Conditions: Ulcerative Colitis
Keywords: Interleukin-23 (IL-23) antibody IL-23p19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1281
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of Mirikizumab in participants with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to, loss of response, or intolerant to conventional or biologic therapy for UC.

Detailed description:

Arms:
arm 1: Placebo given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. arm 2: 300 mg mirikizumab given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. arm 3: Placebo given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. arm 4: 300 mg mirikizumab given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks.

Interventions: intervention 1: Mirikizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol document:
SAP_002.pdf: 
I6T-MC-AMAN Statistical Analysis Plan Version 4.0 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled Induction 
Study of Mirikizumab in Conventional-Failed and Biologic-Failed Patients with Moderately to 
Severely Active Ulcerative Colitis LUCENT 1 
 
NCT03518086  
 
Approval Date: 14-Jan-2021 
 
 
 


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Statistical Analysis  Plan:  I6T-MC-AMAN:  A Phase 3, 
Multicenter, Randomized, Double-Blind, Parallel, Placebo-
Controlled Induction Study of Mirikizumab in Conventional-
Failed and Biologic-Failed Patients with Moderately to 
Severely Active Ulcerative Colitis
LUCENT 1
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Mirikizumab (LY3074828) Ulcerative Colitis
Study I6T-MC-AMAN is a Phase 3, multicenter, randomized, double-blind, parallel, 
placebo-controlled induction study of Mirikizumab in conventional-failed and biologic-failed 
patients with moderately to severely active ulcerative colitis.  The study consists of a 12-
week induction period where subjects will receive 1 of 2 treatment arms (300 mg 
mirikizumab or placebo) every 4 weeks. 
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I6T-MC-AMAN
Phase 3
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly: 
26 October 2018
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly: 
13 December 2019
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly:
28 August 2020
Statistical Analysis Plan Version 4 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 14-Jan-2021 GMT


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1.
Table of Contents
Section
Page
1.
Table of Contents................................................................................................................2
2.
Revision History .................................................................................................................8
3.
Study Objectives...............................................................................................................12
3.1.
Primary and Major Secondary Objectives.....................................................................12
3.2.
Other Secondary and Exploratory Objectives ...............................................................14
4.
Study Design.....................................................................................................................15
4.1.
Summary of Study Design............................................................................................15
4.2.
COVID-19 Addendum .................................................................................................16
4.3.
Electronic Clinical Outcomes Assessment Transcription Error 
Protocol Addenda.........................................................................................................16
4.4.
Determination of Sample Size ......................................................................................16
4.5.
Method of Assignment to Treatment ............................................................................17
5.
A Priori Statistical Methods ..............................................................................................18
5.1.
General Considerations ................................................................................................18
5.1.1.
Analysis Populations............................................................................................18
5.1.2.
Study Time Intervals............................................................................................19
5.1.3.
Definition of Study Baseline ................................................................................20
5.1.4.
Analysis Methods.................................................................................................20
5.2.
Adjustments for Covariates ..........................................................................................22
5.3.
Handling of Dropouts or Missing Data.........................................................................22
5.3.1.
Nonresponder Imputation (NRI)...........................................................................22
5.3.2.
Mixed-effects Model for Repeated Measures (MMRM) .......................................23
5.3.3.
Modified Baseline Observation Carried Forward (mBOCF) .................................23
5.3.4.
Modified Nonresponder Imputation (mNRI) ........................................................24
5.3.5.
Tipping Point Analysis.........................................................................................24
5.4.
Analysis Considerations for the eCOA Error in Turkey and 
Poland..........................................................................................................................25
5.5.
Analysis Considerations for COVID-19-Related Mitigations........................................26
5.6.
Multicenter Studies ......................................................................................................27
5.7.
Multiple Comparisons/Multiplicity...............................................................................27
5.8.
Patient Disposition .......................................................................................................28
5.9.
Patient Characteristics ..................................................................................................29
5.9.1.
Demographics and Baseline Characteristics..........................................................29
5.9.2.
Preexisting Conditions .........................................................................................32
5.10. Treatment Compliance .................................................................................................32


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5.11. Prior and Concomitant Therapy....................................................................................33
5.12. Efficacy Analyses ........................................................................................................34
5.12.1.
Primary Outcome and Methodology.....................................................................49
5.12.2.
Sensitivity Analyses of the Primary Outcome.......................................................49
5.12.3.
Analyses of the Secondary Efficacy Outcomes.....................................................49
5.12.3.1.
Major Secondary Efficacy Outcomes..............................................................49
5.12.3.2.
Sensitivity Analysis of the Major Secondary Efficacy 
Outcomes .......................................................................................................49
5.12.3.3.
Other Secondary Efficacy Outcomes ..............................................................50
5.12.3.4.
Exploratory Efficacy Endpoints......................................................................50
5.13. Health Outcomes/Quality-of-Life Analyses..................................................................50
5.13.1.
Health Care Utilization.........................................................................................50
5.13.2.
Additional Health Outcomes/Quality-of-Life Analyses ........................................50
5.14. Pharmacokinetic/Pharmacodynamic Analyses..............................................................50
5.15. Safety Analyses............................................................................................................51
5.15.1.
Extent of Exposure...............................................................................................52
5.15.2.
Adverse Events ....................................................................................................52
5.15.2.1.
Common Adverse Events ...............................................................................53
5.15.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................53
5.15.4.
Clinical Laboratory Evaluations ...........................................................................53
5.15.5.
Vital Signs and Other Physical Findings...............................................................54
5.15.6.
Electrocardiograms ..............................................................................................54
5.15.7.
Immunogenicity...................................................................................................55
5.15.8.
Special Safety Topics including Adverse Events of Special 
Interest.................................................................................................................55
5.15.8.1.
Hepatic Safety................................................................................................55
5.15.8.2.
Infections, Including Opportunistic Infections and 
Serious Infections ...........................................................................................56
5.15.8.3.
Hypersensitivity..............................................................................................56
5.15.8.4.
Infusion Site Reactions (ISR)..........................................................................57
5.16. Subgroup Analyses.......................................................................................................58
5.16.1.
Efficacy Subgroup Analysis .................................................................................58
5.16.2.
Safety Subgroup Analysis ....................................................................................59
5.16.3.
Analysis for Japan Submission.............................................................................59
5.17. Protocol Violations.......................................................................................................59
5.18. Interim Analysis and Data Monitoring..........................................................................59
5.19. Annual Report Analyses...............................................................................................60
5.20. Clinical Trial Registry Analyses...................................................................................60


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6.
Unblinding Plan................................................................................................................62
7.
References ........................................................................................................................63


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Table of Contents
Table
Page
Table AMAN.3.1.
Primary and Major Secondary Objectives and Endpoints ..........................12
Table AMAN.5.1.
Patient Populations for Analysis ...............................................................18
Table AMAN.5.2.
Definition of Study Period Time Intervals.................................................20
Table AMAN.5.3.
Patient Characteristics (and Variables for Subgroup Analysis) ..................29
Table AMAN.5.4.
Description and Derivation of Efficacy/Health Outcomes Measures and 
Endpoints ......................................................................................................35
Table AMAN.5.5.
Description of Efficacy/Health Outcomes Analyses ..................................45


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Table of Contents
Figure
Page
Figure AMAN.4.1.
Illustration of study design for Clinical Protocol I6T-MC-AMAN.......15
Figure AMAN.5.1.
Graphical approach to control the Type 1 error rate for Study I6T-MC-
AMAN. .........................................................................................................28


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Table of Contents
Appendix
Page
Appendix 1.
Daily Diary Calculations................................................................................65
Appendix 2.
Countries and Regions...................................................................................67
Appendix 3.
Summary of eCOA Transcription Errors........................................................69


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2.
Revision History
Statistical analysis plan (SAP) Version 1 was approved on 30 October 2018 prior to the first 
unblinding and was based on protocol approved on 13 March 2018.
Statistical analysis plan Version 2 was approved on 13 Dec 2019 and was based on protocol 
amendment (a) approved 12 Sep 2019. The following updates were made in Version 2 after the 
first external safety DMC analysis but before the first unblinded analysis by the sponsor:
1. Made the following changes to the primary and major secondary endpoints:
a.
Included “The change from baseline in the Urgency Numeric Rating Scale 
score” as a major secondary endpoint.
b. Included “Histologic-Endoscopic mucosal improvement” as a major 
secondary endpoint.
c.
Included “Alternate clinical remission” as a major secondary endpoint.
2. Updated the sample size calculations and assumptions based on the changed endpoints in 
in the protocol amendment (a) for Study I6T-MC-AMBG.
3. Clarified the study period definitions in Table AMAN.5.2.
4. For general methods Section 5.1.4:
a.
Clarified that the relative risk and risk difference will be adjusted for 
stratification factors.
b. The odds ratio will not be presented for binary efficacy endpoints.
5. The graphical testing scheme (Section 5.7) was updated to reflect additional major 
secondary endpoints.
6. Several modifications to the categories and calculations for baseline characteristics were 
made to Table AMAN.3.1.
7. The specific summary table for prior and concomitant therapy were clarified (Section 5.11).
8. Made the following changes to Table AMAN.5.4 and Table AMAN.5.5:
a.
“Alternate Clinical Remission” endpoint was added.
b. “Alternate Symptomatic Remission” endpoint was added.
c.
“Total Mayo Clinical Remission” and “Total Mayo Clinical Response” were 
added.
d. “UCEIS endoscopic remission” endpoint was added.
e.
EQ-5D-5L items and population-based index will no longer be in the primary 
SAP document.
f.
“Urgency NRS >= 3 Point Improvement” was added. 
g. For histology:
i. The description of the Geboes grades and calculation for the Geboes 
Score were updated.
ii. Description of the “Robarts Histology index (RHI)” and “Nancy 
index” were added.
iii. The endpoints “Primary Histologic Remission,” “RHI < 3,” “Nancy 
Index < 1,” “Histologic Improvement,” and “Alternative Histologic 
Improvement” were added.


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h. The endpoints “Histologic-Endoscopic Improvement” and “Mucosal Healing” 
were added.
i.
Analysis of extraintestinal manifestations was added.
9. Analysis of UC surgeries and hospitalization was added to Section 5.13.
10. Removed by patient listing of exposure in Section 5.15.1.
11. Clarified the analysis AESIs including the analysis of infections (Section 5.15.8.2), 
hypersensitivity (Section 5.15.8.3) and suicidal ideation/behavior and depression 
(Section 5.15.8.7).
12. Altered the calculation of visit date and clarified the calculations for daily diary in 
Appendix 1.
13. Added region definitions in Appendix 2.
Statistical analysis plan Version 3 was approved on 28 August 2020 and was based on protocol 
amendment (a) approved on 12 September 2019. The following updates were made in Version 3 
after the first external safety DMC analysis but before the first unblinded analysis by the 
sponsor:
1. Added the following sections concerning the coronavirus disease 2019 (COVID-19)
pandemic:
a.
A description of the COVID-19 addendum for handling patients during the 
COVID-19 pandemic was added in Section 4.2.
b. A description of analysis considerations related to COVID-19 mitigations was 
added in Section 5.5, and sensitivity analysis added to Table AMAN.5.5.
c.
Clarified that even some mitigations approved under the COVID-19 
addendum will cause patients to be excluded from the per-protocol population 
in Section 5.17
2. Added or edited the following sections based on an error found in some of the electronic 
clinical outcome assessment (eCOA) devices:
a.
A description of the error was added in Section 4.3 and Appendix 3.
b. The definition of the modified intent-to-treat (mITT) population found in 
Table AMAN.5.1 was amended to exclude patients impacted by the eCOA 
transcription error. The safety population will include patients with the eCOA 
transcription error. Concurrence with the Food and Drug Administration (FDA)
on this analyses was obtained based on the FDA Type C written response 
received on 20 July 2020.
c.
A general description of considerations for the primary analysis and sensitivity 
analysis related to the eCOA error was added Section 5.4.
d. Additional ITT summary analysis in several sections, including Section 5.9.1,
Section 5.9.2 and Section 5.11, was added.
3. Wording in Section 5.3.1 on estimands was clarified, and an alternative estimand was 
added.
4. A multiple imputation approach was added as a sensitivity analysis in Section 5.3.4 and
Table AMAN.5.5. The multiple imputation approach will be used for ITT analysis
instead of the previously described nonresponder imputation (NRI) approach.


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5. A summary of sensitivity analysis was added in Section 5.12.2 and Section 5.12.3.2.
6. Added the definition and analysis of “Alternate Clinical Remission 2” in Table AMAN.5.4
and Table AMAN.5.5; added “Alternate Clinical Remission” to Table AMAN.5.5.
7. Changed the definition of ‘Primary histologic remission’ in Table AMAN.5.4.
8. Clarified what populations would be used for analysis of covariance (ANCOVA) analysis 
of Urgency numeric rating scale (NRS) in Table AMAN.5.5.
9. Edited categories and analysis description for extraintestinal manifestations in 
Table AMAN.5.4 and Table AMAN.5.5.
10. In the Table AMAN.5.3 baseline characteristics table, changed the description of several 
variables, removed/added some categories, and edited subgroup analysis.
11. Added additional details about Week 12 and final database lock (DBL) in Section 5.18. 
Moved information about potential pharmacokinetics DBL from Section 6 to Section 5.18
with wording edits.
12. Clarified that changes to the subgroup analysis will not require an amendment to the 
SAP, and added a section on subgroup analysis for the Urgency NRS endpoint in 
Section 5.16; also added the section on the Japan subgroup analysis.
13. Aligned the calculation of the time window for determining the Mayo score with the 
protocol in Appendix 1; stated that when eCOA duplicates exist, the first of the 
duplicates will be used (Appendix 1 and Section 5.12). Added that baseline will be 
imputed if not available for eCOA daily diary assessments.
14. Clarified several places in the SAP that “biologic failed” refers to “biologic (or 
tofacitinib) failed.”
15. Added wording about exploratory endpoints to Section 3.2.
16. Fixed typographical errors in Section 5.14 changing Week 40 to Week 12.
17. Minor edits that did not change meaning:
a.
Induction period described as Treatment/Induction period
b. Changed wording for Mantel-Haenszel estimator.
c.
“Categorical” changed to “binary.”
d. Changed wording “Mucosal Healing” to “Histologic-Endoscopic Mucosal 
Remission”
Statistical analysis plan Version 4 was approved on the date provided on the title page and was 
based on protocol amendment (a) approved on 12 September 2019. The following updates were 
made in Version 4 after the first external safety DMC analysis but before the first unblinded 
analysis by the sponsor:
1. Clarified in Section 5.1.4 that Fishers exact test would only be used as a supportive 
analysis for binary efficacy endpoints.
2. Added a note to Section 5.2 about adjusting for covariates when patients are inadvertent 
randomizations.
3. Added in Section 5.3 and 5.5 that endoscopies performed outside of the window from 
study days 71 to 113 will be considered missing for analysis purposes. This also impacted 
the diary window in Appendix 1.
4. Changed how the multiple imputation will be performed in the modified NRI (mNRI)
analysis in Section 5.3.4.


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5. Clarified in Section 5.3.2 that the estimand associated with the mixed-effects model for 
repeated measures (MMRM) analysis could be justified as consistent with the treatment 
policy strategy.
6. Added the tipping point analysis in Section 5.3.5.
7. Added specific safety sensitivity analysis in Section 5.4 in the mITT population.
8. Changed the definition of treatment compliance to state that a partial dose does not count 
towards compliance (Section 5.10).
9. An analysis of “Urgency Remission” was added to Section 5.12.
10. The MMRM subgroup analysis description was altered in Section 5.16.1.
11. Fixed typos and made other minor edits.




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Objectives
Endpoints

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
endoscopic remission at Week 12

The proportion of patients with endoscopic 
remission at Week 12, defined as:  
o ES = 0 or 1 (excluding friability)

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
symptomatic remission at Week 4

The proportion of patients in symptomatic 
remission at Week 4, defined as:  
o SF= 0, or SF = 1 with a ≥1-point decrease from 
baseline, and
o RB = 0

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
symptomatic remission at Week 12

The proportion of patients in symptomatic 
remission at Week 12, defined as:  
o SF = 0, or SF = 1 with a ≥1-point decrease from 
baseline and
o RB = 0

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
clinical response in the biologic-failed 
population at Week 12

The proportion of patients in the biologic-failed 
population in clinical response at Week 12.  
Clinical response is based on the MMS and is 
defined as:  
o
A decrease in the MMS of ≥2 points and ≥30% 
decrease from baseline, and
o
A decrease of ≥1 point in the RB subscore from 
baseline or an RB score of 0 or 1

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
bowel movement urgency improvement at 
Week 12d

The change from baseline in the Urgency 
Numeric Rating Scale scoree

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
histologic-endoscopic mucosal improvement 
at Week 12f

The proportion of patients with histologic-
endoscopic mucosal improvement at Week 12, 
defined as achieving bothf: 
o
Histologic improvement, defined using Geboes 
scoring system with neutrophil infiltration in 
<5% of crypts, no crypt destruction, and no 
erosions, ulcerations, or granulation tissue.
o
Endoscopic remission, defined as ES = 0 or 1 
(excluding friability)
Abbreviation: FDA = Food and Drug Administration.
a
All primary and major secondary endpoints will be evaluated for mirikizumab versus placebo.  All primary and 
major secondary endpoint analyses will utilize the multiplicity control approach based on ‘graphical multiple 
testing procedure’ to control the overall family-wise type I error rate at a 2-sided alpha level of 0.00125.  The 
graphical multiple testing procedure described in Bretz et al. (2009) will be used.
b
The order of testing of the major secondary endpoints will be determined from the results of the statistical 
simulations.  Therefore, the order of the secondary endpoints does not reflect the order of the statistical testing.
c
Alternate clinical remission was not included as an objective/endpoint in protocol amendment (a).  However, this 
objective/endpoint is designated as “major secondary” (i.e., multiplicity controlled) in the SAP and will 
supersede the protocol amendment (a). The alternate definition of clinical remission is added based on the FDA’s 
feedback on the mirikizumab pediatric program proposal.
d
The statistical analysis plan (SAP) language for this objective supersedes the protocol language, which states “To 
evaluate the efficacy of treatment with mirikizumab compared to placebo in inducing bowel movement urgency 
improvement at Week 12 in patients with bowel urgency symptoms at baseline.”


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e
The SAP language for this endpoint supersedes the protocol language, which states “The proportion of patients 
with bowel movement urgency improvement at Week 12 as defined in the study SAP.”
f
Histologic-endoscopic mucosal improvement was not included as an objective/endpoint in protocol amendment 
(a). However, this objective/endpoint is designated as “major secondary” (i.e., multiplicity controlled) in the 
SAP and will supersede the protocol amendment (a). 
3.2.
Other Secondary and Exploratory Objectives
Other Secondary Endpoints are described in the I6T-MC-AMAN (AMAN) Protocol
Amendment (a), Section 4. The details for these objectives and endpoints can be found in 
Section 5.12 and in Table AMAN.5.4 and Table AMAN.5.5 below, along with additional 
exploratory endpoints not described in the protocol.


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4.
Study Design
4.1.
Summary of Study Design
Study AMAN is a multicenter, randomized, double-blind, parallel-arm, placebo-controlled study 
designed to evaluate the safety and efficacy of mirikizumab, compared with placebo, over a 
12-week induction period (approximately 1160 randomized patients).  The study population 
includes patients with moderately to severely active ulcerative colitis (UC) who have an 
inadequate response to, loss of response to, or are intolerant to conventional (nonbiologic) 
therapy for UC (conventional-failed), and those who have an inadequate response to, loss of 
response to, or are intolerant to biologic therapy or tofacitinib for UC (biologic-failed).  
Throughout this document, the term biologic-failed will be used to refer to failure of either a 
biologic or tofacitinib unless otherwise specified. Complete definitions of the “conventional-
failed” and “biologic-failed” terms are given in Section 6.1, Inclusion Criterion [8] of the 
protocol.  Patients will be randomized with a 3:1 ratio to receive blinded intravenous (IV) 
administration of 300 mg mirikizumab or placebo every 4 weeks (Q4W) at Weeks 0, 4, and 8.  
Randomization will be stratified by (a) biologic-failed status (yes/no), (b) baseline corticosteroid 
use (yes/no), (c) baseline disease activity (modified Mayo score [MMS]:  [4-6] or [7-9]), and 
(d) region (North America/Europe/Other).
Abbreviations:  IV = intravenous; Q4W = every 4 weeks; R = randomization.
Figure AMAN.4.1.
Illustration of study design for Clinical Protocol I6T-MC-AMAN.


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4.2.
COVID-19 Addendum
Study AMAN was ongoing during the global coronavirus disease 2019 (COVID-19) pandemic,
during which many patients were unable or unwilling to conduct on-site clinic visits and/or have 
some study procedures performed. Mitigations for COVID-19 were initially implemented as 
emergency measures which have been formalized in an addendum to the primary protocol. 
Mitigations to allow these patients to continue in the Phase 3 mirikizumab UC program included,
but were not limited to:

Extending the window for the Week 12 endoscopy assessment

Allowing a patient missing the Week 12 endoscopy, despite the window extension, to 
continue into the maintenance study

Extending the window for investigational product (IP) administration

Use of local laboratories if central safety laboratory testing could not be performed

Use of virtual telephone visits if patients were unable to attend in-office visits for
assessments (e.g., adverse events [AEs] and concomitant medications)
Additional details of the mitigations and planned analysis can be found in Protocol Addendum 
I6T-MC-AMAN(15) and in analysis Section 5.5 below.
4.3.
Electronic Clinical Outcomes Assessment Transcription Error 
Protocol Addenda
Questions to assess patient-reported outcome (PRO) measures of stool frequency (SF) and rectal 
bleeding (RB) are recorded using electronic clinical outcome assessment (eCOA) devices. It was 
discovered that the devices for daily diary assessment of RB and SF Mayo subscores contained 
errors in the wording for patients in Poland and Turkey, respectively, as described in Appendix 3.
We will refer to these errors in wording as “transcription” errors, and patients who were enrolled 
into the trial based on this incorrect eCOA assessment will be referred to as “impacted by the 
eCOA transcription errors.” The wording on the devices was corrected after discovery of the 
issues. Any endpoints which make use of the SF and RB data will be difficult to interpret in the 
impacted patients from Poland and Turkey, respectively.  An addendum was created to handle 
these patients by allowing them to roll over to the long-term extension study. Additional details
of the issue and planned analysis can be found in the addendum, Appendix 3, and the analysis 
section, 5.4, below.
4.4.
Determination of Sample Size
The study will randomize approximately 1160 patients with a 3:1 ratio of 300 mg mirikizumab to 
placebo, with an assumption that approximately 1044 patients will complete the study.  
The power calculations for this study assume the following:  
1. The randomized study population will include approximately 50% biologic-failed 
patients and approximately 50% conventional-failed patients.  


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2. The predicted clinical remission rates at Week 12 for mirikizumab versus placebo are 
expected to be 23% versus 7.8% (biologic-failed patients:  16% versus 3.5%; 
conventional-failed patients:  30% versus 12%).
The primary endpoint of this study is to test the hypothesis that mirikizumab is superior to 
placebo in inducing clinical remission at Week 12 in patients with moderately to severely active 
UC.  Given the assumptions described above, a sample size of 1160 patients are expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this 
endpoint, as assessed using a chi-square test with a 2-sided significance level of 0.00125.  
Patients who complete Study AMAN may be eligible to participate in Study I6T-MC-AMBG
(AMBG), a 40-week maintenance study.  The primary objective of Study AMBG is to test the 
hypothesis that mirikizumab is superior to placebo in achieving clinical remission at Week 40 of 
Study AMBG (Week 52 of continuous therapy) amongst patients induced into clinical response 
with mirikizumab at Week 12 of Study AMAN.  A sample size of 1160 patients in Study AMAN 
is predicted to ensure that there will be a sufficient number of biologic-failed patients in clinical 
remission at Week 12 of Study AMAN who will enter Study AMBG, as well as >90% power to 
demonstrate that mirikizumab is superior to placebo in achieving the primary endpoint in Study 
AMBG, as assessed using a chi-square test with a 2-sided significance level of 0.05. 
4.5.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 1.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  To achieve between-group 
comparability, patients will be stratified to these arms based upon (a) biologic-failed status 
(yes/no), (b) baseline corticosteroid use (yes/no), (c) baseline disease activity (MMS:  [4-6] or 
[7-9]), and (d) region (North America/Europe/Other).  This stratification will be controlled by 
IWRS.
Patients will be randomized 3:1 to receive blinded IV administration of 300 mg mirikizumab, or 
placebo Q4W at Weeks 0, 4, and 8.  Duration of treatment with the IP is 12 weeks.


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5.
A Priori Statistical Methods
5.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter 
Lilly) or its designee.  The statistical analyses will be performed using SAS® Version 9.4 or 
higher.  The latest version of the Medical Dictionary for Regulatory Activities (MedDRA®) will 
be used.
Not all displays and analyses described in this statistical analysis plan (SAP) will necessarily be 
included in the clinical study report (CSR).  Not all displays will necessarily be created as a 
“static” display.  Some displays may be incorporated as interactive display tools such as Spotfire 
instead of or in addition to a static display.  Any display described in this SAP and not provided 
in the CSR would be available upon request.
Any change to the data analysis methods described in the protocol will require a protocol 
amendment ONLY if it changes a principal feature of the protocol.  Any other change to the data 
analysis methods described in the protocol and the justification for making the change will be 
described in the CSR. 
Additional exploratory analyses of the data may be conducted as deemed appropriate.  Some of 
these additional supplementary analyses may be prespecified in a separate supplemental SAP.
5.1.1. Analysis Populations
Patient populations are defined in Table AMAN.5.1 along with the analysis they will be used to 
conduct.  The treatment groups and inferential comparisons described in Table AMAN.5.1 will 
be used unless otherwise specified.  Also, unless otherwise specified, for all populations/analysis, 
patients will be analyzed according to the treatment to which they were assigned.
Table AMAN.5.1.
Patient Populations for Analysis
Population
Description
Screening Population
Definition:  All patients who signed informed consent. 
Purpose:  Used for disposition analysis.
Treatment Groups:  None
Inferential Comparisons:  None
Modified Intent-to-
Treat (mITT) 
Population
Definition:  All randomized patients who received any amount of study treatment
excluding patients impacted by the eCOA transcription error in Poland and Turkey
(regardless if the patient does not receive the correct treatment, or otherwise does not 
follow the protocol). 
Purpose:  Used for efficacy and health outcomes analysis.
Treatment Groups (Short Label):  300 mg mirikizumab Q4W IV (MIRI), placebo Q4W 
IV (PBO)
Inferential Comparisons:  300 mg mirikizumab Q4W IV vs. placebo Q4W IV
Safety Population
Definition:  All randomized patients who received any amount of study treatment
(regardless of whether the patient does not receive the correct treatment, or otherwise does 
not follow the protocol). 
Purpose:  Used for safety-related analysis.


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Treatment Groups (Short Label):  300 mg mirikizumab Q4W IV (MIRI), placebo Q4W 
IV (PBO)
Inferential Comparisons: 300 mg mirikizumab Q4W IV vs. placebo Q4W IV
Intent-to-Treat (ITT) 
Population
Definition:  All randomized patients.  Patients will be analyzed according to the treatment 
to which they were assigned.
Purpose:  Used as a sensitivity analysis for the primary and major secondary efficacy 
endpoints.
Treatment Groups (Short Label):  300 mg mirikizumab Q4W IV (MIRI), placebo Q4W 
IV (PBO)
Inferential Comparisons:  300 mg mirikizumab Q4W IV vs. placebo Q4W IV
Per-Protocol 
Population (PP)
Definition:  All mITT patients who are not deemed noncompliant with treatment, who do 
not have significant protocol deviations, and whose investigator site does not have 
significant GCP deviations that require a report to regulatory agencies (regardless of study 
period).  Qualifications and identification of the specific significant protocol deviations that 
result in exclusion from the PP population will be determined while the study remains 
blinded, prior to the database lock (See Section 5.17).
Purpose:  Used as a sensitivity analysis for the primary and major secondary efficacy 
endpoints.
Treatment Groups (Short Label):  300 mg mirikizumab Q4W IV (MIRI), placebo Q4W 
IV (PBO)
Inferential Comparisons:  300 mg mirikizumab Q4W IV vs. placebo Q4W IV
Abbreviations:  eCOA = electronic clinical outcomes assessment; GCP = good clinical practice; IV = intravenous; 
MIRI = mirikizumab; PBO = placebo; Q4W = every 4 weeks.
5.1.2. Study Time Intervals
Table AMAN.5.2 displays a list of study periods along with the definition of which patients will 
be considered to have entered the study period and when the individuals start and end the study 
period.  The table shows both a date and a time. 
To calculate the length of any time interval or time period in this study the following formula 
will be used:
ܮ݁݊݃ݐ݄݋݂݅݊ݐ݁ݎݒ݈ܽሺ݀ܽݕݏሻൌܧ݊݀ܦܽݐ݁െܫ݊ݐ݁ݎݒ݈ܽܵݐܽݎݐܦܽݐ݁൅1
To convert any time length from days to years, the following formula will be used:
ܮ݁݊݃ݐ݄݋݂݅݊ݐ݁ݎݒ݈ܽሺݕ݁ܽݎݏሻൌܮ݁݊݃ݐ݄݋݂݅݊ݐ݁ݎݒ݈ܽሺ݀ܽݕݏሻ/365.25
To convert any time length from days to weeks, the following formula will be used:
ܮ݁݊݃ݐ݄݋݂݅݊ݐ݁ݎݒ݈ܽሺݓ݁݁݇ݏሻൌܮ݁݊݃ݐ݄݋݂݅݊ݐ݁ݎݒ݈ܽሺ݀ܽݕݏሻ/7
Only for the purpose of calculating the length of study period time intervals, the words “prior to” 
in Table AMAN.5.2 should be understood to mean “the day before” while the words “after” 
should be understood to mean “the day after.”  For the purpose of determining whether a 
date/time lies within an interval these words are intended to convey whether the start or end of 
the period is inclusive of the specified date.


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Table AMAN.5.2.
Definition of Study Period Time Intervals
Study Period 
Interval Start Definition
Interval End Definition
Screening:
All patients who sign informed 
consent are considered as entering 
the Screening Period.
Informed consent date
Prior to the start of Induction Period.
Treatment/Induction:
All patients who are randomized 
to the study are considered as 
entering the Induction Period.
At the first study drug 
administration date/timea
following randomization.  
For patients who are 
randomized but not dosed, 
the Induction Period starts on 
the date of randomization.  
The maximum of treatment discontinued date 
or last treatment visit date.
Post-Treatment Follow-Up:  All 
patients who had a Visit 801 or 
802 are considered as entering 
follow-up period.
After the Induction Period 
ends.
The maximum of the last study visit date or 
study disposition date.
a
Missing dose time will be imputed as the earliest time that is consistent with available data about dose time.  For 
example, suppose the minutes are missing but hour is present.  In this case, we would impute the minutes to be 0.
5.1.3. Definition of Study Baseline
The baseline for variables collected as part of the daily diary (including the PRO components SF 
and RB of the Modified Mayo) will be calculated from valid daily diary entries obtained prior to 
baseline endoscopy preparation (see Appendix 1).  The baseline endoscopy component of the 
Mayo will use the endoscopic appearance of the mucosa at the screening endoscopy.  For other 
efficacy, health outcome and safety assessments, baseline is defined as the last nonmissing 
assessment recorded on or prior to the date of the first study drug administration at Visit 1 (Week 0).
Baseline for safety analysis is described in the safety section.
Change from baseline will be calculated as the visit value of interest minus the baseline value.  If 
a baseline values or the value at the visit is missing for a particular variable, then the change 
from baseline is defined as missing.
5.1.4. Analysis Methods
Unless otherwise specified, variables will be analyzed in the original scale on which they are 
measured.  The parametric approach will be employed by default for statistical analysis except 
when nonparametric analysis, such as by a rank-based method, is assessed to be more fitting.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.  All 
hypothesis tests will be 2-sided, and the family-wise type I error rate (FWER) will be controlled 
at an α level of 0.00125 for primary and major secondary endpoints using a pre-specified 
graphical procedure (see Section 5.7). 
Unless otherwise specified, for the analyses of hypotheses with multiplicity control at a family 
wise significance level of 0.00125, a 2-sided 99.875% confidence interval (CI) will be provided 
along with the p-value.  For other analyses of the hypotheses without multiplicity control, the 


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tests will be conducted using a 2-sided significance level of 0.05.  The corresponding p-value 
along with its 95% 2-sided CI will be provided.
For assessments of the primary endpoints and other binary efficacy and health outcomes 
endpoints, the following will be provided unless otherwise specified: 

Crude proportions for each treatment group along with the 2-sided asymptotic (i.e., not 
continuity corrected) CIs will be provided.

The estimated common risk difference along with 2-sided CIs.  The common risk 
difference (Agresti 2013, pp231) is the difference in proportions adjusted for the 
stratification factors.  SAS PROC FREQ will be used for the estimates and CIs, where the 
CIs are calculated by using Mantel-Haenszel estimator of risk differences with standard 
error calculated as described by Sato (1989).  

Cochran-Mantel-Haenszel (CMH) test will be used to compare the treatment groups 
while adjusting for the stratification factors.  The CMH p-value will be reported.  

As a secondary measurement of efficacy, the relative risk along with its 2-sided CI will 
be provided, adjusting for the stratification factors using the Mantel-Haenszel estimator.

If deemed necessary as a supportive analysis, additional analyses of binary efficacy 
variables may be conducted to address sparse data or small sample sizes.  For example, a
Fisher’s exact test may be utilized.

