Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: yes

Brief summary:
The purpose of this study is to compare two different formulations of mirikizumab in healthy participants. This study will compare how much of each formulation gets into the blood stream and how long it takes the body to remove it. Information about any side effects that may occur will also be collected. Participants will remain in the study for about 12 weeks, after receiving study drug.

Detailed description:

Arms:
arm 1: 200 milligram (mg) of mirikizumab as reference formulation (100 mg/mL), 2 × 1-mL pre-filled syringe administered as a subcutaneous (SC) injection into the arm/thigh/abdomen on day 1. arm 2: 200 mg of mirikizumab as test formulation (100 mg/mL), 2 × 1-mL pre-filled syringe administered as a SC injection into the arm/thigh/abdomen on day 1.

Interventions: intervention 1: Mirikizumab
Intervention descriptions: intervention 1: Reference and test formulations of mirikizumab administered as a SC injection.

Protocol document:
Prot_000.pdf: 
Protocol I6T-MC-AMBV (a) 
 
Relative Bioavailability of a Mirikizumab Test Formulation Compared to the Reference 
Formulation in Healthy Subjects 
 
NCT04548219 
 
Approval Date: 17-Aug-2020 
 
 


I6T-MC-AMBV (a) Clinical Pharmacology Protocol
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Protocol I6T-MC-AMBV (a)
Relative Bioavailability of a Mirikizumab Test Formulation 
Compared to the Reference Formulation in 
Healthy Subjects
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 on 
13 December 2019 
Protocol amendment (a) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 17-Aug-2020 GMT


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Table of Contents
Relative Bioavailability of a Mirikizumab Test Formulation 
Compared to the Reference Formulation in Healthy Subjects
Section
Page
Protocol I6T-MC-AMBV (a) Relative Bioavailability of a Mirikizumab 
Test Formulation Compared to the Reference Formulation in 
Healthy Subjects .................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.2.1.
Deaths, Serious Adverse Events, and Discontinuations due to 
an Adverse Event .................................................................................................15
3.2.2.
Other Treatment-Emergent Adverse Events..........................................................15
3.2.3.
Pharmacokinetics .................................................................................................16
3.2.4.
Immunogenicity...................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................18
5.3.
End of Study Definition ...............................................................................................18
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................22
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................25
6.3.1.
Meals and Dietary Restrictions.............................................................................25
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26


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7.1.
Treatment Administered...............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................26
7.1.2.
Medical Device....................................................................................................27
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.3.
Blinding .......................................................................................................................27
7.4.
Dose Modification........................................................................................................27
7.4.1.
Special Treatment Considerations ........................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................28
7.6.
Treatment Compliance .................................................................................................28
7.7.
Concomitant Therapy...................................................................................................28
7.8.
Treatment after the End of the Study............................................................................29
8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................30
8.2.
Discontinuation from the Study....................................................................................30
8.3.
Subjects Lost to Follow-up...........................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.2.
Adverse Events ............................................................................................................31
9.2.1.
Serious Adverse Events........................................................................................32
9.2.1.1.
Adverse Device Effects ..................................................................................32
9.2.1.2.
Adverse Events of Special Interest..................................................................33
9.2.1.3.
Suspected Unexpected Serious Adverse Reactions..........................................33
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................34
9.4.
Safety...........................................................................................................................34
9.4.1.
Laboratory Tests ..................................................................................................34
9.4.2.
Vital Signs ...........................................................................................................34
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.4.
Temperature.........................................................................................................34
9.4.5.
Other Tests...........................................................................................................35
9.4.5.1.
Tuberculosis Testing.......................................................................................35
9.4.5.2.
Injection-Site Bleeding ...................................................................................35
9.4.5.3.
Injection-Site Assessments .............................................................................35
9.4.5.3.1.
Injection-Site Pain ....................................................................................35
9.4.6.
Safety Monitoring ................................................................................................36
9.4.6.1.
Hepatic Safety................................................................................................36


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9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................37
9.6.
Pharmacodynamics ......................................................................................................37
9.6.1.
Immunogenicity Assessments ..............................................................................37
9.7.
Genetics .......................................................................................................................37
9.8.
Biomarkers...................................................................................................................38
9.9.
Health Economics ........................................................................................................38
10.
Statistical Considerations and Data Analysis.....................................................................39
10.1. Sample Size Determination ..........................................................................................39
10.2. Populations for Analyses..............................................................................................39
10.2.1.
Study Participant Disposition ...............................................................................39
10.2.2.
Study Participant Characteristics ..........................................................................39
10.3. Statistical Analyses ......................................................................................................39
10.3.1.
Safety Analyses....................................................................................................39
10.3.1.1.
Clinical Evaluation of Safety..........................................................................39
10.3.1.2.
Statistical Evaluation of Safety.......................................................................40
10.3.1.2.1.
Injection-Site Pain ....................................................................................40
10.3.1.2.2.
Statistical Evaluation of Other Safety Parameters......................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................40
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
10.3.3.
Evaluation of Immunogenicity .............................................................................41
10.3.4.
Data Review during the Study..............................................................................41
10.3.5.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42
12.
Appendices .......................................................................................................................43


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List of Tables
Table
Page
Table AMBV.1.
Objectives and Endpoints .......................................................................17


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................44
Appendix 2.
Clinical Laboratory Tests........................................................................48
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................49
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............52
Appendix 5.
Blood Sampling Summary......................................................................53
Appendix 6.
Allergic/Hypersensitivity Reaction Kit ...................................................54
Appendix 7.
Protocol Amendment I6T-MC-AMBV (a) Summary Relative 
Bioavailability of a Mirikizumab Test Formulation Compared to 
the Reference Formulation in Healthy Subjects.......................................55


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1. Protocol Synopsis
Title of Study:
Relative Bioavailability of a Mirikizumab Test Formulation Compared to the Reference Formulation in 
Healthy Subjects
Rationale: 
Changes in buffer composition are being investigated as a potential way to address injection-site reactions, including 
pain, for mirikizumab.  Study I6T-MC-AMBV (AMBV) is being conducted to evaluate the relative bioavailability 
and tolerability of mirikizumab administered using a new formulation compared to the reference formulation that
has been administered in completed and ongoing clinical studies.
Objectives/Endpoints:
Objectives
                Endpoints
Primary

To evaluate the relative bioavailability of a single 200-mg 
SC dose (2 × 1-mL PFS injections) of Mirikizumab 
Test Formulation compared to the Reference Formulation

Cmax, AUC(0-∞), and AUC(0-
tlast)
Secondary

To evaluate the safety and tolerability of a single 200-mg 
SC dose (2 × 1-mL PFS injections) of Mirikizumab 
Test Formulation compared to the Reference Formulation

TEAEs and SAEs
Abbreviations: 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; Cmax = maximum observed drug concentration; PFS = pre-filled syringe; 
SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse event.
Summary of Study Design:
Study AMBV is a Phase 1, subject-blind, investigator-blind, 2-arm, randomized, single-dose, parallel-design study 
in healthy subjects.
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 and randomized 1:1 to 1 of 
2 possible treatments and, within treatments, 1:1:1 to 3 possible injection locations (arms, thighs, or abdomen) using 
a computer-generated allocation code.  Subjects may be allowed to leave the CRU after completing the 4-hour safety 
assessments on Day 1, at the investigator’s discretion, and will return for pharmacokinetic and immunogenicity 
sampling and safety assessments at predefined outpatient visits up to 12 weeks postdose.  Subjects will also be 
monitored for safety by way of telephone assessment on 3 occasions when outpatient visits are separated by 
2 weeks.  
Safety and tolerability will be assessed from clinical laboratory tests, vital sign measurements, recording of adverse 
events, physical examination, and immunogenicity.  
Treatment Arms and Planned Duration for an Individual Subject:
All subjects will be screened within 28 days prior to enrollment.


