Substrates in Patients with Moderate-to-Severe Plaque Psoriasis 
 
NCT03718884 
 
Approval Date: 09-Aug-2018 


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Protocol I6T-MC-AMBP
Evaluation of the Effect of Mirikizumab 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 
mirikizumab (LY3074828), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.  
Mirikizumab (LY3074828)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
27 June 2018.
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 09-Aug-2018 GMT


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Table of Contents
Evaluation of the Effect of Mirikizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in 
Patients with Moderate-to-Severe Plaque Psoriasis
Section
Page
Protocol I6T-MC-AMBP Evaluation of the Effect of Mirikizumab 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 ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle and/or Dietary Requirements .........................................................................33
6.3.1.
Meals and Dietary Restrictions.............................................................................33
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................34
6.3.3.
Activity................................................................................................................34
6.4.
Screen Failures.............................................................................................................34
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 .......................................................................................................................36


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7.4.
Dose Modification........................................................................................................36
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............................................................................40
8.
Discontinuation Criteria ....................................................................................................41
8.1.
Discontinuation from Study Treatment.........................................................................41
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................42
8.2.
Discontinuation from the Study....................................................................................42
8.3.
Patients Lost to Follow-up............................................................................................42
9.
Study Assessments and Procedures ...................................................................................43
9.1.
Efficacy Assessments...................................................................................................43
9.2.
Adverse Events ............................................................................................................43
9.2.1.
Serious Adverse Events........................................................................................44
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................45
9.2.1.2.
Adverse Event Monitoring with Systematic 
Questionnaires................................................................................................45
9.2.1.2.1.
Columbia-Suicide Severity Scale ..............................................................45
9.2.1.2.2.
Quick Inventory of Depressive Symptomatology-Self 
Report (16 Items)......................................................................................46
9.2.2.
Complaint Handling.............................................................................................46
9.3.
Treatment of Overdose.................................................................................................46
9.4.
Safety...........................................................................................................................47
9.4.1.
Laboratory Tests ..................................................................................................47
9.4.2.
Vital Signs ...........................................................................................................47
9.4.2.1.
Hypertension ..................................................................................................47
9.4.3.
Electrocardiograms ..............................................................................................47
9.4.4.
Immunogenicity Assessments ..............................................................................48
9.4.5.
Safety Monitoring ................................................................................................48
9.4.5.1.
Hepatic Safety................................................................................................48
9.5.
Pharmacokinetics .........................................................................................................49
9.5.1.
Bioanalysis...........................................................................................................49
9.6.
Pharmacodynamics ......................................................................................................49
9.7.
Genetics .......................................................................................................................49
9.8.
Biomarkers...................................................................................................................50
9.9.
Health Economics ........................................................................................................50
10.
Statistical Considerations and Data Analysis.....................................................................51
10.1. Sample Size Determination ..........................................................................................51


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10.2. Populations for Analyses..............................................................................................52
10.2.1.
Study Participant Disposition ...............................................................................52
10.2.2.
Study Participant Characteristics ..........................................................................52
10.3. Statistical Analyses ......................................................................................................52
10.3.1.
Pharmacokinetic Analyses....................................................................................52
10.3.1.1.
Pharmacokinetic Parameter Estimation...........................................................52
10.3.1.2.
Pharmacokinetic Statistical Inference .............................................................53
10.3.1.3.
Pharmacokinetic Exploratory Analyses...........................................................53
10.3.2.
Safety Analyses....................................................................................................53
10.3.2.1.
Clinical Evaluation of Safety..........................................................................53
10.3.2.2.
Statistical Evaluation of Safety.......................................................................54
10.3.3.
Immunogenicity Analyses....................................................................................54
10.3.4.
Exploratory Analyses...........................................................................................54
10.3.4.1.
Efficacy Assessments .....................................................................................54
10.3.4.2.
Biomarker Analyses .......................................................................................54
10.3.5.
Interim Analyses..................................................................................................54
11.
References ........................................................................................................................55


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List of Tables
Table
Page
Table AMBP.1.
Acceptable Sampling Windows for Periods 1 and 2................................14
Table AMBP.2.
Objectives and Endpoints .......................................................................21
Table AMBP.3.
Excluded Classes of Concomitant Medications or Classes with 
Restricted Use ........................................................................................38


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List of Figures
Figure
Page
Figure AMBP.1.
Illustration of study design for Protocol I6T-MC-AMBP. .......................23


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................57
Appendix 2.
Clinical Laboratory Tests........................................................................60
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................61
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............64
Appendix 5.
Blood Sampling Summary......................................................................65
Appendix 6.
Protocol Amendment I6T-MC-AMBP(a) Summary Evaluation of 
the Effect of Mirikizumab on the Pharmacokinetics of Cytochrome 
P450 Substrates in Patients with Moderate-to-Severe Plaque 
Psoriasis .................................................................................................66


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1. Protocol Synopsis
Title of Study:
Evaluation of the Effect of Mirikizumab 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 may be
observed.  Chronic inflammation can, in theory, lead to disease-drug interactions by reducing the expression and 
activity of some cytochrome P450 (CYP) enzymes, thereby altering the systemic exposure of CYP substrates.  
Therefore, treatment of psoriasis with biological products that reduce inflammation could result in changes in CYP 
activity.
Mirikizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for the treatment of autoimmune 
diseases, including psoriasis, in which the IL-23 pathway is thought to have a pathogenic role.  This study seeks to 
determine whether mirikizumab affects CYP activity in patients with psoriasis by using a “probe cocktail” approach, 
whereby the pharmacokinetics (PK) of CYP3A, CYP2C9, CYP2D6, CYP2C19, and CYP1A2 substrates 
midazolam, warfarin, dextromethorphan, omeprazole, and caffeine, respectively, will be evaluated before and after 
multiple mirikizumab doses are administered to patients with moderate-to-severe psoriasis.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To assess the effects of multiple doses of
mirikizumab on the PK of a drug cocktail of CYP 
substrates in patients with moderate-to-severe 
psoriasis.
Ratio of geometric least squares means for Cmax and 
AUC(0-∞) of parent drug between each CYP 
substrate administered alone and in combination with 
mirikizumab.  
Secondary
To evaluate the tolerability of mirikizumab in patients 
with moderate-to-severe psoriasis.
To determine the PK of metabolites where 
appropriate.
Incidence of TEAEs.
Ratio of geometric least squares means for the MR of 
AUC(0-∞) metabolite:AUC(0-∞) parent, as 
appropriate, between CYP substrate administered 
alone and in combination with mirikizumab.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; CYP = cytochrome P450; MR = metabolic ratio; PK = pharmacokinetics; 
TEAE = treatment-emergent adverse event.
Summary of Study Design:  
Study I6T-MC-AMBP is a Phase 1, multicenter, 2-period, fixed-sequence, open-label study to assess the effects of
multiple doses of mirikizumab on the PK of a drug cocktail of CYP substrates (midazolam, warfarin, 
dextromethorphan, omeprazole, and caffeine) in patients with moderate-to-severe psoriasis.


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Blood sampling for assessment of PK of the CYP substrates (and metabolites, as appropriate), inflammatory 
biomarkers, and mirikizumab PK and immunogenicity will be collected at prespecified visits.  Efficacy will be 
evaluated using static Physician’s Global Assessment (sPGA), Psoriasis Area Severity Index (PASI), and percentage 
of body surface area (BSA) assessments at prespecified visits.  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.
Treatment Arms and Planned Duration for Individual Patients:
Each patient will be administered:
2 oral doses (1 dose in each period) of drug cocktail containing:  1 mg midazolam, 10 mg warfarin, 10 mg 
vitamin K, 30 mg dextromethorphan, 20 mg omeprazole, 100 mg caffeine
5 subcutaneous (SC) doses of 250 mg mirikizumab once every 4 weeks in period 2
Planned duration for each patient:
Screening visit:  within 28 days prior to enrollment
Period 1: 6 days; single dose of drug cocktail
Period 2: 120 days; SC doses of mirikizumab once every 4 weeks for 16 weeks beginning Day 1 of Period 2, 
single dose of drug cocktail will be given 3 days (within 48 to 96 hours) after the final mirikizumab dose
Follow-up visit:  approximately 24 days after final PK sample is collected in Period 2
Number of Patients:  
Approximately 30 patients will be enrolled with the assumption that 21 evaluable patients complete the study.  
Statistical Analysis:
Pharmacokinetics:  The PK 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.  Drug cocktail administered in the absence of 
mirikizumab will represent the reference treatments.  Drug cocktail administered with mirikizumab will represent 
the test treatments.  For the primary analysis, log-transformed area under the concentration versus time curve from 
zero to infinity (AUC[0-∞]) and maximum observed drug concentration (Cmax) 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).  The area under the concentration versus time curve from time zero 
to the last time point with a measurable concentration (AUC[0-tlast]) and metabolic ratios will also be analyzed using 
this method.  The time of maximum observed drug concentration (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.  Mirikizumab concentrations will be listed and summarized using descriptive statistics.
Safety:  All AEs will be listed and, if the frequency of events allows, will be summarized using descriptive 
methodology.  The incidence of symptoms for each treatment will be presented by severity and by association with 
study treatment as perceived by the investigator.  Each symptom will be classified by the most suitable term from 
the medical regulatory dictionary.  Any study treatment-related serious AEs will be reported.  Clinical chemistry and 
hematology data, vital signs, C-SSRS scores, Lilly Self-Harm Supplement responses, and QIDS-SR16 scores will be 
listed and summarized using standard descriptive statistics.  Urinalysis data will be listed.  Electrocardiograms and 


I6T-MC-AMBP(a) Clinical Pharmacology Protocol
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physical examinations will be performed for safety monitoring purposes and will not be presented.  Additional 
analysis will be performed if warranted upon review of the data.
Immunogenicity:  The frequency and percentage of patients with preexisting antidrug antibodies (ADAs) and with 
treatment-emergent ADA (TE ADA+) to mirikizumab will be listed and summarized.  The frequency of neutralizing 
antibodies will also be tabulated for TE ADA+ patients.  The relationship between the presence of antibodies and the 
PK parameters and other responses, including safety and efficacy to mirikizumab, may be assessed.
Efficacy Assessments:  The PASI scores, sPGA responses, and percent BSA evaluation results will be listed and 
summarized.  The proportion of patients who achieved sPGA (0, 1) and sPGA (0), and PASI 75, PASI 90, and PASI 
100 (at least a 75%, 90%, and 100% improvement from baseline in PASI score, respectively) will be summarized 
over time using descriptive statistics.  The change from baseline in percent BSA will also be summarized over time 
using descriptive statistics.
Inflammatory Biomarkers:  Concentrations of IL-19 and change from baseline will be listed and quantifiable 
concentrations will be summarized by treatment.