The stratification factors used for common risk difference, relative risk and CMH test are:  
(a) previous biologic therapy failure (yes/no), (b) baseline corticosteroid use (yes/no), (c) 
baseline disease activity (MMS:  [4-6] or [7-9]), and (d) region (North 
America/Europe/Other). For the major secondary endpoint, which includes only
biological failed patients, the stratification factors are:  (b) baseline corticosteroid use 
(yes/no), (c) baseline disease activity (MMS:  [4-6] or [7-9]), and (d) region (North 
America/Europe/Other).  
When specified as a sensitivity analysis for binary endpoints, logistic regression with a Firth 
penalized likelihood will be used (Firth 1993).  The model will include the treatment groups and 
the covariates described in Section 5.2.  The Firth correction can be implemented in PROC 
Logistic by including ‘firth’ as an option in the model statement.  The odds ratio and the 
corresponding CIs, as well as the treatment differences and the corresponding CIs, will be 
reported.  
Treatment comparisons of continuous efficacy and health outcome variables will be made using 
mixed-effects model for repeated measures (MMRM) analysis.  When the MMRM is used, it 
includes:  (a) treatment group, (b) previous biologic therapy failure status (yes/no), (c) baseline 
corticosteroid use (yes/no), (d) baseline disease activity (MMS:  [4-6] or [7-9]), (e) region (North 
America/Europe/Other), (f) baseline value in the model, (g) visit, and (h) the interactions of 
treatment-by-visit and baseline-by-visit as fixed factors.  The covariance structure to model the 
within-patient errors will be unstructured.  If the unstructured covariance matrix results in a lack 
of convergence, the heterogeneous Toeplitz covariance structure, followed by the heterogeneous 
autoregressive covariance structure will be used.  The first structure to yield convergence will be 


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used for inference.  The Kenward-Roger method will be used to estimate the denominator 
degrees of freedom.  Type III sums of squares for the least-squares (LS) means will be used for 
the statistical comparison; the 95% CI will also be reported. Unless otherwise specified, for 
MMRM, reported data from only planned visits will be used as the primary analysis.
Treatment comparisons of continuous efficacy and health outcome variables with a single 
post-baseline timepoint will be made using analysis of covariance (ANCOVA) with:  (a) 
treatment group, (b) previous biologic therapy failure status (yes/no), (c) corticosteroid use 
(yes/no), (d) baseline disease activity (MMS:  [4-6] or [7-9]), (e) region (North 
America/Europe/Other), and (f) baseline value in the model.  Type III sums of squares for least 
square (LS) means will be used for statistical comparison between treatment groups.  The LS 
mean difference, standard error, p-value, and 95% CI, unless otherwise specified, will also be 
reported.  Missing data imputation method for the ANCOVA model is specified in Section 5.3.
The Kaplan-Meier (KM) product limit method will be used to estimate the survival for several 
time-to-event analyses.  The hazard ratio and log-rank test stratified by covariates mentioned in 
Section 5.1.4 will be reported.  Time for all analyses will be described in units of weeks.  
5.2.
Adjustments for Covariates
The randomization is stratified by (a) biologic failed patient (yes/no), (b) baseline corticosteroid 
use (yes/no), (c) baseline disease activity (MMS:  [4-6] or [7-9]) and (d) region (North America/
Europe/Other).  These factors will be adjusted for as described in Section 5.1.4.  Note: when 
adjusting for covariates, the small number of patients (expected to be <1% of randomized 
patients) who are inadvertently enrolled with a baseline MMS <4 will be pooled with the MMS 
[4-6] category.
5.3.
Handling of Dropouts or Missing Data
Intercurrent events (ICH E9R1) are events which occur after the treatment initiation and make it 
impossible to measure a variable or influence how it should be interpreted.  Examples of such 
events include treatment discontinuation due to death or AEs, rescue treatment, and loss to
follow-up.  The missing data methods described below handle intercurrent events in different 
ways and thus are relevant to different estimands.
The Schedule of Activities outlined in the protocol specifies the allowable windows for 
assessments.  In general, assessments performed outside these windows will not be excluded 
from the analysis (unless otherwise specified) but will be reported as a protocol deviation (see 
Section 5.17). However, Week 12 endoscopies that occurred more than 2 weeks early or more 
than 4 weeks late (i.e., from study days 71 to 113) will be considered missing for analysis 
purposes.
5.3.1. Nonresponder Imputation (NRI)
For analysis of binary efficacy and health outcomes variables, missing data will be imputed 
using an NRI method.  Patients will be considered nonresponders for the NRI analysis if they do 


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not meet the binary efficacy criteria, or have missing clinical efficacy data at a time point of 
interest.
The above NRI method can be justified based on the composite strategy (ICH E9R1) for 
handling intercurrent events. In this strategy, patients are defined as responders only if they meet 
the clinical requirements for response at the predefined time AND they complete the study
treatment period without missing relevant data. Failing either criteria by definition makes them 
nonresponders. It should be understood that if the composite strategery for handling intercurrent 
events is used, then the term “imputation” is not technically correct as the data are not missing. 
However, with the above understanding, based on historical usage, we continue to use the 
descriptor “NRI” in this document.
Additionally, we will utilize an alternative sensitivity estimand for the primary endpoint based on
the composite strategy with the following conditions considered as treatment failure: failing to 
meet protocol-defined primary endpoint criteria, missing data to calculate the primary endpoint 
criteria, initiation of systemic corticosteroid treatment, increasing systemic corticosteroid 
treatment dose above baseline, switching corticosteroid treatment or having a UC surgery.
5.3.2.
Mixed-effects Model for Repeated Measures (MMRM)
For continuous variables, the primary analysis will be MMRM with the missing at random 
(MAR) assumption for handling missing data.  This analysis takes into account both missingness 
of data and the correlation of the repeated measurements.  No additional imputation methods will 
be applied to the MMRM analysis. 
As noted by Jin and Liu (2020), the MMRM method may be used both under a treatment policy 
strategy for handling intercurrent events (ICH E9R1) and under a hypothetical strategy for 
handling intercurrent events.  The hypothetical strategy would treat patient data after certain 
intercurrent events as missing, while the treatment policy strategy would use all available data. 
For the MMRM analysis in Study AMAN, data from planned visits prior to treatment 
discontinuation will be used in the analysis regardless of whether the patient took prohibited 
concomitant rescue medication or otherwise violated the protocol during their time in the 
treatment period. Therefore, our analysis under the missing at random assumption may be 
justified as consistent with the treatment policy strategy in intent.
5.3.3. Modified Baseline Observation Carried Forward (mBOCF)
For patients discontinuing IP due to an AE, the baseline observation for the endpoint will be 
carried forward to the corresponding visit for all missing observations after the patient 
discontinued study treatment.  For patients discontinuing IP for any other reason, the last 
nonmissing postbaseline observation before discontinuation will be carried forward to the 
corresponding visit for all missing observations after the patient discontinued. For all patients 
with sporadically missing observations prior to discontinuation, the last nonmissing observation 
before the sporadically missing observation will be carried forward to the corresponding visit.  
Randomized patients without at least 1 postbaseline observation will not be included for 
evaluation with the exception of patients discontinuing study treatment due to an AE.


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The modified baseline observation carried forward (mBOCF) method is based on an estimand 
that handles the intercurrent event of discontinuing study drug due to an AE by defining the 
patient as not receiving any benefit from study drug after the event.  That is the patient is defined 
as reverting back to baseline regardless of any continuing efficacy benefits they may still have 
received after the event.  For other intercurrent events (e.g., discontinuation due to reasons other 
than an AE) or sporadic missingness the “while on treatment” strategy is applied.  That is, the 
endpoint is defined as the last observed value at or before the visit of interest before the patient 
discontinued study treatment.
5.3.4. Modified Nonresponder Imputation (mNRI)
For a sensitivity analysis of the primary endpoint and selected secondary endpoints for patients 
impacted by the eCOA transcription error, missing data will be imputed using mNRI.  Data from 
patients who discontinued treatment due to COVID-19-related reasons, lost to follow-up, or a 
protocol deviation will be imputed. Patients who discontinued from the study treatment period 
for other reasons such as an AE or lack of efficacy will be categorized as nonresponders by 
definition. Patients with sporadically missing daily diary data (i.e., when a patient was still in the 
treatment period but forgot to fill out the daily diary) will be imputed. The endoscopic subscore 
for patient who received an endoscopy outside of the study days 71 to 113 window will be 
imputed.
The multiple imputation will be implemented as follows:

The modified mayo subscores for all scheduled visits will be imputed under the 
multivariate normal assumption. Indicator variables for treatment and for all stratification 
factors will be included in the model. A total of 50 imputed datasets will be created.

Imputed continuous scores for Week 12 Mayo subscores will be rounded using calibrated 
cutoffs to create ordinal scores based on the approach by Yucel et al 2011. In this 
approach, the data will be duplicated prior to imputation with the second copy of the data 
having all Mayo scores from baseline to Week 12 set as missing. The imputed missing 
scores in the duplicate part of the data are used to select the cutoffs. These calibrated 
cutoffs are used so that the imputed values are similar to what is in the observed data. The 
remission status will be calculated using the nonadministrative dropout status and the 
definition of clinical remission for each of 50 imputed datasets.

The Mentel-Haenzel estimate of common risk differences along with standard errors
(Sato 1989) will be calculated for each imputed dataset and combined using Rubin’s 
Rules (Rubin 1996) to calculate estimates and CIs. P-values will be calculated by using
the estimate and standard errors from Rubin’s rules to derive a Z-score.
5.3.5.
Tipping Point Analysis
Tipping point analysis will be conducted as a sensitivity analysis for the primary endpoint.
Within each analysis, the most extreme case will be considered, in which all missing data for 
patients randomized to mirikizumab will be imputed using the worst possible outcomes and all 
missing data for patients randomized to placebo will be imputed with the best possible outcomes:  


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
Missing responses in the mirikizumab group will be imputed with a range of response 
probabilities (probabilities of 0, 0.2, 0.4, 0.6, 0.8, and 1.0).

Missing responses in the placebo group will be imputed with a range of response 
probabilities (probabilities of 0, 0.2, 0.4, 0.6, 0.8, and 1.0).
Multiple imputed datasets will be generated for each response probability. Treatment differences 
between mirikizumab and placebo will be analyzed for each imputed dataset using CMH test 
(Section 5.1.4). Results across the imputed datasets will be aggregated using SAS Proc 
MIANALYZE in order to compute a p-value or 95% CI for the treatment comparisons for the 
given response probability. If the probability values do not allow for any variation between the 
multiple imputed datasets (e.g., all missing responses in the placebo and mirikizumab groups are 
imputed as responders and nonresponders, respectively), then the p-value from the single 
imputed dataset will be used to assess the treatment effect.
5.4.
Analysis Considerations for the eCOA Error in Turkey and 
Poland
Data from patients impacted by the Poland and Turkey eCOA transcription error addendum (as 
described in Section 4.3 and Appendix 3) will be analyzed with the following considerations
(Concurrence with the Food and Drug Administration [FDA] on below analyses was obtained 
based on the FDA Type C written response received on 20 July 2020):

Efficacy Analysis:
o
Impacted patients will be excluded from the primary efficacy analysis for all 
endpoints.
o
Additional sensitivity analysis for efficacy will be performed on primary and 
selected key secondary endpoints by including impacted patients using the ITT 
population with mNRI multiple imputation. The RB score will be imputed for
impacted patients in Poland and the SF score will be imputed for impacted
patients in Turkey.

Safety Analysis:
o
Impacted patients will be included in the primary safety analysis (Section 5.15). 
o
To assess the potential impact of the eCOA errors, sensitivity analysis will be 
performed to summarize key safety results in the modified intent-to-treat (mITT)
population (excluding impacted patients) for the Biologics License Application 
(BLA) submission.  The planned safety analyses will include the following
summary tables: overview of AEs, treatment-emergent adverse events (TEAEs) 
by Preferred Term (PT) nested within System Organ Class (SOC), serious adverse 
events (SAEs) by PT nested within SOC, treatment-emergent abnormal lab results, 
treatment-emergent abnormal vitals, and AEs leading to treatment/study 
discontinuation. 


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5.5.
Analysis Considerations for COVID-19-Related Mitigations
A listing of all patients impacted by the COVID-19-related study disruptions will be provided by 
unique subject identifier and investigator site, with a description of how individual participation 
was altered. COVID-19-related impact will also be summarized by treatment group for the mITT 
population. Summaries will include patients having a COVID-19-related AE, discontinuations
from study treatment due to a COVID-19-related AE, discontinuations from study treatment due 
to COVID-19-related issues (e.g., due to COVID related site / travel restrictions), and important 
deviations/mitigations from the protocol related to COVID-19.
Other analysis considerations for efficacy analysis related to COVID-19 mitigations include the 
following:

Extended window for endoscopy:
o
The primary analysis for all endpoints will include all patients, regardless of
whether the measurement of endoscopy was out of window. However, Week 12 
endoscopies which occurred more than 2 weeks early or more than 4 weeks late
(i.e., study days 71 to 113) will be considered missing for analysis purposes (e.g.,
will be considered nonresponders for NRI analysis).
o
Depending upon the number of patients who are unable to meet the 
protocol-defined endoscopy window, a sensitivity analysis may be performed to 
assess clinical remission (primary endpoint) and endoscopic remission by treating
as nonresponders patients who received their endoscopy outside of the 85 ±14 
study day window.

Missing endoscopies: 
o
For the primary analysis of endoscopy related endpoints, missing Week 12 
endoscopies due to COVID-19 will be treated the same as missing endoscopies
due to other reasons; for example, in the primary endpoint they will be treated as 
nonresponders.
o
Sensitivity analysis will be performed for the primary endpoint using the mNRI 
multiple imputation method of the endoscopy score.

Other mitigations: 
o
The primary analysis of all endpoints will include patients in the analysis 
populations as described in Table AMAN.5.1, regardless of the COVID-19 
mitigations.
o
Sensitivity analysis will include an analysis of primary and key secondary 
endpoints in the per-protocol (PP) population as described in in Section 5.17. No 
additional sensitivity analyses are planned.
Safety analyses will be performed as planned in Section 5.15, unless COVID-19 impact is 
considered substantial enough in the assessment of safety to require a change to an existing 
analysis or a need for additional analyses as outlined in a recent cross industry manuscript


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(Nilsson et. al 2020); for example, if the impact due to COVID-19 is different across treatment 
groups, different or additional analyses will be considered.
5.6.
Multicenter Studies
For the analysis of the primary endpoint, treatment-by-region interaction (for regions:  North
America, Europe, Other) will be added to the logistic regression model as a sensitivity analysis 
and results from this model will be compared to the model without the interaction effect.  If the 
treatment-by-region interaction is significant at a 2-sided alpha level of 0.05, the nature of this 
interaction will be inspected as to whether it is quantitative (i.e., the treatment effect is consistent 
in direction across all regions but not in size of treatment effect) or qualitative (the treatment is 
beneficial in some but not all regions).  If the treatment-by-region interaction effect is found to 
be quantitative, results from the primary model will be presented.  If the treatment-by-region 
interaction effect is found to be qualitative, further inspection will be used to identify in which 
regions mirikizumab is found to be more beneficial.
5.7.
Multiple Comparisons/Multiplicity
A prespecified graphical multiple testing approach (Bretz et al. 2009, 2011) will be implemented 
to control the overall Type I error rate at 2-sided alpha of 0.00125, for all primary and major 
secondary endpoints.  More specifically, we will calculate multiple testing adjusted p-values 
using “Algorithm 2” described by Bretz et al. (2009), and any hypothesis tests with a multiple 
testing adjusted p-value of less than 0.00125 will be considered statistically significant.  This 
graphical approach is a closed testing procedure; hence, it strongly controls the family-wise error 
rate across all endpoints (Bretz et al. 2009, 2011; Alosh et al. 2014).  Each hypothesis is 
represented as a node in a graph.  Directed arrows between the nodes with associated weights 
represent how alpha is passed from its initial allocation to other nodes.  The testing scheme is 
fully specified by the graph (including nodes, arrows and weights) along with the initial alpha 
allocation.  Figure AMAN.5.1 describes the graphical scheme, and all of our alpha will be 
allocated to the primary endpoint initially.  The primary and all major secondary endpoints 
(except Bowel Movement Urgency at Week 12) are binary and will be analyzed using the CMH 
test with NRI imputation.  Bowel Movement Urgency at week 12 will be analyzed using 
MMRM. Unless otherwise specified, there will be no adjustment for multiple comparisons for 
any other analyses.  The testing scheme will be finalized before the first unblinding of efficacy 
data.


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Note: The underlined endpoint is the primary endpoint.
Figure AMAN.5.1.
Graphical approach to control the Type 1 error rate for Study I6T-
MC-AMAN.
5.8.
Patient Disposition
Screen failures and reason for screen failure will be summarized.  The treatment disposition and 
study disposition will be summarized for the mITT population.  Disposition summaries will be 
by treatment group.  Summaries will also include reason for discontinuation from the study 
tabulated by treatment group.








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Abbreviations:  ATC = Anatomical Therapeutic Chemical; eCRF = electronic clinical report form; EQ-5D-5L = The 
European Quality of Life-5 Dimensions-5 Level; IBDQ = Inflammatory Bowel Disease Questionnaire; 
MCS = mental component score; MMX = Multi Matrix System; NRS = numeric rating scale; PCS = physical 
component score; PGA = Physician’s Global Assessment; SF-36 = 36-Item Short Form Survey; TNF = tumor 
necrosis factor; UC = ulcerative colitis; UCEIS = Ulcerative Colitis Endoscopic Index of Severity; VAS = visual 
analog scale; WPAI = Work Productivity and Activity Impairment Questionnaire.
a
Subgroup analysis will be used for efficacy endpoints only.  See Section 5.16 for more details.
b
Age in years will be calculated as length of the time interval from the imputed date of birth (July 1st in the year 
of birth collected in the eCRF) to the informed consent date.
c
Body Mass Index (BMI) will be calculated as:  ܤܯܫሺ݇݃/ ݉ଶሻൌܹ݄݁݅݃ݐሺ݇݃ሻ/ሺܪ݄݁݅݃ݐሺ݉ሻሻଶ.
d
Biologic systemic therapies include:  adalimumab, adalimumab biosimilar, golimumab, infliximab, infliximab 
biosimilar, ustekinumab, vedolizumab. For the purpose of counting the number of prior biologics, adalimumab 
and adalimumab biosimilar will be counted as one biologic. Also, infliximab and infliximab biosimilar will be 
counted as one biologic.
e
Failure defined as reasons for prior treatment discontinuation are:  loss of response, inadequate response or 
intolerance to medication. 
f
Anti-TNF alpha biologics include:  Infliximab, Infliximab biosimilar, Adalimumab, Adalimumab biosimilar, 
Golimumab.
g
Options on the prior med eCRF for Corticosteroids include: prednisone and other corticosteroids. Note that this 
is not exactly the same as the inclusion criteria defined in the protocol.
h
Options on the prior med eCRF for Immunomodulator include: 6-mercaptopurine, azathioprine and other 
thiopurines. Note that this is not exactly the same as the inclusion criteria defined in the protocol.
i
ATC codes for corticosteroid use (including budesonide MMX and beclomethasone) and immunomodulators 
(including methotrexate and thiopurines) are listed in the compound level safety standards.
j
Budesonide MMX will be defined based on a string search of the trade name and reported name with Preferred 
Term of Budesonide with oral route.
k
Beclomethasone will be defined based on a string search of the trade name and reported name with Preferred 
Term of Beclometasone with oral route.
l
Aminosalicilates will be defined using ATC code A07EC (all members).
m Length of the interval from the date of UC diagnosis to the date of informed consent.
n
Age at diagnosis in years will be calculated as the time interval from the imputed date of birth (July 1st in the 
year of birth collected in the eCRF) to the date of UC diagnosis.
5.9.2. Preexisting Conditions
Preexisting condition is defined as the condition/event recorded on the Preexisting Conditions 
and Medical History electronic case report form (eCRF) page with a start date prior to the date of 
informed consent, and no end date (that is, the event is ongoing) or an end date on or after the 
date of informed consent.  In addition, the AEs occurring prior to first dose are also included.  
Notice if a preexisting condition worsens in severity on or after the date of informed consent, it 
will be recorded as an AE on the AE eCRF page with the date of worsening as the start date.  
The number and percentage of patients with preexisting conditions will be summarized by 
treatment group using the MedDRA PT nested within SOC.  Summaries will be performed for 
the mITT and ITT population.  
5.10. Treatment Compliance
Treatment compliance with IP will be summarized for patients who enter the Induction Period.  
Treatment compliance for each patient will be calculated as:


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ܶݎ݁ܽݐ݉݁݊ݐܿ݋݉݌݈݅ܽ݊ܿ݁ሺ%ሻൌ100 ൈ
ܶ݋ݐ݈ܽ݊ݑܾ݉݁ݎ݋݂݂݅݊ݑݏ݅݋݊ݏܽ݀݉݅݊݅ݏݐ݁ݎ݁݀
ܶ݋ݐ݈ܽ݊ݑܾ݉݁ݎ݋݂݂݅݊ݑݏ݅݋݊ݏ݌݈ܽ݊݊݁݀݌݁ݎ݌ݎ݋ݐ݋ܿ݋݈
Here the planned drug administrations per protocol is based on the number of visits before the 
patient discontinued study drug.  Each patient will be defined as having received a dose on a 
given date if they received the planned dose (i.e., a partial dose does not count).  “Overall 
compliance” with therapy is defined as missing no doses before discontinuing study treatment.  
Proportions of patients who meet the definition of overall compliance during the Induction 
Period will be compared between treatment groups using Fisher’s exact test.
Patient treatment compliance will be summarized for the mITT population.  
5.11. Prior and Concomitant Therapy 
Medications will be classified into anatomical therapeutic chemical (ATC) drug classes using the 
latest version of the World Health Organization (WHO) drug dictionary.  Medication start and 
stop dates will be compared to the date of first dose of treatment in each treatment period to 
allow medications to be classified as Concomitant for each treatment period.  
Prior medications are those medications that start and stop prior to the date of first dose of study 
treatment.  Concomitant medications are those medications that start before, on or after the first 
day of study treatment of the defined treatment period and continue into the treatment period.  
Concomitant medications are assigned to the treatment period in which they are actually 
ongoing.  For all summary tables of concomitant medications, preferred terms of concomitant 
medication will be sorted by descending frequency.  Also, summaries will be by treatment group 
and comparisons between treatment groups will use Fisher’s exact test for the mITT population. 
Summary tables include the following:
•
For the mITT and ITT population, summary tables with the number and frequency of 
patients by treatment group will be presented for: 
o
Preferred names of prior therapies ordered by frequency
o
Preferred names of concomitant therapies (use during the induction period) 
ordered by frequency
o
Prespecified prior therapies in the “Prior Therapy:  Indication” eCRF within 
the categories used in the eCRF.  The number and percentage of patients with 
each reason for discontinuation of previous UC therapy will be summarized 
by type and therapy.
•
A summary of concomitant medications within classes of interest will also be provided 
for the mITT and ITT populations.  This will include:  (1) corticosteroid therapy and (2) 
immunomodulatory therapy.  Definition of these two classes of interest will be based on 
compound level safety standards. 


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5.12. Efficacy Analyses
Table AMAN.5.4 includes the description and derivation of the efficacy/health outcomes 
measures and endpoints. Many of these endpoints are collected using a site-facing eCOA device. 
If duplicate entries are made with different responses, the first nonmissing response will be used.
Table AMAN.5.5 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and dosing regimen comparisons for efficacy/health outcomes analyses.  
Note that the details of each analysis will follow the general principles described in Section 5.1.4.  
For example, the “CMH with NRI” analysis will include descriptive statistics and the common 
risk differences.


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Table AMAN.5.4.
Description and Derivation of Efficacy/Health Outcomes Measures and Endpoints 
Measure
Description
Variable
Derivation / Comment
Definition of Missing
Mayo 
Score 
and 
compone
nts
The Mayo score is a composite instrument 
to measure Ulcerative Colitis (UC) disease 
activity.  It is comprised of the following 4 
subscores:
Stool Frequency (SF):  The SF subscore 
is a patient-reported measure.  This item 
reports the number of stools in a 24-hour 
period, relative to the normal number of 
stools for that patient in the same period.  
The normal reference is collected at 
baseline/screening.
Rectal Bleeding (RB):  The RB subscore 
is a patient-reported measure.  This item 
reports the most severe amount of blood 
passed for a given day
Endoscopic Subscore (ES):  The ES is a 
physician-reported measure that reports 
the worst appearance of the mucosa on 
flexible sigmoidoscopy or colonoscopy.
Physician’s Global Assessment (PGA):  
The PGA is a physician-reported 
measure that summarizes the 
investigator’s assessment of the patient’s 
UC disease activity.
Each subscore is on a 4-point scale, 
ranging from 0 to 3.
SF subscore
Calculated by averaging and rounding the 4-point daily 
SF subscore over 3 days as described in Appendix 1.  
Possible values are:  (0) Normal number of stools for 
subject; (1) 1 to 2 stools more than normal; (2) 3 to 4 
stools more than normal; (3) 5 or more stools than 
normal.
Missing if fewer than 3 
available measurements 
in the relevant 7 days.
RB subscore
Calculated by averaging and rounding the 4-point daily 
RB subscore over 3 days as described in Appendix 1.  
Possible values are:  (0) No blood seen; (1) Streaks of 
blood with stool less than half of the time; (2) Obvious 
blood (more than just streaks) or streaks of blood with 
stool most of the time; (3) Blood alone passed
Missing if fewer than 3 
available measurements 
in the relevant 7 days.
ES subscore
Possible values are:  (0) Normal or inactive disease; (1) 
Mild disease (erythema, decreased vascular pattern); (2) 
Moderate disease (marked erythema, absent vascular 
pattern, friability, erosions); (3) Severe disease 
(spontaneous bleeding, ulceration)
Single item.  Missing if 
missing. Missing for 
Week 12 if endoscopy 
date was outside of the 
study days 71 to 113
inclusive window.
PGA subscore
Possible values are:  (0) Normal, (1) Mild disease, (2) 
Moderate disease, (3) Severe disease
Single item.  Missing if 
missing.
Clinical 
Remission
o SF subscore = 0, or SF = 1 with a ≥1-point decrease 
from baseline, and
o RB subscore = 0, and
o ES subscore = 0 or 1 (excluding friability)
Missing if SF, RB or 
ES subscores are 
missing.
Alternate
Clinical 
Remission
o SF subscore = 0 or 1
o RB subscore = 0, and
o ES subscore = 0 or 1 (excluding friability)
Missing if SF, RB or 
ES subscores are 
missing.
Alternate 
Clinical 
Remission 2
o SF subscore = 0 or 1
o RB subscore = 0, and
o ES subscore = 0 (excluding friability)
Missing if SF, RB or 
ES subscores are 
missing.
Modified 
Mayo Score 
(MMS)
Calculated as:  SF + RB + ES.
Missing if SF, RB or 
ES subscores are 
missing.


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Total Mayo 
Score
Calculated as:  SF + RB + ES + PGA.
Missing if SF, RB, ES 
or PGA subscores are 
missing.
Total Mayo 
Clinical 
Remission
o Total Mayo Score <=2, and
No individual subscore (SF, RB, ES, PGA) >1
Missing if Total Mayo 
Score is missing.
Partial Mayo 
Score
Calculated as:  SF + RB + PGA.
Missing if SF, RB or 
PGA subscores are 
missing.
Clinical 
Response
o A decrease in the MMS of ≥2 points and ≥30% 
decrease from baseline, and
o A decrease of ≥1 point in the RB subscore from 
baseline or a RB score of 0 or 1
Missing if baseline or 
Week 12 MMS is 
missing. 
Total Mayo 
Clinical 
Response
o A decrease in the Total Mayo score of >=3 points and 
>=30% decrease from baseline, and
o A decrease of >=1 point in the RB subscore from 
baseline  or a RB score of 0 or 1
Missing if total Mayo 
Score is missing
Endoscopic 
Remission
ES = 0 or 1 (excluding friability).
Missing if ES is 
missing.
Symptomatic 
Remission
o SF = 0, or SF = 1 with a ≥1-point decrease from 
baseline and
o RB = 0
Missing if SF or RB is 
missing.
Alternate 
Symptomatic 
Remission
o SF = 0 or 1
o RB = 0
Missing if SF or RB is 
missing.
Symptomatic 
Response
≥30% decrease from baseline in the composite clinical 
endpoint of the sum of SF and RB subscores.
Missing if SF or RB is 
missing.
Time to first 
Symptomatic 
Remission 
(Response) 
For patients who are observed to meet the remission (or 
response) criteria during the Induction Period, time will 
be from the start of the Induction Period to the first 
measurement date where the patient met the remission 
(or response) criteria based on weekly averages.
Patients not observed to 
meet remission (or 
response) criteria 
during the Induction 
Period will be censored 
after the date of their 
last measurement 


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
during the Induction 
Period.
Endoscopic 
Normalization
ES = 0.
Missing if ES is 
missing.
Total 
Symptomatic 
Score
Calculated as SF + RB.
Missing if SF or RB is 
missing.
Endoscopic 
Response
A decrease in the ES of ≥1 point compared to baseline.
Missing if ES is 
missing.
SF component 
of clinical 
remission
SF = 0, or SF = 1 with a ≥1-point decrease from baseline
Missing if SF is 
missing.
RB component 
of clinical 
remission
RB = 0
Missing if RB is 
missing.
UCEIS
The Ulcerative Colitis Endoscopic Index 
of Severity (UCEIS) will be evaluated at 
the time of endoscopy (Travis 2012).  The 
UCEIS is comprised of the following 3 
subscores:

Vascular Pattern

Bleeding

Erosions and Ulcers
These subscores are combined to form the 
UCEIS score which ranges from 0 to 8.
Vascular 
Pattern
Possible values are:  Normal (0), Patchy loss (1) and 
Obliterated (2).
Single item, missing if 
missing
Bleeding
Possible values are:  None (0), Mucosal (1), Luminal 
mild (2) and Luminal severe (3).
Single item, missing if 
missing.
Erosion and 
Ulcers
Possible values are:  None (0), Erosion (1), Superficial 
Ulcer (2) and Deep ulcer (3).
Single item, missing if 
missing.
UCEIS score
Calculated as the sum of the subscores:  Vascular 
Pattern + Bleeding + Erosion and Ulcers
Missing if any of the 3 
subscores are missing.
UCEIS 
endoscopic 
remission
UCEIS score <=1
Missing if UCEIS score 
is missing.
Urgency 
NRS
The Urgency NRS is a single patient-
reported item that measures the severity 
for the urgency (sudden or immediate 
need) to have a bowel movement in the 
past 24 hours using an 11-point NRS 
ranging from 0 (no urgency) to 10 (worst 
possible urgency).  
Urgency NRS 
Score
Calculated by averaging data from all available daily 
diary entries of Urgency NRS for a 7-day period as 
described in Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days 
(see Appendix 1).
Urgency NRS 
≥3-Point 
Improvement
Decrease from baseline in the NRS Urgency Score is ≥3
Missing if fewer than 4 
available measurements 
in the relevant 7 days 
(see Appendix 1).


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Urgency 
Remission
Urgency NRS = 0 or 1
Missing if urgency 
NRS score is missing.
Abdomin
al Pain 
NRS
The Abdominal Pain NRS is a single 
patient-reported item that measures the 
“worst abdominal pain in the past 24 
hours” using an 11-point NRS ranging 
from 0 (no pain) to 10 (worst possible 
pain).  
Abdominal 
Pain NRS 
Score
Calculated by averaging data from all available daily 
diary entries of Abdominal Pain NRS for a 7-day period 
as described in Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days.
PGRS
Patient’s Global Rating of Severity 
(PGRS) is a 1-item patient-rated 
questionnaire designed to assess the 
patients’ rating of their disease symptom 
severity over the past 24 hours.  Responses 
are graded on a 6-point scale in which a 
score of 1 indicates the patient has no 
symptoms (that is, “none”) and a score of 6 
indicates that the patient’s symptom(s) are 
“very severe.”  
PGRS Score
Calculated by averaging data from all available daily 
diary entries of PGRS for a 7-day period as described in 
Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days.
Nocturna
l Stool
The Nocturnal Stool instrument is a single 
item asking the patient to record the 
number of stools they had during the night 
(or day, for shift workers) causing them to 
wake from sleep.  
Nocturnal 
Stool Score
Calculated by averaging data from all available daily 
diary entries of Nocturnal Stool for a 7-day period as 
described in Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days.
Fatigue 
NRS
The Fatigue NRS is a single item that 
measures the “worst fatigue (weariness, 
tiredness) in the past 24 hours” using an 
11-point NRS ranging from 0 (no fatigue) 
to 10 (fatigue as bad as can imagine).  
Fatigue NRS 
Score
Calculated by averaging data from all available daily 
diary entries of Fatigue NRS for a 7-day period as 
described in Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days.
Bristol 
Stool 
Scale
The Bristol Stool Scale is a single item that 
provides a pictorial and verbal description 
of stool consistency and form ranging from 
Type 1 (Hard Lumps) to Type 7 
(Watery/liquid).  
Bristol Stool 
Scale score
Calculated by using the worst value (i.e., largest number)
from all available daily diary entries of Bristol Stool 
Scale for a 7-day period as described in Appendix 1.
Missing if fewer than 4 
available measurements 
in the relevant 7 days.
Loose Stool
Bristol Stool Scale score of 6 or 7.
Bristol Stool Scale 
score is missing


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
PGRC
Patient’s Global Rating of Change 
(PGRC):  The PGRC scale is a patient-
rated instrument designed to assess the 
patients’ rating of change in their 
symptom(s).  Responses are graded on a 7-
point Likert scale in which a score of 1 
indicates that the subject’s symptom(s) is 
“very much better,” a score of 4 indicates 
that the subject’s symptom has 
experienced “no change,” and a score of 7 
indicates that the subject’s symptom(s) is 
“very much worse.”  
PGRC Score
Single Item.
Single item.  Missing if 
missing.
IBDQ
Inflammatory Bowel Disease 
Questionnaire (IBDQ):  A 32-item patient-
completed questionnaire that measures 4 
aspects of patients’ lives:  symptoms 
directly related to the primary bowel 
disturbance, systemic symptoms, 
emotional function, and social function 
(Guyatt et al. 1989; Irvine et al. 1994; 
Irvine et al. 1996).  Responses are graded 
on a 7-point Likert scale in which 7 
denotes “not a problem at all” and 1 
denotes “a very severe problem.” 
Bowel 
symptoms 
subscore
Calculated as the sum of questions 1, 5, 9, 13, 17, 20, 
22, 24, 26, 29. 
If only one question is 
missing, imputed as the 
mean of the other items 
in the subscore.  
Missing if more than 
one item in the subscore 
is missing
Systemic 
symptoms 
subscore
Calculated as the sum of questions 2, 6, 10, 14, 18. 
Emotional 
function 
subscore
Calculated as the sum of questions 3, 7, 11, 15, 19, 21, 
23, 25, 27, 30, 31, 32. 
Social function 
subscore
Calculated as the sum of questions 4, 8, 12, 16, 28.
IBDQ score
Calculated as the sum of all questions.  Scores range 
from 32 to 224; a higher score indicates a better quality 
of life.
If more than 4 questions 
are missing or more 
than 2 questions for any 
subscore are missing, 
then IBDQ Score is 
missing.  Otherwise, 
missing questions 
imputed as the mean of 
the other items in each 
subscore.