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On Day 1, subjects will receive a single dose consisting of 2 subcutaneous injections of 1 of the following treatment
formulations according to the randomization schedule:

200-mg Mirikizumab Reference Formulation (100 mg/mL), 2 × 1-mL pre-filled syringe (PFS)
(administered in completed and ongoing clinical studies)

200-mg Mirikizumab Test Formulation (100 mg/mL), 2 × 1-mL PFS
Subjects will participate in the study for up to 12 weeks postdose.
Number of Subjects:
Up to 60 subjects may be enrolled to ensure the following number of subjects complete the study:

48 subjects randomized to 2 treatment formulations with approximately
o
24 subjects per Reference and Test Formulations, respectively, and 
o
8 subjects per arms, thighs, and abdomen injection locations, respectively, for each treatment 
formulation.
Statistical Analysis:
Pharmacokinetic parameters will be evaluated to estimate relative bioavailability of Test Formulation compared with 
the Reference Formulation.  Log-transformed maximum observed drug concentration (Cmax) and area under the 
concentration versus time curve (AUC) parameters will be evaluated in a linear mixed-effects model with fixed 
effects for formulation and injection-site location and a random effect for subject.  The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90% confidence interval.
The time of Cmax (tmax) will be analyzed using a Wilcoxon rank sum test.  Estimates of the median difference based 
on the observed medians, 90% CIs, and p-values from the Wilcoxon rank sum test will be calculated.
Safety parameters will be listed and summarized using standard descriptive statistics, where possible.  
The frequency and percentage of subjects with preexisting antidrug antibodies (ADAs) and with treatment-emergent
ADAs that are positive (TE-ADA+) to mirikizumab will be tabulated.  For the TE-ADA+ subjects, the distribution 
of maximum titers will be described.  The frequency of neutralizing antibodies will also be tabulated in 
TE-ADA+ subjects.
Additional analysis will be performed if warranted upon review of the data.


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2. Schedule of Activities


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Study Schedule Protocol I6T-MC-AMBV
Screening
Study Day
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±2d
71
±3d
85
±3d or 
ED
Informed consent
X
Medical history and 
demographics
X
Review and confirm 
inclusion and 
exclusion criteria
X
X
Subject admission to 
CRU
X
Subject discharge 
from CRU
X
Subjects discharged after 
completing the 4-hour safety 
assessments on Day 1, at the 
investigator’s discretion.
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
Safety assessment 
(telephone call)
X
X
X
Randomization
X
Subjects will be randomized 
1:1 to 1 of 2 treatment
formulations and 1:1:1 to 1 of 
3 injection locations per 
treatment formulation.
Height, weight, and 
BMI
X
X
Only weight will be 
measured on Day 85 or ED.
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination
X
X
X
Full physical examination at 
screening or Day -1 (not 
both).  Symptom-directed 
examinations and 
assessments at other times, 
and as deemed necessary by 
the investigator.


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Screening
Study Day
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±2d
71
±3d
85
±3d or 
ED
Vital signs (pulse 
rate, blood pressure, 
and temperature) 
(sitting) (hours)
X
X
P, 
2 to 
4
X
X
X
Day 1:  2- to 4-hour 
assessment (excluding 
temperature) to be conducted 
at least 2 hours after second 
injection and prior to 
discharge at approximately 4 
hours postdose.  Time points 
may be added if warranted 
and agreed upon between 
Lilly and the investigator.
Clinical laboratory 
tests
X
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
Serology
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
QuantiFERON®-TB 
Gold test
X
Ethanol test and 
drug screen
X
X
May be repeated at the 
discretion of the investigator.
FSH test
X
Females only, if applicable.
See Section 6.1.
Pregnancy test
(females only, as 
applicable)
X
X
X
Serum pregnancy test will be 
performed at screening and 
Day -1.  Urine pregnancy 
test will be performed at 
Day 85 or ED.  See Section 
6.1 Inclusion [1b].
Single 12-lead ECG
(supine)
X
X
Single screening ECG but 
may be obtained at additional 
times, when deemed
clinically necessary.


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Screening
Study Day
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±2d
71
±3d
85
±3d or 
ED
Mirikizumab
administration (2 
injections per dose)
X
See Section 7.1. 
Subjects will fast (only water 
is allowed) from 1 hour 
before until 1 hour after 
dosing.  
Injections at Times 0 and 20 
± 2 min.
 
1
Assess within the first minute 
and then, if there is bleeding, 
at 1-min intervals following 
the injection until the 
bleeding stops.  See Section 
9.4.5.2.
 
 
 
 
 
1, 5, 
15, 
30, 
60, 
120, 
240
Assess all injections as 
described in Section 9.4.5.3.  
Time points on Day 1 after 
each injection are
within 1 min,
5 min (±1.5 min)
15 and 30 min (each ±2 
min), and
60, 120, and 240 min 
(each ±5 min). 
For VAS, see Section 
9.4.5.3.1.
Mirikizumab PK 
sample
P
X
X
X
X
X
X
X
X
X
X
X
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Screening
Study Day
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±2d
71
±3d
85
±3d or 
ED
 
P
X
X
X
 
X
AE and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISRs will be reported on 
supplemental ISR form, and 
not as AEs
Abbreviations: AE = adverse event; BMI = body mass index; CRU = clinical research unit; d = day; ECG = electrocardiogram; ED = early discontinuation; 
FSH = follicle-stimulating hormone; ISR = injection-site reaction; min = minutes; P = pre-dose; PK = pharmacokinetic(s); SC = subcutaneous; TB = 
tuberculosis; VAS = visual analog scale.
a
Administration of the pain VAS is mandatory at 1, 5, and 15 min regardless of whether pain is reported as "yes" or "no" during the injection-site assessment. 
At other time points, the VAS is administered only if pain is reported as "yes" during an injection-site assessment.
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3. Introduction
3.1.
Study Rationale
Mirikizumab (LY3074828) as a solution formulation is currently being studied in Phase 3 trials 
for the treatment of psoriasis, ulcerative colitis (UC), and Crohn’s disease.  In Phase 3 UC trials,
a 200-mg dose of mirikizumab (2 × 1-mL injections) is being administered.  In a Phase 3 
Crohn’s disease trial, a 300-mg dose (1 × 2-mL and 1 × 1-mL injections) is being administered.
Injection-site reactions (ISRs), including pain, have been reported in these studies, which use the 
mirikizumab “reference” formulation.  Several solution-associated factors may contribute to pain 
perception associated with injectable therapeutics, including active pharmaceutical ingredient, 
pH, buffer composition, and tonicity (Laursen et al. 2006).  
To potentially lessen ISRs, including pain, Lilly developed an alternate (test) formulation of 
mirikizumab that uses a different combination of buffer and tonicity agents to that of the 
reference formulation.  The
 