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2. Schedule of Activities


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Study Schedule Protocol I6T-MC-AMBP – Period 1
Screening
Baseline
Procedure
D -28 to -2
D -1
D 1
D 2
D 3
D 4
D 5
Outpatient Visit
X
X
X
Patient Admission to CRU
Xa
Patient Discharge from CRU
Xb
Informed Consent
X
Screening Assessments
Medical History
X
TB Testc
X
Chest X-rayd
X
QIDS-SR16
X
Height
X
Weight
X
X
Safety Assessments
Urine Drug Screen
X
X
Ethanol Breath Test
X
Vital Signs (Sitting Blood Pressure and Pulse Rate)
X
X
X
Clinical Laboratory Testse
X
X
X
X
Pregnancy Testf
X
X
Physical Examination/Medical Assessmentg
X
X
X
12-Lead ECG
X
X
C-SSRS
X
X
X
X
X
Self-Harm Supplement Form
X
X
X
X
X
Self-Harm Follow-up Formh
X
X
X
X
X
PASI
X
X
sPGA
X
X
% BSA Assessment
X
X
Review of AEsi
X
Review Concomitant Medications
X
Other Samples
Pharmacogenetic Sample
Predose
hsCRP
X
X


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Screening
Baseline
Procedure
D -28 to -2
D -1
D 1
D 2
D 3
D 4
D 5
Drug Administration
Drug Cocktail Administration
X
PK Samplesj,k
(hours)
Midazolam and 1’-hydroxymidazolam
Predose, 0.5, 1, 2, 3, 4, 6, 8, 12
24
S-Warfarin
Predose, 1, 2, 4, 6, 8, 10
24
48
72
96
Dextromethorphan and Dextrorphan
Predose, 1, 2, 4, 6, 8, 10
24
48
72
Omeprazole and 5-hydroxyomeprazole
Predose, 0.5, 1, 2, 3, 4, 6, 8, 12
24
48
Caffeine and Paraxanthine
Predose, 0.5, 1, 2, 3, 4, 6, 8, 12
24
48
Abbreviations:  AE = adverse event; BSA = body surface area; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; 
ECG = electrocardiogram; hsCRP = high sensitivity C-reactive protein; 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.
a
Patients will be admitted at least 24 hours prior to dose administration to allow sufficient time for caffeine washout prior to dosing.
b
Patients may be discharged after collection of the 48-hour PK sample, at the discretion of the investigator.
c
Approved TB test(s) include PPD, QuantiFERON®-TB Gold, and T-SPOT®, one of which should be used.
d
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).  The 
x-ray may be taken after the initial screening visit but before Day -1.
e
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.  
f
Serum pregnancy test to be performed at screening for all females.  Serum or urine pregnancy test will be performed locally at all other times for females of 
childbearing potential. Additional tests may be performed at the discretion of the investigator.
g
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be performed at screening.  All other 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.
h
Required if triggered by the Self-Harm Supplement Form per instructions (see Section 9.2.1.2.1).
i
If an AE of injection site reaction is reported, then the investigator will complete a supplemental injection site reaction form.
j
Sample times are relative to administration of the drug cocktail.  Separate blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, 
warfarin, dextromethorphan, and midazolam).
k
Specified times are approximate and actual times will be recorded.  Actual sampling time should not exceed acceptable windows indicated in Table AMBP.1.


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Table AMBP.1.
Acceptable Sampling Windows for Periods 1 and 2
Nominal Sample Time
Acceptable Sampling Window
Before study treatment administration (predose)
Within 60 minutes before dosing
0.5 to 2 hours after study treatment dose 
± 5 minutes
3 to 6 hours after study treatment dose
± 10 minutes
8 to 12 hours after study treatment dose
± 20 minutes
24 to 72 hours after study treatment dose
± 30 minutes
>72 hours after study treatment dose
± 2 hours


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Study Schedule Protocol I6T-MC-AMBP – Period 2
Note:  There will be 3 to 7 days between Period 1 Day 5 and Period 2 Day 1.
Period 2
FU/ED
Week 1
Week 4
Week 8
Week 12
Week 16
Week 17
Week 20
Procedure
D 1
D 29
D 57
D 85
D 113
D 115
D 116
D 117
D 118
D 119
D 120
D 144
Visit Window
±2 days
±2 days
±2 days
±1 day
± 1 day
±1 day
±1 daym ±1 daym ±1 daym ±1 daym ±4 days
Outpatient Visit
X
X
X
X
X
X
X
X
Patient Admission to CRU
Xa
Patient Discharge from 
CRU
Xb
Safety Assessments
Review AEsc
X
Review Concomitant 
Medications
X
Pregnancy Testd
Predose
Predose
Predose
Predose
Predose
X
X
Medical Assessmente
Predose
Predose
X
X
12-Lead ECG
Predose
X
Clinical Laboratory Testsf
Predose
Predose
Predose
X
X
X
X
Vital Signs (Sitting Blood 
Pressure and Pulse Rate)
Predose
Predose
Predose
Predose
Predose
X
Predose
X
X
C-SSRS
Predose
Predose
Predose
Predose
Predose
X
X
X
X
X
Self-Harm Supplement 
Form
Predose
Predose
Predose
Predose
Predose
X
X
X
X
X
Self-Harm Follow-up 
Formg
Predose
Predose
Predose
Predose
Predose
X
X
X
X
X
QIDS-SR16
Predose
Predose
Predose
Urine Drug Screen
X
Ethanol Breath Test
X
Efficacy Assessments
PASI
Predose
X
X
X
X
Predose
sPGA
Predose
X
X
X
X
Predose
% BSA Assessment
Predose
X
X
X
X
Predose


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Period 2
FU/ED
Week 1
Week 4
Week 8
Week 12
Week 16
Week 17
Week 20
Procedure
D 1
D 29
D 57
D 85
D 113
D 115
D 116
D 117
D 118
D 119
D 120
D 144
Visit Window
±2 days
±2 days
±2 days
±1 day
± 1 day
±1 day
±1 daym ±1 daym ±1 daym ±1 daym ±4 days
Other Samplesh
Exploratory Inflammatory 
Biomarkers
Predose
Predose
Predose
Predose
Predose
Predose
IL-19
Predose
Predose
Predose
Predose
Predose
Predose
hsCRP
Predose
Predose
Predose
Predose
Predose
X
X
Mirikizumab 
Immunogenicityi
Predose
Predose
Predose
Predose
X
Drug Administration
250 mg Mirikizumab SC
X
X
X
X
X
Drug Cocktail
X j
PK Samples (hours)
Mirikizumabh
Predose
Predose
Predose
Predose
Predose
Predose
X
Midazolam and 
1’-hydroxymidazolamk,l
Predose, 0.5, 1, 
2, 3, 4, 6, 8, 12
24
S-Warfarink,l
Predose, 1, 2, 
4, 6, 8, 10
24
48
72
96
Dextromethorphan and 
Dextrorphank,l
Predose, 1, 2, 
4, 6, 8, 10
24
48
72
Omeprazole and 
5-hydroxyomeprazolek,l
Predose, 0.5, 1, 
2, 3, 4, 6, 8, 12
24
48
Caffeine and 
Paraxanthinek,l
Predose, 0.5, 1, 
2, 3, 4, 6, 8, 12
24
48
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; FU = Follow-up; hsCRP = high sensitivity C-reactive protein; IL = interleukin; PASI = Psoriasis Area 
Severity Index; PK = pharmacokinetic; QIDS-SR16 = Quick Inventory of Depressive Symptomatology-Self Report (16 items); SC = subcutaneous; 
sPGA = static Physicians Global Assessment.
a
Patients will be admitted at least 24 hours prior to dose administration to allow sufficient time for caffeine washout prior to dosing.
b
Patients may be discharged after collection of the 48-hour PK sample, at the discretion of the investigator.
c
If an AE of injection site reaction is reported, then the investigator will complete a supplemental injection site reaction form.


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d
Serum or urine pregnancy test will be performed locally for females of childbearing potential. Additional tests may be performed at the discretion of the 
investigator.
e
Medical assessment includes a symptom directed physical as well as examination of heart, lungs, abdomen, and visual examination of the skin.
f
Clinical laboratory 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.  
g
Required if triggered by the Self-Harm Supplement Form per instructions (see Section 9.2.1.2.1).
h
Sample times are relative to that day’s mirikizumab dose.  
i
Any unscheduled immunogenicity samples should be collected with a time-matched sample for mirikizumab concentration analysis.
j
Drug cocktail will be administered approximately 3 days (within 48 to 96 hours) after the final mirikizumab dose.
k
Sample times are relative to administration of the drug cocktail.  Separate blood samples will be collected for each of the cocktail drugs (caffeine, omeprazole, 
warfarin, dextromethorphan, and midazolam).
l
Specified times are approximate and actual times will be recorded.  Actual sampling time should not exceed acceptable windows indicated in Table AMBP.1.
m Study days are relative to the day of drug cocktail administration.


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3. Introduction
3.1.
Study Rationale
Psoriasis is a chronic inflammatory skin disease in which elevated levels of proinflammatory 
cytokines may be observed.  Chronic inflammation can, in theory, lead to disease-drug 
interactions by reducing the expression and activity of some cytochrome P450 (CYP) enzymes, 
thereby altering the systemic exposure of CYP substrates (Wang et al. 2014).  Therefore,
treatment of psoriasis with biological products that reduce inflammation could result in changes 
in CYP activity.
Mirikizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for the 
treatment of autoimmune diseases, including psoriasis, in which the IL-23 pathway is thought to 
have a pathogenic role.  This study seeks to determine whether mirikizumab affects CYP activity 
in patients with psoriasis by using a “probe cocktail” approach, whereby the pharmacokinetics 
(PK) of CYP3A, CYP2C9, CYP2D6, CYP2C19, and CYP1A2 substrates midazolam, warfarin, 
dextromethorphan, omeprazole, and caffeine, respectively, will be evaluated before and after 
multiple mirikizumab doses are administered to patients with moderate-to-severe psoriasis.
3.2.
Background
Mirikizumab is a humanized IgG4-variant monoclonal antibody that binds with high affinity and 
specificity to IL-23, a naturally occurring proinflammatory cytokine critically involved in the 
maintenance and amplification of T helper (Th)17 cells.  Th17 cells play a central role in the 
pathogenesis of multiple autoimmune and chronic inflammatory diseases, and neutralization of 
IL-23 using mirikizumab results in clinical improvement.
Results from Study I6T-MC-AMAE (Study AMAE), in which healthy subjects received 250-mg
mirikizumab doses in prefilled syringes [PFS], showed that the maximum observed drug 
concentration (Cmax) of mirikizumab was observed 3 days postdose and the half-life associated 
with the terminal rate constant in noncompartmental analysis (t1/2) was 11.6 days.  Preliminary 
analyses of data in patients with ulcerative colitis (UC) and psoriasis indicate that the PK of
mirikizumab in these patients is similar to healthy subjects, and there are no patient factors that 
have a clinically relevant impact on PK.
3.3.
Benefit/Risk Assessment
As of 02 February 2018, there were approximately 819 participants in studies of mirikizumab 
(including 245 patients with psoriasis, 248 patients with UC, 85 patients with Crohn’s disease, 
and 241 healthy subjects) exposed to either placebo or mirikizumab at single doses ranging from 
5 to 1200 mg and multiple doses up to a maximum of 1000 mg intravenously (IV) once every 
4 weeks for 12 weeks and up to 300 mg subcutaneous (SC) once every 8 weeks for 16 weeks.  
Although the mirikizumab SC dose regimen of 250 mg once every 4 weeks has not yet been 
administered in humans, the drug exposure in this study is expected to be less than that of 
1000 mg IV once every 4 weeks for 12 weeks, which has been well tolerated.  