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
IBDQ 
response
≥16-point improvement from baseline in IBDQ score as 
described by Irvine et al. (1996).
If baseline IBDQ score 
or visit IBDQ score is 
missing, then IBDQ 
response is missing.
IBDQ 
remission
IBDQ score ≥170 as described by Irvine (2008). 
Missing if the IBDQ 
score is missing
EQ-5D-
5L 
The European Quality of Life-5 
Dimensions-5 Level (EQ-5D-5L) is a 
standardized measure of health status used 
to provide a simple, generic measure of 
health for clinical and economic appraisal.  
The EQ-5D-5L consists of 2 components:  
a descriptive system of the respondent’s 
health and a rating of his/her current health 
state using a 0- to 100-mm VAS.  
The descriptive system comprises the 
following 5 dimensions: 
Item 1: mobility
Item 2: self-care
Item 3: usual activities
Item 4: pain/discomfort
Item 5: anxiety/depression
The respondent is asked to indicate his/her 
health state by ticking (or placing a cross) 
in the box associated with the most 
appropriate statement in each of the 5 
dimensions.
EQ-5D-5L 
Items
Five health profile dimensions, each dimension has 5 
levels: 
1 = no problems
2 = slight problems
3 = moderate problems
4 = severe problems
5 = extreme problems  
It should be noted that the numerals 1 to 5 have no 
arithmetic properties and should not be used as a 
primary score.
Each dimension is a 
single item, missing if 
missing.
EQ-5D-5L UK
Population-
based index
score
Uses the concatenation of the value of each EQ-5D-5L 
dimension score in the order: Item 1, Item 2, Iitem3; 
Item 4; Item 5.  
Derive EQ-5D-5L UK Population-based index score
according to the link by using the UK algorithm (Szende 
et al. 2006) to produce a patient-level index score 
between -0.59 and 1.0 (continuous variable):
https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/valuation-standard-value-sets/crosswalk-index-
value-calculator/
If any of the items is 
missing or equal to 9, 
the index score is 
missing  
EQ-5D VAS
Range from 0 = “worst imaginable health state” to 100 = 
“best imaginable health state”.  
Note: higher value indicates better health state.
Single item, missing if 
missing


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
SF-36
The SF-36 Version 2 is a 36-item, patient-
completed measure designed to be a short, 
multipurpose assessment of health (The SF 
Community – SF-36 Health Survey 
Update).  The summary scores range from 
0 to 100, with higher scores indicating 
better levels of function and/or better 
health.  
Items are answered on Likert scales of 
varying lengths.  The SF-36 comprises 8 
domain scores and 2 overarching 
component scores.  SF-36 domain scores
are:  (1) Physical functioning, (2) Role-
physical, (3) Role-emotional,  (4) bodily
pain, (5) vitality, (6) social functioning, (7)
mental health and (8) general health.
The component scores are:  (1) the
Physical Component Summary (PCS) and
(2) Mental Component Summary (MCS).
SF-36 Domain
scores and
SF-36
Component
Scores
Per copyright owner, the Quality Metric Health 
Outcomes™Scoring Software will be used to derive SF-
36 domain and component scores.
After data quality-controls, the SF-36 software will re-
calibrate the item-level responses for calculation of the 
domain and component scores.  These raw scores will 
be transformed into the domain scores (t-scores) using 
the 4-week recall period.  This entails exporting the 
patient data in a CSV or tab-delimited file for import, 
generation of the SF-36 scores and reports, and export 
of the calculated scores in a CSV or tab-delimited file 
for integration into SDTM/ADAM datasets. 
Missing data handling 
offered by SF-36 
software will be used.  
Maximum Data 
Recovery will be 
selected for Missing 
Score Estimator in the 
software. 
SF-36 PCS 
MCID 
Response
PCS component score increase (change from baseline) 
≥5 as described by Coteur et al. (2009).
Missing if baseline or 
observed value is 
missing.
SF-36 MCS 
MCID 
Response
MCS component score increase (change from baseline) 
≥5 as described by Coteur et al. (2009).
Missing if baseline or 
observed value is 
missing.
WPAI:U
C
The Work Productivity and Activity 
Impairment- (WPAI:UC) Questionnaire is 
a patient-reported instrument developed to 
measure the impact on work productivity 
and regular activities attributable to a 
specific health problem (Ulcerative 
Colitis).  It contains 6 items that measure:  
1) employment status, 2) hours missed 
from work due to the specific health 
problem, 3) hours missed from work for 
other reasons, 4) hours actually worked, 5) 
degree health affected productivity while 
working, and 6) degree health affected 
Employment 
Status
Yes/No
Missing if question is 
missing
Absenteeism 
Score (%)
ܳ2
ሺܳ2 ൅ܳ4ሻൈ100
Missing if Q2 or Q4 are 
missing.  Also missing 
if Employment Status is 
No.
Presenteeism 
Score (%)
ܳ5
10 ൈ100
Missing if Q5 is 
missing.  Also missing 
if Employment Status is 
No.
Work 
Productivity 
Loss Score 
൤
ܳ2
ܳ2 ൅ܳ4 ൅൬1 െ
ܳ2
ܳ2 ൅ܳ4൰ܳ5
10൨ൈ100
Missing if Q2, Q4 or 
Q5 is missing.  Also 
missing if Employment 


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
productivity in regular unpaid activities.  
(%)
Status is No.
Activity 
Impairment 
Score (%)
ܳ6
10 ൈ100
Missing if Q6 is 
missing.  May still be 
present and nonmissing 
if patient is 
unemployed.
Histopath
ology
The histopathologic images will be read 
centrally in a blinded manner by a 
qualified pathologist and scoring 
performed using the Geboes Score 
(Geboes et al. 2000), Robarts 
Histopathology Index (RHI) (Mosli et al. 
2015) and Nancy index (Marchal-
Bressenot et al. 2017). 
Geboes Grades
Geboes assigns values to each of 7 histological features:  
(0) structural [architectural change] (4 levels) 
(1) chronic inflammatory infiltrate (4 levels) 
(2a) lamina propria eosinophils (4 levels)
(2b) lamina propria neutrophils (4 levels)  
(3) neutrophils in epithelium (4 levels)
(4) crypt destruction (4 levels)
(5) erosion or ulceration (5 levels)
Single items.  Missing 
if missing.
Geboes Score
The highest grade in which there is evidence of disease 
is assigned.  For example, if <50% crypts involved is 
checked (i.e., Geboes Grade 3 is assigned a 2) and Crypt 
destruction is noted as ‘none’ (4.0) and Erosion or 
ulceration is ‘No erosion, ulceration, or granulation 
tissue’ (5.0), the subject will be assigned a score of 3.2. 
Missing if any 
component of the 
definition is missing
Robarts 
Histology 
Index (RHI)
The RHI score is based on the follow components of the 
Geboes:  chronic inflammatory infiltrate, lamina propria 
neutrophils, neutrophils in epithelium, and erosion 
ulceration components (4 levels after combining Geboes 
5.1 and 5.2).  The RHI is calculated as:
RHI = 1 × chronic inflammatory infiltrate level 
+ 2 × lamina propria neutrophils level
+ 3 × neutrophils in epithelium level
+ 5 × erosion or ulceration level
Missing if any 
component of the 
definition is missing


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Nancy item 
scores
The Nancy item scores are: Ulceration, Acute 
inflammatory filtrate, and Chronic inflammatory filtrate.
Single items.  Missing 
if missing.
Nancy Index
Takes on possible grades of 0 to 4 based on the items 
according to the decision tree described by Marchal-
Bressenot et al. (2017).  A grade of 4 represents severely 
active disease while a grade of 0 represents no 
histological significant disease.
Missing if any 
component of the 
definition is missing.
Primary 
Histologic 
Remission
Resolution of mucosal neutrophils, defined by Geboes 
histological subscore of 0 for grades:
o 2b (lamina propria neutrophils), and 
o 3 (neutrophils in epithelium), and 
o 4 (crypt destruction), and 
o 5 (erosion or ulceration)
Missing if any 
component of the 
definition is missing
RHI <3
RHI <3
Missing if any 
component of the 
definition is missing.
Nancy Index 
<1
Nancy Index <1
Missing if any 
component of the 
definition is missing.
Histologic 
Improvement
Geboes histological subscores of:
o 0 (None) or 1 (<5%  of  crypts involved) for parameter 
3 (neutrophils in epithelium), and 
o 0 (None) for parameter 4 (crypt destruction), and 
o 0 (None) for parameter 5 (erosion or ulceration)  
Missing if any 
component of the 
definition is missing.
Alternative 
Histologic 
Improvement
Geboes histological subscores of 0 for parameter:
o 2B (neutrophils in lamina propria), and 
o 3 (neutrophils in epithelium), and 
o 5 (erosion or ulceration)  
Missing if any 
component of the 
definition is missing.
Histo-
Endo
Combined histology and endoscopic 
endpoints.
Histologic-
Endoscopic 
Improvement
Histologic Improvement and endoscopic remission.
Missing if any 
component of the 
definition is missing.


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Histologic-
Endoscopic 
Mucosal 
Remission
Primary histologic remission and endoscopic remission.
Missing if any 
component of the 
definition is missing.
CRP
C-reactive protein (CRP) is a biomarker of 
inflammation. 
CRP
Lab value.  May be transformed if needed.
Single lab value.  
Missing if missing.
Fecal 
calprotect
in
Fecal calprotectin is used as a biomarker of 
intestinal inflammation in clinical practice.  
Fecal 
calprotectin
Lab value.  May be transformed if needed.
Single lab value.  
Missing if missing.
EIMs
Extraintestinal manifestations (EIMs) are 
collected using the medical history and 
adverse event eCRFs. Extraintestinal 
manifestations include, but are not limited 
to:  uveitis, episcleritis, peripheral arthritis, 
dactylitis, enthesitis, sacroileitis, 
ankylosing spondylitis, erythema 
nodosum, pyoderma gangrenosum, 
primary sclerosing cholangitis, and oral 
aphthous ulcers. 
EIM 
Subcategory
EIMs will also be categorized as: (1) Musculoskeletal; 
(2) Mucocutaneous; (3) Hepatic; (4) Occular.
No Imputation.
Baseline EIMs
EIMs ongoing at first dose of study treatment.
No Imputation.
Resolution of 
Baseline EIMs
Complete resolution of baseline EIMs at Week 12. If a 
patient has multiple baseline EIMs, then at least one 
EIM must have resolved.
No Imputation.
Improvement 
or Resolution 
in Baseline 
EIMs
Reduction in the severity of baseline EIMs at Week 12, 
or complete resolution of baseline EIMs at Week 12. If a 
patient has multiple EIMs, then at least one EIM must 
have decreased in severity or resolved.
No Imputation.
New EIMs 
New EIMs at Week 12. 
No Imputation.
Worsening 
from baseline 
of an EIM
Increase in the severity of any baseline EIMs at Week 
12.
No Imputation


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Table AMAN.5.5.
Description of Efficacy/Health Outcomes Analyses
Measure
Variable
Analysis Method
(Section 5.1.4)
Population
(Section 5.1.1)
Time Point(s)a
Mayo Score and 
components
Clinical Remission
(Primary Endpoint)
CMH analysis with NRI
(Primary Analysis)
mITT (this is the primary analysis of the  
primary endpoint); PP
Week 12 Visit
Common Risk Difference
with mNRI
mITT; ITT
Week 12 Visit
Logistic regression analysis 
with NRI
mITT
Week 12 Visit
Clinical Remission – Alternative 
Estimand (Section 5.3.1)
CMH analysis with NRI and 
Alternative Estimand 
(Section 5.3.1)
mITT
Week 12 Visit
Alternate Clinical Remission
CMH analysis with NRI
mITT; PP
Week 12 Visit
Common Risk Difference 
analysis with mNRI
ITT
Week 12 Visit
Alternate Clinical Remission 2
CMH analysis with NRI
mITT
Week 12 Visit
Clinical Response
CMH analysis with NRI
mITT; PP
mITT – In the biologic failed subpopulation; 
PP – In the biologic failed subpopulation;
Week 12 Visit
Common Risk Difference 
analysis with mNRI
ITT;
ITT – In the biologic failed subpopulation
Total Mayo Clinical Remission
CMH analysis with NRI
mITT
Week 12 Visit
Total Mayo Clinical Response
CMH analysis with NRI
mITT
Week 12 Visit
Endoscopic Remission
CMH analysis with NRI
mITT; PP
Week 12 Visit
Common Risk Difference 
analysis with mNRI
ITT
Symptomatic Remission
CMH analysis with NRI
mITT; PP
Week 1 to 12 
Common Risk Difference 
Analysis with mNRI
ITT
Symptomatic Response
CMH analysis with NRI
mITT
Week 1 to 12
SF component of clinical remission
CMH analysis with NRI
mITT 
Week 1 to 12
RB component of clinical remission
CMH analysis with NRI
mITT
Week 1 to 12


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Measure
Variable
Analysis Method
(Section 5.1.4)
Population
(Section 5.1.1)
Time Point(s)a
Endoscopic Response
CMH analysis with NRI
mITT
Week 12 Visit
Endoscopic Normalization
CMH analysis with NRI
mITT
Week 12 Visit
Time to first Symptomatic 
Remission
KM analysis (censoring 
described in 
Table AMAN.5.4)
mITT
During Induction 
Period
Time to first Symptomatic 
Response
KM analysis (censoring 
described in
Table AMAN.5.4)
mITT
During Induction 
Period
Change from baseline in SF, RB 
and Total Symptomatic Score
MMRM; 
ANCOVA with mBOCF
mITT
Week 1 to 12
Change from baseline in ES
ANCOVA with mBOCF
mITT
Week 12 Visit
UCEIS
Change from baseline in UCEIS 
and in individual components of the 
UCEIS
ANCOVA with mBOCF
mITT
Week 12 Visit
UCEIS endoscopic remission
CMH analysis with NRI
mITT
Week 12 Visit
Urgency NRS
Change from baseline in Urgency
NRS Score
MMRM; 
mITT; PP; ITT
Week 1 to 12 
ANCOVA with mBOCF
mITT
Week 1 to 12
Urgency NRS ≥3-Point 
Improvement
CMH analysis with NRI
mITT – In patients with an Urgency NRS ≥3 
at baseline
Week 1 to 12 
Urgency Remission
CMH analysis with NRI
mITT – In patients with an Urgency NRS ≥3 
at baseline
Week 1 to 12
Abdominal Pain NRS
≥30% improvement from baseline
CMH analysis with NRI
mITT – In patients with a NRS abdominal 
pain score ≥3 at baseline
Week 1 to 12
PGRS
Change from baseline in PGRS
Score
MMRM; 
ANCOVA with mBOCF
mITT
Week 1 to 12
Nocturnal Stool
Change from baseline in Nocturnal
Stool Score
MMRM; 
ANCOVA with mBOCF
mITT - In patients with a nocturnal stool
score ≥1 at baseline  
Week 1 to 12
Fatigue NRS
Change from baseline in Fatigue
NRS Score
MMRM; 
ANCOVA with mBOCF
mITT
Week 1 to 12


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Measure
Variable
Analysis Method
(Section 5.1.4)
Population
(Section 5.1.1)
Time Point(s)a
Bristol Stool Scale
Loose Stool
CMH analysis with NRI (i.e.,
patients with missing data are 
assumed to have loose stool)
mITT – In patients with loose stool at 
baseline.
Week 1 to 12
PGRC
Mean PGRC Score
MMRM; 
ANCOVA as observed 
(Baseline will not be 
included as a covariate in 
model) 
mITT
Week 4,8, and 12
IBDQ
Change from baseline in IBDQ 
Total Score and Subscores
ANCOVA with mBOCF
mITT
Week 12 Visit.
IBDQ Response
CMH analysis with NRI
mITT
Week 12 Visit.
IBDQ Remission
CMH analysis with NRI
mITT
Week 12 Visit.
EQ-5D-5L
Change from baseline of EQ-5D
VAS score
ANCOVA with mBOCF
mITT
Week 12 Visit
SF-36
Change from baseline for Domain
Scores and PCS and MCS
Component Scores
ANCOVA with mBOCF
mITT
Week 12 Visit.
SF-36 PCS MCID Response and 
SF-36 MCS MCID Response
CMH analysis with NRI
mITT
Week 1 to 12 
Visit.
WPAI:UC
Change from baseline in WPAI:UC 
Scores (Absenteeism,
Presenteeism, Work Productivity,
Activity Impairment)
ANCOVA with mBOCF
mITT - In patients with baseline employment 
status of yes
Week 12 Visit.
Histopathology
Primary Histologic Remission
CMH analysis with NRI
mITT
Week 12 Visit
RHI <3
CMH analysis with NRI
mITT
Week 12 Visit
Nancy Index <1
CMH analysis with NRI
mITT
Week 12 Visit
Histologic Improvement
CMH analysis with NRI
mITT
Week 12 Visit
Alternative Histologic 
Improvement
CMH analysis with NRI
mITT
Week 12 Visit
Histologic-
Endoscopic
Histologic-Endoscopic 
Improvement
CMH analysis with NRI
mITT
Week 12 Visit
Histologic-Endoscopic Mucosal 
Remission
CMH analysis with NRI
mITT
Week 12 Visit


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Measure
Variable
Analysis Method
(Section 5.1.4)
Population
(Section 5.1.1)
Time Point(s)a
CRP
Change from baseline in CRP
ANCOVA with mBOCF
mITT
Week 12 Visit
Fecal calprotectin
Change from baseline in fecal 
calprotectin 
MMRM;
ANCOVA with mBOCF
mITT
Week 4 and 12 
Visit
Percent change from baseline in 
fecal calprotectin
MMRM;
ANCOVA with mBOCF
mITT – In patients with fecal calprotectin 
>250 μg/g
Week 4 and 12 
Visit
EIMs
“Resolution of Baseline EIMs,” 
“Improvement or Resolution of 
Baseline EIMs”
“New EIMs”
”Worsening from baseline of an 
EIM”
Fisher’s exact test for overall 
EIMs and each subcategory.
mITT – In patients with EIMs
Week 12 Visit
Abbreviations:  ANCOVA = analysis of covariance; CMH = Cochran-Mantel-Haenzel; ITT = intent-to-treat; mBOCF = modified baseline observation carried 
forward; MCID = minimal clinically important difference; mITT = modified intent-to-treat; MMRM = mixed-effects model for repeated measures; 
mNRI = modified nonresponder imputation; NRI = nonresponder imputation; NRS = numeric rating scale; PP = per-protocol; Q = Question; SF-36 = 36-Item 
Short Form Survey; VAS = visual analog scale.
a
MMRM analysis will be performed only for protocol-defined visits.


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5.12.1. Primary Outcome and Methodology
Analysis of the primary endpoint (clinical remission) is described in Table AMAN.5.5.  The 
primary endpoint analysis will utilize the CMH test (see Section 5.1.4) with NRI (see Section 5.3)
for the mITT population (see Section 5.1.1). 
5.12.2. Sensitivity Analyses of the Primary Outcome
The sensitivity analysis of the primary endpoint is described in Table AMAN.5.4 and 
Table AMAN.5.5. Sensitivity analysis for the primary endpoint includes the following:

CMH test with NRI in the PP population

Logistic regression analysis with NRI in the mITT population

Common risk differences calculated with mNRI in the mITT population

Common risk differences calculated with mNRI in the ITT population. Patient data 
impacted by the eCOA error will be imputed via multiple imputation in this approach

CMH test with NRI in the ITT population with alternative estimand as described in 
Section 5.3.1
Depending upon the number of patients who are unable to meet the protocol-defined endoscopy 
window, we may provide the CMH test with NRI in the mITT population, removing patients
who received their endoscopy outside of the 85 ±14 study day window.
5.12.3. Analyses of the Secondary Efficacy Outcomes
5.12.3.1. Major Secondary Efficacy Outcomes 
The analysis of the major secondary endpoints is described in Table AMAN.5.4 and 
Table AMAN.5.5.  The list of major secondary endpoints may be found Table AMAN.3.1.  All 
of these endpoints except for the Urgency NRS endpoint are binary and the primary analysis of 
these endpoints will use the CMH test (see Section 5.1.4) with NRI (see Section 5.3) in the mITT 
population.  The Urgency NRS endpoint will be analyzed using the MMRM analysis, including 
the planned study visits, as described in Section 5.1.4. A multiple testing procedure will be 
utilized to control the FWER at the 0.00125 significance level for the primary analysis of the 
primary endpoint and all major secondary endpoints (see Section 5.7).
5.12.3.2. Sensitivity Analysis of the Major Secondary Efficacy Outcomes
As described Table AMAN.5.4 and Table AMAN.5.5, the following analyses will be performed 
as sensitivity analysis for selected major secondary binary outcomes:

Common risk differences calculated with mNRI in the ITT population. Patient data 
impacted by the eCOA error will be imputed via multiple imputation in this approach

CMH test with NRI in the PP population
For the Urgency NRS endpoint:

MMRM analysis including the planned study visits in the ITT population 


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
MMRM analysis including the planned study visits in the PP population

ANCOVA analysis with mBOCF in the mITT population
Additional sensitivity analysis for selected endpoints, such as using the mNRI multiple 
imputation approach, may also be performed.
5.12.3.3. Other Secondary Efficacy Outcomes 
The analysis of the other secondary endpoints is described in Table AMAN.5.4 and 
Table AMAN.5.5.
5.12.3.4. Exploratory Efficacy Endpoints 
The analysis of exploratory efficacy endpoints is described in Table AMAN.5.4 and 
Table AMAN.5.5.
5.13. Health Outcomes/Quality-of-Life Analyses 
5.13.1. Health Care Utilization
Hospitalization is recorded in the hospitalization events eCRF, which is triggered by the AE
eCRF. Categories of hospitalization include: Emergency Ward, General Ward, Hospital, 
Intensive Care Unit, and Other Care Facility. UC-related hospitalizations may be determined 
from the related adverse event eCRF. Summary statistics will be reported for the number and 
percentage of patients with UC-related hospitalization overall and within each category by 
treatment group. Also, for the hospitalization combined category, we will report: the exposure-
adjusted incidence rates (number of patients with the event / total person years*100) by treatment, 
the relative risk, and p-value. Both the relative risk and p-value will be derived from a Poisson 
regression model with treatment as explanatory variables. The p-value will be based on the 
likelihood ratio test. This analysis will be conducted for the induction period.
UC-related surgery is recorded in the Surgical Procedures eCRF, which is triggered by the AE
eCRF. Types of surgery include proctocolectomy, total colectomy, partial colectomy, and other.
As with hospitalizations, summary statistics will be reported for the number and percentage of 
patients with any surgery, a colectomy surgery (i.e., proctocolectomy, total colectomy, partial 
colectomy) and within each surgery category by treatment group. Also, for the colectomy 
surgery category, analysis of the exposure-adjusted incidence rates may be performed similar to 
the analysis above for hospitalization if a sufficient number of surgeries are performed to justify 
the analysis.
5.13.2. Additional Health Outcomes/Quality-of-Life Analyses
Details of the additional Health Outcome/Quality-of-Life analyses, including the psychometric 
analysis for the Urgency NRS, will be provided in supplemental SAP documents. 
5.14. Pharmacokinetic/Pharmacodynamic Analyses
The pharmacokinetic/pharmacodynamics (PK/PD) analyses will be conducted by the PK/PD and 
Pharmacometrics group at Eli Lilly.  The PK of mirikizumab will be characterized using 


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graphical evaluations and mixed-effect (population PK) modeling approaches.  Various 
structural and error models will be evaluated during development of the mixed-effect model.  
Intrinsic factors (e.g., age, body weight, gender, anti-drug antibodies [ADAs], etc.) and extrinsic 
factors (e.g., co-medications) will be investigated to assess their influence on model parameters.  
Model evaluation will include a visual predictive check.  Estimates of PK model parameters and 
covariate effects and the corresponding 90% CIs will be reported.
Analyses of exposure-response relationships will be conducted using both exploratory graphical 
approaches and model-based approaches.  Exploratory graphical analysis approaches may 
consist of graphs showing the percentage of patients who achieve clinical response, (alternate) 
clinical remission, and endoscopic remission at different percentiles (e.g., quartiles) of exposure 
of mirikizumab at Week 12.  Measures of exposure may include population PK estimated 
average concentrations (Cavg) between Week 0 and Week 12, or estimated or observed trough 
concentrations at Week 12.  Model based analyses will utilize population exposure-response 
logistic regression models, where maximum effect (Emax) or other model structures may be used 
to relate exposure to the probability of achieving clinical response, clinical remission, and 
endoscopic remission.  These models may be used to evaluate patient factors that may impact the 
relationship between exposure and the probability of achieving the endpoint.  Longitudinal 
exposure-response models for SF and RB subscores may be developed, which relate the time 
course and magnitude of mirikizumab exposure to the time course of these subscores.
Additional analyses may be conducted if they are deemed appropriate.  Data from this study may 
be combined with other study data, if appropriate.  Further details on PK and PK/PD analyses 
will be provided separately in the PK/PD analysis plan.
5.15. Safety Analyses
The planned analyses of safety data will be performed with an intent to maintain consistency 
with compound level safety standards.  These standards are based on internal standards which 
were informed by Clinical Data Interchange Standards Consortium (CDISC) standards, 
regulatory guidance (e.g., FDA Clinical Review Template), and cross-industry standardization 
efforts (e.g., Pharmaceutical Users Software Exchange [PhUSE] white papers from the Standard 
Analyses and Code Sharing Working Group provided in the PhUSE Computational Science 
Deliverables Catalog [WWW]).
As detailed in Table AMAN.5.1, the safety analysis population is defined as all randomized 
patients who received any amount of study treatment (regardless if the patient does not receive 
the correct treatment, or otherwise does not follow the protocol).  Inferential comparisons will be 
300 mg mirikizumab Q4W IV vs. placebo Q4W IV.  The analysis period (see Table AMAN.5.2) 
of interest will be the Induction period.  Analysis of the safety data collected for the Follow Up 
period will be performed in the integrated safety analysis.
Unless otherwise noted, Fisher’s exact test will primarily be used to compare percentages, and 
odds ratios will be provided.  Odds ratios will be created with mirikizumab treatment as the 
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Treatment differences in mean change for continuous measurements will be assessed using an 
ANCOVA model containing terms for treatment and the continuous covariate of baseline 
measurement.  Type 3 sums of squares will be used.  The significance of within-treatment group 
changes from baseline will be evaluated by testing whether the treatment group LS mean 
changes from baseline are different from zero using a t-statistic.  
5.15.1. Extent of Exposure 
Duration of exposure to study treatment will be summarized by treatment group for the safety 
population.  For the treatment period of interest associated with the safety analysis population, 
exposure will be calculated as the time period length in years (see Section 5.1.2) with start and 
end dates described in Table AMAN.5.2.  Exposure will be calculated for the Induction Period.
Total patient-years (PY) of exposure will be reported by treatment.  Descriptive statistics (n, 
mean, SD, minimum, first quartile, median, third quartile, and maximum) will be provided for 
patient-weeks of exposure and the frequency of patients falling into different exposure ranges 
will be summarized.  Exposure ranges will generally be reported in weeks using the following as 
a guide:  

>0, ≥4 weeks, ≥8 weeks, ≥12 weeks. 

>0 to <4 weeks, ≥4 weeks to <8 weeks, ≥8 weeks to < 12 weeks, ≥ 12 weeks.
Additional exposure ranges may be considered if necessary.  No p-values will be reported in 
these tables as they are intended to describe the study populations, rather than test hypotheses 
about them.
5.15.2. Adverse Events
A TEAE is defined as an event that first occurred or worsened in severity after baseline.  The 
MedDRA Lowest Level Term (LLT) will be used in the treatment-emergent computation.  The 
maximum severity for each LLT during the baseline period will be used as baseline.  The 
treatment period will be included as post-baseline for the analysis.  For events with a missing 
severity during the baseline period, it will be treated as ‘mild’ in severity for determining 
treatment-emergence.  Events with a missing severity during the postbaseline period will be 
treated as ‘severe’ and treatment-emergence will be determined by comparing to baseline 
severity.  For events occurring on the day of first taking study medication, the start times of the 
study treatment and AE will be used to determine whether the event was pre- versus post-
treatment.  If start time for the AE is missing, it will be assumed to have started in the 
postbaseline period.
Summary tables of AEs to include the following:

Overview of AEs

Summary of TEAE PTs by decreasing frequency

Summary of TEAE PTs occurring in >=1% of patients by decreasing frequency

Summary of TEAE PTs by decreasing frequency within SOC


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
Summary of TEAE PTs by maximum severity by decreasing frequency within SOC

Summary of SAE PTs by decreasing frequency

Summary of AEs leading to study discontinuation

Listing of SAEs
Summary tables will include the number and percentage of patients reporting an event.  For 
events that are gender-specific (as defined by MedDRA), the number of participants at risk will 
include only patients from the given gender.  Comparisons will be performed using Fisher’s 
exact test.  P-values should be interpreted cautiously due to the fact that multiplicity is not 
controlled.
The baseline period and post-baseline periods (see Table AMAN.5.2) will be defined as follows:

The baseline period is the Screening period.

The postbaseline period will be the Induction period interval.
5.15.2.1. Common Adverse Events
The percentages of patients with TEAEs will be summarized by treatment using MedDRA PT 
for the common TEAEs (occurred in ≥1% before rounding of mirikizumab-treated patients).  
Events will be ordered by decreasing frequency in mirikizumab.  
5.15.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
The number and percentage of patients who reported a SAE (including those resulting in death) 
during the treatment period will be summarized by treatment using MedDRA PT nested within 
SOC.  Events will be ordered by decreasing frequency in the mirikizumab group within SOC.  
This analysis will be conducted for the Induction period.  A listing of SAEs will be provided.
The number and percentage of patients who permanently discontinued from study treatment due 
to an AE (including AEs that led to death) during the treatment period will be summarized by 
treatment using MedDRA PT nested within SOC.  Events will be ordered by decreasing 
frequency in the mirikizumab group within SOC.  This summary will be conducted for the 
induction period.  
5.15.4. Clinical Laboratory Evaluations
As described more fully in compound level safety standards and in the laboratory-related PhUSE 
white papers [PhUSE 2013; PhUSE 2015], the clinical laboratory evaluations will be 
summarized with the following displays:

Box plots of observed values (and change from baseline values) by visit. 

Change from baseline to last observation will be summarized within the box plot of 
changes (rightmost column), and descriptive summary statistics will be included in a 
table below the box plot along with a p-value using the ANCOVA model described in 
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
Treatment emergent abnormal high lab values (i.e. patients shifting from a normal/low 
maximum baseline value to a high maximum post-baseline value) or low lab values (i.e. 
patients shifting from normal/high minimum baseline value to a low minimum post-
baseline value)

Scatter plot of maximum (minimum) post-baseline value vs. maximum (minimum) 
baseline value

Shift tables showing the number of patients who shift from each category of maximum 
(minimum) baseline observation to each category of maximum (minimum) post-baseline 
observation.  Here categories may be low, normal or high with cut-offs defined in the 
compound level safety standards.
For these displays, the post-baseline period will be the induction period.  Post-baseline 
measurement for continuous analysis (e.g., boxplots) will include only scheduled measurements, 
while post-baseline categorical analysis (e.g., shifts) will include both scheduled and 
unscheduled measurements.
Measurements are defined to be in the baseline periods as follows:

For analyses of continuous measurements:  the last scheduled or unscheduled nonmissing 
measurement recorded during the Screening Period.

For analyses of categorical measurements:  all scheduled or unscheduled nonmissing 
measurements recorded during the Screening Period.
For any lab performed on the day of first taking study medication at the start of the post-baseline 
period, the start time of the study treatment will be used to determine whether the lab was pre-
versus post-baseline.  If time for the lab is missing, it will be assumed to be in the baseline period 
(i.e. we assume the protocol defined order of procedures was followed).  Following the 
compound level safety standards, for some labs a safety concern may exist for only high (or only 
low) values.  For these labs, displays with only maximum (or minimum) values will be used and 
shift tables will be presented accordingly.
5.15.5. Vital Signs and Other Physical Findings
As described more fully in compound level safety standards and in the vital signs-related PhUSE 
white papers [PhUSE 2013; PhUSE 2015], vital signs will be summarized similarly to the 
clinical laboratory evaluation (see Section 5.15.4).  For vital signs, the low and high limits are 
based on a combination of a specified value and a change or percentage change.  In this case, the 
PhUSE white paper recommends providing scatter plots and shifts to low/high.  Boxplots will 
also be presented.  
5.15.6. Electrocardiograms
Complete electrocardiogram (ECG) data will not be part of the clinical database for the 
individual studies.  Any clinically significant findings from ECGs that result in a diagnosis and 
that occur after the patient receives the first dose of the investigational treatment will be reported 


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to Lilly or its designee as an AE via eCRF.  Aside from standard AE summary tables no 
additional analysis of ECG data will be performed.
5.15.7. Immunogenicity
An individual sample is potentially examined multiple times in a hierarchical procedure to 
produce a sample ADA assay result and potentially a sample neutralizing anti-drug antibodies 
(NAb) assay result.  A patient has treatment-emergent anti-drug antibodies (TE ADA) when 
ADAs are boosted or induced by exposure to study drug.  That is, when at least one postbaseline 
ADAs sample has a 4-fold increase in titers compared to baseline (if ADA were present at 
baseline) or has a titer 2-fold greater than the minimum required dilution of 1:10 (if no ADAs 
were present at baseline).  Compound level safety standards will be followed in the analyses of 
immunogenicity.  Listings of immunogenicity assessments will be provided along with the 
summary of specified TEAEs by TE ADA status.  The summary of TE ADA and NAb status will 
be produced, where the postbaseline period for reporting is the induction period.  Analyses of the 
relationship between immunogenicity and PK will be conducted as part of the PK/PD analyses as 
described in Section 5.14.  Additional assessments of the relationship between immunogenicity 
and efficacy will be performed as deemed appropriate.
5.15.8. Special Safety Topics including Adverse Events of Special 
Interest
This section includes areas of interest whether due to observed safety findings, potential findings 
based on drug class, or safety topics anticipated to be requested by a regulatory agency for any 
reason.  In general, potential adverse events of special interest (AESI) relevant to these special 
safety topics will be identified by one or more standardized MedDRA query(ies) (SMQs), by a 
Lilly defined MedDRA PT listing based upon the review of the most current MedDRA Version, 
or by treatment emergent relevant laboratory changes, as described below.  Additional special 
safety topics may be added as warranted. 
Unless otherwise specified, the AESIs will be summarized for the safety population during the 
induction period using the baseline and postbaseline definitions described in Sections 5.15.2.
Full details of the search terms and rules for deriving AESIs in each of the sections below are 
described in the compound level safety standards along with information about the types of 
summaries and listings to be provided.
5.15.8.1. Hepatic Safety
Hepatic labs include alanine aminotransferase (ALT) and aspartate transaminase (AST), total 
bilirubin (TBL) and serum alkaline phosphatase (ALP).  When criteria are met for hepatic 
evaluations, investigators will complete a follow-up hepatic safety eCRF. 
Analyses will include:


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
ALT and AST:  The percentages of patients with a measurement greater than or equal to 
3 times (3X), 5 times (5X), and 10 times (10X) the performing lab upper limit of normal 
(ULN) during the treatment period for all patients with a post-baseline value and for 
subsets based on various levels of baseline value.  

TBL and ALP:  The percentages of patients with a measurement greater than or equal to 
2 times (2X) the performing lab ULN during the treatment period will be summarized for 
all patients with a post-baseline value and for subsets based on various levels of baseline 
value.  

Plot of maximum post-baseline ALT vs. maximum post-baseline total bilirubin (entire 
safety population).

A listing of the information collected on the hepatic-safety CRF.
5.15.8.2. Infections, Including Opportunistic Infections and Serious Infections
Infections will be defined using the PTs from the MedDRA Infections and Infestations SOC.  
Treatment-emergent infections will be analyzed for:  all infections (by maximum severity), 
serious infections and opportunistic infections (OI).  The MedDRA terms used to identify 
infections considered to be OI in patients with immune mediated inflammatory conditions treated 
with immunomodulatory drugs are based on Winthrop et al. (2015) and are listed in the 
compound level safety standards.  The list contains narrow (more specific) and broad (less 
specific) PTs with respect to these prospectively defined opportunistic infections.  
Analyses will include:

Treatment-emergent (TE) Infections by PT; 

Serious Infections by PT;

Opportunistic Infections:  TE OI by narrow terms and broad terms separately. 
5.15.8.3. Hypersensitivity
Hypersensitivity reactions is used as an overarching term to describe events that are systemic or 
localized reactions that likely have an allergic/hypersensitivity etiology.  The evaluation of study 
drug-related systemic hypersensitivity reactions will be through the unsolicited reporting of 
TEAEs and through the use of the Hypersensitivity, Anaphylactic, and Infusion-Related 
Reaction Follow-up Forms completed by the investigator.
Potential hypersensitivity reaction AEs will be determined using the following SMQs:  
anaphylactic reaction, hypersensitivity, and angioedema.  Potential hypersensitivity AEs will be 
categorized as Immediate (i.e., on day of study drug administration) and non-immediate (i.e., 
occurring after the day of study drug administration) based on the timing of the reaction.  
Analyses will include:


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
For Immediate Hypersensitivity: (1) combined narrow/algorithmic search (i.e., any 
narrow term from any one of the SMQs, or anaphylaxis algorithm), (2) 
narrow/algorithmic search (i.e., any narrow/algorithmic term) by SMQ, (3) broad search 
(i.e., any narrow or broad term) by SMQ, and (4) TEAEs (occurring on the day of study 
drug administration) by PT not in any of the 3 SMQs.