 which are 
commonly used excipients in formulations of monoclonal antibodies. The active ingredient 
concentration and the injection volume remain the same as the reference formulation.  The 
reference formulation contains the inactive ingredients anhydrous citric acid, polysorbate 80, 
sodium chloride, and sodium citrate dihydrate.
Study I6T-MC-AMBV (AMBV) will evaluate the relative bioavailability and tolerability of this 
test formulation compared to the reference formulation when administered subcutaneously (SC) 
using a pre-filled syringe (PFS).  This is the first human administration of the test formulation.
3.2.
Background
Mirikizumab is a humanized immunoglobulin G4‒variant monoclonal antibody that is directed 
against the p19 subunit of interleukin (IL)-23 and does not bind IL-12.  Mirikizumab is being 
developed for the treatment of autoimmune diseases, including UC, in which the IL-23 pathway 
is thought to have a significant pathogenic role.  Neutralization of IL-23 with an anti-mouse IL-
23 surrogate antibody (directed against the p19 subunit) significantly reduced the development of 
arthritis and inhibited ileal inflammation in a mouse model of spondyloarthropathy with bowel 
inflammation (Ruutu et al. 2012).  Additionally, neutralization of IL-23 significantly reduced the 
disease score in the relapsing-remitting experimental autoimmune encephalomyelitis (multiple 
sclerosis-like) model in mice.  Anti-IL-23 antibody also demonstrated some efficacy in 
preclinical arthritis models, depending on the timing of intervention (Cornelissen et al. 2013).  
Ulcerative colitis is a chronic disease of unknown etiology characterized by inflammation of the 
rectum and colon.  Symptoms include diarrhea, rectal bleeding, urgency, and tenesmus (a feeling 
of incomplete evacuation of the rectum after defecation).  Ulcerative colitis has a relapsing–
remitting course, meaning that many patients have intermittent disease flares that are 
interspersed with periods of remission.  Treatment goals in UC include induction of remission 
(typically within a 6- to 12-week time frame) and maintenance of remission in the longer term 
(assessed over 52 weeks of continuous treatment in clinical trials).  Control of intestinal 
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I6T-MC-AMBV (a) Clinical Pharmacology Protocol
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inflammation in UC is also associated with a reduction in the risk of hospitalization, colectomy,
and in the longer term, UC-associated dysplasia and colorectal cancer.
As of the Investigator’s Brochure (IB) cutoff date (06 February 2019), there have been
approximately 1061 participants in studies on mirikizumab.  These include 236 patients with 
psoriasis, 230 patients with UC, 186 patients with Crohn’s disease, and 409 healthy subjects who 
were exposed to either placebo or mirikizumab at single doses ranging from 5 to 2400 mg.  
Across Phase 2 studies, multiple doses of mirikizumab have been studied at a maximum of 
1000 mg intravenous (IV) and 300 mg SC.
Single IV doses of up to 600 mg mirikizumab were evaluated in Study I6T-MC-AMAA 
(AMAA; healthy subjects and patients with psoriasis) and up to 2400 mg in 
Study I6T-JE-AMAD (healthy Caucasian and Japanese subjects). No dose-related safety or 
tolerability issues were observed in these studies or in other ongoing clinical pharmacology 
studies.  Subcutaneous bioavailability was approximately 40% relative to IV administration in 
Study AMAA.  
In addition, 3 completed studies (I6T-MC-AMAL [AMAL], I6T-MC-AMAE [AMAE], and I6T-
MC-AMAQ) and 1 ongoing study (I6T-MC-AMAR) compared the bioavailability, safety, and 
tolerability of various formulations of mirikizumab.  These studies showed that mirikizumab was 
well tolerated; however, asymptomatic reductions in neutrophil counts were seen in a minority of 
subjects.  The incidence of ISRs was highly variable across studies and treatments, but ISRs
were mostly mild to moderate pain and very slight to well-defined erythema.
3.2.1. Deaths, Serious Adverse Events, and Discontinuations due to 
an Adverse Event
In Phase 1 studies with healthy subjects or patients with psoriasis, no deaths, serious adverse 
events (SAEs), or discontinuations due to an adverse event (AE) were reported.  In Phase 2 and 3 
studies with patients having psoriasis, UC, or Crohn's disease:

2 deaths occurred from myocardial infarction and lung cancer, respectively, but neither 
was considered related to study drug, and

serious adverse events and discontinuations due to an AEs are summarized in the IB.
3.2.2. Other Treatment-Emergent Adverse Events
In Phase 1 studies, the most frequently reported (≥5.0%) treatment-emergent adverse events 
(TEAEs) in the 442 healthy subjects and patients with psoriasis treated with mirikizumab in 
clinical pharmacology studies were ISRs (including injection-site pain), nasopharyngitis, and 
headache. Three of the clinical pharmacology studies (AABA, AMAL, and AMAE) actively 
observed injection sites to allow recording of, eg, erythema, swelling, and induration.  
Treatment-emergent adverse events in Phase 2 and 3 studies with patients having psoriasis, UC, 
or Crohn’s disease are summarized in the IB.


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3.2.3. Pharmacokinetics
Phase 1 studies in healthy subjects and patients with psoriasis found that systemic exposure of 
mirikizumab increases in proportion to dose, and that mirikizumab has a half-life 
of approximately 10 days and SC bioavailability of 40%.
 
 
3.3.
Benefit/Risk Assessment
As with other immunomodulatory therapies, mirikizumab may increase the risk of developing an 
infection or may exacerbate an existing infection.  These may include opportunistic infections 
and reactivation of latent infections, such as tuberculosis (TB) and hepatitis B.  Therefore, 
subjects testing positive for hepatitis B/C, human immunodeficiency virus (HIV), or TB at 
screening will not be permitted to participate in this study.  Immunomodulatory therapies may 
increase the risk of malignancies; however, due to the single dose of mirikizumab being 
administered in this study, it is not considered necessary to monitor for such effects.
Immediate hypersensitivity reactions (anaphylactic reaction and infusion-related hypersensitivity 
reaction) including urticaria, angioedema, and anaphylaxis, have rarely been reported with the 
administration of mirikizumab.
No other clinically significant safety or tolerability concerns have been identified to date in 
patients or healthy subjects exposed to mirikizumab at up to the highest doses given (single 
2400-mg IV and SC doses).  Of note, the 2400-mg SC dose of mirikizumab was administered in 
conjunction with human recombinant hyaluronidase as an integral component of the formulation.
Healthy subjects are not expected to derive any benefit from participating in studies in which 
mirikizumab is administered.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of mirikizumab is to be found in the IB.
CCI


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4. Objectives and Endpoints
Table AMBV.1 shows the objectives and endpoints of the study.
Table AMBV.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the relative bioavailability of a 
single 200-mg SC dose (2 × 1-mL PFS 
injections) of Mirikizumab Test Formulation 
compared to the Reference Formulation

Cmax, AUC(0-∞), and AUC(0-tlast)
Secondary

To evaluate the safety and tolerability of a 
single 200-mg SC dose (2 × 1-mL PFS 
injections) of Mirikizumab Test 
Formulation compared to the 
Reference Formulation

TEAEs and SAEs
 
 
 
 
 
 
Abbreviations: 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; Cmax = maximum observed drug concentration; PFS = pre-filled 
syringe; PK = pharmacokinetics; SAE = serious adverse event; SC = subcutaneous; 
TE-ADA = treatment-emergent antidrug antibody; TEAE = treatment-emergent adverse event; 
VAS = visual analog scale.
CCI