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In completed or ongoing clinical pharmacology studies, no dose-related safety or tolerability 
issues were observed.  Injection site pain, of short duration (usually hours), has been reported.  
Data from completed Study AMAE and preliminary data from Study I6T-MC-AMAL
(Study AMAL) showed that most injection site reactions were mild or moderate in severity and 
primarily related to mild erythema and pain, with severe injection site pain reported in 2% of 
injection site reactions in the 250-mg SC test formulation group.  Approximately 6% of subjects 
reported diarrhea following administration of placebo and both the 250-mg test and 250-mg 
reference SC formulations of mirikizumab in Studies I6T-MC-AMAA, I6T-JE-AMAD, AMAL, 
and AMAE.
As of 02 February 2018, Phase 2 Study I6T-MC-AMAF (Study AMAF) examining SC 
mirikizumab doses in patients with moderate-to-severe plaque psoriasis was still ongoing.  In the 
induction period (the first 16 weeks) of this study, patients were randomized to 1 of the 
4 treatment arms (30 mg mirikizumab, 100 mg mirikizumab, 300mg mirikizumab, or placebo) 
and received correspondent doses at Week 0 and Week 8.  At Week 16, patients entered the 
maintenance period (88 weeks) where they were dosed as needed (no higher than 300 mg and no 
more frequent than Q8W) based on the Psoriasis Area Severity Index (PASI) responses. To date, 
evaluation of the unblinded safety data from Study AMAF has not revealed any dose-related 
safety or tolerability issues.  At the 32-week interim analysis, reported treatment-emergent 
adverse events (TEAEs) were generally mild or moderate in severity and the most common 
TEAE was viral upper respiratory tract infection.  One death attributed to lung cancer has been
reported during the maintenance period; however, the death was not considered related to study 
treatment.  Three patients had a serious adverse event (SAE) in the placebo-controlled induction 
period: 2 patients had suicidal ideation and 1 patient had both increased alanine 
aminotransferase (ALT) and increased aspartate aminotransferase (AST). One patient had an 
SAE (endocarditis bacterial) in the maintenance period.  Two patients discontinued treatment 
early due to an adverse event (AE) (maternal exposure during pregnancy and suicidal ideation 
[an SAE]) in the placebo-controlled induction period; 4 patients discontinued treatment early due 
to an AE (maternal exposure during pregnancy, psoriatic arthropathy, rash, and bacterial 
endocarditis [an SAE]) in the maintenance period.  
To assess the nonclinical toxicity of mirikizumab and establish a margin of safety for clinical 
studies, 4-week and 6-month general toxicity studies in healthy, normal cynomolgus monkeys 
were conducted for the evaluation of immunotoxicity, toxicokinetics, safety pharmacology (as 
part of the 4-week study), and fertility (as part of the 6-month study). The weekly administration 
of mirikizumab to cynomolgus monkeys resulted in no adverse mirikizumab-related findings at 
doses of 0 mg/kg (vehicle), 1 and 30 mg/kg (SC), or 100 mg/kg (IV) for 4 weeks, or 0, 10, and 
100 mg/kg (SC) for 6 months.  Based on the lack of any toxicity at exposures exceeding the 
highest clinical exposure and lack of any tissue cross-reactivity, the nonclinical safety profile of 
mirikizumab supports clinical development.  The exposure to mirikizumab in monkeys at the 
no-observed-adverse-effect-level in the 4-week and 6-month studies provided 52- and 22-fold 
margin of safety, respectively, relative to the predicted human exposure of the proposed 
mirikizumab dose in the present study (250 mg administered SC every 4 weeks).


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Given the published literature supporting positive clinical activity following blocking IL-23 in
autoimmune/inflammatory diseases including psoriasis, the favorable safety and PK profile of
mirikizumab, and the initial clinical activity observed for mirikizumab in patients with psoriasis,
the potential benefits of participating in Study AMBP are expected to outweigh the potential
risks.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of mirikizumab are to be found in the Investigator’s Brochure (IB).  
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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4. Objectives and Endpoints
Table AMBP.2 shows the objectives and endpoints of the study.
Table AMBP.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effects of multiple doses of 
mirikizumab on the PK of a drug cocktail of CYP 
substrates in patients with moderate-to-severe 
psoriasis.

Ratio of geometric least squares means for Cmax and 
AUC(0-∞) of parent drug between each CYP 
substrate administered alone and in combination with 
mirikizumab.
Secondary
To evaluate the tolerability of mirikizumab in patients 
with moderate-to-severe psoriasis.
To determine the PK of metabolites where 
appropriate.

Incidence of TEAEs.

Ratio of geometric least squares means for the MR of 
AUC(0-∞) metabolite:AUC(0-∞) parent, as 
appropriate, between CYP substrate administered 
alone and in combination with mirikizumab.
Exploratory
To explore the effects of mirikizumab on the PK of a 
drug cocktail of CYP substrates in the subgroups of 
patients with moderate-to-severe psoriasis who 
respond to mirikizumab treatment at Week 16 and 
those who do not respond.
To evaluate the effects of mirikizumab treatment over
time on inflammatory biomarker concentrations in 
patients with moderate-to-severe psoriasis.
Ratio of geometric least squares means between each 
CYP substrate administered alone and in combination 
with mirikizumab for Cmax and AUC(0-∞) of parent 
drug in responders and nonresponders.
Change from baseline in inflammatory biomarker 
concentrations over time during 16 weeks of 
mirikizumab treatment.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; CYP = cytochrome P450; MR = metabolic ratio; PK = pharmacokinetics; 
TEAE = treatment-emergent adverse event.


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5. Study Design
5.1.
Overall Design
This is a Phase 1, multicenter, 2-period, fixed-sequence, open-label study to assess the effects of 
multiple doses of mirikizumab on the PK of a drug cocktail of CYP substrates (midazolam, 
warfarin, dextromethorphan, omeprazole, and caffeine) in patients with moderate-to-severe 
psoriasis.  Figure AMBP.1 illustrates the study design.
Blood sampling for assessment of PK of the CYP substrates (and metabolites, as appropriate), 
inflammatory biomarkers, and mirikizumab PK and immunogenicity will be collected at 
prespecified visits.  Efficacy will be evaluated using static Physicians Global Assessment 
(sPGA), PASI, and percentage of body surface area (BSA) assessments at prespecified visits.  
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), Lilly Self-Harm Supplement, and electrocardiograms (ECGs).
Study governance considerations are described in detail in Appendix 3.


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Abbreviations:  BSA = body surface area; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; sPGA = static Physicians Global Assessment.
Note:  In Period 2, drug cocktail will be administered 48 to 96 hours after the final mirikizumab dose.  
Figure AMBP.1.
Illustration of study design for Protocol I6T-MC-AMBP.
-1
Day
1
2
Inpatient period
3
4
5
Drug cocktail 
administration
Period 1
X  
□   
116±1
118±1 119±1
17
120±1
Drug Cocktail PK sampling
Drug cocktail 
administration
144±4
20
Follow-up 
1
1
29±1
4
57±1
8
85±1
12
113±1
16
Period 2
250 mg mirikizumab administration
Drug Cocktail PK sampling
Screening 
Day -29 to 
Day -2
X
□ 
X
□ 
X
□ 
X
□ 
X
□ 
Day
Week
115±1
117±1
□ 
X
Mirikizumab immunogenicity and PK samples 
PASI, sPGA, and % BSA assessment and Inflammatory biomarker samples


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5.2.
Number of Participants
Approximately 30 patients will be enrolled with the assumption that 21 evaluable patients 
complete the study.  For purposes of this study, a patient completes the study when all scheduled 
blood samples for drug cocktail PK analyses shown in the Schedule of Activities (Section 2) 
have been collected in Period 2.
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, which is an appropriate approach for the primary PK objectives of 
the study.  The fixed-sequence design is used due to the long half-life of mirikizumab.
This study will be conducted in patients with moderate-to-severe plaque psoriasis as this is one 
of the patient populations for whom mirikizumab treatment is indicated; conducting the study in 
this population allows the assessment of the effect of mirikizumab on CYP enzymes expressed in 
the disease state before and after treatment.
Regulatory agencies recommend conducting a clinical drug interaction study using a drug 
cocktail approach when interactions with multiple CYPs are investigated (EMA 2012; 
FDA 2017; PMDA 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 in Period 1, prior to initiation of mirikizumab dosing, and again on 
Day 116 (3 days post the last mirikizumab dose) of Period 2, when steady-state concentrations of 
mirikizumab should be achieved.  
The total required blood volume of 590 mL is considered acceptable given that blood samples 
are taken during the course of the study which has a minimum duration of approximately 
20 weeks.
5.5.
Justification for Dose
Drug cocktail containing 1 mg midazolam, 10 mg warfarin (+ 10 mg vitamin K to counteract the 
anticoagulation effect of warfarin), 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 


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does not result in conscious sedation yet still provides sufficient exposure to midazolam to assess 
midazolam PK.
The mirikizumab dose level and regimen selected for this study are consistent with that planned 
for the treatment induction period in the Phase 3 Study AMAK and are based primarily on 
analyses of interim PK, safety, and efficacy data from the Phase 2 Study AMAF, safety data 
from other clinical studies evaluating mirikizumab, and nonclinical safety data. 
In Period 2, the drug cocktail will be administered on Day 116 (3 days post the last mirikizumab 
dose), which is approximately at Cmax of mirikizumab concentration at steady state.


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6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, QIDS-SR16, C-SSRS, Lilly Self-Harm Supplement, 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:
Type of Patient and Disease Characteristics
[1]
present with chronic plaque psoriasis based on the investigator-confirmed 
diagnosis of chronic psoriasis vulgaris for at least 6 months prior to screening, 
and meet the following criteria at screening and first admission to the clinical 
research unit (CRU):
A. plaque psoriasis involving ≥10% BSA,
B. absolute PASI score ≥12 in affected skin, and
C. sPGA score of ≥3
[2]
candidate for systemic therapy and/or phototherapy
Patient Characteristics
[3]
males or females
A. male patients:  no male contraception required except in compliance with 
specific local government study requirement
B. female patients:
women not of childbearing potential may participate and include those 
who are:
i.
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis
OR


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ii.
postmenopausal, defined as:
a.
a woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either:
1. cessation of menses for at least 1 year
OR
2. at least 6 months of spontaneous amenorrhea with a follicle 
stimulating hormone >40 mIU/mL
OR
b. a woman 55 years or older not on hormone therapy, who has had 
at least 6 months of spontaneous amenorrhea
OR
c.
a woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy
women of childbearing potential:
i.
must test negative for pregnancy prior to initiation of treatment as 
indicated by a negative serum pregnancy test at the screening visit 
followed by a negative pregnancy test within 24 hours prior to 
exposure in both periods
ii.
must agree to either remain abstinent, if complete abstinence is their 
preferred and usual lifestyle, or remain in same-sex relationships, if 
part of their preferred and usual lifestyle, without sexual relationships 
with males.  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence just 
for the duration of a trial, and withdrawal are not acceptable methods 
of contraception.
OR
must use 2 effective methods of contraception for the entirety of the 
study.  Abstinence or contraception must continue for 12 weeks 
following completion of investigational product administration.
a.
Two effective methods of contraception (such as male or female 
condoms with spermicide, diaphragms with spermicide, or 
cervical sponges) will be used.  The patient may choose to use a 
double-barrier method of contraception.  Barrier protection 
methods without concomitant use of a spermicide are not a 
reliable or acceptable method.  Thus, each barrier method must 
include use of a spermicide.  It should be noted that the use of 
male and female condoms as a double-barrier method is not 
considered acceptable due to the high failure rate when these 
methods are combined.