For Non-Immediate Hypersensitivity: (1) combined narrow search (i.e., any narrow term 
from any one of the SMQs), (2) narrow search (i.e., any narrow term) by SMQ, and (3) 
broad search (i.e., any narrow or broad term) by SMQ.
5.15.8.4. Infusion Site Reactions (ISR)
Infusion site reactions are AEs localized to the immediate site of the administration of a drug.  
The evaluation of study drug related ISRs will be through the unsolicited reporting of ISR 
TEAEs and through the use of an Infusion Site Reaction Follow-up Form completed by the 
investigator for each ISR reported. 
Infusion site reactions will be defined using the following MedDRA High Level Term (HLT):  
Infusion site reaction, excluding certain PTs (e.g., those PTs related to joint). 
Analyses will include:

TE ISRs, HLT, and PT.

The additional data collected on the ISR follow-up form will be summarized in two 
distinct ways:  at the patient level and at the event level.  A by-patient listing of these data 
will be provided.
5.15.8.5. Cerebro-Cardiovascular Events
The cerebro-cardiovascular events reported in the study will be adjudicated by an independent, 
external adjudication committee (AC).  All confirmed events after adjudication will be used for 
the analysis of cerebro-cardiovascular events.  Categories of events include:  Cardiovascular, 
Cerebrovascular and Peripheral Vascular Events.  As detailed in the compound level safety 
standards, the categories are further categorized into subcategories.
Analyses will include:

TE cerebro cardiovascular confirmed events by category, subcategory and PT.

By-patient listing for all patients having a TEAE of cerebro-cardiovascular (confirmed 
event, no event, or insufficient documentation for event determination) at any time.
5.15.8.6. Malignancies
Malignancies will be defined using PTs from the Malignant tumors SMQ.  Malignant tumor 
events will be summarized separately for the categories:  Non-Melanoma skin cancer (NMSC) 
and Malignancies excluding NMSC.
Analyses will include:

TE malignancy by category and PT.

By-patient listing for all patients having a TEAE of malignancy at any time.


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5.15.8.7. Suicidal Ideation/Behavior and Depression 
During the study, suicidal ideation and behavior, and depression will be assessed prospectively 
by the investigator via signs and symptoms and through the use of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) [Screening] and the Quick Inventory of Depressive 
Symptomatology Self Report (QIDS-SR16) [Weeks 0, 12, ETV].  
Analyses will include:

C-SSRS:  Only a listing of the C-SSRS data will be provided.  

QIDS-SR16:  Shift tables will be provided showing the number and percentage of 
patients within each baseline category (maximum value) versus each post-baseline 
category (maximum value) by treatment.  Additionally, outcomes such as any increase in 
depression will be compared between treatments (further described in the compound 
level safety standards).
5.16. Subgroup Analyses
5.16.1. Efficacy Subgroup Analysis
Subgroup analyses will be conducted for all primary and key secondary endpoints (excluding the 
key secondary endpoint which is in the subgroup of biologic-failed patients) in the mITT 
Population.  The subgroups to be analyzed are listed Table AMAN.5.3 along with the 
demographic characteristics.  Additional subgroup analysis which are not based on 
baseline/demographic characteristics in Table AMAN.5.3 include treatment-emergent anti-
mirikizumab antibody status.  Some additional subgroup analyses may be performed to meet 
regulatory requirements in specific countries.  Changes to subgroup analysis will not require an 
amendment to the SAP. 
For binary endpoints, a logistic regression model with treatment, subgroup, and the interaction of 
subgroup-by-treatment, and the covariates mentioned in Section 5.2.  The subgroup-by-treatment
interaction will be tested using the Firth correction (Firth 1993) at the significance level of 0.05.
Within each subgroup category the proportion of responders by treatment, treatment differences 
and 95% CIs will be displayed.  Also, p-values using Fisher’s exact test for treatment 
comparison will be provided.  
For the Week 12 Urgency NRS endpoint, MMRM analysis will be performed for each subgroup
for select subgroups. Within each subgroup, LS means by treatment, LS mean differences, and 
95% CIs will be displayed. To test for interaction, an MMRM model with a subgroup-by-
treatment interaction term for each visit will be fit.
Forest plots may be generated to display the treatment difference and 95% CIs for selected 
efficacy subgroup analyses. If the number of patients in any subgroup category is <10% of the 
total population, only summaries of the efficacy data will be provided (that is, no inferential 
testing for that subgroup).  


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5.16.2. Safety Subgroup Analysis
A summary of TEAEs will be produced for the biologic-failed subgroup.  Additional safety 
subgroup analyses may be performed if there is a potentially relevant finding during the periodic 
study safety reviews.  Also, subgroup analysis for safety related endpoints will be performed 
within the context of the integrated safety analysis.
5.16.3. Analysis for Japan Submission
A subset of the planned analyses (e.g., patient disposition, demographic and baseline 
characteristics, efficacy, health outcomes, and safety analyses) will be reproduced based on 
patients from Japan sites, in support of the regulatory submission in Japan. The list of tables, 
listings, and figures for the patients from Japan sites (Japanese population) will be in a separate 
document.
5.17. Protocol Violations
Protocol deviations will be identified throughout the study. Important protocol deviations (IPDs) 
are defined as those deviations from the protocol that would potentially compromise patients’ 
safety, data integrity, or study outcome.
The important protocol deviations excluded from per-protocol analysis (IPDPPs), which are a 
subset of the important protocol deviations, are the IPDs that might have significant impact on 
the primary efficacy results. The impact of IPDPPs on the efficacy results will be assessed by 
assessing the robustness of the study results and conclusions to the choice of analysis population, 
both by including and excluding patients with IPDPPs. As specified in Table AMAN.5.1, the 
Induction PPS population is defined as all randomized patients who do not have any IPDPPs.
Mitigations approved under the COVID-19 addendum which would otherwise have been 
classified IPDPPs (had they not been approved under the addendum) will still result in patients 
being excluded from PP analysis.
A separate document known as the “The AMAN Trial Issues Management Plan (TIMP)” 
describes the categories and subcategories of important protocol deviations, whether or not these 
deviations are IPDPPs, and how the IPDs would be identified. The TIMP will be finalized before 
the Week 12 database lock (DBL).
The number and percentage of patients having IPDs will be summarized within category and 
subcategory of deviations by dosing regimen for mITT population.
A by-patient listing of IPDs will be provided.
5.18. Interim Analysis and Data Monitoring
Data Monitoring Committee: One Data Monitoring Committee (DMC) consisting of members 
external to Lilly will be established for periodic monitoring of clinical trial data across all Phase 
3 trials for the UC adult program.  This committee will consist of a minimum of 3 members, 
including a physician with expertise in gastroenterology and a statistician.  


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No member of the DMC may have contact with study sites.  A statistical analysis Center (SAC) 
will prepare and provide unblinded data to the DMC.  The SAC members may be Lilly 
employees or from third-party organizations designated by Lilly.  However, they will be external 
to the study team and will have no contact with sites and no privileges to influence changes to 
the ongoing studies.  The timing and frequency of the periodic clinical trial data review by the 
DMC will be detailed in the DMC charter for the UC adult program.
The DMC is authorized to evaluate unblinded interim efficacy and safety analyses.  The DMC 
will make recommendation to the Lilly Research Laboratories Senior Management Designee, 
who may order the immediate implementation of the DMC recommendation, or may convene an 
internal review committee (IRC), which is independent from the study team, to review the 
recommendation according to standard Lilly policy.  Study sites will receive information about 
interim results ONLY if it is required for the safety of their patients.
Week 12 DBL: An unblinded analysis will be performed after all patients have completed the 
Week 12 Visit or discontinued study treatment. This DBL will include all data collected by the 
cutoff date, including follow-up data from patients that have begun the posttreatment follow-up 
period. This is the final analysis for the efficacy endpoints up to Week 12. However, the study 
may be ongoing for the posttreatment follow-up period for patients remaining in the study at the
time of this DBL.
Final DBL: A final DBL will occur if needed after the posttreatment follow-up period from all 
active patients is completed.
Pharmacokinetics Analysis:  In addition, a limited number of preidentified, internal Lilly 
personnel that are not in contact with clinical sites may gain access to unblinded data, including 
PK, as specified in the unblinding plan.  The unblinded data will be restricted and will NOT be 
shared with anyone outside this preidentified group until after the Week 12 DBL.  Unblinding 
details will be provided in the unblinding plan.
5.19. Annual Report Analyses
Based on regulatory requirements for the Development Safety Update Report (DSUR), reports 
will be produced (if not already available from the study CSR) for the reporting period covered 
by the DSUR
5.20. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file.  Both 
SAEs and ‘Other’ AEs are summarized:  by treatment group, by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.


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
An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.


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6.
Unblinding Plan
Details will be provided in a separate unblinding plan document.


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7.
References 
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical trials. Stat 
Med. 2014;33(4):693-713.
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes or parametric tests. Biom J.
2011;53(6):894-913. 
Coteur G, Feagan B, Keininger DL, Kosinski M. Evaluation of the meaningfulness of 
health-related quality of life improvements as assessed by the SF-36 and the EQ-5D VAS in 
patients with active Crohn's disease. Aliment Pharmacol Ther. 2009;29:1032-1041.
Firth D. Bias reduction of maximum likelihood estimates. Biometrika. 1993;80 (1):27-38.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for 
histological assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):404-409. 
International Conference on Harmonization. ICH E9 (R1): Addendum to statistical principles for 
clinical trials on choosing appropriate estimands and defining sensitivity analyses in clinical 
trials. 2017. Available at: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM582738.pdf.
Irvine EJ. Quality of life of patients with ulcerative colitis: past, present, and future. Inflamm 
Bowel Dis. 2008;14: 554-565.
Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. 
J Pediatr Gastroenterol Nutr. 1999;28: S23-S27.
Jin M, Liu G. Estimand framework: delineating what to be estimated with clinical questions of 
interest in clinical trials. Contemp Clin Trials. 2020;96:106093.
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, Bastien C, Cahn V, Cadiot G, Diebold 
MD, Danese S, Reinisch W, Schreiber S, Travis S, Peyrin-Biroulet L. Development and 
validation of the Nancy histological index for UC. Gut. 2017;66(1):43-49. 
Metha CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stats Med. 2011;30(28):3267-3284.
Mosli M, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, Shackelton LM, Walker 
CW, Nelson S, Vandervoort MK, Frisbie V, Samaan MA, Jairath V, Driman DK, Geboes K, 
Valasek MA, Pai RK, Lauwers GY, Riddell R, Stitt LW, Levesque BG. Development and 
validation of a histological index for UC. Gut. 2015;0:1-9.
Nilsson M, Crowe B, Anglin G, Ball G, Munsaka M, Shahin S, Wang W. Clinical trial drug 
safety assessment for studies and submissions impacted by COVID-19 [published online 
August 05, 2020]. Stat Biopharm Res.


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Pharmaceutical Users Software Exchange [PhUSE] resources page. PhUSE web site. Available 
at https://www.phuse.eu/css-deliverables. Accessed September 18, 2017. 
Pharmaceutical Users Software Exchange [PhUSE resources page. Analyses & Displays 
Associated with Demographics, Disposition, & Medications in Phase 2-4 Clinical Trials & 
Integrated Summary Documents. 2018. Available at: 
https://www.phuse.eu/documents//working-groups/deliverables/analyses-displays-associated-
with-demographics-disposition-medications-in-phase-2-4-clinical-trials-version-20-02-mar-18-
11808.pdf. Accessed October 23, 2018.
Pharmaceutical Users Software Exchange [PhUSE] resources page. Analyses and Displays 
Associated with Measures of Central Tendency – Focus on Vital Sign, Electrocardiogram, and 
Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Submission 
Documents. 2013. Available at: 
https://www.phusewiki.org/docs/CSS%20White%20Papers%202016/CSS_WhitePaper_Centr
alTendency_v1.0.pdf. Accessed October 23, 2018.
Pharmaceutical Users Software Exchange [PhUSE] resources page. Analyses and Displays 
Associated with Outliers or Shifts from Normal to Abnormal: Focus on Vital Signs, 
Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and 
Integrated Summary Documents. 2015. Available at 
https://www.phusewiki.org/docs/CSS%20White%20Papers%202016/CS_WhitePaper_Outlier
sShifts_v1.0.pdf. Accessed October 23, 2018.
Pharmaceutical Users Software Exchange [PhUSE] resources page. Analysis and Displays 
Associated with Adverse Events: Focus on Adverse Events in Phase 2-4 Clinical Trials and 
Integrated Summary Document. 2017. Available at 
https://www.phuse.eu/documents//working-groups/cs-whitepaper-adverseevents-v10-
4442.pdf. Accessed October 23, 2018.
Rubin DB. Multiple imputation after 18+ years. J Am Stat Assoc. 1996;91(434):473-489.
Szende A, Oppe M, Devlin N, eds. EQ-5D Value Sets: Inventory, Comparative Review and User 
Guide. Dordrecht, Netherlands: Springer; 2007.
Sato, T. On the variance estimator of the Mantel-Haenszel risk difference [editorial]. Biometrics. 
1989;45(4):1323-1324.
Travis SP, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel JF, Feagan BG, Hanauer 
SB, Lémann M, Lichtenstein GR, Marteau PR, Reinisch W, Sands BE, Yacyshyn BR, 
Bernhardt CA, Mary JY, Sandborn WJ. Developing an instrument to assess the endoscopic 
severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). 
Gut. 2012;61(4):535-542.
Yucel RM, He Y, Zaslavsky AM. Gaussian-based routines to impute categorical variables in 
health surveys. Stat Med. 2011;30(29):3447-3460.


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Appendix 1.
Daily Diary Calculations
Weekly summary measures of daily diary data will be created for each patient.  The 7-day period 
associated with each week will be defined using a visit centric approach.  The table below 
displays the interval for each week,
Week (Visit)
Start Daya
End Daya
Screening 
Max(Informed Consent Date, Week 0 Visit Date - 14)
Week 0 Visit Date - 8
Baseline
Week 0 Visit Date - 7
Week 0 Visit Date - 1
Week 1
Max(Week 0 Visit Date, Week 2 Visit Date - 14) 
Week 2 Visit Date - 8
Week 2 (V2)
Max(Week 0 Visit Date, Week 2 Visit Date - 7) 
Week 2 Visit Date - 1 
Week 3
Max(Week 2 Visit Date, Week 4 Visit Date - 14)
Week 4 Visit Date - 8
Week 4 (V3)
Max(Week 2 Visit Date, Week 4 Visit Date - 7) 
Week 4 Visit Date - 1
Week 5
Max(Week 4 Visit Date, Week 8 Visit Date - 28) 
Week 8 Visit Date - 22
Week 6
Max(Week 4 Visit Date, Week 8 Visit Date - 21)
Week 8 Visit Date -15
Week 7
Max(Week 4 Visit Date, Week 8 Visit Date - 14) 
Week 8 Visit Date - 8
Week 8 (V4)
Max(Week 4 Visit Date, Week 8 Visit Date - 7)
Week 8 Visit Date - 1
Week 9
Max(Week 8 Visit Date, Week 12 Visit Date - 28) 
Week 12 Visit Date - 22
Week 10
Max(Week 8 Visit Date, Week 12 Visit Date - 21) 
Week 12 Visit Date - 15
Week 11
Max(Week 8 Visit Date, Week 12 Visit Date - 14) 
Week 12 Visit Date - 8
Week 12 (V5)
Max(Week 8 Visit Date, Week 12 Visit Date - 7) 
Week 12 Visit Date - 1
Abbreviation:  V = Visit.
a
If End Day < Start Day, do not assign specified visit week. Visit date will be calculated by selecting the first date 
from the following list (i.e., first in list order): (1) date of earliest bowel preparation if bowel preparation date is 
available, (2) date of endoscopy if endoscopy was performed, (3) date of treatment if treatment was given, or 
(4) office visit date if available, or (5) date of visit center of the protocol-defined window for that visit (i.e. study 
day 85). For patients who received their endoscopy outside of the window from study days 71 to 113, the visit 
date will be calculated as study day 85. The screening endoscopy is assumed to be associated with the Week 0 
visit.
For the Mayo SF and RB subscores, the most recent 3 nonmissing days of the 7-day period in the 
table above will be averaged and rounded to the nearest integer to calculate the weekly score for 
each patient.  Patients with less than 3 measurements in the 7 day period will be considered 
missing.
For the Bristol Stool Scale the worst (i.e. maximum) of the available measures during the 7 
period in the table above will be used to calculate a weekly score for each patient.  If fewer than 


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4 days are available (i.e., not missing), the patient will be considered to be missing data for that 
week. 
For all other daily diary measures, all available days of the 7 days will be averaged and rounded 
to the nearest integer to calculate the weekly score for each patient.  If fewer than 4 days are 
available (i.e., not missing), the patient will be considered to be missing data for that week. 
If multiple diary assessments on a single day are present, use the earliest nonmissing assessment.
Data from the following days will be considered missing: (i) days when patients receive bowel 
preparation, (ii) the day of an endoscopy, and (iii) the day after an endoscopy.
If the baseline assessment is missing per the above rules, the first available postbaseline 
assessment starting with Week 1 will be used to impute the baseline so that the patient can be 
included in the analysis.


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Appendix 2.
Countries and Regions
Country
Region 1
Region 2
AUSTRIA 
Europe
Western Europe
BELGIUM 
Europe
Western Europe
CROATIA 
Europe
Eastern Europe
CZECH 
REPUBLIC
Europe
Eastern Europe
DENMARK 
Europe
Western Europe
FRANCE 
Europe
Western Europe
GERMANY 
Europe
Western Europe
HUNGARY 
Europe
Eastern Europe
IRELAND 
Europe
Western Europe
ITALY 
Europe
Western Europe
LATVIA 
Europe
Eastern Europe
LITHUANIA 
Europe
Eastern Europe
NETHERLANDS 
Europe
Western Europe
POLAND 
Europe
Eastern Europe
ROMANIA 
Europe
Eastern Europe
SLOVAKIA 
Europe
Eastern Europe
SPAIN 
Europe
Western Europe
SWITZERLAND 
Europe
Western Europe
UNITED 
KINGDOM
Europe
Western Europe
CANADA 
North 
America
North America
UNITED STATES
North 
America
North America


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ARGENTINA 
Other
Central America/S 
America
AUSTRALIA 
Other
ROW
BRAZIL 
Other
Central America/S 
America
CHINA 
Other
Asia
INDIA 
Other
Asia
ISRAEL 
Other
ROW
JAPAN 
Other
Asia
KOREA, SOUTH
Other
Asia
MALAYSIA 
Other
Asia
MEXICO 
Other
Central America/S 
America
RUSSIAN 
FEDERATION
Other
ROW
SAUDI ARABIA
Other
ROW
SERBIA 
Other
ROW
TAIWAN 
Other
Asia
TURKEY 
Other
ROW
UKRAINE 
Other
ROW
Abbreviation:  ROW = Rest of World.


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Appendix 3.
Summary of eCOA Transcription Errors
Rectal Bleeding (RB) electronic clinical outcomes assessment (eCOA) Error in Poland
Rectal bleeding is a patient-reported outcome (PRO) measure and a component of the Mayo 
score. The score normally requires patients to indicate the degree of blood seen with bowel 
movements and includes the following options:
(0) No blood seen
(1) Streaks of blood with stool less than half of the time
(2) Obvious blood (more than just streaks) or streaks of blood with stool most of the time
(3) Blood alone passed
The transcription error on the eCOA device resulted in option (3) having a label of “No blood 
seen.”  Patients in Poland saw the options:
(0) No blood seen
(1) Streaks of blood with stool less than half of the time
(2) Obvious blood (more than just streaks) or streaks of blood with stool most of the time
(3) No blood seen
Thus, patients with no RB may have selected the option normally assigned to the worst grade (3) 
or may have selected the appropriate grade (0). Patients who had severe bleeding would not have 
been able to select “Blood alone passed” and could have selected a less-severe RB option.  
This error in the electronic daily diary impacted all 112 patients from Poland enrolled in the 
I6T-MC-AMAN (AMAN) (induction) study at the time the error was discovered. Of the 112 
impacted patients, 98 had already completed Study AMAN and entered Study I6T-MC-AMBG
(AMBG) (maintenance).
Stool Frequency eCOA Error in Turkey
Stool frequency is a PRO measure and a component of the Mayo score. In completing the daily 
diary, the patient should have seen the question:
“How many stools did you have in the past 24 hours?”
Instead, the patient saw a duplicate of the Nocturnal Stool question, as follows:
“How many stools did you have during the night causing you to waken from 
sleep?”
This error in the electronic daily diary impacted all 6 patients from Turkey enrolled in AMAN
(induction) study at the time the error was discovered. Of the 6 impacted patients, 3 had already 
completed Study AMAN and entered Study AMBG (maintenance).


Leo Document ID = 9fb256cc-09d9-442a-bc5c-ff9c561b1e80
Approver: 
Approval Date & Time: 14-Jan-2021 22:54:06 GMT
Signature meaning: Approved
PPD

SAP_003.pdf: 
Statistical Analysis Plan (China) I6T-MC-AMAN
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled 
Induction Study of Mirikizumab in Conventional-Failed and Biologic-Failed Patients 
with Moderately to Severely Active Ulcerative Colitis (LUCENT 1)
NCT03518086
Approval Date: 02-MAR-2021


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1.
Statistical Analysis Plan for Maximum Extended 
Enrollment Addendum for I6T-MC-AMAN:  
A Phase 3, Multicenter, Randomized, Double-Blind, 
Parallel, Placebo-Controlled Induction Study of 
Mirikizumab in Conventional-Failed and Biologic-Failed 
Patients with Moderately to Severely Active Ulcerative 
Colitis
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Mirikizumab (LY3074828) Ulcerative Colitis
Study I6T-MC-AMAN is a Phase 3, multicenter, randomized, double-blind, parallel,
placebo-controlled induction study of Mirikizumab in conventional-failed and biologic-failed
patients with moderately to severely active ulcerative colitis. The study consists of a 12-
week induction period where subjects will receive 1 of 2 treatment arms (300-mg
mirikizumab or placebo) every 4 weeks. 
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I6T-MC-AMAN
Phase 3
Statistical Analysis Plan Addendum Version 1 electronically signed and approved by
Lilly on date provided below.
Approval Date: 02-Mar-2021 GMT


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
Page 2
LY3074828
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Maximum Extended Enrollment 
Addendum for I6T-MC-AMAN:   A Phase 3, Multicenter, 
Randomized, Double-Blind, Parallel, Placebo-Controlled Induction 
Study of Mirikizumab in Conventional-Failed and Biologic-Failed 
Patients with Moderately to Severely Active Ulcerative Colitis...........................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................3
4.
Study Design of Protocol Addendum ..................................................................................5
5.
A Priori Statistical Methods ................................................................................................6
5.1.
General Considerations ..................................................................................................6
5.2.
Analysis Methods...........................................................................................................6
6.
Unblinding Plan..................................................................................................................7


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
Page 3
LY3074828
Table of Contents
Figure
Page
Figure AMAN.5.1. Milestones for Global and ME2 Cohort enrollment through 
global and local submissions.......................................................................5


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
Page 4
LY3074828
3.
Revision History
I6T-MC-AMAN (AMAN) ME2 Statistical Analysis Plan (SAP) Addendum Version 1 was 
approved prior to the Week 12 database lock of patients for Study I6T-MC-AMAN (AMAN) 
primary study cohort.


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
Page 5
LY3074828
4.
Study Design of Protocol Addendum
The detailed rationale and description for the study design of the protocol Maximum Extended 
Enrollment (ME2) addendum for Study AMAN is described in the Protocol Addendum 
I6T-MC-AMAN(5).
Once the protocol milestone of last-patient-enters-treatment (LPET) for the Global Cohort is 
reached, enrollment will continue for those countries participating in the ME2 cohort, if needed, 
until sufficient numbers of patients are enrolled to meet the regulatory needs for those countries. 
Enrollment in the Global Cohort from the respective country is required before enrolling patients 
in the ME2 Cohort from the same country.  
Figure AMAN.5.1 shows the milestones for enrollment in Study AMAN (Global Cohort and 
ME2 Cohort) through global and local submissions.
Abbreviations:  DBL = database lock; EU = European Union; FPV = first patient visit; 
LPET = last patient entered treatment; LPV = last patient visit; ME2 = Maximized 
Extended Enrollment; US = United States. 
Figure AMAN.5.1.
Milestones for Global and ME2 Cohort enrollment through global 
and local submissions.
Approximately 184 patients from China (from the primary study cohort and ME2 cohort 
combined) were planned to be enrolled.


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
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5.
A Priori Statistical Methods
5.1.
General Considerations
As described in the Study AMAN ME2 protocol addendum, the global cohort includes all 
patients who are enrolled for the purpose of primary study Week 12 database lock. The ME2 
cohort includes additional Chinese patients enrolled to meet country-specific sample size 
requirements. Patients who are randomized in China on or after the date 28 October 2020 will be 
considered to be in the China ME2 cohort.
The analyses for the Study AMAN protocol will be conducted on the global cohort. The details 
of the analyses are described in the global AMAN SAP. This China ME2 SAP addendum 
describes the efficacy and safety analyses based on the Chinese patients, defined as all 
randomized patients from sites in China for both the primary study cohort and the ME2 cohort.
The analysis of this Chinese population will be based upon statistical considerations provided in 
the global AMAN SAP. The China ME2 SAP addendum will not need to be updated solely to 
change which subset of tables, figures, and listings will be produced for the China population. 
Additional displays/analyses may be performed as deemed necessary.
5.2.
Analysis Methods
All analysis endpoint definitions, data handling, analysis population definitions and statistical 
analysis methods will be the same as in the global AMAN SAP unless otherwise specified. 
Descriptive summary statistics such as means and proportions will be reported. Analysis 
considerations such as those presented in the global cohort SAP will be used. For binary efficacy 
endpoints, the common risk differences (i.e., adjusted for baseline stratification factors) will be 
estimated. All analyses will be for descriptive purpose only. P-values for between-treatment 
comparisons may not be displayed for all analysis, and multiplicity adjustment will not be 
applied.
The analyses of patient disposition, important protocol deviations, patient characteristics, prior 
and concomitant therapy will be as described in the global AMAN SAP. The efficacy analysis 
will be as described in the global AMAN SAP, except that country or region will be excluded
from the analysis model. The safety analysis will be the same as described in the global AMAN
SAP. The subgroup analysis will be as describe in global AMAN SAP except that the racial 
origin, ethnicity, and geographical region will not be included. The sensitivity analysis, if 
conducted, will be the same as in AMAN SAP. No interim analyses are planned for the patients 
enrolled in ME2 cohort.


I6T-MC-AMAN ME2 Statistical Analysis Plan Addendum Version 1
Page 7
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6.
Unblinding Plan
Patients and site personnel will remain blinded until the ME2 final analysis is conducted, at the
addendum completion, prespecified study team members will remain blinded to patient’s
treatment assignment in the ME2 cohort until the ME2 cohort final database lock. Details will be 
provided in a separate unblinding plan for Study AMAN, including the global main cohort and 
ME2 cohort.


Leo Document ID = 6902da51-e4ec-4b54-a0ae-96145c4b2818
Approver: 
Approval Date & Time: 02-Mar-2021 00:52:44 GMT
Signature meaning: Approved
PPD

Prot_001.pdf: 
Protocol Addendum I6T-MC-AMAN (5) 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled Induction 
Study of Mirikizumab in Conventional-Failed and Biologic-Failed Patients with Moderately to 
Severely Active Ulcerative Colitis: Maximized Extended Enrollment Addendum 
 
NCT03518086  
 
Approval Date: 19-Mar-2018 
 
 


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 1
LY3074828
1. Protocol Addendum I6T-MC-AMAN(5)
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, 
Placebo-Controlled Induction Study of Mirikizumab in 
Conventional-Failed and Biologic-Failed Patients with 
Moderately to Severely Active Ulcerative Colitis: 
Maximized Extended Enrollment Addendum
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
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)
This addendum is to be performed in addition to all procedures required by protocol 
I6T-MC-AMAN or any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum(5) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 19-Mar-2018 GMT


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 2
LY3074828
2. Table of Contents
Protocol Addendum I6T-MC-AMAN (5)
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, 
Placebo-Controlled Induction Study of Mirikizumab in 
Conventional-Failed and Biologic-Failed Patients with 
Moderately to Severely Active Ulcerative Colitis: 
Maximized Extended Enrollment Addendum
Section
Page
1.
Protocol Addendum I6T-MC-AMAN(5) A Phase 3, Multicenter, 
Randomized, Double-Blind, Parallel, Placebo-Controlled Induction 
Study of Mirikizumab in Conventional-Failed and Biologic-Failed 
Patients with Moderately to Severely Active Ulcerative Colitis:  
Maximized Extended Enrollment Addendum......................................................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................4
4.
Protocol Additions ..............................................................................................................5
4.1.
Extended Enrollment......................................................................................................5
4.2.
Investigational Plan........................................................................................................5
4.3.
Discontinuation of Study in Extended Enrollment Phase ................................................5
4.4.
Statistical and Analytical Plans.......................................................................................6
4.4.1.
Determination of Sample Size................................................................................6
4.4.2.
Statistical and Analytical Plans...............................................................................6
4.4.2.1.
General Considerations.....................................................................................6
4.4.2.2.
Interim Analyses...............................................................................................6


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 3
LY3074828
List of Figures
Figure
Page
Figure AMAN(5).1.
Milestones for Global and ME2 Cohort enrollment through 
global and local submissions............................................................................5


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 4
LY3074828
3. Rationale for Addendum
Regulatory agencies of some countries require local patient data from a specific number of 
patients for registration in their countries.  This addendum provides a mechanism to meet these 
country-level registration requirements in a single pivotal study.
The purpose of this addendum is to enable patient enrollment to continue in these countries if the 
prespecified number of patients from the respective countries cannot be enrolled in the main 
protocol (Study I6T-MC-AMAN [AMAN]).  Hereafter, patients enrolled in the main protocol 
will be referred to as the Global Cohort, and patients enrolled under the extended enrollment 
addendum will be referred to as the Maximized Extended Enrollment (ME2) Cohort.  The 
number of patients enrolled in the ME2 Cohort will depend on the local guidelines and the 
number of patients from those countries already enrolled in the Global Cohort.


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 5
LY3074828
4. Protocol Additions
4.1.
Extended Enrollment
Once the protocol milestone of last-patient-enters-treatment (LPET) for the Global Cohort is 
reached, enrollment will continue for those countries participating in the ME2 cohort, if needed, 
until sufficient numbers of patients are enrolled to meet the regulatory needs for those countries.
Enrollment in the Global Cohort from the respective country is required before enrolling patients 
in the ME2 Cohort from the same country.
Figure AMAN(5).1 shows the milestones for enrollment in Study AMAN (Global Cohort and 
ME2 Cohort) through global and local submissions.
Abbreviations:  DBL = database lock; EU = European Union; FPV = first patient visit; 
LPET = last patient entered treatment; LPV = last patient visit; ME2 = Maximized 
Extended Enrollment; US = United States. 
Figure AMAN(5).1.
Milestones for Global and ME2 Cohort enrollment through global 
and local submissions.
4.2.
Investigational Plan
The objectives, enrollment criteria, randomization ratio, treatment, and evaluations of 
risk/benefit for patients enrolled in the ME2 Cohort will be identical to those for patients 
enrolled in the Global Cohort from these countries, including both those described in the main 
protocol, as well as in any applicable protocol addenda.
4.3.
Discontinuation of Study in Extended Enrollment Phase
Enrollment in the ME2 Cohort will be discontinued if results from the Global Cohort 
demonstrate futility, lack of efficacy, and/or an unacceptable safety profile.


I6T-MC-AMAN(5) Maximized Extended Enrollment Protocol Addendum
Page 6
LY3074828
4.4.
Statistical and Analytical Plans
4.4.1. Determination of Sample Size
The total number of patients enrolled in each country is based on the minimum number of 
patients needed to support local registration.  The number of patients enrolled in the ME2 Cohort 
is dependent on the number of patients enrolled from each of the respective countries in Global 
Cohort as part of the protocol-defined sample size of 1160 patients. If a country fully meets
patient enrollment needs in the Global Cohort, no patient will be enrolled under this addendum 
for that country.
4.4.2. Statistical and Analytical Plans
4.4.2.1.
General Considerations
The benefit/risk profile to support global registrations will be based on the safety and efficacy 
analyses of Global Cohort.  Patients enrolled in the ME2 Cohort will not be included in the 
primary global analysis, as described in the statistical methods outlined in the main protocol of 
Study AMAN.  
Patients enrolled in the ME2 Cohort will be analyzed separately using the statistical 
methodology described in the main protocol of Study AMAN.  The data from the ME2 Cohort 
will be used in the respective countries to demonstrate similarity between local patients and the 
intent to treat (ITT) population enrolled in the Global Cohort.  Patients in the ME2 Cohort (and 
their investigators) will remain blinded until the ME2 Cohort is locked and unblinded.
As necessary, country-specific efficacy and safety analyses will be summarized for enrolled 
patients from each of the participating countries by pooling each country’s patients from the 
Global Cohort and the ME2 Cohort.  All analyses will be for descriptive purposes only.  Details 
of the analyses are described in the statistical analysis plan.
4.4.2.2.
Interim Analyses
No interim analyses are planned for the ME2 Cohort.