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5. Study Design
5.1.
Overall Design
Study AMBV is a Phase 1, subject-blind, investigator-blind, 2-arm, randomized, single-dose,
parallel-design study in healthy subjects.
All subjects will be screened within 28 days prior to enrollment.  Eligible subjects will be 
admitted to the clinical research unit (CRU) on Day -1 and randomized 

1:1 to 2 treatment formulations and 

within each treatment formulation, 1:1:1 to 3 injection sites (arm, thigh, or abdomen)
using a computer-generated allocation code (Section 7.2).  On Day 1, subjects will receive a 2 ×
1-mL (200 mg mirikizumab) SC dose of 1 of the following treatments according to the 
randomization schedule:  

200 mg Mirikizumab Reference Formulation (100 mg/mL), 2 × 1-mL PFS
(administered in completed and ongoing clinical studies [see Section 3.2])

200 mg Mirikizumab Test Formulation (100 mg/mL), 2 × 1-mL PFS
The maximum total dose of mirikizumab a subject will receive is 200 mg.
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments on 
Day 1, at the investigator’s discretion, and will return for pharmacokinetic (PK) and 
immunogenicity sampling and safety assessments at predefined times up to 12 weeks postdose.  
Subjects will be monitored for safety between outpatient visits by way of telephone assessment.  
Subjects will participate in the study for up to 12 weeks after last dose.
Safety and tolerability will be assessed through clinical laboratory tests, vital sign measurements, 
recording of AEs, physical examination, and immunogenicity.  At prospectively defined time 
points, injection-related assessments will be made including a pain visual analog scale (VAS). 
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 60 subjects may be enrolled so that 48 subjects (24 subjects per formulation with 
approximately 8 subjects per treatment formulation and injection site) complete the study.  For 
the purposes of this study, a subject completes the study when all procedures shown in the 
Schedule of Activities (Section 2) have been completed.
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 subject.


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5.4.
Scientific Rationale for Study Design
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.  A population of healthy subjects is 
frequently used in the assessment of the relative bioavailability of both small and 
large molecules.
Single doses of mirikizumab and the PK sampling time points have been selected to generate 
PK profiles sufficient to fulfill the study objectives.
Subjects will be randomized to receive injections in the arms, thighs, or abdomen, as injection 
location has been observed to have an impact on bioavailability in some studies 
with mirikizumab.
A parallel-group design was chosen because a crossover design is impractical for mirikizumab, 
which has a half-life of approximately 10.5 days.  Additionally, a crossover study could 
confound PK data if subjects develop neutralizing antidrug antibodies (ADAs).  
5.5.
Justification for Dose
The 200-mg dose of mirikizumab chosen for this study is based on 

200 mg being found safe and tolerable in Phase 2 studies

200 mg being evaluated in the Phase 3 UC development program, and

the volume of solution that can be delivered through 2 PFS (1 mL per PFS) and the 
solubility of mirikizumab (100 mg/mL).


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG) at 
screening.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.  Laboratory tests at screening and Day -1 may be repeated once 
at the discretion of the investigator for any results that are outside the reference range.
Screening may occur up to 28 days prior to enrollment.  Subjects 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, is not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[1]
are overtly healthy male or female subjects, as determined through medical 
history and physical examination
[1a]
male subjects:

no male contraception required, except in compliance with specific local 
government study requirements
[1b]
female subjects:

All female subjects must test negative for pregnancy prior to initiation of 
treatment, as indicated by negative serum pregnancy test at the screening visit and
on Day -1 prior to initial exposure to mirikizumab

Women of childbearing potential who are abstinent (if this is complete abstinence,
as their preferred and usual lifestyle) or in a same-sex relationship (as part of their 
preferred and usual lifestyle) must agree to either remain abstinent or stay in a 
same-sex relationship without sexual relationships with males.  Periodic 
abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of the study, and withdrawal are not 
acceptable methods of contraception

Otherwise, women of childbearing potential participating in this study must agree 
to use 1 highly effective method (<1% failure rate) of contraception or a 
combination of 2 effective methods of contraception from the time of signing the 
informed consent form (ICF) to 12 weeks following dosing with the 
investigational product [IP])


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o
Either 1 highly effective method of contraception (such as combination 
oral contraceptives, implanted contraceptives, an intrauterine device, or 
vaginal ring) or a combination of 2 effective methods of contraception 
(such as male or female condoms with spermicide, diaphragms with 
spermicide, or cervical sponges) will be used.  The subject may choose to 
use a double-barrier method of contraception.  Barrier protection methods 
without concomitant use of a spermicide are not reliable or acceptable 
methods.  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

Women not of childbearing potential may participate and include those who are
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, tubal ligation, or bilateral salpingectomy) or congenital 
anomaly such as Müllerian agenesis; or
o
postmenopausal, defined as 1 of the following:

A woman at least 50 years of age with an intact uterus, not on 
hormone replacement therapy, who has had either:

cessation of menses for at least 1 year; or

at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone level >40 mIU/mL at 
screening; or 

A woman at least 55 years of age, not on hormone replacement 
therapy, who has had at least 6 months of spontaneous 
amenorrhea; or

A woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy
[2]
are between 18 and 75 years of age at the time of screening
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference ranges for the 
study site, or results with acceptable deviations that are judged to be not 
clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
agree not to donate blood or plasma until after the end of their participation in 
the study
[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
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or Day -1:
[9]
are site staff directly affiliated with this study and their immediate families.  
Immediate family is defined as a spouse, biological or legal guardian, child, or 
sibling
[10] are Lilly employees or are employees of a third-party organization involved in the 
study 
[11] are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study
[12] have participated in a clinical trial involving an IP within 30 days or 
5 half-lives (whichever is longer) prior to screening.  If the clinical trial 
involved treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs), at least 3 months or 5 half-lives (whichever is 
longer) should have elapsed prior to Day 1
[13] have previously completed or withdrawn from this study or any other study 
investigating mirikizumab, and have previously received the IP
[14] have ever received anti-IL-12p40 antibodies (eg, ustekinumab [Stelara®]) or 
anti-IL-23p19 antibodies (eg, risankizumab [BI-655066], brazikumab 
[MEDI2070], guselkumab [CNTO 1959], or tildrakizumab [MK-3222]) for 
any indication, including investigational use
[15] have known allergies to mirikizumab, related compounds, or any components 
of the formulation, or history of significant atopy
[16] have self-perceived dullness or loss of sensation in either arm or thigh or on 
either side of the abdomen
[17] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[18] have an abnormal blood pressure, pulse rate, or temperature as determined to 
be clinically significant by the investigator
[19] have a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the IP; or of interfering with the 
interpretation of data