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b. Of note, one of the 2 methods of contraception may be a highly 
effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted 
contraceptives, or intrauterine devices).
[4]
are at least 18 years of age at the time of screening
[5]
have adequate organ function, including:
A. hematologic:  
i.
absolute neutrophil count 1.5 × 109/L (1.5 × 103/µL or 1.5 GI/L)
ii.
platelet count 100 × 109/L (100 × 103/µL or 100 GI/L)
iii.
hemoglobin level 10.0 g/dL (100 g/L)
iv.
lymphocyte count >500 cells/µL (>0.50 × 103/µL or >0.50 GI/L)
v.
total white blood cell count 3.0 × 109/L (3.0 × 103/µL or 3.0 GI/L)
B. chemistry:
i.
serum creatinine ≤2× the upper limit of normal (ULN)
ii.
ALT ≤2× ULN
iii.
AST ≤2× ULN
iv.
total bilirubin level (TBL) <1.5× ULN (patients with Gilbert’s 
syndrome must have serum direct bilirubin <1.5 mg/dL or 
<25.7 µmol/L)
v.
alkaline phosphatase (ALP) <1.5× ULN
(Note:  The tests for AST and ALT may be repeated once within a week if 
the initial response exceeds this limit, and the repeat value may be accepted 
if it meets this criterion.  Other laboratory tests should not be repeated 
unless there is a technical error or clinical reasons to believe a result may be 
erroneous, and requires approval by the Lilly-designated medical monitor.)
[6]
have venous access sufficient to allow for blood sampling as per the protocol
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[8]
are able and willing to give signed informed consent


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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:  
Medical Conditions
[9]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[10]
have an unstable or uncontrolled illness, including, but not limited to, a 
cerebro-cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, 
hematologic, or neurologic disease or abnormal laboratory values at screening 
that, in the opinion of the investigator, would potentially affect patient safety 
within the study or of interfering with the interpretation of data
[11]
presence of significant uncontrolled neuropsychiatric disorder or judged 
at-risk of suicide in the opinion of the investigator
OR
scores a 3 for Item 12 (Thoughts of Death or Suicide) on the QIDS-SR16 at 
screening
OR
a “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with 
Specific Plan and Intent) on the “Suicidal Ideation” portion of the C-SSRS at 
screening or at first admission to the CRU
OR
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 and the ideation or behavior 
occurred within 1 month prior to screening or at first admission to the CRU
[12]
have human immunodeficiency virus (HIV)/acquired immune deficiency 
syndrome or test positive for HIV antibodies at screening
[13]
have hepatitis C or test positive for hepatitis C virus (HCV) at screening, 
defined as:  positive result for hepatitis C antibody and positive confirmatory 
HCV RNA test.  Patients in sustained virologic response after HCV therapy, 
and patients who have spontaneously cleared HCV infection can be included 
in this study.
[14]
have hepatitis B or test positive for hepatitis B virus (HBV) at screening, 
defined as:  
A.
positive for hepatitis B surface antigen
OR


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B.
positive for hepatitis B core antibody in conjunction with positive confirmatory 
HBV DNA test
OR
C.
positive HBV DNA test, regardless of anti-hepatitis B surface antibody status
[15]
have had serious, opportunistic, or chronic/recurring infection within 
3 months prior to screening.  Examples include, but are not limited to, 
infections requiring IV antibiotics, hospitalization, or prolonged treatment.
[16]
have received a systemic (including oral) anti-infective agent for an infection 
within 28 days of first admission to the CRU
[17]
have had, according to the investigator, clinically significant herpes zoster 
within 3 months prior to screening
[18]
have evidence of active or latent tuberculosis (TB), as documented by medical 
history and physical examination, chest x-rays (posterior anterior), 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 Bacillus Calmette-Guerin [BCG] or other vaccination history) or 
a negative (not indeterminate) QuantiFERON-TB Gold test or T-SPOT.  If the 
QuantiFERON-TB Gold test or T-SPOT is indeterminate, one repeat test is 
permitted.  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).
[19]
have received a BCG vaccination within 12 months or received live vaccine(s) 
(including attenuated live vaccines) within 12 weeks of first admission to the 
CRU or intend to receive either during the study
[20]
have active or history of lymphoma, leukemia, or any malignancy. The
following conditions are not exclusionary: successfully treated basal cell skin 
carcinoma, squamous cell skin carcinoma, or cervical carcinoma in situ, with 
no evidence of recurrence or metastatic disease within the 5 years prior to first 
admission to the CRU.
[21]
have any other skin conditions (excluding plaque psoriasis) that would affect 
interpretation of the results (including, but not limited to, scleroderma, 
eczema, drug-induced psoriasis, guttate psoriasis, pustular psoriasis, 
parapsoriasis, or cutaneous manifestations of other autoimmune diseases such 
as systemic lupus erythematosus)


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[22]
have a known allergy or hypersensitivity to any component of the 
mirikizumab product formulation or the drug cocktail that would pose an 
unacceptable risk to the patient if participating in this study
[23]
are women who are breastfeeding or plan to breastfeed during study
[24]
have donated blood of >500 mL within 14 days prior to first admission to the 
CRU, or intend to donate blood during the course of the study
[25]
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
[26]
have a history of uncompensated heart failure, fluid overload, or myocardial 
infarction, or evidence of new-onset ischemic heart disease or other serious 
cardiac disease, within 12 weeks prior to first admission to the CRU
[27]
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.)
[28]
have any other condition that precludes the patient from following and 
completing the protocol, in the opinion of the investigator
[29]
clinically significant increased prothrombin time at screening
Prior/Concomitant Therapy
[30]
have received systemic nonbiologic psoriasis therapy (including, but not 
limited to, oral psoralen and ultraviolet A [PUVA] light therapy; cyclosporine; 
corticosteroids; methotrexate; oral retinoids; apremilast; tofacitinib; 
mycophenolate mofetil; thioguanine; hydroxyurea; sirolimus; tacrolimus; 
azathioprine; lefludimide; fumaric acid derivatives; or 1,25-dihydroxy vitamin 
D3 and analogues) or phototherapy (including either oral and topical PUVA 
light therapy, ultraviolet B, excimer laser, or self-treatment with tanning 
booths or therapeutic sunbathing) within 4 weeks prior to the first 
administration of the drug cocktail
[31]
have received topical treatment for psoriasis or any other skin condition
(including, but not limited to, corticosteroids [mild or least potent topical 
steroids will be permitted for use limited to the face, axilla, or genitalia], 
crisaborole, anthralin, calcipotriene, topical vitamin D derivatives, retinoids, 
tazarotene, pimecrolimus, tacrolimus, emollients and other nonprescription 
topical products containing urea, >3% salicylic acid, alpha- or beta-hydroxy
acids, or medicated shampoos [eg, those that contain >3% salicylic acid, 


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corticosteroids, coal tar, or vitamin D3 analogues]) within 14 days prior to the 
first administration of the drug cocktail
[32]
have received anti-Tumor Necrosis Factor targeting biologics within 8 weeks 
prior to baseline, or anti-IL-17 targeting biologics within 12 weeks prior to the 
first administration of the drug cocktail
[33]
have previous exposure to any biologic therapy targeting IL-12/23 (p40 
subunit) or IL-23 (p19 subunit), either marketed or investigational, or 
exposure to other biological immunomodulating treatments
[34]
are unable or unwilling to 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
[35]
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 until Period 2 Day 120 assessments are complete
[36]
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 until Period 2 Day 120 assessments are 
complete, at the discretion of the investigator and by agreement with the Lilly 
clinical research physician (CRP), or clinical pharmacologist (CP), or 
designee
[37]
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 until Period 2 Day 120 assessments 
are complete
Prior/Concurrent Clinical Study Experience
[38]
are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study
[39]
have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed 
prior to screening.
[40]
have previously completed or withdrawn from this study or any other study 
investigating mirikizumab
Study Restrictions
[41]
are unwilling to comply with the dietary requirements/restrictions during the 
study which include:  


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A. Consume, during the inpatient visits, only the meals provided, and
B. 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 until Period 2 Day 120 assessments are 
complete
[42]
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
[43]
are currently or have been smokers or users of tobacco or nicotine 
replacement products within 1 month prior to first admission to the CRU
[44]
intend to consume caffeine- or xanthine-containing food or beverages (eg, tea, 
coffee, colas, and chocolate) 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
[45]
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)
Other Exclusions
[46]
have CYP2D6 genotype, if known, indicative of a poor metabolizer
[47]
are investigative site personnel directly affiliated with this study and their
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[48]
are Lilly employees or employees of third-party organization involved with 
the study who require exclusion of their employees
[49]
are unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor for any reason that may compromise the patient’s safety or confound 
data interpretation
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 (Day 1 of 
Period 1) until the last drug cocktail PK sample is collected in Period 2.  


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6.3.2. Caffeine, Alcohol, and Tobacco
Patients are not allowed to consume caffeine- or xanthine-containing food or beverages from
5 days prior to each drug cocktail administration (Period 1 Day 1 and Period 2 Day 116) until 
collection of the 48-hour drug cocktail PK samples in each period.
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 may be rescreened only 1 time for failure due to Exclusion Criteria [16] or [18].  
Patients who do not qualify at screening under Exclusion Criteria [16] (recent systemic 
anti-infective treatment) may be rescreened (1 time) 4 or more weeks after documented 
resolution of underlying condition being treated.  Patients who test positive for latent TB
(Exclusion Criteria [18]) at screening may be rescreened (1 time) if they meet the following 
requirements:

Have received at least 4 weeks of appropriate ongoing prophylactic therapy for latent TB
as per local standard of care, and

Have no evidence of treatment hepatotoxicity (ALT and AST levels must remain 
≤2× ULN upon retesting of serum ALT and AST levels prior to first dose)
Each time rescreening is performed, the individual must sign a new informed consent form (ICF)
and will be assigned a new identification number.
Patients who have had previous screening chest radiography and TB tests as per protocol within 
3 months of their rescreening date of consent do not need to repeat these procedures but may do 
so at the discretion of the investigator.
Repeat testing to confirm laboratory test results will not be considered rescreening.