Leo Document ID = a6acf895-ab55-4624-9612-4f848da2b73a
Approver: 
Approval Date & Time: 19-Mar-2018 15:42:35 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Mar-2018 15:42:35 GMT
Signature meaning: Approved
PPD
PPD

Prot_000.pdf: 
Protocol I6T-MC-AMAN(a) 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled Induction 
Study of Mirikizumab in Conventional-Failed and Biologic-Failed Patients with Moderately to 
Severely Active Ulcerative Colitis LUCENT 1 
 
NCT03518086  
 
Approval Date: 12-Sep-2019 
 
 


I6T-MC-AMAN(a) Clinical Protocol
Page 1
LY3074828
Protocol I6T-MC-AMAN(a)
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, 
Placebo-Controlled Induction Study of Mirikizumab in 
Conventional-Failed and Biologic-Failed Patients with 
Moderately to Severely Active Ulcerative Colitis
LUCENT 1
EUDRA CTA: 2017-003229-14
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
mirikizumab, 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
Protocol Electronically Signed and Approved by Lilly: 13-Mar-2018 
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 12-Sep-2019 GMT


I6T-MC-AMAN(a) Clinical Protocol
Page 2
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Table of Contents
Section
Page
Protocol I6T-MC-AMAN(a) A Phase 3, Multicenter, Randomized, 
Double-Blind, Parallel, Placebo-Controlled Induction Study of 
Mirikizumab in Conventional-Failed and Biologic-Failed Patients 
with Moderately to Severely Active Ulcerative Colitis LUCENT 1.....................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................16
3.
Introduction ......................................................................................................................22
3.1.
Study Rationale............................................................................................................22
3.2.
Background..................................................................................................................22
3.2.1.
Disease State and Treatment Goals.......................................................................22
3.2.2.
Currently Available Treatments and Unmet Need.................................................22
3.2.3.
Interleukin-23 as a Therapeutic Target in Ulcerative Colitis .................................23
3.2.4.
Preclinical and Clinical Studies of Mirikizumab...................................................23
3.2.5.
Other Interleukin-23 Targeted Therapies in Humans ............................................25
3.3.
Benefit/Risk Assessment..............................................................................................25
4.
Objectives and Endpoints..................................................................................................27
5.
Study Design.....................................................................................................................31
5.1.
Overall Design .............................................................................................................31
5.2.
Number of Participants.................................................................................................32
5.3.
Definition of Baseline ..................................................................................................32
5.4.
Definition of Enrollment ..............................................................................................32
5.5.
End of Study Definition ...............................................................................................32
5.6.
Scientific Rationale for Study Design...........................................................................33
5.7.
Justification for Dose ...................................................................................................33
6.
Study Population...............................................................................................................35
6.1.
Inclusion Criteria..........................................................................................................35
6.2.
Exclusion Criteria ........................................................................................................40
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................44
6.3.
Lifestyle Restrictions....................................................................................................45
6.4.
Screen Failures.............................................................................................................45
7.
Treatments........................................................................................................................47
7.1.
Treatments Administered .............................................................................................47
7.1.1.
Packaging and Labeling .......................................................................................47


I6T-MC-AMAN(a) Clinical Protocol
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7.2.
Method of Treatment Assignment ................................................................................48
7.2.1.
Selection and Timing of Doses.............................................................................48
7.3.
Blinding .......................................................................................................................48
7.4.
Dosage Modification....................................................................................................49
7.5.
Preparation/Handling/Storage/Accountability...............................................................49
7.6.
Treatment Compliance .................................................................................................49
7.7.
Concomitant Therapy...................................................................................................49
7.8.
Treatment after the End of the Study............................................................................50
7.8.1.
Study Extensions..................................................................................................50
7.8.2.
Treatment after Study Completion........................................................................50
7.8.3.
Special Treatment Considerations ........................................................................50
7.8.3.1.
Premedication for Infusions............................................................................50
7.8.3.2.
Management of Hypersensitivity, Infusion Related 
Events, and Infusion Site Reactions ................................................................51
8.
Discontinuation Criteria ....................................................................................................53
8.1.
Discontinuation from Study Treatment.........................................................................53
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................53
8.1.2.
Temporary Interruption (Withholding) of Study Treatment ..................................55
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................55
8.2.
Discontinuation from the Study....................................................................................56
8.3.
Lost to Follow-Up........................................................................................................56
9.
Study Assessments and Procedures ...................................................................................57
9.1.
Efficacy Assessments...................................................................................................57
9.1.1.
Primary Efficacy Assessment...............................................................................57
9.1.1.1.
Primary Endpoint ...........................................................................................57
9.1.1.2.
Mayo Score ....................................................................................................57
9.1.1.3.
Endoscopy......................................................................................................59
9.1.1.4.
Endoscopic Biopsies.......................................................................................60
9.1.2.
Secondary Efficacy Assessments..........................................................................61
9.1.2.1.
Major Secondary Endpoints............................................................................61
9.1.2.1.1.
Patient Reported Outcome Instruments .....................................................61
9.1.2.2.
Other Secondary Endpoints ............................................................................61
9.1.2.2.1.
Physician Reported Instrument..................................................................61
9.1.2.2.2.
Patient Reported Outcome Instruments .....................................................61
9.1.2.2.3.
Histopathology Scoring Instrument...........................................................62
9.1.2.2.4.
Inflammatory Biomarkers .........................................................................62
9.1.3.
Exploratory Efficacy Assessments .......................................................................62
9.1.3.1.
Exploratory Endpoints....................................................................................62


I6T-MC-AMAN(a) Clinical Protocol
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9.1.3.1.1.
Patient Reported Outcome Instruments .....................................................62
9.1.3.2.
Extraintestinal Manifestations.........................................................................62
9.1.4.
Appropriateness of Assessments ..........................................................................63
9.2.
Adverse Events ............................................................................................................63
9.2.1.
Serious Adverse Events........................................................................................64
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................64
9.2.2.
Adverse Events of Special Interest .......................................................................65
9.2.3.
Complaint Handling.............................................................................................66
9.3.
Treatment of Overdose.................................................................................................66
9.4.
Safety...........................................................................................................................66
9.4.1.
Vital Signs ...........................................................................................................66
9.4.2.
Electrocardiograms ..............................................................................................66
9.4.3.
Laboratory Tests ..................................................................................................66
9.4.3.1.
Pregnancy Testing ..........................................................................................67
9.4.4.
Immunogenicity Assessments ..............................................................................67
9.4.5.
Other Tests...........................................................................................................68
9.4.5.1.
Physical Examination .....................................................................................68
9.4.5.2.
Chest Radiography .........................................................................................68
9.4.5.3.
Tuberculosis Screening...................................................................................69
9.4.5.4.
Hepatitis B Testing.........................................................................................71
9.4.5.5.
Hepatitis C Testing.........................................................................................72
9.4.5.6.
Depression and Suicidality .............................................................................72
9.4.5.7.
Stool Testing ..................................................................................................73
9.4.6.
Safety Monitoring ................................................................................................74
9.4.6.1.
Hepatic Safety Monitoring..............................................................................74
9.5.
Pharmacokinetics .........................................................................................................75
9.6.
Pharmacodynamics ......................................................................................................76
9.8.
Biomarkers...................................................................................................................76
9.9.
Medical Resource Utilization and Health Economics ...................................................77
10.
Statistical Considerations ..................................................................................................78
10.1. Sample Size Determination ..........................................................................................78
10.2. Populations for Analyses..............................................................................................79
10.3. Statistical Analyses ......................................................................................................79
10.3.1.
General Statistical Considerations ........................................................................79
10.3.1.1.
Missing Data Imputation ................................................................................81
10.3.1.2.
Adjustment for Multiple Comparisons ............................................................81
CCI


I6T-MC-AMAN(a) Clinical Protocol
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10.3.2.
Treatment Group Comparability...........................................................................81
10.3.2.1.
Patient Disposition..........................................................................................81
10.3.2.2.
Patient Characteristics ....................................................................................82
10.3.2.3.
Concomitant Therapy .....................................................................................82
10.3.2.4.
Treatment Compliance....................................................................................82
10.3.3.
Efficacy Analyses ................................................................................................82
10.3.3.1.
Primary Analyses ...........................................................................................82
10.3.3.2.
Secondary Analyses........................................................................................83
10.3.4.
Safety Analyses....................................................................................................83
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................83
10.3.6.
Evaluation of Immunogenicity .............................................................................84
10.3.7.
Other Analyses.....................................................................................................84
10.3.7.1.
Subgroup Analyses.........................................................................................84
10.3.8.
Interim Analyses..................................................................................................84
11.
References ........................................................................................................................86
12.
Appendices .......................................................................................................................92


I6T-MC-AMAN(a) Clinical Protocol
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List of Tables
Table
Page
Table AMAN.1. Schedule of Activities....................................................................................17
Table AMAN.2. Objectives and Endpoints...............................................................................27
Table AMAN.3. Treatment Regimens......................................................................................47
Table AMAN.4. Endpoint Definitions......................................................................................57


I6T-MC-AMAN(a) Clinical Protocol
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List of Figures
Figure
Page
Figure AMAN.1. Illustration of study design for Clinical Protocol I6T-MC-AMAN. ................32


I6T-MC-AMAN(a) Clinical Protocol
Page 8
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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................93
Appendix 2.
Clinical Laboratory Tests...............................................................................98
Appendix 3.
Study Governance Considerations................................................................101
Appendix 4.
Risk Factors for Latent Tuberculosis Infection.............................................106
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................108
Appendix 6.
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity......110
Appendix 7.
Patient Reported Outcome Instruments ........................................................112
Appendix 8.
Examples of Infections that May Be Considered Opportunistic in the 
Setting of Biologic Therapy.........................................................................116
Appendix 9.
Prohibited Medications................................................................................118
Appendix 10.
Permitted Medications with Dose Stabilization............................................122
Appendix 11.
Additional Information on Systemic Drug Administration Reactions ...........124
Appendix 12.
Additional Information on the Columbia Suicide Severity Rating Scale, 
and Quick Inventory of Depressive Symptomatology (self report) ...............126
Appendix 13.
Protocol Amendment I6T-MC-AMAN(a) Summary A Phase 3, 
Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled 
Induction Study of Mirikizumab in Conventional-Failed and Biologic-
Failed Patients with Moderately to Severely Active Ulcerative Colitis
LUCENT 1..................................................................................................128










I6T-MC-AMAN(a) Clinical Protocol
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Treatment Groups and Duration:  
Patients will be randomized with a 3:1 ratio to receive blinded intravenous administration of 
300 mg mirikizumab or placebo every 4 weeks at Weeks 0, 4, and 8.  Randomization will be 
stratified by (a) biologic-failed status (yes/no), (b) baseline corticosteroid use (yes/no),
(c) baseline disease activity (modified Mayo score [MMS]:  [4-6] or [7-9]), and (d) region (North 
America/Europe/Other).  Duration of treatment with the investigational product is 12 weeks.  
The total duration of participation in this study may be up to approximately 32 weeks, as detailed 
below.
Screening Period:  up to 28 days.
Treatment Period:  12 weeks.
Post-Treatment Follow-Up Period: 16 weeks after last visit for those who discontinue 
treatment prior to the Week 12 assessment, or those who are unable or are not willing to 
participate in the maintenance study.  
Number of Planned Patients:  
Screened:  approximately 2230
Randomized:  approximately 1160
Completed:  approximately 1044
Statistical Analysis:
The study will randomize approximately 1160 patients with a 3:1 ratio of 300 mg mirikizumab to 
placebo, with an assumption that approximately 1044 patients will complete the study.  Patients 
will be stratified by (a) biologic-failed status (yes/no), (b)baseline corticosteroid use (yes/no), 
(c) baseline disease activity (MMS:  [4-6] or [7-9]), and (d) region (North 
America/Europe/Other).
The power calculations for this study assume the following:  
(1) The randomized study population will include approximately 50% biologic-failed patients 
and approximately 50% conventional-failed patients.  
(2) The predicted clinical remission rates at Week 12 for mirikizumab versus placebo are 
expected to be 23% versus 7.8% (biologic-failed patients: 16% versus 3.5%; conventional-failed 
patients: 30% versus 12%).
The primary endpoint of this study is to test the hypothesis that mirikizumab is superior to 
placebo in inducing clinical remission at Week 12 in patients with moderately to severely active 
UC.  Given the assumptions described above, a sample size of 1160 patients are expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this 
endpoint, based on a chi-square test with a 2-sided significance level of 0.00125.
Patients who complete Study AMAN may be eligible to participate in Study AMBG, a 40-week 
maintenance study. The primary objective of Study AMBG is to test the hypothesis that 


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mirikizumab is superior to placebo in achieving clinical remission at Week 40 of Study AMBG 
(Week 52 of continuous therapy) amongst patients induced into clinical response with 
mirikizumab at Week 12 of Study AMAN.  A sample size of 1160 patients in Study AMAN is 
predicted to ensure that there will be a sufficient number of biologic-failed patients in clinical 
remission at Week 12 of Study AMAN who will enter Study AMBG. This is expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving the 
primary endpoint in Study AMBG, based on a chi-square test with a 2-sided significance level of 
0.05.  
Summary statistics for continuous variables may include mean, standard deviation (SD), median, 
and minimum and maximum values. Categorical variables will be presented as counts and 
percentages.  Unless otherwise specified, variables will be analyzed in the original scale on 
which they are measured. All hypothesis tests will be 2-sided, and the family-wise type I error 
rate (FWER) will be controlled at an α level of 0.00125 for primary and major secondary 
endpoints using a pre-specified graphical procedure.  Weights and alpha propagations will be 
finalized and included in the Statistical Analysis Plan (SAP) prior to first unblinding of efficacy 
data.
For assessments of the primary endpoint and other categorical efficacy endpoints, the Cochran–
Mantel–Haenszel (CMH) chi-square test will be used to compare the 2 treatment groups with the 
following stratification factors: (a) previous biologic therapy failure status (yes/no), (b) baseline 
corticosteroid use (yes/no), (c) baseline disease activity (MMS:  [4-6] or [7-9]), and (d) region 
(North America/Europe/Other).  
The 2-sided CMH chi-square p-value and the relative risk along with its 99.875% 2-sided 
confidence interval (CI) will be provided for the primary and major secondary endpoints.  
Patients who have missing data for the endpoint will be assumed to have not responded (referred 
to as nonresponder imputation).
Unless otherwise specified, analysis of hypotheses will be tested under multiplicity control at a 
family wise significance level of 0.00125. A 2-sided 99.875% CI will be provided along with 
the p-value.  For other analyses, statistical tests without multiplicity control will be conducted 
using a 2-sided  significance level of 0.05.  The corresponding p-value along with its 95% 2-
sided CI will be provided.  These analyses will also include subgroup analyses for the primary 
and the major secondary endpoints, except for the subgroup which is included in the scope of 
multiplicity control.
Treatment comparisons of continuous efficacy and health outcome variables with multiple 
postbaseline time points will be made using the mixed-effects model for repeated measures 
(MMRM).  The MMRM will include the following effects and covariates: (a) treatment group, 
(b) previous biologic therapy failure status (yes/no), (c) corticosteroid use (yes/no), (d) disease 
activity (MMS:  [4-6] or [7-9] at baseline), (e) region (North America/Europe/Other), (f) baseline 
value in the model, (g) visit, and (h) the interactions of treatment-by-visit and baseline-by-visit as 
fixed factors. Treatment comparisons of continuous efficacy and health outcome variables with 
a single postbaseline time point will be made using analysis of covariance (ANCOVA) with the 
following in the model:  (a) treatment group, (b) previous biologic therapy failure status (yes/no), 


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(c) corticosteroid use (yes/no), (d) disease activity (MMS:  [4-6] or [7-9]) at baseline), (e) region 
(North America/Europe/Other), and (f) baseline value.  
Multiplicity controlled analyses will be performed to test the primary and major secondary 
hypotheses in order to control the overall FWER at 0.00125.  A prespecified graphical multiple 
testing approach will be used.  The graphical approach is a closed testing procedure.  Hence, it 
strongly controls the FWER across all endpoints.  Details of the specific graphical testing 
scheme (including testing order, interrelationships, type I error allocation for the major 
secondary endpoints, and the associated propagation of alpha) will be prespecified in the SAP 
prior to first unblinding of efficacy data.
The Fisher exact test will be used to perform the between-treatment group comparisons for 
adverse events (AEs), discontinuations, and other categorical safety data.  The change from 
baseline in continuous vital signs, physical characteristics, and other continuous safety variables, 
including laboratory variables, will be summarized visit and by treatment.  The change from 
baseline to last observation value will be analyzed with ANOVA model with baseline as a 
covariate.  The last non-missing observation in the treatment period will be used as the last 
observation.
Shift tables for categorical safety analyses (for example, high or low laboratory test results) will 
also be produced.  


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2. Schedule of Activities










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Abbreviations:  ADA = anti-drug antibody; AE = adverse event; anti-HBc+ = positive for anti hepatitis B core antibody; BP = blood pressure; C-SSRS = 
Columbia-Suicide Severity Rating Scale; CXR = chest x-ray; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EIM = extraintestinal manifestation; 
EQ-5D-5L = European Quality of Life 5–Dimension 5 Level; ETV = early termination visit; FSH = follicle-stimulating hormone; HBsAg- = negative for 
hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive 
protein; IBDQ = Inflammatory Bowel Disease Questionnaire; IP = investigational product; LV = last visit; PGA = Physician’s Global Assessment; PGRC = 
Patient’s Global Rating of Change; PK = pharmacokinetic; PR = pulse  rate; QIDS-SR16 = Quick Inventory of Depressive Symptomatology-Self Report (16 
items); RB = rectal bleeding; SF = stool frequency; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; T = temperature; UV = 
unscheduled visit; V = visit; WPAI:UC = Work Productivity and Activity Impairment Questionnaire Ulcerative Colitis.
a
Visit 2 (Week 2) is a telephone visit.  These assessments will be made by a telephone call to the patient.
b ETV may occur on any day without regard to visit interval.
c
Additional study procedures can be performed at an unscheduled visit at the discretion of the investigator.
d This test will be performed on a sub-set of study patients, as described in the Notes column of the applicable row.
e
These tests will be run from the “chemistry” sample.
f
Clostridium difficile tests at V5 and ETV may be performed for patients who do not move into Study AMBG.
g Clostridium difficile test at UV may be performed if visit is due to worsening SF and/or RB.


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3. Introduction
3.1.
Study Rationale
Mirikizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody 
that binds to the p19 subunit of interleukin-23 (IL-23), a cytokine that has been implicated in 
mucosal inflammation.  Study I6T-MC-AMAN (AMAN) is a Phase 3 clinical trial that is 
designed to evaluate the safety and efficacy of mirikizumab in inducing remission at Week 12 in 
patients with moderately to severely active ulcerative colitis (UC).  The study population 
includes patients with moderately to severely active UC who have an inadequate response to, 
loss of response to, or are intolerant to conventional therapy for UC (defined as corticosteroids, 
azathioprine [AZA] or 6-mercaptopurine [6-MP] for this study; “conventional-failed”), and those 
who have an inadequate response to, loss of response to, or are intolerant to biologic therapy for 
UC (“biologic-failed”).  
3.2.
Background
3.2.1.
Disease State and Treatment Goals
Ulcerative colitis is a chronic disease of unknown etiology that is characterized by inflammation 
of the rectum and colon.  Symptoms include diarrhea, rectal bleeding (RB), 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).  In both clinical 
practice and in clinical trials, clinical response and clinical remission are assessed by a 
combination of endoscopy (improvement in the endoscopic appearance of the mucosa and 
healing of ulcers) and patient-reported outcomes, including a reduction in stool frequency (SF) 
and a resolution of RB (Levesque et al. 2015).  Control of intestinal 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.
3.2.2.
Currently Available Treatments and Unmet Need
Medications used for the treatment of UC include 5-aminosalicylic acid (5-ASA)–containing 
medications (sulfasalazine, mesalazine, balsalazide, olsalazine), corticosteroids,
immunomodulators such as AZA and 6-MP, and biologic medications.  A significant proportion
of patients with moderately to severely active UC may have an inadequate response to medicines 
such as 5-ASAs or corticosteroids, be unable to maintain a clinical response to 5-ASAs or AZA, 
or be unable to discontinue corticosteroids without a relapse in disease activity (reviewed in 
Dignass et al. 2012). Many of these patients require additional treatment with the next line of 
therapy, which could include medical treatment with a biologic medication or surgical treatment 
with a colectomy.  Biologics, including antitumor necrosis factor (TNF) antibodies (infliximab, 
adalimumab, golimumab) and vedolizumab, an anti-α4β7 integrin antibody, are indicated for the 
treatment of UC in patients who fail to respond to, have an inadequate response to, or are 


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intolerant to other medications used in the treatment of UC medications, and as a first-line 
treatment for UC in selected patients.  However, in the pivotal ACT1 and ACT2 studies of 
infliximab therapy in patients with moderately to severely active UC and in the pivotal 
PURSUIT studies of golimumab in the same patient population, only approximately 50% to 65% 
of the patients achieved clinical response (as defined by complete Mayo score) at the induction 
time point (Weeks 6 to 8), with approximately 50% of the patients maintaining clinical response 
to Week 54 (Rutgeerts et al. 2005; Sandborn et al. 2014a, 2014b).  In the pivotal ULTRA studies 
of adalimumab in the same patient population, 16.5% of patients achieved clinical remission at 
Week 8 (Sandborn et al. 2012a). Similarly, in the pivotal GEMINI 1 study of vedolizumab in
patients with moderately to severely active disease, 47% achieved a clinical response at Week 6 
and up to 45% of these patients were in clinical remission at Week 52 (Feagan et al. 2013).  
These data illustrate the unmet need for new medications in UC.  
3.2.3.
Interleukin-23 as a Therapeutic Target in Ulcerative Colitis
IL-23 is a member of the IL-12 family of cytokines.  It is a heterodimeric protein composed of 
2 subunits: the IL-12p40 subunit, which is shared by IL-12, and the IL-23p19 subunit, which is 
specific to IL-23.  
IL-23 is a pro-inflammatory cytokine.  It is expressed by activated innate immune cells, 
including dendritic cells and tissue-resident macrophages.  IL-23 stabilizes the differentiation 
and maturation of pro-inflammatory IL-23 receptor-expressing (IL-23R+) IL-17+ CD4+ T cells 
(Th17 cells) through multiple mechanisms, including the maintenance of Rorc and Il17 gene 
expression, the induction of pro-inflammatory cytokine expression (Il22, Csf2, and Ifng)and 
positive feedback by inducing expression of its own receptor, IL-23R.  IL-23 also activates other 
IL-23R+ immune cells, including γδ T cells, natural killer cells, and group 3 innate lymphoid 
cells (Gaffen et al. 2014; Teng et al. 2015).
Genetic deletion or pharmacologic inhibition of IL-23p19 in mice ameliorates or prevents 
inflammation in mouse models of rheumatoid arthritis (collagen-induced arthritis), multiple 
sclerosis (experimental autoimmune encephalomyelitis), and intestinal inflammation (Kikly et al. 
2006).  
IL-23 expression is enriched in the intestine of patients with active UC and active Crohn’s 
disease.  In addition, recent genome-wide association scans identified common variants (single 
nucleotide polymorphisms) in molecules in the IL-23 signaling pathway that modify the risk of 
UC and/or Crohn’s disease in humans, including IL-23R, STAT3, and Janus kinase 2 (Jostins 
et al. 2012).  Taken together, these data provide evidence for IL-23 as a therapeutic target in UC.  
3.2.4.
Preclinical and Clinical Studies of Mirikizumab
Mirikizumab binds the IL-23p19 subunit of human IL-23 and prevents binding of IL-23 to the 
IL-23R, neutralizing the activity of human IL-23 in vitro.  Mirikizumab also neutralizes human 
IL-23 in vivo, ameliorating the development of psoriasis-like skin inflammation in mice 
following subcutaneous (SC) injection of human IL-23.  Mirikizumab does not prevent IL-12 
signaling in vitro.


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LSN2479016 is the mouse anti-mouse surrogate antibody for mirikizumab.  This was developed 
to enable preclinical testing in mice, as mirikizumab does not cross-react with mouse IL-23.  
LSN2479016 inhibits the development of skin inflammation in the imiquimod-induced psoriasis-
like mouse model, inhibits the development of colonic inflammation in the CD45RBhi adoptive 
transfer mouse model of colitis, and reduces the development of curdlan-induced 
spondyloarthritis and Crohn’s disease-like intestinal inflammation in SKG mice.  Additional 
preclinical data are summarized in the Investigator’s Brochure (IB).
A number of clinical trials of mirikizumab have been completed or are currently ongoing in 
patients with psoriasis, UC and Crohn’s disease.  
Study 16T-MC AMAA (AMAA) is a Phase 1, single-dose administration (up to 600 mg), 
dose-escalation study that included 40 subjects with psoriasis and 5 healthy controls.  Efficacy 
data from this study show improvement of psoriasis at Week 12, assessed by the Psoriasis Area 
and Severity Index (PASI), after a single dose of mirikizumab in the higher-dose cohorts.  
Study 16T-MC-AMAF (AMAF) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with psoriasis, for which preliminary primary analysis results are 
available.  Patients with moderate-to-severe plaque psoriasis received placebo (n=52) or 
mirikizumab 30 mg (n=51), 100 mg (n=51) or 300 mg (n=51) (SC) at Weeks 0 and 8.  The 
primary objective was to evaluate the superiority of mirikizumab over placebo in achieving 
≥90% improvement in PASI (“PASI 90”) response at Week 16.  The primary efficacy end point 
at Week 16 was met for each dose group with PASI 90 responses of 0%, 29.4% (p<.01), 58.8% 
(p<.001) and 66.7% (p<.001), respectively, for patients treated with placebo and mirikizumab 30 
mg, 100 mg and 300 mg (Reich et al. 2017a).
Study 16T-MC-AMAC (AMAC) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with moderate-to-severe UC, for which preliminary primary analysis 
results are available.  Patients with moderately to severely active UC received placebo (n=63) or 
mirikizumab 50 mg (n=63), 200 mg (n=62) or 600 mg (n=61) IV at Weeks 0, 4 and 8.  
Exposure-based dose adjustments was applied in two treatment groups.  Based on plasma
concentrations of mirikizumab, dose levels in subjects in the 50 mg and 200 mg groups could be 
increased at the Week 4 and Week 8 visits if the projected trough concentrations for those visits 
fell below prespecified thresholds: 73% of patients in the 50 mg mirikizumab group and 44% of 
patients in 200 mg mirikizumab group experienced exposure-based dose adjustments before 
Week 12, resulting in group mean doses of 100 mg and 250 mg, respectively in these groups.  
The 600-mg dose group remained on a fixed dose throughout the induction period. 
The primary efficacy endpoint of Study AMAC was clinical remission at Week 12.  Clinical 
remission rates at Week 12 were 4.8%, 15.9% (p=.07), 22.6% (p<.01) and 11.5% (p=.14) for 
patients treated with placebo and mirikizumab 50 mg, 200 mg and 600 mg, respectively.  
Clinical response rates at Week 12 were 20.6%, 41.3%, 59.7% and 49.2% for patients treated 
with placebo and mirikizumab 50 mg, 200 mg and 600 mg, respectively.  Endoscopic healing 
rates (ES=0 or 1, excluding friability; termed “endoscopic remission” in this protocol) were 
numerically higher in the 50-mg mirikizumab group (23.8%) and 200-mg mirikizumab group 


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(30.6%) compared to placebo (6.3%).  Symptomatic remission rates were numerically higher in 
the 200-mg mirikizumab group (58.1%) and 600-mg mirikizumab group (45.9%) compared to 
placebo (20.6%).
Study 16T-MC-AMAG (AMAG) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with active Crohn’s disease.  At the time of writing, this study is 
ongoing.
Additional clinical trial data are summarized in the IB.
3.2.5.
Other Interleukin-23 Targeted Therapies in Humans
IL-23-targeted therapy is the mechanism of action for several compounds under development for 
the treatment of inflammatory diseases, including the human IL-12 and IL-23 antagonist 
ustekinumab, which is a monoclonal antibody against IL-12p40, and the human IL-23 
antagonists guselkumab, risankizumab, tildrakizumab, and brazikumab, which are monoclonal 
antibodies against IL-23p19.  
Ustekinumab binds IL-12p40, the subunit common to both IL-12 and IL-23, targeting both 
cytokines, rather than IL-23 specifically.  Ustekinumab was the first biologic therapy with an 
anti-IL-23 action to show clinical benefit in psoriasis (Leonardi et al. 2008; Papp et al. 2008), 
psoriatic arthritis (Gottlieb et al. 2009) and Crohn’s disease (Sandborn et al. 2012b; Feagan et al.
2016).  Blockade of the IL-12 pathway may prevent type 1 T helper cell (Th1)-induced inhibition 
of Th17 cell development, thus potentially limiting the clinical activity of IL-12p40-targeting 
antibodies.  Experimental studies suggest that blocking the IL-23/Th17/IL-17 immune axis, 
without blocking the IL-12/Th1/IFN-γ axis, is sufficient to treat autoimmune inflammation 
(Monteleone et al. 2009).  
To date, guselkumab, an IL-23p19 antibody, has been approved for the treatment of psoriasis and 
other agents specifically targeting the IL-23p19 subunit, including mirikizumab, have 
demonstrated clinical activity in psoriasis (Sofen et al. 2014; Kopp et al. 2015; Krueger et al. 
2015; Papp et al. 2015; Blauvelt et al. 2017; Papp et al. 2017; Reich et al. 2017b).  IL-23p19 
inhibition is also under investigation for the treatment of inflammatory bowel disease and several 
anti-IL-23p19 antibodies have shown efficacy in the treatment of Crohn’s disease (Deepak and 
Sandborn 2017; Feagan et al. 2017; Sands et al. 2017).
3.3.
Benefit/Risk Assessment
Ulcerative colitis remains an important public health challenge.  The data for currently available 
treatments demonstrate the unmet need for new medications for UC (Section 3.2.2), and 
published literature supports the concept of IL-23 as a therapeutic target for UC therapies 
(Section 3.2.3).  Based on data from the Phase 2 study of mirikizumab in patients with UC 
(Study AMAC, Section 3.2.4), potential benefits to patients who may receive mirikizumab while 
participating in Study AMAN may be reasonably anticipated.
At the time of this benefit/risk assessment, evaluation of unblinded safety data from the 
completed or ongoing clinical studies, including the unblinded period of the Study AMAC, 


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which tests mirikizumab doses up to 600 mg IV every 4 weeks (Q4W), have not revealed any 
dose-related safety or tolerability concerns.  In addition, evaluation of blinded safety data in 
ongoing studies in psoriasis, UC and Crohn’s disease (CD) with doses up to 200/300 mg SC 
Q4W administered up to 92 weeks, and up to 1000 mg IV Q4W for up to 52 weeks have not 
revealed safety or tolerability concerns.  Across ongoing studies, immediate hypersensitivity 
reactions, including serious nonfatal anaphylaxis, have been reported at the onset or during IV 
infusion of mirikizumab.  As noted in the IB, such reactions are considered by the sponsor to be 
related to mirikizumab and hence have been identified as adverse drug reactions (ADRs) .  
Consult the most current IB for information regarding ADRs and potential risks with 
mirikizumab.  
Adverse events of special interest (AESIs)—which are not necessarily ADRs but are of special 
interest based on standard drug registration topics, safety findings from previous studies in 
development program, potential risks associated with biologic immunomodulators as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations—are noted in Section 9.2.2 of this protocol.  For all AESIs, including 
hypersensitivity events, the protocol and IB provide monitoring or management guidance to the 
investigator.  In addition, an independent, external data monitoring committee (DMC) will 
review clinical trial data at prespecified, regular intervals during the study (Section 10.3.8).  This 
independent assessment of clinical trial data will contribute to the overall ongoing evaluation and 
management of potential risks associated with mirikizumab administration.
The dose levels and regimens to be used in Study AMAN were chosen based on nonclinical 
safety data and based on analyses of safety, efficacy, and pharmacokinetic (PK) data from the 
primary analysis of Study AMAC (Section 5.7).
In summary, the efficacy and safety data from the Phase 2 UC study support the continued 
clinical development of mirikizumab as a treatment for patients with UC.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of mirikizumab are to be found in the IB.








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Objectives
Endpoints

To evaluate the efficacy of mirikizumab 
compared to placebo in mucosal healing at 
Week 12

The proportion of patients with mucosal healing at 
Week 12, defined as achieving both:  
o Histologic remission, as described in the SAP, 
and
o Endoscopic remission, defined as ES = 0 or 1 
(excluding friability)

To evaluate the efficacy of mirikizumab 
compared to placebo on changes in fatigue at 
Week 12

Change from baseline in Fatigue NRS scores at 
Week 12 
a
All primary and major secondary endpoints will be evaluated for mirikizumab versus placebo.  All primary and 
major secondary endpoint analyses will utilize the multiplicity control approach based on ‘graphical multiple 
testing procedure’ to control the overall family-wise type I error rate at a 2-sided alpha level of 0.00125.  The 
graphical multiple testing procedure described in Bretz et al. (2009) will be used.
b
The order of testing of the major secondary endpoints will be determined from the results of the statistical 
simulations.  Therefore  the order of the secondary endpoints does not reflect the order of the statistical testing.


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5. Study Design
5.1.
Overall Design
Study AMAN is a multicenter, randomized, double-blind, parallel-arm, placebo-controlled study 
designed to evaluate the safety and efficacy of mirikizumab, compared with placebo, over a 
12-week induction period.  The study population includes patients with moderately to severely 
active UC who have an inadequate response to, loss of response to, or are intolerant to 
corticosteroid or immunomodulator therapy for UC (termed “conventional-failed” in this 
protocol), and those who have an inadequate response to, loss of response to, or are intolerant to 
biologic therapy for UC (termed “biologic-failed” in this protocol).  Complete definitions of the 
“conventional-failed” and “biologic-failed” terms are given in Section 6.1, Inclusion Criterion 
[8]. Patients will be randomized with a 3:1 ratio allocation across the 2 treatment groups: 
300 mg mirikizumab and placebo IV Q4W.  
Patients who complete Study AMAN through Week 12 will either complete post-treatment 
follow-up within Study AMAN or be eligible to participate in the maintenance Study AMBG.  
Patients who discontinue treatment prior to the Week 12 assessment, or those who are unable or 
are not willing to participate in the maintenance Study AMBG will complete post-treatment 
follow-up 16 weeks after their last visit.  Figure AMAN.1 illustrates the study design.
Study governance considerations are described in detail in Appendix 3.


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Abbreviations:  IV = intravenous; R = randomization.
Figure AMAN.1.
Illustration of study design for Clinical Protocol I6T-MC-AMAN.
5.2.
Number of Participants
Approximately 2230 patients will be screened to achieve approximately 1160 randomized 
patients. 
5.3.
Definition of Baseline
Visit 1 (Week 0) is the baseline randomization visit.  The baseline modified Mayo score is 
calculated from valid daily diary entries obtained prior to endoscopy during the screening period 
and the endoscopic appearance of the mucosa at this screening endoscopy (Section 9.1.1.2).  For 
other efficacy, health outcome and safety assessments, baseline is defined as the last non-missing 
assessment recorded on or prior to the date of Visit 1 (Week 0).
5.4.
Definition of Enrollment
A patient is considered enrolled in the study once the patient is randomized and assigned to 
treatment.
5.5.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.


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5.6.
Scientific Rationale for Study Design
The Phase 3 clinical trial program of mirikizumab in patients with moderate-to-severe UC 
consists of the following studies:

Study AMAN:  This 12-week induction study, including both 
conventional-failed and biologic-failed patients.

Study I6T-MC-AMBG (AMBG):  A maintenance study with a 40-week 
treatment duration.  