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[20] Infections:
[20a] have had a serious infection (eg, pneumonia, cellulitis, sepsis); have been 
hospitalized or have received IV antibiotics for an infection within 
12 weeks prior to Day 1; have had a serious bone or joint infection within 
24 weeks prior to Day 1 or have ever had an infection of an artificial joint; 
or are immunocompromised to an extent that participation in the study 
would pose an unacceptable risk to the subject as determined by the 
investigator
[20b] have or have had an infection typical of an immunocompromised host 
and/or that occurs with increased incidence in an immunocompromised 
host (including, but not limited to, Pneumocystis jirovecii pneumonia, 
histoplasmosis, or coccidioidomycosis) or have a known 
immunodeficiency
[20c] have or have had a herpes zoster infection or any other clinically apparent 
varicella-zoster virus infection within 12 weeks of Day 1
[20d] have had any other active or recent infection within 4 weeks of Day 1 
that, in the opinion of the investigator, would pose an unacceptable risk to 
the subject if participating in the study; these subjects may be re-screened 
(once) ≥4 weeks after documented resolution of symptoms
[21] have known or ongoing psychiatric disorders deemed clinically significant by 
the investigator
[22] regularly use known drugs of abuse and/or show positive findings on 
drug screening
[23] show positive HIV antibodies
[24] show positive hepatitis C antibody
[25] show positive hepatitis B surface antigen or hepatitis B core antibody
[26] are women who are lactating
[27] intend or are likely to use over-the-counter or prescription medication for pain
or inflammation within 7 days prior to dose administration. Subjects on stable
doses of other medications (eg, statins and antihypertensives) may be eligible
for enrolment following discussion with the sponsor (Section 7.7)
[28] have donated blood or plasma of more than 500 mL within 1 month prior to 
screening
[29] have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), have a positive test for ethanol, or are 
unwilling to abide by the alcohol restrictions described in Section 6.3.2 of 
3 units per day (males) or 2 units per day (females) (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)


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[30] have a tobacco consumption of more than 10 cigarettes per day (or 
equivalent), or who are unwilling to abide by the CRU smoking guidelines 
described in Section 6.3.2
[31] show evidence of active or latent TB, as documented through medical history, 
examination, and TB testing (positive [not indeterminate] 
QuantiFERON®-TB Gold test; if a repeat test is also indeterminate, the 
subject will not be eligible); or have had household contact with a person with 
active TB, unless appropriate and documented prophylaxis treatment has been 
given.  Subjects with any history of active TB are excluded from the study, 
regardless of previous or current TB treatments
[32] have received live vaccine(s), including attenuated live vaccines and those 
administered intranasally, within 8 weeks of screening, or intend to during the 
study (non-live or inactivated vaccinations are not allowed 2 weeks prior to,
or 2 weeks after mirikizumab dosing, and then they must be given at an 
injection site remote from mirikizumab administration)
[33] have been treated with oral steroids within 1 month of screening, or intend to 
during the study (mild topical steroid creams/ointments are permitted, with the 
exception of the injection day as specified in Section 7.7)
[34] have significant allergies to humanized monoclonal antibodies
[35] have clinically significant multiple or severe drug allergies, or intolerance 
to topical corticosteroids, or severe posttreatment hypersensitivity 
reactions (including, but not limited to, erythema multiforme major, 
linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis)
[36] have had lymphoma, leukemia, or any malignancy within the past 5 years,
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years
[37] have had breast cancer within the past 10 years
[38] have any condition that could affect pain perception from an injection
[39] have excessive tattoos over either arm, either arm, either thigh, or either side 
of the abdomen that would interfere with injection-site assessments
[40] in the opinion of the investigator, are unsuitable for inclusion in the study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion criteria [9] and [10] prevent conflict of interest in study subjects.  Exclusion 
criteria [11] through [39] exclude items including, but not limited to medical conditions, 
medication intolerance, and concomitant medication use that may confound the assessment 
of study endpoints.


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6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  Female subjects will also be required to adhere to 
contraceptive requirements, as outlined in the inclusion criteria (Section 6.1).
6.3.1. Meals and Dietary Restrictions
Subjects will receive a light breakfast on the morning of Day 1 but are required to fast (water is 
permitted) from 1 hour prior to dosing until 1-hour postdose.  Standard meals will be provided 
at all other times while subjects are resident at the CRU, per the CRU’s policy.
6.3.2. Caffeine, Alcohol, and Tobacco
Subjects will not be allowed to consume caffeinated products during study visits and while 
resident at the CRU, but otherwise subjects will be allowed to maintain their regular caffeine 
consumption.
Alcohol consumption is not permitted while subjects are resident at the CRU and for 24 hours 
prior to each study visit.  Alcohol intake during outpatient periods should not exceed 3 units per 
day for males or 2 units per day for females.  In addition, subjects must abide by the CRU 
smoking restrictions during study visits and while resident at the CRU.
6.3.3. Activity
Subjects will be advised to maintain their regular levels of physical activity/exercise; however, 
they should not undertake vigorous or prolonged exercise within 48 hours prior to any visit in
which laboratory safety tests will occur (Day -1, Day 15, Day 29, and Day 85).  While certain 
study procedures are in progress at the site, subjects may be required to remain recumbent or 
sitting.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened, except as described in exclusion criterion Section 6.2 [20d].


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7. Treatment
7.1.
Treatment Administered
One 200-mg dose of IP will consist of 2 1-mL SC injections using 2 PFS of 100 mg 
mirikizumab into the arms, thighs, or abdomen, according to the randomization schedule.  
Subjects randomized to a group with the arm or thigh as the injection area will have 
1. the first injection administered to the left limb, and 
2. the second injection administered to the corresponding (contra-lateral) right limb.  
Subjects randomized to the group with the abdomen as the injection area will have 
1. the first injection administered to the lower left quadrant, and
2. the second injection administered to the lower right quadrant of the abdomen.  
The second injection should be administered 20 (±2) minutes after the first injection.
This study will compare single doses of 2 formulations:

200 mg of Mirikizumab Reference Formulation (100 mg/mL), 2 × 1-mL PFS
(administered in completed and ongoing clinical studies [see Section 3.2])

200 mg of Mirikizumab Test Formulation (100 mg/mL), 2 × 1-mL PFS
Trained site staff will administer all doses.  Prior to the PFS injections, the investigator or 
designee will clean the subject’s skin.  The injections will be administered according to the 
instructions provided by the sponsor.
The investigator or designee is responsible for

explaining the correct use of the IP to the site staff

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection, and

returning all unused medications to Lilly or its designee at the end of the study
Note: In some cases, site may destroy the material if, during the investigational-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 or its designee in accordance with current good 
manufacturing practice, labeled according to the country’s regulatory requirements, and supplied 
with lot numbers, expiry dates, and certificates of analysis, as applicable.
Each 1-mL syringe of mirikizumab (100 mg/mL) is designed to deliver 100 mg of mirikizumab.  
The following products will be supplied by Lilly, with study-specific labels, for use in the study:


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
Mirikizumab Reference Formulation (solution for injection) in 1-mL single-dose, 
pre-filled, disposable manual syringes

Mirikizumab Test Formulation (solution for injection) in 1-mL single-dose, pre-filled, 
disposable manual syringes
7.1.2. Medical Device
The investigator or designee will ensure that the instructions have been followed properly,
maintaining accurate records of study devices, dispensing, and collection.  The used or unused 
PFS may be destroyed by a qualified vendor.  However, a used PFS that is associated with a 
product complaint will need to be returned to Lilly.
7.2.
Method of Treatment Assignment
Subjects will be randomly assigned to 1 of 2 possible treatments and 1 of 3 possible injection 
sites (arms, thighs, or abdomen) using a computer-generated allocation code (Section 5.1).
7.2.1. Selection and Timing of Doses
Each subject will be administered 2 injections approximately 20 minutes apart to complete the 
single dose.  The actual time of all injections will be recorded in the subject’s electronic case 
report form (eCRF).
7.3.
Blinding
Blinding will be in place for subjects and for site staff conducting any injection-site assessments.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.4.1. Special Treatment Considerations
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include, but are not limited to, rash, pruritus (itching), 
urticaria (hives), angioedema (swelling of the lips and/or tongue), and anaphylactic reaction.  
Sometimes these reactions can be life-threatening.  Proteins may also cause redness, itching, 
swelling, or pain locally at the injection site.  Therefore, all subjects should be 