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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 administered alone to that when administered 
following multiple doses of mirikizumab.
Drug cocktail and mirikizumab will be administered at the site by clinical staff at the time points 
specified in the Schedule of Activities (Section 2).  Detailed instructions for study treatment
administration will be provided by the Sponsor.
Mirikizumab
Mirikizumab will be administered by SC injection.  Each 250-mg mirikizumab dose will be 
supplied as two 1-mL PFS.
Drug cocktail
The drug cocktail will contain midazolam, warfarin (plus vitamin K), dextromethorphan, 
omeprazole, and caffeine. The cocktail drugs will be coadministered orally with approximately 
240 mL of room temperature water, in a sitting position. Administration of each cocktail drug 
will be according to the respective instructions for use.  
Midazolam
The 1-mg oral dose will be administered as 0.5 mL of 2-mg/mL commercially available 
midazolam syrup.
Warfarin
The 10-mg oral doses will be administered as 2 × 5-mg tablets of commercially available
warfarin plus 2 × 5-mg tablets of commercially available vitamin K.
Dextromethorphan
The 30-mg oral dose will be administered as 2 × 15-mg liquid gel capsules of commercially 
available dextromethorphan.
Omeprazole
The 20-mg oral dose will be administered as 1 × 20-mg tablet of commercially available
omeprazole.
Caffeine
The 100-mg (caffeine base) oral dose will be administered as 10 mL of 20-mg/mL commercially 
available caffeine citrate solution (with 10 mg caffeine base per 1 mL solution).


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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 materials.  
7.1.1. Packaging and Labeling
Mirikizumab will be supplied by the sponsor as single-use, solution PFS.  The 1-mL syringe of 
mirikizumab is manufactured to contain 125 mg.  Syringes will be supplied in cartons, with the 
appropriate quantity 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.  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.  
The investigational product will be labeled according to the country’s regulatory requirements.  
All investigational products will be stored, inventoried, reconciled, and returned or 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
All patients will receive the dose regimen as specified in the Schedule of Activities (Section 2).
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.  


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7.5.
Preparation/Handling/Storage/Accountability
Mirikizumab should be transported and stored in refrigerated conditions of 2°C to 8°C (36°F to 
46°F).  Detailed instructions regarding supplies and preparation and handling of investigational 
products will be provided by the sponsor.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all investigational product received 
and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational products 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.
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
The study treatment will be administered at the clinical site, and documentation of treatment 
administration will occur at the site.
7.7.
Concomitant Therapy
All concomitant medications taken during the study must be recorded on the Concomitant 
Medication eCRF.  All patients should maintain their usual medication regimens for concomitant 
conditions or diseases throughout the study unless those medications are specifically excluded in 
the protocol.
Patients taking concomitant medications should be on stable dosages at the time of baseline and 
should remain at stable dosages throughout the study unless changes need to be made because of 
AEs.  Additional systemic drugs are to be avoided during the study, unless required to treat AEs. 
If the need for concomitant medication arises for an AE or for appropriate medical management 
(including the limited use of therapeutic agents which, if used under treatment regimens other 
than for treating an AE or for appropriate medical management, might be considered psoriasis 
therapies), inclusion or continuation of the patient may be at the discretion of the investigator 
after consultation with a Lilly CP or CRP.  Other medications may be allowed if they are 
approved by the sponsor or its designee.
Use of nonlive (killed, inactivated, or subunit) vaccinations are allowed for all patients; however, 
their efficacy with concomitant mirikizumab is unknown.  Use of live, attenuated vaccines is 
prohibited.
Classes of therapies not permitted during the course of the study, or permitted with use 
restrictions, are specified in Table AMBP.3 (also see the Exclusion Criteria [Section 6.2]).


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Table AMBP.3.
Excluded Classes of Concomitant Medications or Classes with Restricted Use
Drug Class
Allowed 
Prior to 
First Dose
Allowed During Study
Allowed 
with 
Restrictions
Conditions for Allowed Use
Treatment with midazolam, warfarin, 
dextromethorphan, omeprazole, or caffeine
N
within 
14 days
N
until final PK assessments 
are complete
N
Drugs contraindicated with midazolam, 
warfarin, dextromethorphan, omeprazole, or 
caffeine (per the prescribing label and Package 
Insert for each drug)
N
within 
14 days
N
until final PK assessments 
are complete
N
Known inhibitors of CYP3A, CYP2C9, 
CYP2D6, CYP2C19, or CYP1A2; inducers of 
CYP3A or CYP1A2; or rifampin (inducer of 
multiple CYPs)
N
within 
14 days
N
until final PK assessments 
are complete
N
Known substrates of CYP3A, CYP2C9, 
CYP2D6, CYP2C19, or CYP1A2 with narrow 
therapeutic indices
N
within 
14 days
N
until final PK assessments 
are complete
Y
At the discretion of the investigator and by 
agreement with the Lilly CRP or designee.
Topical treatment for psoriasis or any other skin 
condition
(eg, corticosteroids, crisaborole, anthralin, 
vitamin D analogues, pimecrolimus, retinoids, 
salicylvaseline, salicylic acid, lactic acid, 
tacrolimus, tar, urea, -hydroxy acids, or fruit 
acids)
N
within 
14 days
N
until final PK assessments 
are complete
N
Topical treatment for psoriasis limited to face, 
axilla, or genitalia
N
within 
2 days
N
within 24 hours prior to 
study visits
Y
Mild or least potent topical steroids will be 
permitted for use limited to the face, axilla, and/or 
genitalia, as needed.  
Photochemotherapy
(eg, PUVA)
N
within 
4 weeks 
N
N
Phototherapy
(eg, UVA, UVB, excimer laser)
N
within 
4 weeks 
N
N
Anti-TNF biological agents
(eg, etanercept, adalimumab, infliximab, 
certolizumab)
N
within 
8 weeks
N
N


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Drug Class
Allowed 
Prior to 
First Dose
Allowed During Study
Allowed 
with 
Restrictions
Conditions for Allowed Use
Anti-IL-17 biological agents
(eg, secukinumab, ixekizumab)
N
within 
12 weeks
N
N
Biological therapy targeting IL-12/23 or IL-23
(eg, briakinumab, ustekinumab)
N
N
N
Biological immunomodulating agents
(eg, alefacept, efalizumab)
N
N
N
Other systemic immunomodulating treatments
(eg, MTX, cyclosporine A, corticosteroids, 
cyclophosphamide)
N
within 
4 weeks 
N
N
Systemic immunomodulating treatments 
(corticosteroids only)
N
N
Y
Limited use of systemic corticosteroids ONLY as 
needed for limited, short-term medical management 
of TEAE may be considered.  Such drug class might 
be considered psoriasis therapy if used under other 
regimens.  Limited use during TEAE management is 
considered to not be consistent with psoriasis 
therapy.
Systemic psoriasis therapies
(eg, retinoids, fumarates, apremilast) 
N
within 
4 weeks 
N
N
BCG or live virus vaccinations  
N
N
N
Any investigational treatment
N
N
N
Abbreviations:  BCG = Bacillus Calmette-Guerin; CRP = clinical research physician; CYP = cytochrome P450; MTX = methotrexate; N = No; 
PK = pharmacokinetics; PUVA = psoralen and ultraviolet A; TEAE = treatment-emergent adverse event; TNF = tumor necrosis factor; UVA = ultraviolet A; 
UVB = ultraviolet B; Y = Yes.


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7.8.
Treatment after the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
Patients discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
Patients discontinuing from the study prematurely for any reason must complete AE and other 
follow-up procedures per Section 2 of this protocol.
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 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST >5× ULN.

ALT or AST >3×ULN sustained for more than 2 weeks.

ALT or AST >3× ULN and TBL >2× ULN or international normalized ratio >1.5.

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

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:

Total white blood cell count <2000 cells/L (<2.00 × 103/µL or <2.00 GI/L).

Lymphocyte count <500 cells/μL (<0.50 × 103/µL or <0.50 GI/L).

Platelet count <50,000 cells/μL (<50 × 103/µL or <50 GI/L).  

Changes in BP (systolic BP at ≥160 mm Hg plus ≥20 mm Hg increase from baseline; 
and/or diastolic BP at ≥100 mm Hg plus ≥10 mm Hg increase from baseline) that do not 
respond following maximal allowed intervention (further explanation in Section 9.4.2.1).  

The patient becomes pregnant.

It is recommended that the patient be assessed by an appropriately trained professional to 
assist in deciding whether the patient is to be discontinued from study treatment and the 
study if the patient:
i.
Scores a 3 for Item 12 (Thoughts of Death or Suicide) on the QIDS-SR16;
OR


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ii.
Develops active suicidal ideation with some intent to act with or without a 
specific plan (“yes” to Question 4 or 5 on the “Suicidal Ideation” portion 
of the C-SSRS);
OR
iii.
Develops suicide-related behaviors as recorded on the C-SSRS;
OR
iv.
Develops self-injurious behaviors that would be classified as non-suicidal 
self-injurious behavior.
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 study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

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.
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 
(including tolerance limits for 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.
9.1.
Efficacy Assessments
Efficacy will be evaluated using PASI, sPGA, and percentage of BSA assessments according to 
the Schedule of Activities (Section 2).  
The PASI is an accepted and commonly used primary endpoint to measure psoriasis severity in 
clinical studies (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 (scaling), erythema (redness), and plaque induration/infiltration (thickness) in 
each anatomical region, yielding an overall score of 0 for no psoriasis to 72 for severe disease 
(Fredriksson and Pettersson 1978).  A clinically meaningful response is a PASI 75, which 
represents at least a 75% decrease (improvement) from the baseline PASI score.  Higher levels of 
clearance (PASI 90), as well as complete resolution of psoriasis (PASI 100), have become 
additional endpoints because of the increasing recognition of the association of higher clearance 
with greater health-related quality of life (Puig 2015).
The sPGA is the physician’s global assessment of the patient’s psoriasis lesions evaluated at a 
given time point (EMA 2004).  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).
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.


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Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
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 potential cause and effect relationship between 
the study treatment (ie, drug cocktail, mirikizumab, or drug cocktail + mirikizumab), study 
device, and/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.
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.
If an AE of injection site reaction is reported, then the investigator will complete a supplemental 
injection site reaction form.  The injection site reaction form documents the presence of 
erythema, induration, pain (mild, moderate, or severe), pruritus, and edema.
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

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above


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
when a condition related to the PFS necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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 to the 
sponsor 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.
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 reports as related to investigational product or procedure.  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.
9.2.1.2.
Adverse Event Monitoring with Systematic Questionnaires
Before administering the C-SSRS or QIDS-SR16, study site personnel will question the patient 
about any change in the preexisting condition(s) and the occurrence and nature of any AEs.  
Nonserious AEs obtained through the questionnaires are recorded and analyzed separately.  Only 
serious AEs elicited through the C-SSRS or QIDS-SR16 are to be recorded as AEs via eCRF and 
reported to Lilly or its designee within 24 hours as SAEs.
9.2.1.2.1. Columbia-Suicide Severity Scale
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 


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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.
Suicide-related events (behavior and/or ideations) will be assessed and evaluated with the 
administration of the C-SSRS, Self-Harm Supplement Form, and Self-Harm Follow-up Form.  
The C-SSRS 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 Self-Harm 
Forms focus on behaviors (suicidal and non-suicidal self-harm). If the number of behavioral 
events identified on the Self-Harm Supplement Form is greater than zero, it will lead to the 
completion of the Self-Harm Follow-up Form.  The Self-Harm Follow-up Form is a series of 
questions that provides a more detailed description of the behavior cases.  The C-SSRS is 
administered by an appropriately trained healthcare professional with at least 1 year of patient 
care/clinical experience.  For this study, the scale has been adapted (with permission from the 
scale authors) to include only the portion of the scale that captures the occurrence of the 
11 preferred ideation and behavior categories.
9.2.1.2.2. 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, 5th Edition (APA 2013).  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.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or PFS so that the situation can be 
assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of mirikizumab or the cocktail drugs is considered 
any dose higher than the assigned dose.  
In case of suspected mirikizumab overdose, hematology, chemistry, vital signs, and oxygen 
saturation should be monitored and supportive care provided as necessary.  There is no known 
antidote for mirikizumab.