Study I6T-MC-AMAP (AMAP):  A long-term extension study.
Study AMAN is designed to evaluate the safety and efficacy of mirikizumab in inducing clinical 
remission at Week 12 of treatment.  Nonbiologic background therapy (for example, 5-ASA, 
corticosteroids, AZA or 6-MP) is allowed in Study AMAN, subject to concomitant medication 
and dose stabilization criteria.  The use of a placebo comparator is justified in this study, as 
mirikizumab can be added to pre-existing background therapy (EMA/CHMP [WWW]; FDA 
2001 [WWW]).  
The timing of the primary endpoint was based on characterization of the safety and efficacy of 
mirikizumab at Week 12 of continuous treatment in Study AMAC, the Phase 2, placebo-
controlled, double-blind clinical trial of mirikizumab in moderately to severely active UC. 
As detailed in Section 10, the study is powered to the primary endpoint of demonstrating a 
statistically significant difference in clinical remission between mirikizumab therapy and placebo 
at Week 12.  The 3:1 randomization scheme to 300 mg mirikizumab or placebo arms IV Q4W is 
designed to maximize the chance that a patient will receive mirikizumab in this study (3:1 
chance).  
Patients who complete Study AMAN through Week 12 will either complete post-treatment 
follow-up within Study AMAN or be eligible to participate in the maintenance Study AMBG.  
There is no rescue arm in Study AMAN.  However, patients who complete Study AMAN 
through Week 12 (with an acceptable safety profile) who did not achieve a clinical response to 
mirikizumab at Week 12 may be eligible to receive an induction dose of mirikizumab in 
Study AMBG.  Patients who complete Study AMBG through Week 40 (with an acceptable 
safety profile) may be eligible to participate in the long-term extension Study AMAP.  
5.7.
Justification for Dose
The dose levels and regimens selected for this study were based primarily on analyses of interim 
PK, safety, and efficacy data from the Phase 2 Study AMAC, safety data from other clinical 
studies evaluating mirikizumab, and nonclinical safety data.
Safety Considerations
The safety data collected in completed and ongoing clinical studies and in nonclinical toxicology 
studies support the proposed dose regimen.  In particular, there were no dose-related safety or 


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tolerability issues observed in Study AMAC in ulcerative colitis subjects for a period of up to 92 
weeks with doses up to200 mg SC Q4W .  
Single intravenous (IV) doses of up to 600 mg were evaluated in Study AMAA (healthy subjects 
and psoriasis patients) and up to 1200 mg in Study I6T-JE-AMAD (AMAD) (healthy subjects).  
No dose-related safety or tolerability issues were observed in either study.  Study AMAG is 
evaluating dose regimens of up to 1000 mg IV Q4W for up to 52 weeks in patients with CD, and 
up to 92 weeks with 300 mg SC Q4W.  Evaluation of the unblinded safety data available to date 
in the ongoing Phase 2 study in patients with psoriasis (Study AMAF) and of the blinded safety 
data available to date in the ongoing Phase 2 study in patients with CD (Study AMAG) has not 
revealed a safety concern that differs from the safety findings noted above for Study AMAC.
The nonclinical safety profile of mirikizumab supports the proposed clinical study on the basis of 
the no-observed-adverse-effect levels (NOAELs) established in studies in monkeys.  The margin 
of safety for the 300 mg Q4W (IV) dose regimen proposed relative to the NOAEL level in the 
6-month nonclinical toxicology study in cynomolgus monkeys is 6.5, based on area under the 
plasma concentration versus time curve.
Considerations of Efficacy and Exposure–Response Relationship
Significant efficacy relative to placebo was observed at Week 12 in the 50 mg and 200 mg IV 
Q4W cohorts in the Phase 2 study AMAC.  Due to the application of exposure-based dose 
adjustments in Study AMAC, the overall average induction dose received by subjects in the 50 
and 200 mg cohorts were 100 and 250 mg, respectively.  Although exposure increased in 
proportion to dose, patients in the 600 mg mirikizumab cohort did not respond better to treatment 
at Week 12 than patients in the 200 mg mirikizumab cohort.  
Examination of the relationship between observed individual subject mirikizumab exposures and 
Week 12 clinical response and remission and model based analyses of these relationships 
suggests that the probability of a subject achieving these clinical endpoints was not strongly 
dependent on exposure within the range of exposures that were evaluated in Study AMAC.  
However, model based analyses of the relationship between mirikizumab exposure and reduction 
in the modified Mayo Score at Week 12 indicated that doses below 300 mg may lead to 
decreased efficacy, while doses above 300 mg are not likely to provide meaningful 
improvements in efficacy.  Furthermore, a dose of 300 mg is expected to produce a median 
average concentration that covers approximately 90% of individual subject exposures observed 
in the 200 mg cohort in Study AMAC.  
Therefore, the observed results in Study AMAC and the analyses of exposure-response 
relationships supports the selection of 300 mg IV Q4W for this study.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.  
6.1.
Inclusion Criteria
Patients with UC are eligible for enrollment only if they meet all of the following criteria during 
screening:
Informed Consent
[1.]
have given written informed consent approved by the ethical review board 
(ERB) governing the site.
Patient Characteristics
[2.]
are male or female patients ≥18 and ≤80 years of age at the time of initial 
screening.
[2a.]
male patients:
no male contraception required except in compliance with specific local 
government study requirements,
[2b.]
female patients:
women of childbearing potential:
A. must test negative for pregnancy prior to initiation of treatment as indicated by a 
negative serum pregnancy test at the screening visit followed by a negative urine 
pregnancy test within 24 hours prior to exposure.
AND
B. must agree to either remain abstinent, if complete abstinence is their preferred and 
usual lifestyle, or remain in same-sex relationships, if part of their preferred and 
usual lifestyle, without sexual relationships with males.  Periodic abstinence (for 
example, calendar, ovulation, symptothermal, or post ovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.
OR
must use 2 effective methods of contraception for the entirety of the study.  
Abstinence or contraception must continue following completion of study 
drug administration for 20 weeks


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i.
two 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 a reliable or acceptable method.  Thus, each barrier 
method must include use of a spermicide.  It should be noted that the use 
of male and female condoms as a double barrier method is not considered 
acceptable because of the high failure rate when these methods are 
combined.
ii. of note, 1 of the 2 methods of contraception may be a highly effective 
(less than 1% failure rate) method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine devices).
women not of childbearing potential may participate and include those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal 
ligation), congenital anomaly such as mullerian agenesis; or
B. postmenopausal – defined as either:  
i.
a woman at least 50 years of age with an intact uterus, not on hormone 
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 (FSH) level >40 mIU/mL; or
ii. a woman 55 years or older not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea; or
iii. a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
[3.]
venous access sufficient to allow blood sampling and IV administration as per 
the protocol.
Disease-Specific Inclusion Criteria
[4.]
have had an established diagnosis of UC of ≥3 months in duration before 
baseline (Week 0), which includes endoscopic evidence of UC and a 
histopathology report that supports a diagnosis of UC (see Section 9.1.1.3).  
Supportive endoscopy and histopathology reports must be available in the source 
documents.  Patients with rectal sparing on baseline endoscopy must have 
documentation of rectal involvement on a prior endoscopy and histopathology 
report to confirm UC diagnosis.


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[5.]
have moderately to severely active UC as defined by a modified Mayo score 
(MMS) of 4 to 9 with an endoscopic subscore (ES) ≥2, with endoscopy 
performed within 14 days before baseline.
[6.]
have evidence of UC extending beyond the rectum (more proximal to the 
rectosigmoid junction).  The rectosigmoid junction lies approximately 10 to 
15 cm from the anal margin.
[7.]
have documentation of:
[7a.] a surveillance colonoscopy (performed according to local standard) within 
12 months before baseline for:

patients with pancolitis of >8 years’ duration, or

patients with left-sided colitis of >12 years’ duration, or

patients with primary sclerosing cholangitis.
OR
[7b.] in patients for whom Inclusion Criterion [7a] does not apply, up-to-date 
colorectal cancer surveillance (performed according to local standard).  
At the discretion of the investigator, a colonoscopy (instead of a flexible 
sigmoidoscopy) can be performed as the screening endoscopy for this study.  
Patients who do not have a colonoscopy report available in source 
documentation will have a colonoscopy at screening.
Prior Medication Failure Criteria
[8.]
patients must have an inadequate response to, loss of response to, or intolerance 
to at least 1 of the medications described in Inclusion Criteria [8a] OR [8b].  
Documentation of dose, frequency, route of administration and duration of 
the prior failed treatment is required.  
[8a.] Conventional-failed patients:  Patients who have an inadequate response 
to, loss of response to, or are intolerant to at least one of the following 
medications: 

corticosteroids
o
corticosteroid-refractory colitis, defined as signs and/or symptoms of 
active UC despite oral prednisone (or equivalent oral corticosteroid 
excluding budesonide MMX and beclomethasone dipropionate gastro-
resistant prolonged-release tablet) at doses of at least 30 mg/day for a 
minimum of 2 weeks; or
o
corticosteroid-dependent colitis, defined as:
a.
an inability to reduce corticosteroids below the equivalent of 
prednisone 10 mg/day within 3 months of starting corticosteroids 
without a return of signs and/or symptoms of active UC; or


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b. a relapse within 3 months of completing a course of 
corticosteroids; or
o
history of intolerance of corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, or 
neuropsychiatric side-effects, including insomnia, associated with 
corticosteroid treatment).

immunomodulators:
o
signs and/or symptoms of persistently active disease despite at least 3 
months’ treatment with one of the following:

oral AZA (≥1.5 mg/kg/day) or 6-MP (≥0.75 mg/kg/day), or 

oral AZA or 6-MP within a therapeutic range as judged by 
thioguanine metabolite testing, or

a combination of a thiopurine and allopurinol within a therapeutic 
range as judged by thioguanine metabolite testing
o
history of intolerance to at least 1 immunomodulator (including but not 
limited to nausea/vomiting, abdominal pain, pancreatitis, liver function 
test abnormalities, and lymphopenia)
AND

have neither failed nor demonstrated an intolerance to a biologic medication 
(anti-TNF antibody or anti-integrin antibody) that is indicated for the treatment 
of UC
[8b.] Biologic-failed patients:  Patients who have an inadequate response to, loss 
of response to, or are intolerant to biologic therapy for UC (such as anti-
TNF antibodies or anti-integrin antibodies) or to janus kinase (JAK) 
inhibitors (such as tofacitinib).  The medication used to qualify the patient 
for entry into this category must be approved for the treatment of UC. 
Investigators must be able to document an adequate clinical trial of the 
medication.  Patients should fulfill 1 of the following criteria:  

Inadequate response:  Signs and symptoms of persistently active disease 
despite induction treatment at the approved induction dosing that was indicated 
in the product label, or

Loss of response: Recurrence of signs and symptoms of active disease during 
approved maintenance dosing following prior clinical benefit (discontinuation 
despite clinical benefit does not qualify as having failed or being intolerant to 
UC biologic therapy), or

Intolerance:  History of intolerance to infliximab, adalimumab, golimumab,
vedolizumab, tofacitinib or other approved biologics or JAK inhibitors
(including but not limited to infusion-related event, demyelination, congestive 
heart failure, or any other drug-related AE that led to a reduction in dose or 
discontinuation of the medication).


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Patients previously exposed to biologic therapy who do not meet Inclusion Criterion 
[8b] must still meet Inclusion Criterion [8a] in order to be eligible to participate in the 
study.  
Patients previously exposed to investigational therapies for the treatment of UC must 
still meet Inclusion Criteria [8a] OR [8b].
Patients who meet both Inclusion Criteria [8a] and [8b] will be considered to be 
“biologic-failed”, for the purpose of this study.
UC Medication Dose Stabilization Criteria
[9.]
stable doses of the following drugs are permitted (see Appendix 10):
[9a.] oral 5-ASA therapy:  if the prescribed dose has been stable for at least 2 
weeks prior to the screening endoscopy.
[9b.] oral corticosteroid therapy (prednisone ≤20 mg/day or equivalent, or 
budesonide extended release tablets 9 mg/day [budesonide MMX]); if the 
prescribed dose has been stable for at least 2 weeks before the screening 
endoscopy
[9c.] AZA, 6-MP, and methotrexate:  if these immunomodulators have been 
prescribed at a stable dose for at least 8 weeks before the screening 
endoscopy.  
Study Procedure Inclusion Criteria
[10.] are willing and able to complete the scheduled study assessments, including 
endoscopy and daily diary entry.
[11.] have clinically acceptable central laboratory test results at screening (retesting is 
allowed for hematology and chemistry), including:
[11a.] hematology:  absolute neutrophil count ≥1.5 times (x) 109/L (≥1.5x103/L 
or ≥1.5 GI/L), platelet count ≥100x109/L (≥100x103/L or ≥100 GI/L), 
hemoglobin ≥8.5 g/dL (≥85 g/L) for males and >8.0 g/dL (>80 g/L) for 
females, lymphocyte count ≥500 cells/L (>0.50x103/ L or >0.50 GI/L), 
and total white blood cell count ≥3.0x109/L (≥3.0x103/L or ≥3.0 GI/L)
[11b.] chemistry:  

serum creatinine ≤2x upper limit of normal (ULN).  

total bilirubin level (TBL) ≤1.5xULN.

alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2xULN.  

alkaline phosphatase (ALP) ≤1.5xULN.

patients with an established diagnosis of Gilbert’s syndrome (requires 
source documentation showing unconjugated hyperbilirubinemia, with no 
evidence of hemolysis) can be included with bilirubin levels ≤3xULN.


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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria within 
the screening period, which is ≤28 days prior to the start of study treatment, unless specifically 
defined otherwise.
Gastrointestinal Exclusion Criteria:
[12.] have a current diagnosis of Crohn’s disease, inflammatory bowel disease-
unclassified (IBD-U) (formerly known as indeterminate colitis), or UC proctitis 
(disease limited to the rectum, that is, distal to the recto-sigmoid junction, which 
lies approximately 10-15 cm from anal margin).
[13.] have an inherited immunodeficiency syndrome or a known monogenic cause of 
UC-like colonic inflammation.
[14.] previous bowel resection or intestinal or intra-abdominal surgery:  

have had extensive colonic surgery for UC or for other reasons (for example, 
subtotal colectomy), or are likely to require surgery for the treatment of UC 
during the study.  Patients who have had limited colonic surgery (for example, 
segmental colonic resection) may be allowed in the study, if this does not affect 
the assessment of efficacy.  Discussion with the sponsor should occur prior to 
screening of such patients.  

have had any small bowel or colonic surgery within 6 months prior to baseline.

have had any nonintestinal intra-abdominal surgery within 3 months of baseline.
[15.] have evidence of toxic megacolon, intra-abdominal abscess, or stricture/stenosis 
within the small bowel or colon.  
Adenoma, Dysplasia, and Gastrointestinal Cancer Exclusion Criteria:
[16.] any history or current evidence of cancer of the gastrointestinal tract.  
[17.] any current sporadic adenoma without dysplasia (adenomatous polyps occurring 
proximal to known areas of colitis) that has not been removed.  Once completely
removed, the patient is eligible for study.  
[18.] dysplasia  occurring in flat mucosa, sporadic adenomas containing dysplasia, and 
dysplasia-associated lesions or masses (DALMs) will be managed as follows:
[18a.] any history or current evidence of high-grade dysplasia is exclusionary.
[18b.] any history or current evidence of dysplasia occurring in flat mucosa is 
exclusionary.  This includes histopathology reporting “indefinite for 
dysplasia,” low-grade dysplasia, and high-grade dysplasia.  
[18c.] any history or current evidence of a nonadenoma-like DALM, with or 
without evidence of dysplasia, is exclusionary.  


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[18d.] any current sporadic adenoma containing dysplasia or any current 
adenoma-like DALM that has not been removed is exclusionary.  Once 
completely removed the patient is eligible for the study.  
Criteria for Prohibited Medications
[19.] have received any of the following for treatment of UC within the time frames 
specified below:  
[19a.] corticosteroid enemas, corticosteroid suppositories, oral budesonide 
standard formulation, or a course of IV corticosteroids within 2 weeks prior 
to screening endoscopy.
[19b.] 5-ASA enemas or 5-ASA suppositories within 2 weeks prior to screening 
endoscopy.
[19c.] immunomodulatory medications, including oral cyclosporine, IV 
cyclosporine, tacrolimus, mycophenolate mofetil, thalidomide or Janus 
kinase inhibitors (for example, tofacitinib) within 4 weeks prior to the 
screening endoscopy.  
AZA, 6-MP, and methotrexate are allowed (see Inclusion Criterion [9b]).  
other immunomodulatory medications should be discussed with the sponsor 
prior to screening.  
[19d.] anti-TNF antibodies (for example, infliximab, adalimumab, or 
golimumab) within 8 weeks prior to screening endoscopy.
[19e.] anti-integrin antibodies (for example, vedolizumab) within 8 weeks prior 
to screening endoscopy.
[19f.] agents that deplete B or T cells (for example, rituximab, alemtuzumab, or 
visilizumab) within 12 months of baseline.  Patients remain excluded if 
there is evidence of persistent targeted lymphocyte depletion at the time of 
screening endoscopy.  
[19g.] any investigational nonbiologic therapy within 4 weeks prior to the 
screening endoscopy or within 5 half-lives prior to the screening endoscopy, 
whichever is longer.  
[19h.] any investigational biologic therapy within 8 weeks prior to the screening 
endoscopy or within 5 half-lives prior to the screening endoscopy, 
whichever is longer.  
[19i.]
leukocyte apheresis (leukapheresis, for example, Adacolumn) within 
3 weeks prior to screening endoscopy.
[19j.] interferon therapy within 8 weeks prior to screening endoscopy.


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[20.] have ever received anti-IL12p40 antibodies (for example, ustekinumab 
[Stelara®]) or anti-IL-23p19 antibodies (for example, risankizumab [BI-655066], 
brazikumab [MEDI-2070], guselkumab [CNTO1959], or tildrakizumab 
[MK-3222]) for any indication, including investigational use.
[21.] have failed 3 or more biologic therapies for UC.
Infectious Disease Exclusion Criteria:
[22.] patients who:
[22a.] have evidence of active tuberculosis (TB), or
[22b.] have a past history of active TB, regardless of treatment, or
[22c.] are diagnosed with latent tuberculosis infection (LTBI) at screening. 
Patients diagnosed with LTBI at screening may be allowed to re-screen for the study, 
provided they fulfil the criteria described in Section 9.4.5.3.  Patients who have a 
documented history of completing an appropriate TB prophylaxis regimen with no 
history of risk of reexposure since their treatments were completed and no evidence of 
active TB are eligible to participate in the study.
[23.] have received a Bacillus Calmette-Guerin (BCG) vaccination within 12 months 
or received live attenuated vaccine(s) within 3 months of baseline or intend to 
receive such during the study.
[24.] have human immunodeficiency virus/acquired immune deficiency syndrome
(HIV/AIDS) or test positive for HIV antibodies at screening.
[25.] have acute or chronic hepatitis B infection; or test positive for hepatitis B virus 
(HBV) at screening, which is defined as:
[25a.] positive for hepatitis B surface antigen (HBsAg+)
OR
[25b.] negative for hepatitis B surface antigen (HBsAg-) and positive for 
anti-hepatitis B core antibody (anti-HBc+) in conjunction with detectable 
HBV DNA (see Section 9.4.5.4).
OR
[25c.] detectable HBV DNA (see Section 9.4.5.4).
[26.] have current hepatitis C infection; or test positive for hepatitis C virus (HCV) at 
screening, defined as:  

positive for hepatitis C antibody and detectable HCV RNA (see Section 
9.4.5.5).


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[27.] had Clostridium difficile or other intestinal infection within 30 days of screening 
endoscopy, or test positive at screening for C. difficile or for other intestinal 
pathogens.  Patients with a confirmed diagnosis of cytomegalovirus-associated 
colitis should have adequate treatment and resolution of symptoms at least 3 
months prior to screening endoscopy.
[28.] patients with serious, opportunistic or chronic/recurring extraintestinal infections  
should be adequately treated and off antibiotics for 30 days without recurrence of 
symptoms prior to screening, including but not limited to the following:·
[28a.] infections requiring IV antibiotics.· 
[28b.] infections requiring hospitalization.  
[28c.] infections that are considered “opportunistic” (examples are listed in
Appendix 8)
[28d.] chronic, recurrent infections (e.g. osteomyelitis, recurring cellulitis). 
Patients with an opportunistic infection or chronic, recurrent infection 
(within the last 60 days) should be discussed on a case-by-case basis with the 
medical monitor.  
[29.] Patients with nonserious extraintestinal infections not adequately treated prior to 
screening.  
[30.] have evidence of active/infectious herpes zoster infection ≤8 weeks prior to 
screening.  Herpes zoster infections remain active until all vesicles are crusted 
over.
General Exclusion Criteria:
[31.] have had lymphoma, leukemia, or any malignancy within the past 10 years.  
Exceptions:  the following conditions are not exclusionary:  a) basal cell or 
squamous epithelial carcinoma of the skin that has been adequately treated with
no evidence of metastatic disease for 1 year, or b) cervical carcinoma in situ that 
has been adequately treated with no evidence of recurrence within the 3 years 
prior to baseline.
[32.] are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[33.] are Lilly employees or employees of third-party organizations involved with 
the study.  
[34.] are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[35.] have previously completed or discontinued from this study or any other study 
investigating mirikizumab.  This criterion does not apply to patients undergoing 
rescreening procedures.


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[36.] have had extra-abdominal surgery and have not recovered fully following 
surgery, including complete wound healing, before screening.  
[37.] presence of significant uncontrolled neuropsychiatric disorder or judged at risk 
of suicide in the opinion of the investigator; 
OR
marked “yes” to Columbia-Suicide Severity Rating Scale (C-SSRS) Question 4 or 5 on 
ideation during the screening period prior to dosing at Visit 1;
OR
marked yes to C-SSRS suicide behaviors questions during the screening period prior to 
dosing at Visit 1;
AND 
the ideation or behavior occurred within the past month.
[38.] have an unstable or uncontrolled illness, including but not limited to 
cerebrocardiovascular, respiratory, gastrointestinal (excluding UC), hepatic, 
renal, endocrine, hematologic, or neurological disorders that would potentially 
affect patient safety within the study or confound efficacy assessment.  Patients 
requiring systemic corticosteroids for non-UC conditions (except corticosteroids 
to treat adrenal insufficiency) are excluded.
[39.] have a known hypersensitivity to any component of this investigational product.
[40.] have a solid organ transplant or hematopoietic stem cell transplantation.  
[41.] are unwilling or unable to comply with the use of a data collection device to 
directly record data from the patient daily for the duration of Study AMAN, or 
unable to complete other study procedures.
[42.] are unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor for any reason that may compromise the subject’s safety or confound 
data interpretation.
[43.] unable to complete study procedures.
[44.] are pregnant, breastfeeding, or planning pregnancy (women only) while enrolled
in the study, or within 20 weeks after receiving the last dose of study agent.
[45.] current or history of alcohol dependence and/or drug abuse within the last year.
6.2.1.
Rationale for Exclusion of Certain Study Candidates
Both male and female patients are allowed to participate in this study.  Patients will not be 
excluded on the basis of gender.  
Patients aged between 18 and 80 years of age at screening will be included in this study. Patients 
>80 years of age at screening will not be allowed in the study for the following reasons.  Elderly 
patients are at increased risk of ischemic colitis and segmental colitis associated with diverticula, 


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which may confound efficacy assessment.  Elderly patients are also at increased risk of 
hospitalization and poorer outcomes following hospitalization for UC, which include an 
increased risk of venous thromboembolism and mortality.  Elderly patients who require surgery 
for UC also have increased rates of postoperative complications and increased length of hospital 
stay compared with younger patients (Ananthakrishnan and Binion 2009).  These factors may 
increase the risk to patients >80 years of age in participating in a clinical trial of an 
investigational product.  
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study
and for 20 weeks following their last dose. In order to participate in the study, patients must 
agree to the contraception, reproduction, and breastfeeding criteria detailed in Inclusion Criterion 
[2] and Exclusion Criterion [44].
6.4.
Screen Failures
Patients who have failed screening because of the following Inclusion/Exclusion Criteria may be 
rescreened when the reason for screen failure has resolved: [4] to [11], [14], [17 (once polyps 
are removed)], [18d (once all of the following have been removed: sporadic adenoma[s]
containing dysplasia, or adenoma like-DALM[s] containing an area diagnosed as “indefinite for 
dysplasia” or low grade dysplasia)], [19], [22c (if treated for latent tuberculosis infection [LTBI] 
for at least 4 weeks and compliant with LTBI therapy while on study, see Section 9.4.5.3)], [23], 
[28] to [31], [34], [36], [38], and [44] to [45].  Individuals may be rescreened up to 2 times, for a 
maximum total of 3 screens.  The interval between rescreenings should be at least 4 weeks, 
unless a shorter interval has been agreed with the study’s medical monitor.  Each time 
rescreening is performed the individual must sign a new informed consent form (ICF) and will 
be assigned a new identification number.
Patients who have failed screening because of Exclusion Criterion [27] may be rescreened once
when the reason for screen failure has resolved.  It is recommended that the investigator confirms 
the patient has a negative stool for C. difficile stool culture/stool ova and parasites (as applicable) 
before performing additional rescreening investigations (see Section 9.4.5.7).
Patients who have failed screening because of the following Exclusion Criteria may not be 
rescreened: [12], [13], [15], [16], [18a] to [18c], [20], [21], [22a and 22b (if current or past 
history of active TB)], [24] to [26], [32], [33], [35], [37], and [39] to [43].  
Retesting of screening investigations (without a requirement for screen failure and rescreening) 
is allowed at the discretion of the medical monitor.  The screening investigations specified below 
may be retested once at the discretion of the investigator.  

Screening hematology and chemistry blood tests:  where 1 or more results are outside 
the acceptable range for inclusion in the study but may be within the acceptable range for 
inclusion on retesting, due to test-retest variability.  

Stool testing:  if there is a technical difficulty in performing or reporting the C. difficile
or stool culture assays.


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
Retesting or confirmatory testing with an interferon-γ release assay (IGRA):  for 
example, QuantiFERON®-TB Gold or T-SPOT® assay) in selected patients as part of 
screening for LTBI (see Section 9.4.5.3 for details).  

Endoscopy:  where the endoscopist is unable to adequately visualize the mucosa (e.g. 
due to poor bowel preparation, technical issues with equipment) or where the central 
reader is unable to determine the centrally read Mayo ES (e.g. failure of the recording 
equipment).
Retesting of all other screening investigations should be discussed with the medical monitor 
prior to retesting.  


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of IV administration of mirikizumab versus placebo during a 
12-week induction period.  Table AMAN.3 shows the treatment regimens.
Table AMAN.3.
Treatment Regimens
Treatment Group
Description
Induction Period 
Mirikizumab Dose Arm 1
300 mg given as an intravenous infusion (Weeks 0, 4, 8)
Control
Placebo given as an intravenous infusion (Weeks, 0, 4, 8)
Intravenous infusion of mirikizumab or placebo will occur over at least 30 minutes.  All subjects 
should be monitored for 1 hour or longer after dosing, according to investigator practice or local 
standard of care.  Sites must have resuscitation equipment, emergency medications, and 
appropriately trained staff available during the infusion and monitoring period.  Detailed 
instructions for investigational product administration will be provided separately by the sponsor.  
Investigational product will be prepared at the site by blinded pharmacists or other trained and 
qualified personnel as designated by the investigator.  Investigational product will be 
administered at the site by blinded nurse, pharmacist, or other trained and qualified personnel as 
designated by the investigator.  
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1.
Packaging and Labeling
Mirikizumab and placebo will be supplied to the investigator by Lilly or its designee.  Clinical 
trial materials will be labeled according to the country’s regulatory requirements.  All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations.  Clinical trial materials are manufactured in accordance with current 
Good Manufacturing Practices (GMP).
Study drug will be supplied as a single-use solution vial containing mirikizumab or placebo with 
study-specific labels.  The 15-mL vial of mirikizumab is manufactured to deliver 300 mg 
(20 mg/mL).  Mirikizumab cannot be distinguished visually from placebo.  Vials will be supplied 


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in cartons, with the appropriate quantity specific to the planned dispensing schedule of the 
investigational product.  
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 1.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  To achieve between-group 
comparability, patients will be stratified to these arms based upon (a) biologic-failed status 
(yes/no) (see Inclusion Criterion [8b]), (b) baseline corticosteroid use (yes/no), (c) baseline 
disease activity (MMS:  [4-6] or [7-9])), and (d) region (North America/Europe/Other); this 
stratification will be controlled by IWRS.
7.2.1.
Selection and Timing of Doses
Patients will be assigned to treatment groups and are planned to receive their assigned treatment 
as outlined in Section 7.1.  The actual time of all dose administrations will be recorded in the 
patient’s electronic case report form (eCRF).  
7.3.
Blinding
This is a double-blind study.  To preserve the blinding of the study, a minimum number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
complete.  These personnel will not have communication with site personnel.  No unblinding at 
the investigational site for investigational product preparation will be required.  A blinded study 
site pharmacist or other trained and qualified person will prepare investigational product.  
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system. This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All notifications resulting in an unblinding event are recorded and reported by the 
IWRS.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  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.  
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from study drug and must complete the early termination visit (ETV) and 
posttreatment follow-up as per protocol. In cases where there are ethical reasons to have the 
patient continue on study drug, the investigator must obtain specific approval from the sponsor 
or designee for the patient to continue in the study.


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7.4.
Dosage Modification
Dose adjustments are not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
Detailed instructions regarding supplies and preparation and handling of mirikizumab will be 
provided by the sponsor.
Investigational products will be supplied by Lilly or its designee, in accordance with current 
GMP and will be supplied with lot numbers, expiry dates, and certificates of analysis, as 
applicable.
Mirikizumab and placebo should be stored in refrigerated conditions 2°C to 8°C (36°F to 46°F).
7.6.
Treatment Compliance
All doses of study drug will be administered at the study site by site personnel.  Deviations from 
the prescribed dosage regimen should be recorded in the eCRF.
Every attempt will be made to select patients who have the ability to understand and comply with 
study instructions.  The investigator is responsible for discussing methods to ensure high 
treatment compliance with the patient before randomization.  
If a patient is noncompliant with study procedures and/or investigational product administration, 
the investigator should assess the patient to determine the reason for noncompliance and educate 
and/or manage the patient as appropriate to improve compliance.  Overall compliance with 
therapy is defined in the statistical analysis plan (SAP).  If, in consultation with Lilly or its 
designee, the noncompliance is deemed to be significant or if further noncompliance occurs, the 
patient may be discontinued from the study.
7.7.
Concomitant Therapy
All concomitant medications taken during the study must be recorded on the Concomitant 
Medication eCRF.  All patients are encouraged to maintain their usual medication regimens for 


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concomitant conditions or diseases throughout the study unless those medications are 
specifically excluded (Appendix 9).  
Patients taking permitted UC concomitant medications are to keep doses stable unless 
modifications are needed due to AEs and follow the instructions regarding dose stabilization as 
detailed in Appendix 10.  Use of such medications should not be withheld if, in the opinion of 
the investigator, failure to prescribe them would compromise patient safety.  Patients who 
require a prohibited medication to treat their UC (see Appendix 9) need to be discontinued from 
study drug and complete an ETV and posttreatment follow-up visits. 
If a concomitant medication is needed to treat an AE or for appropriate medical management, the 
investigator should base decisions on the patient and clinical factors, considering prohibited 
medication.  Local administration of corticosteroids (e.g intranasal, inhaled, intraarticular, 
topical) are allowed as required for the management of pre-existing conditions and AEs.  A 
patient who initiates a prohibited medication for a non-UC indication may either discontinue the 
study drug, or discontinue the prohibited medication.
Use of BCG vaccination is prohibited throughout the duration of the study and for 12 months 
after discontinuation of study drug.  Use of nonlive (killed, inactivated or subunit) vaccinations 
are allowed for all patients; however their efficacy with concomitant mirikizumab is unknown.  
Use of live, attenuated vaccines are prohibited during the study and for 3 months after 
discontinuation of study drug.  
The list of prohibited medications and the list of permitted medications with dose stabilization 
guidance are provided in Appendix 9 and Appendix 10, respectively.
7.8.
Treatment after the End of the Study
7.8.1.
Study Extensions
Patients who complete the 12-week treatment period, irrespective of clinical response status, may 
be eligible to participate in the maintenance study, Study AMBG, provided the eligibility criteria 
for Study AMBG are met.
7.8.2.
Treatment after Study Completion
Mirikizumab will not be made available to patients after conclusion of the study.
7.8.3.
Special Treatment Considerations
7.8.3.1.
Premedication for Infusions
Premedication for the infusions is not planned. Any premedication for infusions should be 
discussed with the medical monitor.  Any premedication given will be documented as a 
concomitant therapy.


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7.8.3.2.
Management of Hypersensitivity, Infusion Related Events, and Infusion 
Site Reactions
During and after study drug administration, patients should be closely monitored for signs or 
symptoms of AEs, including hypersensitivity events, other infusion-related events, and infusion 
site reactions.  
Hypersensitivity Events
If a patient experiences a systemic hypersensitivity reaction involving the skin or mucous 
membranes, respiratory, cardiovascular, gastrointestinal or urinary systems, during or up to 
6 hours after an infusion of study drug, the following guidance should be followed (see 
Appendix 11 for additional information): 

Study drug infusion should be stopped immediately and appropriate supportive care 
provided according to local standard practice (for example, administration of epinephrine, 
anti-histamine, systemic steroids and/or bronchodilators).

After patient’s stabilization, an ADA and PK sample should be collected; additional 
samples should be obtained 4 and 12 to 16 weeks after the event. These samples will also 
be used for tryptase, complement (C3/C4), and cytokine panel assays. 

The patient should be monitored until resolution or stabilization of the symptoms, as 
clinically appropriate. 

Study drug should be permanently discontinued after a systemic drug administration 
reaction.  The patient should undergo post-treatment follow-up procedures after study 
drug discontinuation.

The medical monitor should be notified as soon as feasible.
Other Infusion-Related Events and Infusion Site Reactions
If a patient experiences a reaction consisting of headache, rigors and/or temperature >38°C (in 
the absence of other signs or symptoms of a systemic hypersensitivity reaction), or an infusion 
site reaction, including urticaria, pruritus or angioedema localized to the IV infusion site (in the 
absence of systemic hypersensitivity signs or symptoms), during or up to 6 hours after an 
infusion of study drug, the following guidance should be followed:

Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, NSAIDS, anti-pyretics or antihistamines).

An ADA and PK sample should be collected at the time of the event (or as soon as 
possible after the event occurs) and 4 and 12 to 16 weeks after the event. These samples 
will also be used for tryptase, complement (C3/C4), and cytokine panel assays.

Resumption of study drug infusion after interruption, possibly at a slower rate of 
administration, can be considered if symptoms resolve and it is deemed to be medically 
appropriate based on investigator discretion, and considering the risk/benefit of 
readministration.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity reaction.  Patient should 
remain in observation as is clinically appropriate for the patients symptoms.


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
Premedication prior to subsequent study drug administration may be considered as 
judged by the investigator to be appropriate for the individual patient.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1.
Permanent Discontinuation from Study Treatment
Study treatment may be permanently discontinued during the study.  Patients who discontinue 
study treatment early will undergo early termination procedures, which include an ETV and 
posttreatment follow-up visits.
The investigator will also complete any AE reporting and follow-up that may be required (if 
applicable, see Section 9.2).  
Possible reasons leading to permanent discontinuation of investigational product include (list is 
not exhaustive):
Patient Decision

The patient requests to discontinue investigational product.
Discontinuation due to a Hepatic Event or Liver Test Abnormality

Patients who are discontinued from investigational product because of a hepatic event or 
liver test abnormality should have additional hepatic safety data collected via the hepatic 
eCRF packet.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets 1 of the following conditions after 
consultation with the Lilly designated medical monitor:

ALT or AST >8xULN

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and TBL >2xULN or international normalized 
ratio >1.5

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

ALP >3xULN

ALP >2.5xULN and TBL >2xULN

ALP >2.5xULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)


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Safety Criteria for Study Drug Discontinuation

The patient requires treatment for exacerbation of UC with medication(s) at doses higher 
than those specified in the “dose stabilization” inclusion criterion (for example, 
prednisone >20 mg/day; Inclusion Criterion [9]), or with prohibited medications specified 
in the “prohibited medications” exclusion criterion (for example, a course of IV 
corticosteroids, or a single dose of infliximab or IV cyclosporine; Exclusion Criterion 
[19]) (see also Appendix 9).  

The patient requires a colectomy, proctocolectomy, or partial colectomy during the study.

A diagnosis of cancer other than squamous cell or basal cell carcinoma of the skin, during 
the study.  

Dysplasia occurring in flat mucosa or DALM.

A diagnosis of active TB during the study.

A diagnosis of HIV/AIDS during the study.

A diagnosis of hepatitis B during the study or development of detectable HBV DNA 
during the study (see Section 9.4.5.4).

A diagnosis of hepatitis C during the study or development of detectable HCV RNA 
during the study (see Section 9.4.5.5).

The patient becomes pregnant.  Pregnant patients will not undergo an endoscopy at the 
ETV.

The patient experiences an AE or SAE that, in the opinion of the investigator or sponsor,
would preclude him/her from continuing to receive study drug.

Systemic hypersensitivity event or anaphylaxis to study drug.
It is recommended that the patient be assessed by an appropriately trained professional to assist 
in deciding whether the patient is to be discontinued from the study if:

The patient scores a 3 for Item 12 (Thoughts of Death or Suicide) on the Quick Inventory 
of Depressive Symptomatology – Self Report (16 items) (QIDS-SR16) at any time in the 
study, or

The patient reports suicidal ideation or suicidal behaviors during the study.
Other Reasons for Study Drug Discontinuation

If an investigator, site personnel performing assessments, or patient is unblinded, the 
patient must be discontinued from the study drug and continue to posttreatment 
follow-up.  In cases where there are ethical reasons to have the patient continue on study 
drug, the investigator must obtain specific approval from the sponsor or designee for the 
patient to continue in the study.