closely monitored for signs or symptoms that could result from such reactions

educated on the signs or symptoms of these types of reactions, and 


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
instructed to contact the study site immediately if they experience any of these symptoms 
after discharge from the CRU.  
If a subject experiences an acute allergic/hypersensitivity reaction after an injection of IP, he or 
she should be managed appropriately and receive relevant supportive care.  The event should be 
recorded as an AE and a hypersensitivity cytokine panel (Appendix 6) should be collected.
7.5.
Preparation/Handling/Storage/Accountability
Investigational products will be stored under refrigerated conditions at 2°C to 8°C (36°F to 46°F) 
in its original carton to protect from light.  Investigational products should not be frozen or 
shaken.
Site will be required to monitor the temperature of on-site IP storage conditions.  The 
investigator or designee must confirm that appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all IPs received and must confirm 
that any discrepancies are reported and resolved before use of the IPs.
Unblinded site staff will be responsible for handling and administering IP. Unblinded site staff
are also responsible for ensuring that subjects remain blinded to treatment (ie, subjects must not 
see the syringe before, during, or after IP administration).  Blinded assessors of any injection-site 
assessments and bleeding will not have access to the IP.
Only subjects enrolled in the study may receive IPs or study materials, and only authorized site 
staff may supply or administer IPs.  All IPs 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 is responsible for IP accountability, reconciliation, and record maintenance 
(such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IPs will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their
regular, unchanged dose throughout the study. Permitted concomitant medications, at the
discretion of the investigator, include hormonal contraceptives, hormone replacement therapy,
and thyroid replacement. In addition, occasional acetaminophen is acceptable at the discretion of
the investigator. However, acetaminophen should not be administered on the dosing day within
4 hours prior to the first injection and until at least 4 hours after the second injection. No more 
than 3 g of acetaminophen will be permitted in any 24-hour period. Inclusion of subjects on any 
other concomitant medication (eg, statins and anti-hypertensives) is contingent upon approval
following consultation with the sponsor.


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Subjects will be restricted from applying any creams or lotions on the arm, thigh, or abdominal
skin within 24 hours prior to and after the injection and subjects should not receive any 
additional SC injections at the site of mirikizumab administration for the duration of the study.
If the need for any additional concomitant medication arises, inclusion or continuation of the
participant may be at the discretion of the investigator after consultation with a Lilly clinical
pharmacologist (CP) or clinical research physician (CRP). Any medication used during the
study must be documented.
7.8.
Treatment after the End of the Study
This section is not applicable for this study.


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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason should complete AE and other 
Day 85/early discontinuation procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Not applicable in this single-dose study.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject 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 subject 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 subject to continue in the study.  If the subject received IP, he or she will 
continue to be monitored for safety and tolerability for the planned duration of the study.
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study 
prior to receiving IP in this study.  If the subject received IP, he or she will continue to be 
monitored for safety and tolerability for the planned duration of the study.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).

Investigator decision
o
the investigator decides that the subject should be discontinued from the study

Subject decision
o
the subject, or legal representative, requests to be withdrawn from the study
8.3.
Subjects Lost to Follow-up
A subject 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 staff are expected to make diligent 
attempts to contact subjects 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
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects 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 subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed up 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.
The investigator will record all relevant AE and SAE information in the eCRF.  After the 
informed consent form is signed, site staff will record, via eCRF, the occurrence and nature of 
each subject’s preexisting conditions.  Additionally, site staff 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, study device, 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 IP, 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.


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Prospective collection of ISRs at predefined time points is included as part of this protocol.  As 
such, any identified ISRs will not be collected as AEs but will instead be recorded using the 
predefined ISR collection tools. 
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, 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 subject or may require intervention to prevent 1
of the other outcomes listed in the definition above
Site staff must alert the Lilly CRP/CP, or its designee, of any SAE as soon as practically 
possible.
Additionally, site staff 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 up 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 subject has signed informed consent and has received IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, 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 subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Pregnancy (maternal or paternal exposure to IP) 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.
Adverse Device Effects
Any AE believed to have a reasonable possibility of being related to or associated with an issue 
with the PFS, such as a malfunction or a deficiency, is considered an adverse device event.  


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These events must be clearly indicated as such in the eCRF and reported to the sponsor.  A 
product complaint should also be reported.
For the purposes of this protocol, “unanticipated” serious adverse device effect means any SAE 
alleged to have a reasonable possibility of being associated with or related to the device, which 
was not previously defined as anticipated in study documents, such as the device IB or 
Instructions for Use.  The SAE relatedness must be clearly indicated as such in the eCRF, and 
reported to the sponsor within 24 hours of site knowledge of the event.  A product complaint
should also be reported.
9.2.1.2.
Adverse Events of Special Interest
The following AEs of special interest will be used to determine the safety and tolerability of 
mirikizumab formulations administered through PFS in this clinical study.
Adverse events of special interest for mirikizumab are

Infection

systemic allergic/hypersensitivity reactions
If infections or allergic/hypersensitivity reactions are reported, site staff will provide details on 
these events as instructed on the eCRF.  A PK, immunogenicity, and hypersensitivity cytokine 
panel (Appendix 6) will be collected when possible for any subject who experiences an AE of 
systemic allergic/hypersensitivity reaction during the study.
9.2.1.3.
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 IP 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.
9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials to 
ensure the safety of study subjects, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the IP or drug delivery system so that the situation can be assessed.
The investigator or designee is responsible for handling the following aspects of the product 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed Product Complaint Form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he or she will return a copy of 
the product complaint form with the product.


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9.3.
Treatment of Overdose
For the purposes of this study, an overdose of mirikizumab is considered any dose higher than 
the 200-mg dose assigned through randomization.  Syringes used in this study can deliver a 
1-mL volume of mirikizumab and each dose will require 2 syringes.
There is no specific antidote for mirikizumab.  In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented.
Refer to the mirikizumab IB for further details.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  Additional vital signs may be measured during the study, if warranted.
Blood pressure and pulse rate should be measured after the subject has been sitting for at least 
5 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.
9.4.3. Electrocardiograms
For each subject, a single 12-lead ECG should be collected according to the Schedule of 
Activities (Section 2).
Electrocardiograms must be recorded before collecting any blood samples.  Subjects 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 study site.
Electrocardiograms will be interpreted by a qualified investigator (the physician or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings 
be identified.
9.4.4. Temperature
Body temperature will be assessed at the times indicated in the Schedule of Activities (Section 2).




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9.4.6. Safety Monitoring
The Lilly-assigned 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 trends in safety data, laboratory analytes, and AEs.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.6.1.
Hepatic Safety
If a study 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 (Appendix 4) should be repeated within 3 to 5 days including ALT, 
aspartate aminotransferase, 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 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

elevation of 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

subject 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), venous blood samples 
of approximately 3 mL each will be collected to determine the serum concentrations of
mirikizumab.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
CCI


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CCI


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9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.
CCI


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 60 subjects may be enrolled to ensure that 48 subjects (24 subjects per treatment 
formulation with approximately 8 subjects per treatment formulation and injection site [arm, 
thigh, or abdomen]) complete the study.
Based on previous trials, it is expected that the coefficient of variation for area under the 
concentration versus time curve (AUC) and maximum observed drug concentration (Cmax) to be
approximately 40%. A sample size of 48 completed subjects (24 subjects per treatment
formulation) will provide >90% probability that the limits of the 90% confidence interval (CI) 
for the ratio of geometric means will be within 24% of the estimate.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
48 subjects (24 per treatment formulation) complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or 
its designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive mirikizumab
and have evaluable PK data.
Safety analyses will be conducted for all enrolled subjects, regardless of whether they complete 
all protocol requirements.
.  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. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
CCI




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The tmax will be analyzed using a Wilcoxon rank sum test.  Estimates of the median difference 
based on the observed medians, 90% CIs, and p-values from the Wilcoxon rank sum test will 
be calculated.
 