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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, sitting vital signs (BP and pulse rate) should be measured after resting for at 
least 5 minutes at times indicated in the Schedule of Activities (Section 2), and prior to blood 
sampling or administration of study treatment.
Additional vital signs may be measured during each study period if warranted.  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 then stand for at least 2 minutes.
9.4.2.1.
Hypertension
Patients who experience changes in BP (systolic BP at ≥160 mm Hg plus ≥20 mm Hg increase 
from baseline; and/or diastolic BP at ≥100 mm Hg plus ≥10 mm Hg increase from baseline) on 
2 consecutive visits are to receive intervention for the management of hypertension.  Intervention 
may begin with lifestyle changes and could lead to the maximal intervention of withholding the 
dose of investigational product (see Section 8.1) and/or the introduction of antihypertensive 
agent(s) as medically appropriate.
9.4.3. Electrocardiograms
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 
samples.  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 (the investigator or qualified 
designee) 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/QTc 
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 clinically relevant findings should be reported as an AE.


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9.4.4. Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against mirikizumab.  To interpret the results 
of immunogenicity, a venous blood sample will be collected at the same time points to determine 
the serum concentrations of mirikizumab.  All samples for immunogenicity should be taken 
predose when applicable and possible.  In the event of drug hypersensitivity reactions 
(immediate or non-immediate), additional samples will be collected as close to the onset of the 
event as possible, at the resolution of the event, and 30 days following the event.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and 24-hour clock time of each sampling will be recorded.  
Treatment-emergent antidrug antibodies (TE ADAs) are defined in Section 10.3.3.  If the 
immunogenicity titer at the last scheduled assessment or discontinuation visit is increasing 
(compared to previous measurements) or remains high (titer greater than 1:1000), additional 
samples may be taken until the titer reaches a plateau/decreases (if increasing) or remains the 
same/decreases (if high).  
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADAs) in the presence of the mirikizumab at a laboratory approved by the sponsor.  Antibodies 
may be further characterized and/or evaluated for their ability to neutralize the activity of the 
mirikizumab.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
mirikizumab.  Any samples remaining after 15 years will be destroyed.
9.4.5. Safety Monitoring
The Lilly CP or CRP/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 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

AEs
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1.
Hepatic Safety
If a study patient experiences elevated ALT ≥3× ULN, ALP ≥2× ULN, or elevated TBL
≥2× ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 


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worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP.  Monitoring should continue until levels normalize and/or 
are returning to approximate baseline levels.  
Additional safety data should be collected if 1 or more of the following conditions occur:  

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

patient discontinued from treatment due to a hepatic event or abnormality of liver tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), separate venous blood 
samples will be collected to determine 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 will also be collected to determine serum concentrations of mirikizumab.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and 24-hour clock time of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  Plasma concentrations of each analyte in the drug cocktail will be 
assayed using a validated method.  Serum concentrations of mirikizumab will be measured using 
a validated enzyme-linked immunosorbent assay method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last patient visit for the study.  
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
mirikizumab 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.  


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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, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of mirikizumab or after mirikizumab is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, 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 to measure IL-19. Samples are collected for C-reactive protein 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 mirikizumab, pathways associated with psoriasis, 
mechanism of action of mirikizumab, 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.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the
development of mirikizumab or after mirikizumab is commercially available.  
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 evaluable patients 
complete the study.
Midazolam
For midazolam area under the concentration versus time curve (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.  
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 (HMA 2009).  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, body mass index, and other demographic 
characteristics will be recorded.  Baseline disease severity (PASI, 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 and listed.  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 
mirikizumab PK, the full analysis set includes all data from all patients receiving at least one 
dose of mirikizumab with evaluable PK data.  For patients with serum mirikizumab 
concentrations that are less than the drug exposure range expected after multiple doses, the drug 
cocktail PK results for Period 2 may be excluded from the analysis and the rationale will be 
provided in the study report.
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.
Biomarker analyses will be conducted for all patients receiving at least one dose of mirikizumab 
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.


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For midazolam and 1’-hydroxymidazolam, S-warfarin, dextromethorphan and dextrorphan, 
omeprazole and 5-hydroxyomeprazole, and caffeine and paraxanthine, the primary parameters 
for analysis will be Cmax, AUC from zero to infinity (AUC[0-∞]), and metabolic ratio (MR).  
Metabolic ratios will be calculated as AUC(0-∞) metabolite/AUC(0-∞) parent corrected for 
molecular weight.  Other noncompartmental parameters such as time of maximum observed drug 
concentration (tmax), AUC from time zero to the last time point with a measurable concentration 
(AUC[0-tlast]), t1/2, apparent clearance, and apparent volume of distribution will be reported.  
For mirikizumab, sparse sampling is conducted to obtain concentrations over the time course of 
the study, which will be listed and summarized using descriptive statistics.  
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 mirikizumab will represent the reference treatments and will be 
analyzed separately.  Each drug administered with mirikizumab will represent the test treatments
and will be analyzed separately. 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 derive ratios of geometric least squares means and the corresponding 90% 
CIs. The MR and AUC(0-tlast) will also be analyzed using this method.
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.
10.3.1.3. Pharmacokinetic Exploratory Analyses
The same model used for the primary PK analysis will be applied to the subgroups of responders 
to mirikizumab and nonresponders.  A responder to mirikizumab will be defined as a patient with 
an sPGA equal to 0 or 1 at Day 116 in Period 2.  A nonresponder will be defined as a patient 
with sPGA >1 at Day 116 in Period 2.  The treatment differences for each subgroup will be 
back-transformed to present ratios of geometric least squares means and the corresponding 
90% CIs.
10.3.2. Safety Analyses
10.3.2.1. Clinical Evaluation of Safety
All study treatment and protocol procedure AEs will be listed and, if the frequency of events 
allows, will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with study treatment 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 study treatment-related SAEs will be reported.


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10.3.2.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, 
C-SSRS scores, Lilly Self-Harm Supplement responses, and QIDS-SR16 scores.  Clinical 
chemistry and hematology data, vital signs, C-SSRS scores, Lilly Self-Harm Supplement
responses, and QIDS-SR16 scores will be listed and summarized using standard descriptive 
statistics.  Urinalysis data will be listed.  Electrocardiograms and physical examinations will be 
performed for safety monitoring purposes and will not be presented.  Additional analysis will be 
performed if warranted upon review of the data.
10.3.3. Immunogenicity Analyses
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA).  
The frequency and percentage of patients with preexisting ADAs and with TE ADA+ to 
mirikizumab will be listed and summarized.  The frequency of neutralizing antibodies will also 
be tabulated for TE ADA+ patients.
The relationship between the presence of antibodies and the PK parameters and other responses, 
including safety and efficacy to mirikizumab, may be assessed.
10.3.4. Exploratory Analyses
10.3.4.1. Efficacy Assessments
The PASI scores, sPGA responses, and percent BSA evaluation results will be listed and 
summarized.  The proportion of patients who achieved sPGA (0, 1) and sPGA (0), and PASI 75, 
PASI 90, and PASI 100 (at least a 75%, 90%, and 100% improvement from baseline in PASI 
score, respectively) will be summarized over time using descriptive statistics.  The change from 
baseline in percent BSA will also be summarized over time using descriptive statistics.
10.3.4.2. Biomarker Analyses
Concentrations of IL-19 and changes from baseline will be listed and summarized by treatment.  
10.3.5. Interim Analyses
An interim analysis may be performed after all enrolled subjects have completed the outpatient 
visit and PK sample collection on Day 120 in Period 2.  The purpose of this interim analysis is to 
provide PK results to support a regulatory submission.  No changes to the study design are 
planned.


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11.
References
[APA] American Psychiatric Association. Diagnostic and statistical manual of mental disorders.
5th ed. Washington, DC: American Psychiatric Association; 2013.
Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. 
1983;24(1):93-98.
[EMA] European Medicines Agency. Committee for medicinal products for human use (CHMP). 
Guideline on clinical investigation of medicinal products indicated for the treatment of 
psoriasis. CHMP/EWP/2454/02 corr. November 2004.
[EMA] European Medicines Agency. Guideline on the investigation of drug interactions. 
CPMP/EWP/560/95/Rev. 1 Corr 2**. June 2012.
[FDA] United States Food and Drug Administration. Center for Drug Evaluation and Research. 
Clinical Drug Interaction Studies - Study Design, Data Analysis, and Clinical Implications. 
Guidance for Industry. October 2017.
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.
[HMA] Heads of Medicines Agency. Public Assessment Report Scientific Discussion 
Omeprazol “Copyfarm” Omeprazole. DK/H/1650/001-003/MR. April 2009. Available at:  
http://www.hma.eu/fileadmin/dateien/pipar/dk1650/parmod5_dk1650omeprazolcopyfarm.pdf
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.
[PMDA] Pharmaceuticals Medical Devices Agency. Draft Guideline on Drug Interactions. 2013.
Puig L. PASI90 response: the new standard in therapeutic efficacy for psoriasis. J Eur Acad 
Dermatol Venereol. 2015;29(4):645-648.
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. 


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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
Term
Definition
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An 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-Guerin
BP
blood pressure
BSA
body surface area
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 study-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
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
IL
interleukin
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, 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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.


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IV
intravenous
MR
metabolic ratio
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
PFS
prefilled syringe
PK
pharmacokinetic(s)
PPD
purified protein derivative
PUVA
psoralen and ultraviolet A
QIDS-SR16
Quick Inventory of Depressive Symptomatology-Self Report (16 items)
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
sPGA
static Physicians Global Assessment
SUSARs
suspected unexpected serious adverse reactions
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
TB
tuberculosis
TBL
total bilirubin level
TE ADA
treatment-emergent antidrug antibody
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.
Th
T helper
tmax
time of maximum observed drug concentration
UC
ulcerative colitis
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety 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)
Platelets
Uric acid
Absolute counts of:
Total cholesterol
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Urinalysisa
Creatinine
Specific gravity
Gamma-glutamyl transferase (GGT)
pH
Protein
Additional testsa
Glucose
Ethanol testingb
Ketones
Urine drug screenb
Bilirubin
PPD/QuantiFERON-TB Gold/T-SPOTc
Urobilinogen
Hepatitis C antibodyc
Blood
Hepatitis B core antibody (HBcAb+)c
Nitrite
Hepatitis B surface antigenc
Urine leukocyte esterase
Hepatitis B virus DNA
Microscopic examination of sedimentd
HIVc
Pregnancy test (females, as appropriate)e
FSH (females, as appropriate)c
Coagulation parametersa
PT (INR)
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; INR = international 
normalized ratio; PPD = purified protein derivative; PT = prothrombin time; RBC = red blood cells; TB = 
tuberculosis; WBC = white blood cells.
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
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities (Section 2).  
c
Performed at screening only.
d
Test only if dipstick result is abnormal.  
e
Serum pregnancy test to be performed at screening for all females.  Serum or urine pregnancy test will be 
performed locally at all other times for females of childbearing potential. Additional tests may be performed 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 nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current mirikizumab Investigator’s Brochure, drug cocktail package inserts, and 
updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
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.
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 final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
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 electronic case report forms 
(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.