Inadvertent enrollment (see Section 8.1.3)


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Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2.
Temporary Interruption (Withholding) of Study Treatment
Some possible reasons for temporarily withholding the investigational product include (but are 
not limited to):

Patient develops a clinically important intestinal or extraintestinal infection during the 
study (including LTBI), see Exclusion Criteria [27] and [28].

Patient requires major surgery (administration of the investigational product may be 
restarted only after adequate wound healing).

Patient develops a confirmed absolute neutrophil count <1x109/L (<1x103/L or 
<1 GI/L) (2 assessments below this threshold).

Patient develops absolute lymphocyte count <500 cells/L (<0.5x103/L or 
<0.50 GI/L).  AZA, 6-MP or MTX must be discontinued, if applicable, for a 
confirmed absolute lymphocyte count <0.5x103/L (2 assessments below this 
threshold). The hematology must be repeated in 2 weeks. If the absolute lymphocyte 
count remains <0.5x103/L, the hematology will be repeated again in 2 weeks (that 
is, prior to the next dose of study drug). If the absolute lymphocyte count remains 
<0.5x103/L, the next dose of study drug will not be administered. The hematology 
will be repeated again in 2 weeks. If the absolute lymphocyte count remains 
<0.5x103/L, study drug will be permanently discontinued. White blood cell and 
lymphocyte counts will be followed for these patients until they return to an 
acceptable level.
Cases that may merit temporary withholding of the study treatment should be discussed with the 
medical monitor.  The medical monitor, in consultation with the investigator, will determine 
when it is appropriate to recommence study treatment.  
8.1.3.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor agree it is medically appropriate to continue
on study treatment, the investigator must obtain documented approval from the sponsor to allow 
the inadvertently enrolled patient to continue in the study. Patients who are discontinued from 
study treatment should have safety follow-up is as outlined in Section 2 (Schedule of Activities),
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.


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8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:  

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice 

investigator decision
o
the investigator decides that the patient should be discontinued from the 
study
o
if the patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of 
the new agent

patient decision
o
the patient requests to be discontinued from the study
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and
Section 9.4 (Safety) of this protocol.  
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or are otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Table AMAN.4.
Endpoint Definitions 
Endpoint
Definition
Clinical remission
Stool frequency (SF) subscore = 0, or SF = 1 with a ≥1-point decrease from baseline, 
and
Rectal bleeding (RB) subscore = 0, and
Endoscopic subscore (ES) = 0 or 1 (excluding friability)
Clinical response
A decrease in the modified Mayo score (MMS) of ≥2 points and ≥30% decrease from 
baseline, and 
A decrease of ≥1 point in the RB subscore from baseline or a RB score of 0 or 1
Endoscopic remission
ES = 0 or 1 (excluding friability)
Endoscopic response
A decrease in the ES of ≥1 point compared to baseline
Symptomatic remission
SF = 0, or SF = 1 with a ≥1-point decrease  from baseline, and
RB = 0
Symptomatic response
≥30% decrease from baseline in the composite clinical endpoint of the sum of SF and 
RB subscores
Histologic remission 
This definition will be specified in the statistical analysis plan (SAP)
Mucosal healing
Histologic remission as described in the SAP, and
Endoscopic remission defined as ES = 0 or 1 (excluding friability)
Bowel movement urgency 
improvement
This definition will be specified in the SAP
9.1.1.
Primary Efficacy Assessment
9.1.1.1.
Primary Endpoint
The primary endpoint is clinical remission at Week 12 (mirikizumab versus placebo).  Clinical 
remission is based on the MMS and is defined in Table AMAN.4.  
9.1.1.2.
Mayo Score
This study utilizes components and permutations of the Mayo score (Schroeder et al. 1987) to 
assess UC disease activity for the primary and major secondary endpoints (see Appendix 6).  
Complete and accurate daily recording of the Mayo SF and RB subscores by patients in 
their daily electronic diary is necessary for the success of the study.  Adequate bowel 


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preparation and an endoscopy with adequate visualization of the mucosa will enable calculation 
of the Mayo ES.  
The Mayo score is a composite instrument comprised of the following 4 subscores:
Stool Frequency (SF):  The SF subscore is a patient-reported measure.  This item reports the 
number of stools in a 24-hour period, relative to the normal number of stools for that patient in 
the same period, on a 4-point scale (see Appendix 6).  A stool is defined as a trip to the toilet 
when the patient has either a bowel movement, or passes blood alone, blood and mucus, or 
mucus only.  The total number of stools passed in a 24-hour period will be recorded by the 
patient in a daily electronic diary. The reference “normal” SF for that patient will be recorded 
electronically at the screening visit.  Study software will use the patient-reported daily SF and the 
reference normal SF to automatically calculate the Mayo SF subscore.  The patient will record 
this in an electronic diary (Appendix 7).  Further details on the analysis of daily diary items are 
contained in the SAP.  
Normal SF: The Normal SF is a patient-reported measure. This item reports the number of 
stools in a 24-hour period when the patient was in remission or, if the patient has never achieved 
remission, the reported SF before initial onset of signs and symptoms of UC.  Remission refers to 
a period of time since being diagnosed with UC when the patient is not experiencing any signs or 
symptoms relating to UC. This period of time may last a few weeks or a few months or may 
even last several years. The patient will record this electronically as source data in the tablet 
device at the screening study visit.
Rectal Bleeding (RB):  The RB subscore is a patient-reported measure.  This item reports the 
most severe amount of blood passed per rectum for a given day, on a 4-point scale (see 
Appendix 6).  The patient will record this in a daily electronic diary (Appendix 7).
Endoscopic Subscore (ES):  The ES is a physician-reported measure that reports the worst 
appearance of the mucosa on flexible sigmoidoscopy or colonoscopy, on a 4-point scale (see 
Appendix 6).  Determination of the ES is further detailed in Section 9.1.1.3.  Consistent with 
current clinical practice and regulatory advice, this study excludes friability from the definition 
of an ES of 1.  
Physician’s Global Assessment (PGA):  The PGA is a physician-reported measure that 
summarizes the investigator’s assessment of the patient’s UC disease activity on a 4-point scale 
(see Appendix 6).  The investigator will record the PGA electronically as source data in the 
tablet device at appropriate study visits. Consistent with regulatory guidance, the PGA will not 
be used for efficacy assessment in this study.
Each subscore is scored on a 4-point scale, ranging from 0 to 3, to give a maximum Mayo score 
of 12.  The modified Mayo score (MMS) is a sum of the Mayo SF, RB and ES, giving a 
maximum MMS of 9.  Additional permutations of the Mayo score have been described, and may 
be used in analyzing data from this study.  


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9.1.1.3.
Endoscopy
Endoscopy will be used to determine the Mayo ES at screening and Week 12 (or ETV).  Site and 
blinded central reading of endoscopies will be used to determine ES.
A flexible sigmoidoscopy or colonoscopy will be performed on all patients during screening, 
within 14 days prior to randomization.  The endoscopy report and histopathology report (if 
biopsies sent to the local histopathology laboratory) must be available in the source documents.  
Prior to performing the screening endoscopy, investigators should ensure that patients have 
clinically acceptable central laboratory test results, including stool tests that are “negative” for 
C. difficile and other intestinal pathogens (see Inclusion Criterion [11] and Exclusion 
Criteria [22] and [24] to [27]).
Flexible sigmoidoscopy is recommended for all patients, except the following patients for whom 
colonoscopy is the required endoscopic procedure at screening:
1. Patients who require surveillance for UC-associated dysplasia and malignancy, who have 
not had a surveillance colonoscopy, including random and targeted biopsies, within 
12 months of baseline.  These include:  
a.
Patients with pancolitis of >8 years’ duration.  
b. Patients with left-sided colitis of >12 years’ duration.  
c.
Patients with primary sclerosing cholangitis.
In these patients, the investigator can obtain additional biopsies to surveille for dysplasia 
at the screening colonoscopy. This screening colonoscopy will be performed according 
to local guidelines and biopsies will be sent to the local histopathology laboratory.  
Chromoendoscopy may be an acceptable method of targeting biopsies, if allowed 
according to local guidelines.  
2. Patients who require screening for colorectal cancer, who do not have a current screening 
colonoscopy according to local guidelines.  This may include:
a.
Patients with family history of colorectal cancer.
b. Personal history indicating increased colorectal cancer risk, for example, previous 
adenomatous polyps.
c.
Patients 50 years, or with other known risk factor.
3. Patients who do not have the report of a completed, full colonoscopy available in source 
documents to establish extent of the disease.  Patients with rectal sparing on baseline 
endoscopy must have documentation of rectal involvement on a prior endoscopy. 
4. Where, in the opinion of the investigator, a colonoscopy is indicated at screening, for 
example, to confirm that a recent removal of an adenomatous polyp is complete prior to 
randomization.  
If a patient already has up-to-date surveillance for dysplasia and/or up-to-date screening for 
colorectal cancer, the endoscopy report and histopathology report (if applicable) used to support 
this must be available in the source documents, in order to satisfy Inclusion Criterion [7].


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Patients who undergo colonoscopy at screening do not require a separate flexible sigmoidoscopy
in the same screening period.
At Week 12 (or ETV), a flexible sigmoidoscopy is recommended for all patients.  Colonoscopy 
can be performed instead of flexible sigmoidoscopy at Week 12 for clinically indicated reasons 
in the judgement of the investigator and after discussion with the medical monitor as appropriate.  
The endoscopy report and histopathology report (if biopsies are sent to the local histopathology 
laboratory) must be available in the source documents.  Patients who undergo a flexible 
sigmoidoscopy at an ETV will not  undergo additional endoscopies within the study. Patients 
who discontinue the study drug because of pregnancy will not undergo a flexible sigmoidoscopy 
at their ETV.
If a patient undergoes early termination soon after screening endoscopy, the need for ETV 
endoscopy should be discussed with the medical monitor.
The endoscopist will be a licensed physician, who is qualified by education, training, and 
experience to perform colonoscopies.  Investigators may delegate endoscopy to other members 
of the study team.  However, all study staff performing endoscopy must receive training from the 
sponsor or designee in the determination and calculation of the Mayo ES.  The site endoscopist 
will determine the site-read Mayo ES at each endoscopy and record this in the eCRF.
All endoscopic procedures will be video recorded using a storage medium provided by the 
sponsor or designee.  The video images will be sent for independent central reading.  A detailed 
image review charter from the central reading laboratory will outline the standard study 
procedures used to capture and transmit video recordings of endoscopic procedures throughout 
the study, and the qualifications required of the central reader.  
The central reader will determine the centrally-read Mayo ES at each colonoscopy in a blinded 
manner, as detailed in the image review charter.  
Disagreement between the site and central read will be adjudicated by an additional blinded 
central reader, as detailed in the image review charter.  The adjudicated Mayo ES will be 
provided to the site prior to randomization at Visit 1 to enable determination of the MMS for 
eligibility.  
9.1.1.4.
Endoscopic Biopsies
A histopathology report supporting the diagnosis of UC must be available in the source 
documents prior to randomization, in order to satisfy Inclusion Criterion [4].  If a histopathology 
report is not available, the investigator can obtain additional biopsies for this purpose at the 
screening endoscopy (sent to the local histopathology laboratory).
Biopsies will be obtained at each endoscopy to support assessment of the histopathology 
endpoints in this study and, where permitted, for the assessment of exploratory biomarkers.  
These will be sent to the central study laboratory for processing. Histopathologic scoring of 
these biopsies will be performed by a blinded central reader.  A detailed histopathology charter 
will outline the procedures to be used for secure specimen transfer, processing, slide preparation 


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and digitization of slides for histopathologic scoring.  These results will not be made available to 
study sites.  
9.1.2.
Secondary Efficacy Assessments
9.1.2.1.
Major Secondary Endpoints
The MMS and the composite SF and RB score, derived from assessment of the Mayo score (see 
Section 9.1.1.2), will be used to determine the major secondary endpoints (see Table AMAN.4
for definitions).  The major secondary endpoints are as follows:

Clinical response at Week 12.  

Endoscopic remission at Week 12.  

Symptomatic remission at Week 4.  

Symptomatic remission at Week 12.  

Clinical response at Week 12 in the biologic-failed population.

Bowel movement urgency improvement at Week 12.
9.1.2.1.1. Patient Reported Outcome Instruments
The Urgency Numeric Rating Scale (NRS) (see Appendix 7 for description) is a patient-reported 
outcome (PRO) instrument collected using a patient eDiary. The Urgency NRS will be used to 
determine the secondary endpoint for bowel movement urgency improvement.
9.1.2.2.
Other Secondary Endpoints
Other secondary endpoints are found in Table AMAN.2.
9.1.2.2.1. Physician Reported Instrument
The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a physician-reported instrument 
for measuring the endoscopic disease activity of UC on flexible sigmoidoscopy or colonoscopy, 
that includes 3 descriptors of vascular pattern, bleeding, and erosions/ulcerations (Arai et al.
2016; Ikeya et al. 2016; Tontini et al. 2014).  Only blinded central reading of endoscopies will be 
used to determine the UCEIS score for each endoscopy.
9.1.2.2.2. Patient Reported Outcome Instruments
The following are additional PRO instruments collected using a patient eDiary.  Please see 
Appendix 7 for additional descriptions

Abdominal Pain NRS

Fatigue NRS
The following are additional PRO instruments collected using a tablet device. Please see 
Appendix 7 for additional descriptions.

Inflammatory Bowel Disease Questionnaire (IBDQ)

European Quality of Life 5-Dimension 5 Level (EQ-5D 5L)

Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Version 2

Work Productivity and Activity Impairment Questionnaire:  Ulcerative Colitis 
(WPAI:UC)


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9.1.2.2.3. Histopathology Scoring Instrument 
The histopathology instruments that will be used for the evaluation of microscopic inflammation 
and histopathologic disease activity will be specified in the histopathology charter.  
9.1.2.2.4. Inflammatory Biomarkers
C-reactive protein (CRP): CRP is an acute phase protein expressed by hepatocytes in response 
to inflammatory cytokines, particularly IL-6, TNF, and IL-1β (Sands 2015). CRP will be 
obtained at time points described in the Schedule of Activities (Section 2).  Investigators will be 
blinded to CRP results.  
Fecal calprotectin: Fecal calprotectin is a complex consisting of the calcium-binding proteins 
S100A8 and S100A9 (Sands 2015).  It is expressed by activated neutrophils (and to a lesser 
extent by macrophages and monocytes) and fecal levels correlate with the number of neutrophils 
in the gut.  It is used as a biomarker of intestinal inflammation in clinical practice.  Fecal 
calprotectin will be obtained at time points described in the Schedule of Activities (Section 2).  
Investigators will be blinded to fecal calprotectin results. 
9.1.3.
Exploratory Efficacy Assessments
9.1.3.1.
Exploratory Endpoints
Exploratory endpoints are defined in the SAP.
9.1.3.1.1. Patient Reported Outcome Instruments
The Patient UC Symptom Diary is a set of 8 items that assess UC-related symptoms in the past 
24 hours (Appendix 7).  In addition to stool frequency and rectal bleeding discussed in
Section 9.1.1.2, and abdominal pain and urgency discussed in Section 9.1.2.2.1, fatigue is 
measured using an 11-point NRS, where ‘0’ = “No Symptom” and ‘10’ = “Symptom as bad as I 
could imagine”.  The diary also includes items that asks the patient to report stool consistency, 
the frequency of night-time stools, fatigue, and overall disease severity.
The following exploratory endpoints will be assessed daily via the electronic diary tool:

Nocturnal Stool

Bristol Stool Scale

Patient’s Global Rating of Severity (PGRS)
In addition to those exploratory endpoints assessed by the Symptom Diary, the Patient’s Global 
Rating of Change (PGRC) will be administered at applicable study visits using the tablet device.
Additional descriptions of these PRO instruments can be found in Appendix 7.
9.1.3.2.
Extraintestinal Manifestations
Review of extraintestinal manifestations (EIMs) will be performed at the time points described in 
the Schedule of Activities (Section 2).  EIMs present at screening will be documented as 
preexisting conditions.  EIMs that occur after baseline or existing EIMs that change in severity
will be documented as AEs.  EIMs include, but are not limited to:  uveitis, episcleritis, peripheral 
arthritis, dactylitis, enthesitis, sacroileitis, ankylosing spondylitis, erythema nodosum, pyoderma 
gangrenosum, primary sclerosing cholangitis and oral aphthous ulcers.


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9.1.4.
Appropriateness of Assessments
The clinical safety parameters in this study are routine elements of clinical health assessment and 
Phase 3 drug development.  The disease activity measurements are used in clinical practice and 
UC clinical trials.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  
In addition, site personnel will record any change in the condition(s), including exacerbation of 
UC, and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure or investigational product, via eCRF.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.  The investigator 
answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.  


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9.2.1.
Serious Adverse Events
An SAE is any AE from this study that results in any of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent 1 of the other outcomes listed in the definition above. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic AE should have additional data collected using the 
hepatic eCRF packet.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Investigator’s Brochure and that the investigator identifies as related to investigational 
product or procedure.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 


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2001/20/EC and the associated detailed guidances or national regulatory requirements in 
participating countries require the reporting of SUSARs.  Lilly has procedures that will be 
followed for the identification, recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances.
9.2.2.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are AEs which the Sponsor specifies as being of 
special interest based on standard drug registration topics, safety findings from previous studies 
in development program, potential risks associated with biologic immunomodulators as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations.  The AESIs for this study are defined in the SAP, and may include but not 
be limited to:

opportunistic infections

hypersensitivity events, including anaphylaxis 

injection site events

cerebro-cardiovascular events

malignancies

depression, or suicidal ideation and behavior

hepatic AEs.
For some AESIs, sites should provide additional information regarding the event, as instructed 
on the eCRF.
Opportunistic Infections
Infections will be categorized by Lilly as opportunistic according to Opportunistic Infections and 
Biologic Therapies in Immune-Mediated Inflammatory Diseases:  Consensus Recommendations 
for Infection Reporting during Clinical Trials and Postmarketing Surveillance by Winthrop et al. 
(2015).
Hypersensitivity Events 
Site personnel should educate patients and/or caregivers about the symptoms and signs of 
hypersensitivity events and provide instructions on dealing with these events.  For 
recommendations on the management and follow-up of hypersensitivity events, see 
Section 7.8.3.2.
Cerebro-Cardiovascular Adjudication
Data collected regarding a potential or actual cerebro-cardiovascular AE will be provided to, and 
adjudicated by, an independent, external adjudication committee.  The role of the committee is to 
adjudicate the reported cardiovascular AEs in a blinded, consistent, and unbiased manner 
throughout the course of the study, thereby ensuring that all such reported events are evaluated 
uniformly.


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9.2.3.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
In case of suspected overdose, hematology, chemistry, vital signs, and oxygen saturation should 
be monitored and supportive care provided as necessary. There is no known antidote for 
mirikizumab.  
9.4.
Safety
When multiple safety assessments are scheduled for the same time point, the preferred order of 
completion is as follows:  vital signs, electrocardiogram (ECG) and then blood sampling. 
9.4.1.
Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Sitting blood pressure and pulse rate should be measured after the patient has been sitting for at 
least 5 minutes.  Any clinically significant findings from vital signs measurement that result in a 
diagnosis and that occur after the patient receives the first dose of study treatment should be 
reported to Lilly or its designee as an AE via eCRF.
9.4.2.
Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).  
ECGs should be completed prior to any blood draw.  Patients should be supine for approximately 
5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.  
ECGs will be read locally.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the patient receives the first dose of the investigational treatment 
should be reported to Lilly or its designee as an AE via eCRF.
9.4.3.
Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). Retesting is allowed during the screening period (see 
Section 6.4).  Except where otherwise stated, laboratory tests should be obtained prior to dosing.
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  The investigator or designee is expected to review 
laboratory reports in a timely manner throughout the study.


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Any clinically significant findings from laboratory tests that result in a diagnosis and require 
medical or surgical intervention or result in study treatment discontinuation and that occur after 
the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.3.1.
Pregnancy Testing
Pregnancy testing is to be performed on all females ≤60 years, unless they meet the criteria 
describing women not of childbearing potential, outlined in Inclusion Criterion [2b].  
Serum pregnancy test will be done at screening only and results will be confirmed by the central 
laboratory.  Patients determined to be pregnant will be discontinued from the study.
Urine pregnancy testing will be performed locally during designated scheduled visits through 
Week 12.  The urine pregnancy test must be “negative” within 24 hours prior to administration 
of investigational product.  
Urine pregnancy testing may be performed at additional time points during the treatment period 
and/or follow-up period, at the discretion of the investigator or if this is required by local 
regulations.
If a urine pregnancy test is not available, a serum pregnancy test is an acceptable alternative.  
Assessment of FSH levels can assist in determining if a woman meets the definition of 
“postmenopausal,” as outlined in Inclusion Criterion [2b].  FSH can be optionally obtained 
during screening, at the discretion of the investigator.  FSH can also be optionally obtained 
during the study, as indicated in the Schedule of Activities (Section 2), to determine
postmenopausal status.  
9.4.4.
Immunogenicity Assessments
Venous blood samples will be collected prior to dosing to determine antibody production against 
mirikizumab at the visits and times specified in the Schedule of Activities (Section 2). To aid 
interpretation of these results, a blood sample for PK analysis will be collected at the same time 
points.  
In the event of a drug hypersensitivity event (immediate or nonimmediate), additional samples 
for ADA and PK will be collected as close to the onset of the event as possible and at 4 and 12 to 
16 weeks after the event.  These samples will also be used for tryptase, complement (C3/C4), 
and cytokine panel assays. 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 should 
be recorded.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
mirikizumab.  Any samples remaining after 15 years will be destroyed.


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9.4.5.
Other Tests
9.4.5.1.
Physical Examination
Physical examination will be performed as specified in the Schedule of Activities (Section 2).  
Physical examination should include a symptom-directed evaluation as well as examination of 
heart, lungs, abdomen, and visual examination of the skin, and exclude pelvic, rectal, and breast 
examinations.  The physical examination at screening will assist the investigator in determining
whether the subject meets criteria required to participate in the study and will also serve as a 
monitor for preexisting conditions and as a baseline for treatment-emergent AE assessment.  
Physical examination is mandated at screening and Week 12 (or ETV).  Physical exam can also 
be performed at the discretion of the investigator at any additional time points, for example, to 
assist in the evaluation of a new symptom during the study. Any clinically significant findings 
from physical examination that result in a diagnosis and that occur after the patient receives the 
first dose of investigational product should be reported to Lilly or its designee as an AE via 
eCRF.
9.4.5.2.
Chest Radiography
A posterior-anterior (PA) chest x-ray (CXR) will be obtained at screening (Visit 0).  A lateral 
CXR can also be obtained, if in the opinion of the investigator, a lateral view is indicated.  
Patients with documentation of a CXR, read by a qualified radiologist, that is sufficient for TB 
evaluation according to local standard of care, performed within 3 months before initial 
screening, may not need to repeat CXR at screening, based on the judgement of the investigator.  
In either case, the CXR film(s)/image(s) or a radiology report must be available to the 
investigator for review.
Patients with CXR findings consistent with active TB or a past history of TB are excluded from 
the study (Exclusion Criterion 22).  In addition, patients with CXR findings consistent with 
untreated infection (Exclusion Criteria 28 and 29), or unstable or uncontrolled illness (Exclusion 
Criterion 38) are excluded from the study.


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9.4.5.3.
Tuberculosis Screening
Initial Screening
All patients will be screened for active and LTBI. Screening for LTBI (Visit 0) will include the 
following:

Medical history, and physical examination as described in Section 9.4.5.1, 

CXR, as described in Section 9.4.5.2 above, and 

A test to assess immune response to mycobacterial antigens: 
o
Interferon-γ release assay (IGRA, eg, QuantiFERON-TB Gold or T-SPOT.TB), or 
o
Tuberculin skin test (TST, also called a purified protein derivative [PPD] or 
Mantoux test).  
Tests for Immune Response to Mycobacterial Antigens
In people aged 5 years and over, IGRA is the preferred screening test for LTBI, and should be 
performed for LTBI screening in this study in preference to TST.  IGRA is also the preferred 
screening test for LTBI in patients who have received a BCG vaccination.  In countries where 
the TST is available and is preferred (in the judgment of the investigator) as an alternative 
screening test for LTBI, that test may be used instead of an IGRA for appropriate patients.  
Patients with documentation of a “negative” IGRA or TST within 3 months before initial 
screening may not need to repeat TB testing at screening, based on judgment of the investigator.  
Source documentation must include the original laboratory report (for IGRA) or a record of the 
size in millimeters of the induration response (for TST).  A TST recorded as “negative” without 
documenting the size of induration in millimeters will not be acceptable and will require a retest.
Interpretation of Screening Tests for LTBI 
The QuantiFERON-TB Gold assay will be reported as negative, indeterminate, or positive.  The 
T-SPOT.TB assay will be reported as negative, borderline, or positive.
The TST should be read 48 to 72 hours after test application.  Skin induration ≥5mm in diameter 
is interpreted as positive for the purpose of this study, regardless of BCG vaccination history.  
Patients with a diagnosis of LTBI, based on a positive IGRA test result or a positive TST 
response, and no evidence of active TB on medical history, physical examination and chest x-
ray, may be rescreened once and enrolled if they are treated for LTBI and meet the following 
requirements (as well as all other study entry criteria):

have received at least 4 weeks of appropriate ongoing prophylactic therapy for LTBI, 
based on the United States Centers for Disease Control and Prevention guidance (CDC
[WWW]) for the United States or the World Health Organization guidance for the 
treatment of LTBI for all countries outside of the United States (WHO LTBI [WWW])

have no evidence of hepatotoxicity (ALT and AST levels must remain ≤2xULN) upon 
retesting of serum ALT and AST levels before randomization)


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Such patients must meet all other inclusion and exclusion criteria for participation, and also 
continue and complete appropriate LTBI therapy during the course of the study to remain 
eligible for participation in the study.
Retesting and Confirmatory Testing
One retest is allowed for patients with an “indeterminate” QuantiFERON-TB Gold assay or 
“borderline” T-SPOT assay.  Patients with 2 indeterminate QuantiFERON-TB Gold assays or 
2 borderline T-SPOT assays will be excluded.  
Confirmatory testing with an IGRA is allowed for selected patients who have a positive 
QuantiFERON-TB Gold assay, positive T-SPOT.TB assay, or positive TST who meet all of the 
following criteria, and are assessed by the investigator as likely having a false-positive test 
result:  no risk factors for LTBI, no risk factors for increased likelihood of progressing from 
LTBI to active TB, and have never resided in a high-burden country (detailed in Appendix 4).  If 
the confirmatory test is positive, the patient will be excluded from the study unless they 
complete at least 4 weeks of appropriate therapy for LTBI, based on national or international 
guidelines (as defined above) and have no evidence of hepatotoxicity (ALT and AST levels 
must remain ≤2xULN) upon retesting of serum ALT and AST levels after at least 4 weeks of 
LTBI treatment.  Such patients must continue and complete appropriate full course of LTBI 
therapy during the course of the study to remain eligible to participate.  If the confirmatory test is 
negative, these results will be discussed with the medical monitor in order to determine 
eligibility for the study.  
Patients with a negative TST or IGRA can be re-tested with an IGRA where, in the judgement of 
the investigator, the initial test result may be a false negative, e.g. due to a technical difficulty in 
administering the TST or due to concomitant immunosuppressant therapy. 
Diagnosis of LTBI during Study
Patients diagnosed with LTBI during the study must have study drug interrupted.  If treatment 
for LTBI is considered to be appropriate, the patient must complete at least 4 weeks of 
appropriate therapy for LTBI, based on national or international guidelines (as defined above), 
and have no evidence of hepatotoxicity (ALT and AST levels must remain ≤2xULN) upon 
retesting of serum ALT and AST levels after at least 4 weeks of LTBI treatment.  Such patients 
may then resume study drug treatment and must continue with and complete a full course of 
treatment for LTBI in order to continue on study drug.  Noncompliance with LTBI treatment 
during the study is a reason for permanent discontinuation from study drug.  
Household Contact
Patients who have had household contact with a person with active TB must be evaluated for TB
infection.  


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Prior Treatment for LTBI 
Patients who have a documented history of completing an appropriate TB prophylaxis regimen 
with no history of risk of reexposure since their treatments were completed and no evidence of 
active TB are eligible to participate in the study.  These patients should not undergo TST or 
IGRA testing unless advised to do so based on local guidelines.  
Active TB 
Patients with any history of active TB are excluded from the study, regardless of previous or 
current TB treatments.  
Patients diagnosed with active TB at screening will be excluded and should be referred by the 
investigator for appropriate TB treatment and follow-up.  
If a patient is diagnosed with active TB during the study, the study drug will be discontinued, the 
patient will undergo an ETV and then enter the post-treatment follow-up period.  The patient 
should also be referred by the investigator for appropriate TB treatment and follow-up..
9.4.5.4.
Hepatitis B Testing
HBV Screening and Interpretation
Patients with acute or chronic hepatitis B infection are excluded from the study.  
Screening for HBV in this study is performed as follows:  an initial test for hepatitis B surface 
antigen (HBsAg) and hepatitis B core antibody (anti-HBc), followed by a test for HBV DNA in 
patients who are HBsAg-, anti-HBc+.
Exclusion Based on HBV Serology and HBV DNA Testing
Patients with the following screening test results will be excluded from the study:

HBsAg+, irrespective of anti-HBc result, or

HBsAg-, anti-HBc+ with detectable HBV DNA.

Detectable HBV DNA, irrespective of HBsAg or anti-HBc result.
Patients Potentially Allowed into the Study, Based on HBV Serology and HBV DNA 
Testing
Patients with the following screening test results may be eligible for inclusion, provided they 
meet the other inclusion/exclusion criteria:

HBsAg-, anti-HBc-.

HBsAg-, anti-HBc+ with no HBV DNA detected.
Management of patients with the following HBV serology at baseline:  HBsAg-, anti-HBc+,
HBV DNA not detected
Randomized patients with this serological pattern at screening will undergo HBV DNA 
monitoring at Week 12 and, if applicable, at the “Last Visit +16 Weeks” visit in the 
post-treatment follow-up period.


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In addition, if such patients experience an elevated ALT or AST level >3xULN during the study, 
they must have a HBV DNA test and be managed appropriately based on the results of that test.
Management of Patients with Detectable HBV DNA During the Study
If HBV DNA is detected during the study, the study drug will be discontinued, an early 
termination visit will take place and the patient will then enter the post-treatment follow-up 
period.  The sponsor recommends that a hepatologist (or a physician with a specialist interest in 
viral hepatology) is consulted and that it is determined whether it is appropriate to start antiviral 
therapy prior to discontinuation of any immunosuppressant or immunomodulatory therapy, or the
study drug.  Such patients should also receive appropriate follow-up medical care.  
If HBV DNA is detected during the study, the investigator should consider using one of the 
following terms to report the adverse event:

“Detectable HBV DNA”, if HBV DNA is detected without an increase in 
aminotransferase levels.  