 
 
 
 
 
 
10.3.4. Data Review during the Study
Review of the PK and safety data may be conducted during the conduct of this study to inform 
internal Chemistry, Manufacturing, and Control processes with regard to the test mirikizumab 
formulation development.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP/CRP/investigator or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.
CCI


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11.
References
Cornelissen F, Asmawidjaja PS, Mus AM, Corneth O, Kikly K, Lubberts E. IL-23 dependent and 
independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 
inhibition in collagen-induced arthritis. PLoS One. 2013;8(2):e57553.
Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media 
containing different buffers. Basic Clin Pharmacol Toxicol. 2006;98(2):218-221.
Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, Alexander K, Velasco J, 
Strutton G, Tran A, Benham H, Rehaume L, Wilson RJ, Kikly K, Davies J, Pettit AR, 
Brown MA, McGuckin MA, Thomas R. β-glucan triggers spondylarthritis and Crohn’s 
disease-like ileitis in SKG mice. Arthritis Rheum. 2012;64(7):2211-2222.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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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
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 last the 
time point with a measurable concentration
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignments.  Unless otherwise specified, blinding will remain in effect until final database 
lock.
A single-blind study is one in which the investigator and/or site staff are aware of the 
treatment, but the subject is not, or vice versa; or when the sponsor is aware of the 
treatment, but the investigator, site staff, and the subject are not.  A double-blind study is 
one in which neither the subject nor any of the investigator or sponsor staff who are 
involved in the treatment or clinical evaluation of the subjects are aware of the treatment 
received.
BMI
body mass index
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 re-tested 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
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects 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
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IL
interleukin
informed consent
A process by which a subject 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 subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
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.
IP
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.
ISR
injection-site reaction
IV
intravenous
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.


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PFS
pre-filled syringe
PK
pharmacokinetic(s)
randomize
The process of assigning subjects to an experimental group on a random basis
SAE
serious adverse event
SC
subcutaneous; subcutaneously
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.  
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
TB
tuberculosis
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibody
TE-ADA+
treatment-emergent antidrug antibody positive
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time of maximum observed drug concentration
UC
ulcerative colitis
ULN
upper limit of normal
VAS
visual analog scale


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorous
Leukocytes (WBC) 
Glucose (random)
BUN
Cell morphology
Uric acid
Absolute counts of:
Total cholesterol
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Direct bilirubin
Basophils
ALP
Platelets
AST
ALT
Urinalysis
Creatinine
Specific gravity
pH
Protein
Other Tests
Glucose
Ethanol testingb,c
Ketones
Urine drug screenb,c
Bilirubin
Pregnancy test (females only, if applicable)
Urobilinogen
FSHa
Blood
QuantiFERON®-TB Golda
Nitrite
Microscopy (if dipstick abnormal)
Serology
Hepatitis B surface antigena
Hepatitis B core antibodya
Hepatitis C antibodya
HIVa
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; 
RBC = red blood cell; TB = tuberculosis; WBC = white blood cell.
a
Performed at screening only.
b
Performed at screening and Day -1 only.
c
Urine drug screen and ethanol level may be repeated at other times indicated in the Schedule of Activities
(Section 2).


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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

ensuring that subjects understand 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 subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’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 subjects.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
materials should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the study site(s).  Lilly or its representatives must approve the ICF before it is 
used at the study site(s).  All ICFs must be compliant with the ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and Summary of Product Characteristics and updates during the course of 
the study

ICF, and

relevant curricula vitae.
Regulatory Considerations


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This study will be conducted in accordance with the protocol and with

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines

applicable ICH GCP Guidelines, and

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 investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study site, as appropriate.

Provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the site staff through email, 
telephone, or fax.

Review and evaluate eCRF data and/or use standard computer edits to detect errors in 
data collection.

Conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject 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.


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The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to 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 subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Site
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 subjects in consultation with Lilly or its designated CRP.
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
Anti-smooth Muscle Antibody 
(or Anti-actin Antibody)a
CPK
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and 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, clinical laboratory, PK, immunogenicity, and bioanalytical assays) 
during the study.
Protocol I6T-MC-AMBV Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12
4
48
Pharmacokinetics 
3
15b
45
Immunogenicity
10
4
40
Pharmacogenetics
10
1
10
Total
188
Total for clinical purposes
190
a
Additional samples may be drawn if needed for safety purposes.
b
Includes additional 3 samples, if required.


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Appendix 6.
Allergic/Hypersensitivity Reaction Kit
Selected tests may be obtained in the event of anaphylaxis or generalized urticaria.
Hypersensitivity Testsa
Anti-mirikizumab antibodies (immunogenicity)
Tryptase
Mirikizumab concentration (PK)
N-methylhistamine
Drug-specific IgEb
Basophil activation testb
Complements
Cytokine panel
Abbreviations:  Ig = immunoglobulin; PK = pharmacokinetics.
a
Assayed by Lilly-designated laboratory.
b
Basophil activation test will be performed if a drug-specific IgE assay is unavailable.


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Appendix 7.
Protocol Amendment I6T-MC-AMBV (a) 
Summary Relative Bioavailability of a Mirikizumab Test 
Formulation Compared to the Reference Formulation in 
Healthy Subjects
Overview
Protocol I6T-MC-AMBV, “Relative Bioavailability of a Mirikizumab Test Formulation 
Compared to the Reference Formulation in Heathy Subjects”, 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:

Expanded exclusion criterion [10] to exclude employees of any third-party organization 
to be involved in the study

The language in exclusion criteria [23], [24], and [25] is modified to clarify subjects with 
positive HIV antibodies, hepatitis C antibodies, hepatitis B surface antigen or hepatitis B 
core antibodies will be excluded

Included timeframe for subjects who have had household contact with a person with 
active TB to be excluded from study

Throughout the protocol changes have been made to reflect the fact that the study will be 
conducted at a single study site. These changes are not presented in the revised section 
below.