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
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.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
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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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 clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
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
Alkaline phosphatase isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
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.  
Protocol I6T-MC-AMBP Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
36
1
36
Clinical laboratory testsa
16
10
160
Pharmacokinetics :
Midazolam and 1’-hydroxymidazolam
2
20
40
S-warfarin
2
22
44
Dextromethorphan and dextrorphan
2
20
40
Omeprazole and 5-hydroxyomeprazole
2
22
44
Caffeine and paraxanthine
2
22
44
Mirikizumab
2
7
14
Blood discard for cannula patency
1
22
22
Immunogenicity
10
5
60
High sensitivity C-reactive protein
2.5
9
22.5
Interleukin-19
2.5
6
15
Exploratory inflammatory biomarkers
5
6
30
Pharmacogenetics
10
1
10
Total
581.5
Total for clinical purposes rounded up to nearest 10 mL
590
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment I6T-MC-AMBP(a)
Summary Evaluation of the Effect of Mirikizumab on the 
Pharmacokinetics of Cytochrome P450 Substrates in 
Patients with Moderate-to-Severe Plaque Psoriasis
Overview
Protocol I6T-MC-AMBP Evaluation of the Effect of Mirikizumab 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 7.1, a dosing volume error for midazolam has been corrected.  The 
administered midazolam volume has been updated to 0.5 mL to achieve a 1-mg 
midazolam dose from 2 mg/mL midazolam syrup.  

In the Study Schedule for Period 2 (Section 2), an error in the footnote letter designations 
within the table has been corrected.  The footnote for mirikizumab PK samples has been 
updated from “g” to “h”.  


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2.
Schedule of Activities
Study Schedule Protocol I6T-MC-AMBP – Period 2
PK Samples (hours)
Mirikizumabh g
Predose
Predose
Predose
Predose
Predose
Predose
X
7.1.
Treatment Administered
The 1-mg oral dose will be administered as 0.1 0.5 mL of 2-mg/mL commercially available midazolam syrup.


Leo Document ID = 96c8d19e-cd1d-4e20-b25c-5cb9c555c304
Approver: 
Approval Date & Time: 09-Aug-2018 23:02:56 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 09-Aug-2018 23:02:56 GMT
Signature meaning: Approved

SAP_001.pdf: 
Statistical Analysis Plan I6T-MC-AMBP 
 
Evaluation of the Effect of Mirikizumab on the Pharmacokinetics of Cytochrome P450 
Substrates in Patients with Moderate-to-Severe Plaque Psoriasis 
 
NCT03718884 
 
Approval Date: 04-Sep-2018 


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             Page 1 of 22
STATISTICAL ANALYSIS PLAN
Evaluation of the Effect of Mirikizumab on the Pharmacokinetics of Cytochrome P450 
Substrates in Patients with Moderate-to-Severe Plaque Psoriasis
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  29-August-2018
Study Drug:  Mirikizumab (LY3074828)
Sponsor Reference:  I6T-MC-AMBP
Covance CRU Study: 1000071-8388871
Clinical Phase I
Approval Date: 04-Sep-2018 GMT


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             Page 2 of 22
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary .........................................................................................................................6
4.2
Secondary......................................................................................................................6
4.3
Exploratory ...................................................................................................................6
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
9.
STATISTICAL METHODOLOGY ...................................................................................10
9.1
General........................................................................................................................10
9.2
Demographics and Subject Disposition........................................................................10
9.3
Pharmacokinetic Assessment.......................................................................................10
9.3.1
Pharmacokinetic Analysis...................................................................................10
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................15
9.3.3
Pharmacokinetic Exploratory Statistical Methodology........................................15
9.4
Safety and Tolerability Assessments............................................................................16
9.4.1
Adverse events ...................................................................................................16
9.4.2
Concomitant medication.....................................................................................16
9.4.3
Clinical laboratory parameters............................................................................16
9.4.4
Vital signs ..........................................................................................................16
9.4.5
Electrocardiogram ..............................................................................................16
9.4.6
Injection-site Reaction........................................................................................17
9.4.7
Columbia-Suicide Severity Scale (C-SSRS) and Self-Harm Supplement ............17
9.4.8
Quick Inventory of Depressive Symptomatology-Self Report (16 items) 
(QIDS-SR16) .....................................................................................................17
9.4.9
Hepatic Monitoring ............................................................................................17
9.4.10
Other assessments...............................................................................................17
9.4.11
Safety and Tolerability Statistical Methodology..................................................17
9.5
Efficacy Assessments ..................................................................................................18
9.5.1
Static Physicians Global Assessment (sPGA) .....................................................18
9.5.2
Psoriasis Area Severity Index (PASI) .................................................................18
9.5.3
Percentage of Body Surface Area (%BSA) Assessment ......................................20


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
9.6
Immunogenicity Analyses ...........................................................................................21
9.7
Biomarker Analyses ....................................................................................................21
9.7.1
High Sensitivity-C Reactive Protein (HS-CRP) ..................................................21
10. INTERIM ANALYSES .....................................................................................................21
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............21
12. REFERENCES ..................................................................................................................21
13. DATA PRESENTATION ..................................................................................................22
13.1 Derived Parameters .....................................................................................................22
13.2 Missing Data ...............................................................................................................22
13.3 Insufficient Data for Presentation ................................................................................22


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
  %AUC(tlast-)
percentage of AUC(0-∞) extrapolated
ADA
antidrug antibody
AE
adverse event
AUC
area under the concentration versus time curve
  AUC(0-)
area under the concentration versus time curve from time zero to infinity
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
BP
blood pressure
BQL
below the lower limit of quantitation
BSA
body surface area
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale 
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
CV
coefficient of variation
CYP
cytochrome P450
EC
Early Clinical 
ECG
electrocardiogram
e.g.
for example (Latin: exempli gratia)
HS-CRP
High Sensitivity-C Reactive Protein
ICH
International Council on Harmonisation
IL
interleukin
LLOQ
lower limit of quantification
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
MR
metabolic ratio
MW
Molecular weight
NA
not applicable
PASI
Psoriasis Area Severity Index
PK
pharmacokinetic
QIDS-SR16
Quick Inventory of Depressive Symptomatology-Self Report (16 items)
SAP
Statistical Analysis Plan
SD
standard deviation 
sPGA
static Physicians Global Assessment
TE ADA
treatment-emergent antidrug antibody
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
  Vss/F
apparent volume of distribution at steady state after extra-vascular 
administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
27 June 2018) and Protocol Amendment (a) (final version dated 09 August 2018).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned 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 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 subject 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 

To assess the effects of multiple doses of mirikizumab on the PK of a drug cocktail of 
cytochrome P450 (CYP) substrates in patients with moderate-to-severe psoriasis.
4.2
Secondary

To evaluate the tolerability of mirikizumab in patients with moderate-to-severe psoriasis.

To determine the PK of metabolites where appropriate.
4.3
Exploratory 

To explore the effects of mirikizumab on the PK of a drug cocktail of CYP substrates in 
the subgroups of patients with moderate-to-severe psoriasis who respond to mirikizumab 
treatment at Week 16 and those who do not respond.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP

To evaluate the effects of mirikizumab treatment over time of inflammatory biomarker 
concentrations in patients with moderate-to-severe psoriasis. 
5. STUDY DESIGN
This is a Phase 1, multicenter, 2-period, fixed-sequence, open-label study to assess the effects of 
multiple doses of mirikizumab on the PK of a drug cocktail of CYP substrates 
(midazolam, warfarin, dextromethorphan, omeprazole, and caffeine) in patients with 
moderate-to-severe psoriasis. Figure AMBP.1 illustrates the study design.
Blood sampling for assessment of PK of the CYP substrates (and metabolites, as appropriate), 
inflammatory biomarkers, and mirikizumab PK and immunogenicity will be collected at 
prespecified visits. 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.  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), Lilly Self-Harm Supplement, and 
electrocardiograms (ECGs).
Figure AMBP.1. Illustration of study design.
Abbreviations: BSA = body surface area; PASI = Psoriasis Area Severity Index; PK = pharmacokinetic; 
sPGA = static Physicians Global Assessment.
Note: In Period 2, drug cocktail will be administered 48 to 96 hours after the final mirikizumab dose.
-1
Day
1
2
Inpatient period
3
4
5
Drug cocktail 
administration
Period 1
X  
□   
116±1
118±1 119±1
17
120±1
Drug Cocktail PK sampling
Drug cocktail 
administration
144±4
20
Follow-up 
1
1
29±1
4
57±1
8
85±1
12
113±1
16
Period 2
250 mg mirikizumab administration
Drug Cocktail PK sampling
Screening 
Day -29 to 
Day -2
X
□ 
X
□ 
X
□ 
X
□ 
X
□ 
Day
Week
115±1
117±1
□ 
X
Mirikizumab immunogenicity and PK samples 
PASI, sPGA, and % BSA assessment and Inflammatory biomarker samples


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the safety TFLs.
Study Treatment Name
Abbreviation
Treatment order 
in TFL
1 mg Midazolam + 10 mg Warfarin (plus vitamin K) + 
30 mg Dextromethorphan + 20 mg Omeprazole + 
100 mg Caffeine (Period 1)
Drug Cocktail (Period 1)
1
250 mg Mirikizumab SC Q4W (Period 2)
250 mg Mirikizumab SC (Period 2)
2
1 mg Midazolam + 10 mg Warfarin (plus vitamin K) + 
30 mg Dextromethorphan + 20 mg Omeprazole + 
100 mg Caffeine (Period 2)
Drug Cocktail (Period 2)
3
The following is a list of the study treatment abbreviations that will be used in the PK TFLs.
Study Treatment Name
Abbreviation
Treatment order 
in TFL
1 mg Midazolam (Period 1)
1 mg Midazolam (Period 1)
1
10 mg Warfarin (plus vitamin K) (Period 1)
10 mg Warfarin (Period 1)
2
30 mg Dextromethorphan (Period 1)
30 mg Dextromethorphan (Period 1)
3
20 mg Omeprazole (Period 1)
20 mg Omeprazole (Period 1)
4
100 mg Caffeine (Period 1)
100 mg Caffeine (Period 1)
5
250 mg Mirikizumab SC Q4W (Period 2)
250 mg Mirikizumab SC (Period 2)
6
1 mg Midazolam  (Period 2)
1 mg Midazolam (Period 2)
7
10 mg Warfarin (plus vitamin K) (Period 2)
10 mg Warfarin (Period 2)
8
30 mg Dextromethorphan (Period 2)
30 mg Dextromethorphan (Period 2)
9
20 mg Omeprazole (Period 2)
20 mg Omeprazole (Period 2)
10
100 mg Caffeine (Period 2)
100 mg Caffeine (Period 2)
11
7. SAMPLE SIZE JUSTIFICATION
Approximately 30 patients will be enrolled with the assumption that 21 evaluable patients
complete the study.
Midazolam
For midazolam area under the concentration versus time curve (AUC) and maximum observed 
drug concentration (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 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8388871
Sponsor Reference I6T-MC-AMBP
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%,
respectively3. 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%, respectively4. 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%5 and 
23.4%6, 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
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
mirikizumab PK, the full analysis set includes all data from all patients receiving at least one
dose of mirikizumab with evaluable PK data. For patients with serum mirikizumab
concentrations that are less than the drug exposure range expected after multiple doses, the drug
cocktail PK results for Period 2 may be excluded from the analysis and the rationale will be
provided in the study report.
Safety analyses will be conducted for all enrolled patients, whether or not they completed all
protocol requirements.