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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.
6.2 Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or Day -1:
[9]
are site staff directly affiliated with this study and their immediate families.  
Immediate family is defined as a spouse, biological or legal guardian, child, or 
sibling
[10] are Lilly or Covance employees or are employees of a third-party organization 
involved in the study 
[23] show evidence of HIV infection and/or positive HIV antibodies
[24] show evidence of hepatitis C and/or positive hepatitis C antibody
[25] show evidence of hepatitis B and/or positive hepatitis B surface antigen or hepatitis 
B core antibody
9.4.5.1 Tuberculosis Testing
Subjects who have had household contact with a person with active TB within 1 year of 
screening must be excluded


Leo Document ID = 9dc24504-fe1f-4a57-8b01-c4098bb8ebf9
Approver: 
Approval Date & Time: 17-Aug-2020 14:09:30 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Aug-2020 15:49:23 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I6T-MC-AMBV 
 
 
Relative Bioavailability of a Mirikizumab Test Formulation Compared to the Reference 
Formulation in Healthy Subjects 
 
 
NCT04548219 
 
Approval Date: 18-Dec-2020 
 
 
 


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             Page 1 of 17
STATISTICAL ANALYSIS PLAN
Relative Bioavailability of a Mirikizumab Test Formulation Compared to the Reference 
Formulation in Healthy Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 05-June-2020
Study Drug: Mirikizumab (LY3074828)
Sponsor Reference: I6T-MC-AMBV
Covance CRU Study: 1000071-8418427
Clinical Phase I
Approval Date: 18-Dec-2020 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General.................................................................................................................... 7
9.2
Demographics and Subject Disposition.................................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 12
9.4
Safety and Tolerability Assessments...................................................................... 13
9.4.1
Adverse events ............................................................................................. 13
9.4.2
Concomitant medication............................................................................... 13
9.4.3
Clinical laboratory parameters...................................................................... 13
9.4.4
Vital signs .................................................................................................... 14
9.4.5
Body temperature ......................................................................................... 14
9.4.6
Electrocardiogram (ECG)............................................................................. 14
9.4.7
Hepatic Monitoring ...................................................................................... 14
9.4.8
Immunogenicity Assessments....................................................................... 14
9.4.9
Injection-Site Assessment............................................................................. 15
9.4.10
Injection-Site Pain ........................................................................................ 15
9.4.11
Hypersensitivity reactions............................................................................. 16
9.4.12
Other assessments......................................................................................... 16
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 16
12. REFERENCES ............................................................................................................ 16
13. DATA PRESENTATION ............................................................................................ 17
13.1 Derived Parameters ............................................................................................... 17
13.2 Missing Data ......................................................................................................... 17
13.3 Insufficient Data for Presentation .......................................................................... 17


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
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
Anti-drug 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
BQL
Below the quantifiable lower limit of the assay
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CRU
Clinical Research Unit
CSR
Clinical Study Report
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PFS
Pre-filled syringe
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
TE ADA
Treatment-emergent antidrug antibody
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings


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CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vss/F
Apparent volume of distribution at steady state after extravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
13 December 2019).
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 with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. 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 with
Eli Lilly and Company 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 
Conference 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 AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the relative bioavailability 
of a single 200-mg subcutaneous (SC)
dose (2 x 1-mL pre-filled syringe [PFS]
injections) of Mirikizumab Test 
Formulation compared to the Reference 
Formulation

Maximum observed drug concentration 
(Cmax), area under the concentration 
versus time curve from time zero to 
infinity [AUC(0-∞)], and area under the 
concentration versus time curve from 
time zero to time t, where t is the last 
timepoint with a measurable 
concentration [AUC(0-tlast)]
Secondary

To evaluate the safety and tolerability 
of a single 200-mg SC dose (2 x 1-mL 
PFS injections) of Mirikizumab Test 
Formulation compared to the Reference 

Treatment-emergent adverse events 
(TEAEs), and serious adverse events 
(SAEs)




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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
Study Treatment Name
Injection Site
Abbreviation
Treatment order in TFL
200 mg Mirikizumab Reference 
Formulation (100 mg/mL) 2 x 1-mL PFS
Arm
Reference (Arm)
1
Thigh
Reference (Thigh)
2
Abdomen
Reference (Abdomen)
3
200 mg Mirikizumab Test Formulation 
(100 mg/mL) 2 x 1-mL PFS
Arm
Test (Arm)
4
Thigh
Test (Thigh)
5
Abdomen
Test (Abdomen)
6
7. SAMPLE SIZE JUSTIFICATION
Up to 60 subjects may be enrolled to ensure that 48 subjects (24 subjects per treatment 
formulation with approximately 8 subjects per treatment formulation and injection site [arm, 
thigh, or abdomen]) complete the study. 
Based on previous trials, it is expected that the coefficient of variation for area under the 
concentration versus time curve (AUC) and Cmax to be approximately 40%. A sample size of 48 
completed subjects (24 subjects per treatment formulation) will provide >90% probability that 
the limits of the 90% confidence interval (CI) for the ratio of geometric means will be within 
24% of the estimate. 
Subjects who are randomized but not administered any treatment formulation may be replaced to 
ensure that 48 subjects (24 per treatment formulation) complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects who received at least one dose of 
mirikizumab, regardless of whether they complete all protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
mirikizumab and have evaluable PK data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
mean and geometric coefficient of variation 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 by treatment 
formulation and injection site and listed. All other demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 8.1 or later).
Serum concentrations of mirikizumab will be used to determine the following PK parameters, 
when possible:  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
Parameter
Units
Definition
AUC(0-tlast)
day*µg/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
day*µg/mL
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
µg/mL
maximum observed drug concentration
tmax
day
time of maximum observed drug concentration
t1/2
day
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/day
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate.
PK parameters may also be normalized by body weight in the event that there are differences in 
body weight between the cohorts. 
The software and version used for the final analyses will be specified in the clinical study report. 
Any exceptions or special handling of data will be clearly documented within the final study 
report.
 
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. 

Cmax and the time of maximum observed drug concentration (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 concentrations above the lower limit of quantification, with at least one of 
these concentrations following Cmax. 
CCI


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV

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 serum 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on observed last quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations below the quantifiable lower limit 
of the assay (BQL).  Serum 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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
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 
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 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.  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
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 
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
PK parameters will be evaluated to estimate the relative bioavailability of the Test Formulation 
compared with the Reference Formulation. PK parameters will be summarized by treatment 
formulation and injection site. 
Log-transformed Cmax, AUC(0-tlast), and AUC(0-∞) parameters will be evaluated in a linear 
fixed-effects model with fixed effects for treatment formulation and injection-site location. The 
differences between the test and reference formulations will be back-transformed to present the 
ratios of geometric least squares means and the corresponding 90% CI. 
Example SAS Code:
proc mixed data=xxx;
by parameter;
class formulation location;
model log_pk = formulation location / residual;
lsmeans formulation / alpha=0.1 cl pdiff;
ods output lsmeans=lsmeans;
ods output diffs=diffs;
run;


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
The tmax will be analyzed using a Wilcoxon rank sum test. Estimates of the median difference 
based on the observed medians, 90% CIs, and p-values from the Wilcoxon rank sum test will be 
calculated.
In addition, the following comparisons will be made:

Test versus Reference separately at each injection site (injection site will be removed 
from the model above)

Arm versus abdomen and thigh versus abdomen separately for each formulation
(formulation will be removed from the model above)
Additional PK analyses may be conducted if deemed appropriate.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the case report form, 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 TEAE 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. TEAEs will be summarized by treatment formulation, injection site, 
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 TEAEs will 
be summarized by treatment formulation, Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0 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 by the 
investigator. Any SAEs will be listed.
Discontinuations due to AEs will be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version MAR20B3). 
Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment
formulation, and listed. Urinalysis data will be listed. Changes from baseline, Day -1, will also 
be presented. Additionally, clinical chemistry, hematology and urinalysis data outside the 
reference ranges will be listed and flagged on individual subject data listings.








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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8418427
Sponsor Reference I6T-MC-AMBV
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
Unless otherwise stated, there are no plans to impute missing data. Missing data will not be 
displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = d9099ab8-2c15-4fd9-9c7b-6a373ef0d734
Approver: 
Approval Date & Time: 18-Dec-2020 02:49:39 GMT
Signature meaning: Approved
PPD