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Biomarker analyses will be conducted for all patients receiving at least one dose of mirikizumab
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.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that are 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. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject 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 only.
Furthermore, baseline disease characteristics (PASI score, sPGA score, percent total BSA of 
psoriasis, age of psoriasis onset, and previous psoriasis therapy type) will also be summarized 
and listed.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameter estimates will be determined by standard non-compartmental procedures using a 
validated software program (Phoenix WinNonlin Version 6.4 or later).


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Covance Clinical Study No. 1000071-8388871
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Plasma concentrations of midazolam, 1’-hydroxymidazolam, S-warfarin, dextromethorphan, 
dextrorphan, omeprazole, 5’-hydroxyomeprazole, caffeine and paraxanthine will be used to 
determine the following PK parameters, when possible:  
Parameter
Units
Definition
Cmax
ng/mLa
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mLa
area under the concentration versus time curve from time 
zero to infinity
AUC(0-tlast)
ng.h/mLa
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(tlast-)
%
percentage of AUC(0-∞) extrapolated
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 (midazolam, S-warfarin, 
dextromethorphan, omeprazole and caffeine only)
Vz/F
L
apparent volume of distribution during the terminal phase 
after extra-vascular administration (midazolam, S-warfarin, 
dextromethorphan, omeprazole and caffeine only)
Vss/F
L
apparent volume of distribution at steady state after 
extra-vascular administration (midazolam, S-warfarin, 
dextromethorphan, omeprazole and caffeine only)
MR
metabolic ratio
Metabolic ratios (MR) will be calculated as follows for AUC(0-). If for any reason the 
AUC(0-) is not calculable then an alternative AUC such as AUC(0-tlast) may be used:
MR = AUC(0 −) (metabolite)
AUC(0 −) (parent)
×
MW (parent)
MW (metabolite)
Parent
MW*
Metabolite
MW*
Midazolam
325.77
1’-hydroxymidazolam
341.77
Dextromethorphan
271.40
Dextrorphan
257.38
Omeprazole
345.42
5’-hydroxyomeprazole
364.42
Caffeine
194.19
Paraxanthine
180.17
Abbreviation: MW = Molecular weight.
* Molecular weights obtained from PubChem7
Serum concentrations of mirikizumab (LY3074828) will be listed and summarized using 
descriptive statistics.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 


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Covance Clinical Study No. 1000071-8388871
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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 quantification (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.

Half-life (t1/2) 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 subject 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 t1/2 is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t1/2 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 minimum observed drug concentration (Clast) will be 
reported.


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Statistical Analysis Plan 
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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 subject 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.

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 within the 
sampling time window specified in the protocol or ± 10%. An average concentration 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8388871
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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:
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 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8388871
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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 mirikizumab (Period 1) will represent the reference treatments and will be
analyzed separately. Each drug administered after multiple dosing of mirikizumab (Period 2) 
will represent the test treatments and will be analyzed separately. 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 derive ratios of geometric least squares (LS)
means and the corresponding 90% CIs. The MR and AUC(0-tlast) will also be analyzed using 
this method.
Example SAS code:
proc mixed data=DATA;
    by parameter;
    class patient treatment;
    model log_pk = treatment / alpha=0.1 cl residual ddfm=kr;
    random patient;
    lsmeans treatment / alpha=0.1 cl pdiff;
    ods output lsmeans=lsm;
    ods output diffs=diff;
run;
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.
A sensitivity analysis will also be performed including only subjects with evaluable PK data in 
both treatment periods. Subject will be fitted as a fixed effect for this analysis.
The inter- and intra-subject variability, expressed as a CV, will be reported for each drug (using 
the statistical model from the primary analysis).
9.3.3
Pharmacokinetic Exploratory Statistical Methodology
The same model used for the primary PK analysis will be applied to the subgroups of responders
to mirikizumab and nonresponders. A responder to mirikizumab will be defined as a patient with
an sPGA equal to 0 or 1 at Day 116 in Period 2. A nonresponder will be defined as a patient


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8388871
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with sPGA >1 at Day 116 in Period 2. The treatment differences for each subgroup will be
back-transformed to present ratios of geometric LS means and the corresponding 90% CIs.
9.4
Safety and Tolerability Assessments
9.4.1
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 subject 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.
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 subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 21.0 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 listed. In Period 2, AEs by day of onset will be presented.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2018).
Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. 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 subject data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day -1 in Period 1 and Day 1 predose in Period 2. Furthermore, values for 
individual subjects will be listed.
9.4.5
Electrocardiogram
ECGs will be performed for safety monitoring purposes and will not be presented.  Any 
clinically relevant findings will be reported as an AE.


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Statistical Analysis Plan 
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9.4.6
Injection-site Reaction
If an AE of injection site reaction is reported, then the investigator will complete a supplemental 
injection site reaction form. The injection site reaction form documents the presence of 
erythema, induration, pain (mild, moderate, or severe), pruritus, and edema.
Injection-site reaction data will be listed and summarized in frequency tables.
9.4.7
Columbia-Suicide Severity Scale (C-SSRS) and Self-Harm Supplement
The C-SSRS and self-harm supplement data will be listed and summarized by treatment.
9.4.8
Quick Inventory of Depressive Symptomatology-Self Report (16 items) 
(QIDS-SR16)
The QIDS-SR16 scores will be listed and summarized by treatment. 
9.4.9
Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be 
listed. Any concomitant medication of acetaminophen/paracetamol will be listed. Results from 
any hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and 
a biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed.  Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.10
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.
9.4.11
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


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Statistical Analysis Plan 
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9.5
Efficacy Assessments
9.5.1
Static Physicians Global Assessment (sPGA)
The proportion of patients who achieve sPGA (0,1) and sPGA (0) will be summarized by 
treatment and timepoint, and listed. The following table details the derivation for these 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
lesions at a given time point.  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
9.5.2
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 by treatment and 
timepoint, and listed. The following table details the derivation for these measures:


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
with Missing 
Components
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 most severe 
disease8.  
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 
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
PASI total 
score
Sum the 3 scores for each body region 
to give a lesion score sum.
Multiply 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


 
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Statistical Analysis Plan  
 
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Measure 
Description 
Variable 
Derivation / Comment 
Imputation 
Approach if 
with Missing 
Components 
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 percent 
improvement 
from baseline 
Calculated as:   
ܲ݁ݎܿ݁݊ݐ݅݉݌ݎ݋ݒ݁݉݁݊ݐ݂ݎ݋݉ ܾܽݏ݈݁݅݊݁ 
ൌ  
100 ൈ
஻௔௦௘௟௜௡௘ ௉஺ௌூିை௕௦௘௥௩௘ௗ ௉஺ௌூ
஻௔௦௘௟௜௡௘ ௉஺ௌூ
   
 
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 
 
9.5.3 
Percentage of Body Surface Area (%BSA) Assessment 
The change from baseline in the %BSA will be summarized by treatment and timepoint, and 
listed. The following table details the derivation: 
Measure 
Description 
Variable 
Derivation / Comment 
Imputation 
Approach if 
with Missing 
Components 
BSA 
 
Percentage of Body 
Surface Area (BSA):  
The investigator will 
evaluate the percentage 
involvement of psoriasis 
on each patient’s BSA 
on a continuous scale 
from 0% (no 
involvement) to 100% 
(full involvement), in 
which 1% corresponds 
to the size of the 
patient’s hand 
(including the palm, 
fingers, and thumb)9. 
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 
BSA change 
from baseline 
Calculated as:  observed BSA – baseline 
BSA  
Missing if 
baseline or 
observed 
value is 
missing 
 


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9.6
Immunogenicity Analyses
Treatment-emergent antidrug antibodies (TE ADAs) are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution (1:10) if no ADAs were detected at 
baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared 
to baseline if ADAs were detected at baseline (treatment-boosted ADA).
The frequency and percentage of patients with preexisting ADAs and with TE ADA+ to 
mirikizumab will be listed and summarized. The frequency of neutralizing antibodies will also 
be tabulated for TE ADA+ patients.
The relationship between the presence of antibodies and the PK parameters and other responses, 
including safety and efficacy to mirikizumab, may be assessed.
9.7
Biomarker Analyses
Exploratory biomarkers, including concentrations of interleukin (IL-19), will be summarized by 
treatment together with changes from baseline, where baseline is defined as Day 1 predose of 
Period 2. Individual values will be listed.
9.7.1
High Sensitivity-C Reactive Protein (HS-CRP)
HS-CRP data and its change from baseline (Day 1 predose of Period 2) will be summarized by 
treatment and listed.
10.
INTERIM ANALYSES
An interim analysis may be performed after all enrolled subjects have completed the outpatient
visit and PK sample collection on Day 120 in Period 2. The purpose of this interim analysis is to
provide PK results to support a regulatory submission. No changes to the study design are
planned.  The PK analyses detailed in Section 9.3.1 may be deemed final after this interim 
analyses (as all scheduled PK samples are included) and may not be repeated.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
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.


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3. 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.
4. [HMA] Heads of Medicines Agency. Public Assessment Report Scientific Discussion 
Omeprazol “Copyfarm” Omeprazole. DK/H/1650/001-003/MR. April 2009. Available at:  
http://www.hma.eu/fileadmin/dateien/pipar/dk1650/parmod5 dk1650omeprazolcopyfarm.pdf
5. Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin 
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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. Unless otherwise stated, there are no plans to 
impute missing data.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects 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 = e810f0f1-e35b-49ec-ab7f-a0e2f365e08d
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Approval Date & Time: 29-Aug-2018 13:18:27 GMT
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Approval Date & Time: 29-Aug-2018 19:08:11 GMT
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Approver: 
Approval Date & Time: 03-Sep-2018 11:48:08 GMT
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Approver: 
  
Approval Date & Time: 04-Sep-2018 19:48:13 GMT
Signature meaning: Approved