“Reactivation of hepatitis B”, if HBV DNA is detected, in concert with an increase in 
aminotransferase levels and/or symptoms and signs of liver disease.
9.4.5.5.
Hepatitis C Testing
Patients with current hepatitis C infection are excluded from the study.
Screening for HCV in this study is performed as follows:  an initial test for HCV antibody, 
followed by a test for HCV RNA if the HCV antibody test is positive.  Patients with a positive 
HCV antibody test and detectable HCV RNA, will be excluded from the study. 
Patients who test negative for HCV antibody will not be tested for HCV RNA and may be 
eligible for inclusion in the study.  
Patients who have spontaneously cleared hepatitis C infection, defined as (i) a positive HCV 
antibody test and (ii) a negative HCV RNA test, with no history of anti-HCV treatment, may be 
eligible for inclusion in the study, provided they have no detectable HCV RNA on screening for 
this study.  Any patient with a history of hepatitis C infection who develops elevated 
ALT >3xULN within the study will be tested for HCV RNA.
Patients with a previous diagnosis of hepatitis C who have been treated with antiviral therapy 
and achieved a sustained virologic response (SVR) may be eligible for inclusion in the study, 
provided they have no detectable HCV RNA at screening.  Sustained virologic response is 
defined as an undetectable HCV RNA level 12 weeks after completion of a full, documented 
course of an approved, potentially curative antiviral therapy for HCV.  
If a patient is diagnosed with hepatitis C during the study (detectable HCV RNA), the study drug 
will be discontinued, an early termination visit will take place and the patient will then enter the 
post-treatment follow-up period and should receive appropriate follow-up medical care.
9.4.5.6.
Depression and Suicidality
Suicide-related events (behavior and/or ideations) will be assessed at screening (Visit 0) with the 
administration of the C-SSRS,  the Self-Harm Supplement Form, and the Self-Harm “Follow-Up” 


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Form (if applicable). Depressive symptomology will be assessed with the QIDS-SR16 at 
Week 0, and Week 12 or ETV.  These assessments are described below, and further information 
is provided in Appendix 12.
Columbia Suicide Severity Rating Scale:  The C-SSRS (Columbia University Medical 
Center [WWW]) is a scale that captures the occurrence, severity and frequency of 
suicide-related ideations and behaviors during the assessment period.  The scale includes 
suggested questions to solicit the type of information needed to determine if suicidal 
ideation and/or behavior occurred.  The C-SSRS is administered by an appropriately 
trained health care professional with at least 1 year of patient care/clinical experience.  
Patient data for the C-SSRS will be recorded in the eCRF.
Self-Harm Supplement Form:  The Self-Harm Supplement Form is a single question to 
enter the number of suicidal behavior events, possible suicide behaviors, or nonsuicidal 
self injurious behaviors the patient has experienced since the last assessment. For each 
unique event identified, a questionnaire (Self-Harm “Follow-Up” Form) that collects 
supplemental information on the self-injurious behavior is to be completed. This 
information is then documented in the eCRF. 
Quick Inventory of Depressive Symptomatology—Self-Report (16 Items):  The 
QIDS-SR16 is a self-administered, 16-item instrument intended to assess the existence 
and severity of symptoms of depression as listed in the American Psychiatric 
Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) (APA 2013).  Patients will record their responses to the QIDS-SR16 
electronically as source data in the tablet device according to the Schedule of Activities 
(Section 2).
Spontaneous AE collection should occur prior to the collection of the C-SSRS or QIDS-SR16. If 
a suicide-related event is discovered during the C-SSRS but was not captured during the 
spontaneous AE collection, sites should not change the AE form.  If an event is serious or leads 
to discontinuation, this is an exception where the SAE and/or AE leading to discontinuation 
should be included on the AE form and the process for reporting SAEs should be followed.
9.4.5.7.
Stool Testing
Stool Culture 
A stool sample for culture will be obtained at screening.  The stool culture assay will screen for 
the following pathogens:  Campylobacter, Salmonella, Shigella, Escherichia coli 0157:H7 and 
Yersinia enterocolitica.  
Patients must have a “negative” stool culture result in order to be randomized (Exclusion 
Criterion [27]).  Re-testing is allowed within the same screening period if there is a technical 
difficulty in performing or reporting the stool culture assay. 
Patients who have a “positive” stool culture result are excluded from the study (Exclusion 
Criterion [27]).  These patients can be re-screened once, provided they have been adequately 
treated and are off antibiotics for 30 days.  If antibiotics were not prescribed, these patients can 


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be re-screened once, provided that 30 days or more has elapsed since resolution of acute 
symptoms and signs associated with the underlying intestinal infection.  A stool culture should 
be repeated prior to rescreening, as a “negative” result will be required prior to randomization.  
C. difficile
A stool sample for C. difficile toxin will be obtained at screening.  This assay tests for the
presence of C. difficile toxin protein, followed by a confirmatory test for C. difficile toxin gene 
expression in the stool sample. 
Patients should test negative for C. difficile in order to be randomized (Exclusion Criterion 27).  
Re-testing is allowed within the same screening period if there is a technical difficulty in 
performing or reporting the C. difficile assays, or if in the judgement of the investigator, the 
patient’s symptoms or signs are not consistent with C. difficile infection.
Patients who test positive at screening for C. difficile can be re-screened once for the study, 
provided that they have been adequately treated and off antibiotics for 30 days.  Patients who 
have been adequately treated for C. difficile with fecal microbial transplantation or IV
immunoglobulin therapy can be re-screened once for the study, 30 days after completing their 
therapy.  Testing for C. difficile should be repeated prior to re-screening, as a “negative” result is 
required prior to randomization.  
9.4.6.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the individual or group level, additional analyses of the safety data can be performed by 
members of the external data monitoring committee (DMC) (see Section 10.3.8) or by the 
sponsor, through its internal review committee process.
9.4.6.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3xULN, ALP ≥2xULN, or elevated TBL ≥2xULN,
liver testing (Appendix 5) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.  
If a study patient experiences an ALT or AST >3xULN and TBL >2xULN or international 
normalized ratio >1.5, the study medical monitor should be consulted as soon as possible for 
further guidance on evaluation of the laboratory abnormalities.  
Hepatic Safety Data Collection
Additional safety data should be collected via the hepatic eCRF packet if 1 or more of the 
following conditions occur:  


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
elevation of serum ALT to ≥5xULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2xULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2xULN on 2 or more consecutive blood tests

patient discontinued from treatment because of a hepatic event or abnormality 
of liver tests

hepatic event considered to be an SAE

patient with a history of HCV infection develops elevated ALT >3xULN.  
Patient will be tested for HCV RNA

patient experiences an ALT or AST >3xULN and TBL >2xULN or 
international normalized ratio >1.5.  The study medical monitor should be 
consulted as soon as possible for further guidance 
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the serum concentrations of 
mirikizumab.  
Pre-dose samples will be obtained at Weeks 0, 4 and 8.  Additional PK samples will be taken at 
Week 12, ETV or UV, and post-treatment follow-up Visit 802.  Post dose samples will be 
obtained at Weeks 0 and 4.  These can be taken up to 2 hours after dosing.  The time of dosing 
and time of sample collection should be noted.  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  Serum concentrations of mirikizumab will be determined using a 
validated enzyme-linked immunosorbent assay. It is not intended that samples collected from 
placebo treated patients will be analyzed. Additional samples may be collected and used for 
exploratory analyses such as bioanalytical method development or validation exercises.
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.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
 
 
CCI


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9.6.
Pharmacodynamics
See Section 9.8.
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
.
CCI
CCI
CCI
CCI


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9.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.
CCI


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10. Statistical Considerations
10.1. Sample Size Determination
The study will randomize approximately 1160 patients with a 3:1 ratio of 300 mg mirikizumab to 
placebo, with an assumption that approximately 1044 patients will complete the study.  Patients 
will be stratified by (a) biologic-failed status (yes/no), (b)baseline corticosteroid use (yes/no), 
(c) baseline disease activity (MMS:  [4-6] or [7-9]), and (d) region (North 
America/Europe/Other).
The power calculations for this study assume the following:  
(1) The randomized study population will include approximately 50% biologic-failed patients 
and approximately 50% conventional-failed patients.  
(2) The predicted clinical remission rates at Week 12 for mirikizumab versus placebo are 
expected to be 23% versus 7.8% (biologic-failed patients:  16% versus 3.5%; conventional-failed 
patients:  30% versus 12%).
The primary endpoint of this study is a test the hypothesis that mirikizumab is superior to 
placebo in inducing clinical remission at Week 12 in patients with moderately to severely active 
UC.  Given the assumptions described above, a sample size of 1160 patients are expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this 
endpoint, based on a chi-square test with a 2-sided significance level of 0.00125.  
Patients who complete Study AMAN may be eligible to participate in Study AMBG, a 40-week 
maintenance study.  The primary objective of Study AMBG is to test the hypothesis that 
mirikizumab is superior to placebo in achieving clinical remission at Week 40 of Study AMBG 
(Week 52 of continuous therapy) amongst patients induced into clinical response with 
mirikizumab at Week 12 of Study AMAN.  A sample size of 1160 patients in Study AMAN is 
predicted to provide a sufficient number of biologic-failed patients in clinical remission at Week 
12 of Study AMAN who will enter Study AMBG. This is expected to provide >90% power to 
demonstrate that mirikizumab is superior to placebo in achieving the primary endpoint in Study 
AMBG, based on a chi-square test with a 2-sided significance level of 0.05.  


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10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Intent-to-Treat (ITT) 
Population 
All randomized patients.  Patients will be analyzed according to the treatment to which 
they were assigned
Modified Intent-to-Treat 
(mITT) Population
All randomized patients who receive at least 1 dose of study treatment (regardless if 
the patient does not receive the correct treatment, or otherwise does not follow the 
protocol). Patients will be analyzed according to the treatment to which they were 
assigned
Safety Population
Same as mITT Population
Per-Protocol (PP) 
Population
All mITT patients who are not deemed noncompliant with treatment, who do not have 
significant protocol deviations (defined in the SAP), and whose investigator site does 
not have significant GCP deviations that require a report to regulatory agencies 
(regardless of study period).  Qualifications and identification of the specific 
significant protocol deviations that result in exclusion from the PP population will be
determined while the study remains blinded, prior to the database lock.
Pharmacokinetic
Evaluable
All patients who receive at least 1 dose of investigational product and have sufficient 
blood sampling to allow for pharmacokinetic evaluation.
Abbreviations:  GCP = good clinical practice; SAP = statistical analysis plan.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  
Efficacy analyses will be conducted on the modified intent-to-treat population. Safety analyses 
will be conducted on the modified intent-to-treat population (Safety population).  The efficacy 
analysis of the primary endpoint and major secondary endpoints will be repeated for intent-to 
treat population and the per-protocol population. Additional safety analyses may be performed 
as deemed appropriate.
The baseline modified Mayo score is calculated from valid daily diary entries obtained prior to 
endoscopy during the screening period and the endoscopic appearance of the mucosa at this 
screening endoscopy (Section 9.1.1.2).  For other efficacy, health outcome and safety
assessments, baseline is defined as the last non-missing assessment recorded on or prior to the 
date of Visit 1 (Week 0).
Summary statistics for continuous variables may include mean, SD, median, and minimum and 
maximum values.  Categorical variables will be presented as counts and percentages.  Unless 
otherwise specified, variables will be analyzed in the original scale on which they are measured. 
The parametric approach will be employed by default for statistical analysis except when 
nonparametric analysis, such as by a rank-based method, is assessed to be more fitting.  
Additional exploratory analyses of the data will be conducted as deemed appropriate. All 
hypothesis tests will be 2-sided, and the family-wise type I error rate (FWER) will be controlled 
at an α level of 0.00125 for primary and major secondary endpoints using a pre-specified 


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graphical procedure (see Section 10.3.1.2).  Weights and alpha propagations will be finalized and 
included in the SAP prior to first unblinding of efficacy data 
Unless otherwise specified, analysis of hypotheses will be tested under multiplicity control at a 
family wise significance level of 0.00125.  A 2-sided 99.875% CI will be provided along with 
the p-value.  For other analyses, statistical tests without multiplicity control will be conducted 
using a 2-sided  significance level of 0.05.  The corresponding p-value along with its 95% 2-
sided CI will be provided.  These analyses will also include subgroup analyses for the primary 
and the major secondary endpoints, except for the subgroup which is included in the scope of 
multiplicity control.
For assessments of the primary endpoint and other categorical efficacy endpoints, the Cochran–
Mantel–Haenszel (CMH) chi-square test will be used to compare the 2 treatment groups with the 
following stratification factors: (a) previous biologic therapy failure status (yes/no), (b) baseline 
corticosteroid use (yes/no), (c) baseline disease activity (MMS:  [4-6] or [7-9])), and (d) region 
(North America/Europe/Other).  The CMH chi-square p-value and the relative risk along with its 
2-sided CI will be provided.  In addition, the absolute treatment difference in proportions will be 
provided along with the 2-sided CI estimate.  The differences between each treatment group and 
placebo will also be tested separately using a logistic regression model that controls for:  
(a) previous biologic therapy failure status (yes/no) and (b) corticosteroid use (yes/no). If 
deemed necessary, additional analyses of categorical efficacy variables may be conducted to 
address sparse data and/or small sample sizes.  
Treatment comparisons of continuous efficacy and health outcome variables with multiple 
postbaseline time points will be made using mixed-effects model for repeated measures 
(MMRM) analysis.  The MMRM will include the following effects and covariates: (a) treatment 
group, (b) previous biologic therapy failure status (yes/no), (c) corticosteroid use (yes/no), (d) 
disease activity (MMS:  [4-6] or [7-9]) at baseline), (e) region (North America/Europe/Other), (f) 
baseline value in the model, (g) visit, and (h) the interactions of treatment-by-visit and baseline-
by-visit as fixed factors.  The covariance structure to model the within-patient errors will be 
unstructured.  If the unstructured covariance matrix results in a lack of convergence, the 
heterogeneous Toeplitz covariance structure, followed by the heterogeneous autoregressive 
covariance structure, will be used.  The Kenward-Roger method will be used to estimate the 
denominator degrees of freedom.  Type III sums of squares for the least squares (LS) means will 
be used for the statistical comparison; the 95% CI will also be reported.
Treatment comparisons of continuous efficacy and health outcome variables with a single 
postbaseline time point will be made using ANCOVA with the following in the model:  (a) 
treatment group, (b) previous biologic therapy failure status (yes/no), (c) corticosteroid use 
(yes/no), (d) disease activity (MMS:  [4-6] or [7-9]) at baseline), (e) region (North 
America/Europe/Other), and (f) baseline value.  Type III sums of squares for LS means will be 
used for statistical comparison between treatment groups.  The LS mean difference, standard 
error, p-value, and 95% CI, unless otherwise specified, will also be reported.  Missing data 
imputation method for the ANCOVA model will be specified in the SAP.


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Any change to the data analysis methods and/or imputation methods described in the protocol 
will require an amendment ONLY if it changes a principal feature of the protocol.  Any other 
change to the data analysis methods and/or imputation methods described in the protocol, along 
with the rationale for making the change, will be described in the clinical study report (CSR).  
Additional exploratory analyses of the data will be conducted as deemed appropriate.
10.3.1.1. Missing Data Imputation
While every effort will be made to minimize missing data, the missing data imputation methods 
described below will be used to provide a conservative approach for assessing efficacy endpoints 
when patients are permanently discontinued from study drug or otherwise have missing data.

Nonresponder imputation (NRI): For analysis of categorical efficacy and health 
outcomes variables, missing data will be imputed using an NRI method.  Patients will be 
considered nonresponders for the NRI analysis if they do not meet the categorical 
efficacy criteria or have missing clinical efficacy data at a time point of interest.

MMRM: For continuous variables, the primary analysis will be MMRM with the 
missing at random assumption for handling missing data.  This analysis takes into 
account both missingness of data and the correlation of the repeated measurements.  No 
additional imputation methods will be applied to the MMRM analysis.  
Additional missing data imputation methodologies, for example, modified baseline observation 
carried forward (mBOCF) may be considered as sensitivity analyses and will be fully detailed in 
the SAP.  Using mBOCF imputation, patients who discontinue the investigational product due to 
an AE or lack of efficacy will have their baseline observation carried forward to the 
corresponding primary endpoint for evaluation.  For patients discontinuing investigational 
product for any other reason, the last nonmissing postbaseline observation before discontinuation 
will be carried forward to the corresponding primary endpoint for evaluation.  Those sensitivity 
analyses and other additional methods of handling missing data or analyzing the data that may be 
required to satisfy regulatory needs will be specified in the SAP.  
10.3.1.2. Adjustment for Multiple Comparisons
Multiplicity controlled analyses will be performed to test the primary and major secondary 
hypotheses in order to control the overall FWER at 0.00125. A prespecified graphical multiple 
testing approach (Bretz et al. 2009, 2011) will be used.  The graphical approach is a closed 
testing procedure. Hence, it strongly controls the FWER across all endpoints (Alosh et al. 2014).  
Details of the specific graphical testing scheme (including testing order, interrelationships, type I 
error allocation for the major secondary endpoints, and the associated propagation of alpha) to be 
implemented will be prespecified in the SAP prior to first unblinding of efficacy data.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number of randomized patients will be summarized.  Frequency counts and percentages of 
all patients who are randomized, complete the study, and those who discontinue the study drug


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or the study early will be presented.  Reasons for discontinuing the study drug or the study will 
be summarized.  
10.3.2.2. Patient Characteristics
Year of birth, sex, weight, height, tobacco/nicotine use, previous biologic therapy, corticosteroid 
use and other demographic characteristics will be recorded.  Age and body mass index will be 
calculated.  Demographic and baseline disease characteristics will be summarized for each 
treatment group. Certain characteristics, such as weight, that are collected after baseline, will be 
reported as a listing.
10.3.2.3. Concomitant Therapy
Concomitant therapy will be collected at each visit and the reported term will be classified by the 
WHO drug dictionary.  Previous concomitant therapy (reported before randomization and after 
ICF) will be listed. The current concomitant therapy (reported after randomization) will be 
presented separately in frequency tables by drug name for all randomized patients.  
10.3.2.4. Treatment Compliance
Patients who are noncompliant will be listed by treatment.  The details of noncompliance will be 
defined in the SAP.  A contingency table of numbers of noncompliant patients by treatment will 
be provided.  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy end point of clinical remission will be assessed using the MMS, a 9-point 
instrument that includes the SF, RB and ES subscores of the Mayo Score (see Section 9.1.1.1; 
Table AMAN.4).
At the screening visit, each patient will be asked to identify how many stools he or she had in a 
24-hour period when in remission from UC.  If the patient does not report that he or she has 
achieved remission, then he/she will be asked to identify the number of stools he/she had per day 
before initial onset of signs and symptoms of UC.  The response to these questions will be used 
as the reference SF for the calculation of the Mayo SF subscore. 
For the study visits that are associated with an endoscopy (eg, Week 0, Week 12, ETV and 
possibly unscheduled visits), the SF and RB subscores of the Mayo Score will be calculated from 
daily electronic diary data by separately averaging the most recent 3 days out of the 7 days prior 
to commencing bowel preparation for endoscopy. The 3 days of patient diary data used for SF 
and RB calculation will exclude data from the following days:  (i) days when patients receive 
bowel preparation, (ii) the day of an endoscopy, and (iii) the day after an endoscopy.  
At other visits without endoscopy, the SF and RB subscores of the Mayo Score will be calculated 
from daily electronic diary data by separately averaging the most recent 3 days (possibly 
nonconsecutive) out of 7 days prior to that visit.  
If data are available for fewer than 3 days in the 7-day window, the subscores will be considered
missing.  


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To calculate the SF subscore, the reference stool frequency will be subtracted from the 3-day 
averaged stool frequency. The subtracted stool frequency value will then be rounded to the 
nearest integer and then mapped to obtain Mayo SF subscore.
Rectal bleeding subscore will be rounded to the nearest integer value of the 3-day averaged RB.  
Rates of clinical remission at Week 12, as defined in Section 9.1.1.1, will be analyzed.  Patients 
who do not achieve clinical remission or who do not reach the Week 12 assessment will be 
considered to be nonremitters.  
The primary endpoint analysis will utilize the CMH test as described in Section 10.3.1.
Additional analyses of the primary endpoint may be considered and details will be provided in 
the SAP.
10.3.3.2. Secondary Analyses
The secondary efficacy and health outcome endpoints of the trial are presented in 
Table AMAN.2 and details of the analysis methods that will be utilized are provided in 
Section 10.3.1.
Additional analyses of the secondary efficacy and health outcome endpoints may be considered 
and details will be provided in the SAP.
10.3.4. Safety Analyses
The Fisher exact test will be used to perform the between-treatment group comparisons for AEs, 
discontinuations, and other categorical safety data.  The change from baseline in continuous vital 
signs, physical characteristics, and other continuous safety variables, including laboratory 
variables, will be summarized visit and by treatment.  The change from baseline to last 
observation value will be analyzed with ANOVA model with baseline as a covariate.  The last 
non-missing observation in the treatment period will be used as the last observation.
Shift tables for categorical safety analyses (for example, high or low laboratory test results) will 
also be produced.  
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
The PK of mirikizumab will be characterized using graphical evaluations and mixed-effect 
(population PK) modeling approaches.  Various structural and error models will be evaluated 
during development of the mixed-effect model.  Intrinsic factors (such as age, body weight, 
gender, ADA, etc.) and extrinsic factors (such as comedications) will be investigated to assess 
their influence on model parameters.  Model evaluation will include a visual predictive check.  
Estimates of PK model parameters and covariate effects and corresponding 90% CIs will be 
reported.
Analyses of exposure-response relationships will be conducted using both exploratory graphical 
approaches and model based approaches.  Exploratory graphical analysis approaches may consist 
of graphs showing the percentage of patients that achieve clinical response, clinical remission, 
and endoscopic normalization at different percentiles (for example, quartiles) of exposure of 


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mirikizumab at Week 12.  Measures of exposure may include population PK estimated average 
concentrations (Cavg) between Week 0 and Week 12, or estimated or observed trough 
concentrations at Week 12.  Model based analyses will utilize population exposure-response 
logistic regression models, where maximum effect (Emax) or other model structures may be used 
to relate exposure to the probability of achieving clinical response, clinical remission, and 
endoscopic normalization.  These models may be used to evaluate patient factors that may 
impact the relationship between exposure and the probability of achieving the endpoint.  
Longitudinal exposure-response models for SF and RB subscores may be developed, which 
relate the time course and magnitude of mirikizumab exposure to the time course of these 
subscores.
Additional analyses may be conducted if they are deemed appropriate.  Data from this study may 
be combined with other study data, if appropriate.  Further details on PK and PK/PD analyses 
will be provided in the PK/PD analysis plan.  
10.3.6. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting (baseline) ADA, ADA at any time 
postbaseline, and with treatment-emergent anti-drug antibody (TEADA) to mirikizumab will be 
tabulated.  If no ADA are detected at baseline, TEADA are defined as those with a titer 2 fold 
(1 dilution) greater than the minimum required dilution (MRD) of the assay.  For samples with 
ADA detected at baseline, TEADA are defined as those with a 4-fold (2 dilutions) increase in 
titer compared to baseline.  For patients who have TEADA, the distribution of maximum titers 
will be described.  The frequency of neutralizing antibodies will also be tabulated.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to mirikizumab will be assessed.
10.3.7. Other Analyses
10.3.7.1. Subgroup Analyses
Additional subgroup analyses will be conducted for the primary endpoint and select secondary 
endpoints.  Subgroups to be evaluated include sex, age category, body weight, race, geographic 
region, baseline disease severity and activity, duration and location of disease, previous systemic 
therapy, previous biologic therapy, and concomitant therapy for UC.  If any group within the 
subgroup is less than 10% of the total population, only summaries of the efficacy data will be 
provided (that is, no inferential testing).  Additional subgroup analysis will be defined in the 
SAP.
10.3.8. Interim Analyses
One DMC consisting of members external to Lilly will be established for periodic monitoring of 
clinical trial data across all Phase 3 trials for the UC adult program. This committee will consist 
of a minimum of 3 members, including a physician with expertise in gastroenterology and a 
statistician. 


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No member of the DMC may have contact with study sites. A statistical analysis Center (SAC) 
will prepare and provide unblinded data to the DMC. The SAC members may be Lilly 
employees or from third-party organizations designated by Lilly. However, they will be external 
to the study team and will have no contact with sites and no privileges to influence changes to
the ongoing studies. The timing and frequency of the periodic clinical trial data review by the 
DMC will be detailed in the DMC charter for the UC adult program.
The DMC is authorized to evaluate unblinded interim efficacy and safety analyses. The DMC 
will make recommendation to the Lilly Research Laboratories Senior Management Designee, 
who may order the immediate implementation of the DMC recommendation, or may convene an
internal review committee (IRC), which is independent from the study team, to review the 
recommendation according to standard Lilly policy.  Study sites will receive information about 
interim results ONLY if it is required for the safety of their patients.
In addition to the DMC, SAC and potential IRC if needed, a limited number of pre-identified 
individuals may gain access to unblinded data, as specified in the unblinding plan, prior to the 
interim or final database lock, in order to initiate the final population PK/PD model development 
processes for interim or final analyses.  Information that may unblind the study during the 
analyses will not be shared with study sites or the blinded study team until the study has been 
unblinded.  Unblinding details will be specified in the unblinding plan section of the SAP or a 
separate unblinding plan document.  


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ACT1 and ACT2
Active Ulcerative Colitis Trials 1 and 2 
ADA
anti-drug antibody
ADR
adverse drug reactions
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse event of special interest
AIDS
acquired immune deficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HBc
hepatitis B core antibody
5-ASA
5-aminosalicylic acid
AST
aspartate aminotransferase
AZA
azathioprine
BCG
Bacillus Calmette-Guerin
blinding
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
clinical research 
physician 
Individual responsible for the medical conduct of the study.  Responsibilities of the 
clinical research physician may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CMH
Cochran–Mantel–Haenszel
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice, and applicable regulatory 
requirements.
CRP
C-reactive protein


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CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTA
clinical trial application
CXR
chest x-ray
DALM
dysplasia-associated lesion or mass
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
EIM
extraintestinal manifestation
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D 5L
European Quality of Life 5–Dimension 5 Level
ERB
ethical review board
ES
endoscopic subscore(s)
ETV
early termination visit
EUDRA
European Union Drug Regulatory Authorities
FSH
follicle-stimulating hormone
FWER
family-wise type I error rate
GCP
good clinical practice
GEMINI 1
Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction 
and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in 
Patients with Moderate to Severe Ulcerative Colitis
GMP
Good Manufacturing Practices
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Council for Harmonisation
IGRA
interferon-γ release assay
IL-23
Interleukin-23
IV
intravenous
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intent to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients allocated to a treatment group should be followed up, assessed, and analyzed 
as members of that group irrespective of their compliance to the planned course 
of treatment.
IWRS
interactive web-response system
LS
least squares
LTBI
latent tuberculosis infection
MMRM
mixed-effects model for repeated measures
MMS
modified Mayo score
6-MP
6-mercaptopurine
NRI
nonresponder imputation
NRS
numeric rating scale
PASI
Psoriasis Area and Severity Index


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PD
pharmacodynamic(s)
PGA
Physician’s Global Assessment
PGRC
Patient’s Global Rating of Change
PGRS
Patient’s Global Rating of Severity
PK
pharmacokinetic(s)
PURSUIT
Program of Ulcerative Colitis Research Studies Utilizing an Investigational 
Treatment−Subcutaneous
Q4W
every 4 weeks
QIDS-SR16
Quick Inventory of Depressive Symptomatology –Self-Report (16 items)
RB
rectal bleeding
SAE
serious adverse event
SAP
statistical analysis plan
SF
stool frequency
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
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
SVR
sustained virologic response
TB
tuberculosis
TBL
total bilirubin level
TEADA
treatment-emergent anti-drug antibody
TNF
tumor necrosis factor
TST
tuberculin skin test
UC
ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
ULN
upper limit of normal
ULTRA 
Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab 
WPAI:UC
Work Productivity and Activity Impairment Questionnaire:  Ulcerative Colitis


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Appendix 2.
Clinical Laboratory Tests 


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Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBCs)
Chloride
Mean cell volume 
Bicarbonate
Mean cell hemoglobin
Potassium
Mean cell hemoglobin concentration 
Total bilirubin
Leukocytes (WBCs)
Total protein
Cell morphology
Direct bilirubin
Neutrophils, segmented
Alkaline phosphatase (ALP)
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Gamma-glutamyl transferase (GGT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Uric acid
Urinalysisa,b
Calcium
Specific gravity
Glucose
pH
Albumin
Protein
Cholesterol (total)
Glucose
Triglycerides
Ketones
Lipid Panel (fasting)c
Bilirubin
High-density lipoprotein
Urobilinogen
Low-density lipoprotein
Blood
Creatine kinase (CK)
Nitrite
Urine leukocyte esterase
Other Testsa
Microscopic examination of sediment
Hepatitis B core antibody b,d
Hepatitis B surface antigenb,d  
HBV DNAb,e
Hepatitis C antibodyb,d,f
HIVb,d
Pregnancy test (serumb,d and urine,g)
FSHb
QuantiFERON-TB Gold testd or T-SPOT or TST
 
Anti-mirikizumab antibodies (immunogenicity)
Serum mirikizumab concentration (PK)
C-reactive protein, high-sensitivity
Clostridium difficileb,h and Stool Cultureb,h
Fecal calprotectin
Tryptasei
Complement (C3/C4)i
Cytokine paneli
Footnotes on next page.
CCI
CCI


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Abbreviations:  ADA = anti-drug antibody; ETV = early termination visit; FSH = follicle-stimulating hormone; 
HBV = hepatitis B virus; HIV = human immunodeficiency virus; PK = pharmacokinetics; RB = rectal bleeding; 
RBC = red blood cell; SF = stool frequency; TST – tuberculin skin test; UV = unscheduled visit; V = visit; 
WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Results will be confirmed by the Central Laboratory/other at the time of initial testing.
c
For the fasting lipid profile, patients should not eat or drink anything except water for 12 hours prior to test.
d
Performed at screening only.  
e
Hepatitis B DNA testing will be performed in patients who test positive for anti-hepatitis B core antibody (at 
protocol-specified intervals).  
f
A positive hepatitis C antibody laboratory assessment will be confirmed with an additional test method.  
g
Urine pregnancy test will be evaluated locally.
h
Clostridium difficile tests at V5 and ETV may be performed for patients who do not move into Study AMBG. 
Clostridium difficile test at UV may be performed if visit is due to worsening SF and/or RB.
i
Test performed only in the event of systemic allergic/hypersensitivity events, along with ADA and PK.


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Appendix 3.
Study Governance Considerations


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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that 
their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  
This includes obtaining the appropriate signatures and dates on the ICF prior to 
the performance of any protocol procedures and prior to the administration of 
investigational product.

answering any questions the patient/patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patient’s/patient’s legal representative willingness to 
continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.  
Appendix 3.1.2.
Recruitment
Lilly and its designee are responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  
Appendix 3.1.3.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERB(s), before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator’s
Brochure, and updates during the course of the study

ICF


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
other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in gastroenterology will participate as investigators in this clinical 
trial.  Site-specific contact information may be provided in a separate document.  
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The CSR coordinating investigator will be selected by the study team.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures.


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
make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An eCRF system will be used in this study. The site maintains a separate source for the data 
entered by the site into the sponsor-provided eCRF system.  The eCRF data will be encoded and 
stored in a clinical trial database.
Electronic clinical outcome assessment (eCOA) measures (for example, questionnaires, scales, 
self-reported diary data, etc.) will be collected by the patients and site personnel at the time that 
the information is obtained.  In these instances, where there is no prior written or electronic 
source data at the site, the eCOA data record will serve as the source.  The eCOA data will be 
stored at a third party site.  Investigator sites will have continuous access to the source 
documents during the study and will receive an archival copy at the end of the study for 
retention.  Any data for which the eCOA instrument record will serve to collect source data will 
be identified and documented by each site in that site’s study file. 
Data managed by a central vendor, such as laboratory test data or endoscopic data, will be stored 
electronically in the central vendor’s database system. Data will subsequently be transferred
from the central vendor to the Lilly data warehouse.  
Data from compliant forms submitted to Lilly will be encoded and stored in the global product 
compliant management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.


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Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I6T-MC-AMAN is described in the letters of agreement 
between the sponsor and the investigators and institutions.


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Appendix 4.
Risk Factors for Latent Tuberculosis Infection


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Risk Factors for Latent Tuberculosis Infection
Household contact or recent exposure to an active case
Birth or residency in a high burden country (>20/100,000)
Residents and employees of high risk congregate settings, for example, prisons, homelessness, intravenous drug use
Source:  adapted from Horsburgh and Rubin 2011 and Lewinsohn et al. 2017.
Risk Factors for Increased Likelihood of Progression from LTBI to Active TB
Household contact or close contact with an active case
HIV
Radiographic evidence of old, healed TB that was not treated
Silicosis
Treatment with ≥15 mg prednisone (or equivalent) per day
Children <5 years of age
Chronic renal failure
Treatment with an anti-TNF antibody
Poorly controlled diabetes
Intravenous drug use
Weight ≥10% below normal
Smoking
Abbreviations:  HIV = human immunodeficiency virus; LTBI = latent tuberculosis infection; TB = tuberculosis; 
TNF = tumor necrosis factor.
Source:  adapted from Horsburgh and Rubin 2011.
World Health Organization List of High Burden Countries
Angola
India
Peru
Azerbaijan
Indonesia
Philippines
Bangladesh
Kenya
Russian Federation
Belarus
Kazakhstan
Sierra Leone
Botswana
Democratic People’s Republic of Korea
Somalia
Brazil
Kyrgyzstan
South Africa
Cambodia
Lesotho
Swaziland
Cameroon
Liberia
Tajikistan
Central African Republic
Malawi
United Republic of Tanzania
Chad
Republic of Moldova
Thailand
China
Mozambique
Uganda
Congo
Myanmar
Ukraine
Democratic Republic of the Congo
Namibia
Uzbekistan
Ethiopia
Nigeria
Vietnam
Ghana
Pakistan
Zambia
Guinea-Bissau
Papua New Guinea
Zimbabwe
Source: WHO TB [WWW].


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Appendix 5.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality


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Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, or clinical 
research physician.  These tests will be performed at a Lilly-designated laboratory.
Hepatic Monitoring Tests
Hepatic Hematology
Haptoglobin
Hemoglobin
Hematocrit
Hepatic Coagulation
RBCs
Prothrombin time
WBCs
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa
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 Chemistry
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody
AST
GGT
Alkaline phosphatase isoenzymes
CPK
Anti-smooth muscle antibody (or anti-actin antibody)
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
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 6.
Mayo Scoring System for the Assessment of 
Ulcerative Colitis Activity


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Stool Frequency Subscore
Score
Normal number of stools for subject
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
5 or more stools than normal
3
Rectal Bleeding Subscore
Score
No blood seen
0
Streaks of blood with stool less than half of the time
1
Obvious blood (more than just streaks) or streaks of blood with stool most of the 
time
2
Blood alone passed
3
Endoscopic Subscore
Score
Normal or inactive disease
0
Mild disease (erythema, decreased vascular pattern)
1
Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
2
Severe disease (spontaneous bleeding, ulceration)
3
Physician’s Global Assessment
Score
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
Mayo Score = Stool Frequency + Rectal Bleeding + Endoscopic Subscore + Physician's Global Assessment
Note:  The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  Modified Mayo 
score excludes the Physician’s Global Assessment and ranges from 0 to 9.  Composite stool frequency and rectal 
bleeding score ranges from 0 to 6.  The original description of the Mayo score included friability in the definition 
of an endoscopic subscore of 1.  Consistent with current clinical practice and regulatory guidance, this study 
excludes friability from the definition of an endoscopic subscore of 1.
Stool frequency reports the number of stools in a 24-hour period, relative to the normal number of stools for that 
patient. The reference “normal” stool frequency for that patient will be recorded electronically at the screening visit.  
The Normal SF (stool frequency) refers to when the patient was in remission or, if the patient has never achieved 
remission, the reported stool frequency before initial onset of signs and symptoms of ulcerative colitis.  Remission 
refers to a period of time since being diagnosed with ulcerative colitis when the patient is not experiencing any signs 
or symptoms relating to ulcerative colitis.  This period of time may last a few weeks or a few months or may even 
last several years. The patient will record this electronically as source data in the tablet device at the screening study 
visit.
Source:  adapted from Schroeder et al. 1987, Scherl et al. 2009.


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Appendix 7.
Patient Reported Outcome Instruments


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Daily Diary Review
Rectal Bleeding
Stool Frequency
Urgency NRS
Abdominal Pain NRS
PGRS
Nocturnal Stool
Fatigue NRS
Bristol Stool Scale
Abbreviations:  NRS = numeric rating scale; PGRS = Patient’s Global Rating of Severity
The following are descriptions of additional PRO instruments used in study AMAN using Patient 
eDiary or Tablet Device:

Urgency NRS:  A single item that measures the severity for the urgency (sudden or 
immediate need) to have a bowel movement in the past 24 hours using an 11-point NRS 
ranging from 0 (no urgency) to 10 (worst possible urgency).  Patients will be provided 
with an electronic diary tool during screening to record information daily pertaining to 
their severity of urgency.

Abdominal Pain Numeric Rating Scale (NRS): A single item that measures the “worst 
abdominal pain in the past 24 hours” using an 11-point NRS ranging from 0 (no pain) to 
10 (worst possible pain).  Patients will be provided with an electronic diary tool during 
screening to record information daily pertaining to their worst abdominal pain 
experience.

Patient’s Global Rating of Severity (PGRS): The PGRS is a 1-item patient-rated 
questionnaire designed to assess the patients’ rating of their disease symptom severity 
over the past 24 hours. Responses are graded on a 6-point scale in which a score of 1 
indicates the patient has no symptoms (that is, “none”) and a score of 6 indicates that the 
patient’s symptom(s) are “very severe.” Patients will be provided with an electronic 
diary tool during screening to record information daily pertaining to their disease 
experience.

Nocturnal Stool: The Nocturnal Stool instrument is a single item asking the patient to 
record the number of stools they had during the night (or day, for shift workers) causing 
them to waken from sleep.  Patients will be provided with an electronic diary tool during 
screening to record information daily pertaining to their nocturnal stool count.

Fatigue NRS:  The Fatigue NRS is a single item that measures the “worst fatigue 
(weariness, tiredness) in the past 24 hours” using an 11-point NRS ranging from 0 (no 
fatigue) to 10 (fatigue as bad as you can imagine). Patients will be provided with an 
electronic diary tool during screening to record information daily pertaining to their worst 
fatigue experience.

Bristol Stool Scale: The Bristol Stool Scale is a single item that provides a pictorial and 
verbal description of stool consistency and form ranging from Type 1 (Hard Lumps) to 
Type 7 (Watery/liquid).  Patients will be provided with an electronic diary tool during 
screening to record information daily pertaining to their stool.


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
Patient’s Global Rating of Change (PGRC): The PGRC scale is a patient-rated 
instrument designed to assess the patients’ rating of change in their 
symptom(s). Responses are graded on a 7-point Likert scale in which a score of 1 
indicates that the subject’s symptom(s) is “very much better,” a score of 4 indicates that 
the subject’s symptom has experienced “no change,” and a score of 7 indicates that the 
subject’s symptom(s) is “very much worse.” Patients will record their response to the 
PGRC electronically as source data in the tablet device at appropriate visits.

Inflammatory Bowel Disease Questionnaire (IBDQ):  A 32-item patient-completed 
questionnaire that measures 4 aspects of patients’ lives:  symptoms directly related to the 
primary bowel disturbance, systemic symptoms, emotional function, and social function 
(Guyatt et al. 1989; Irvine et al. 1994; Irvine et al. 1996).  Responses are graded on a 7-
point Likert scale in which 7 denotes “not a problem at all” and 1 denotes “a very severe 
problem.” Scores range from 32 to 224; a higher score indicates a better quality of life.
Patients will record their responses to the IBDQ electronically as source data in the tablet 
device at appropriate visits.

European Quality of Life 5-Dimension 5 Level (EQ-5D 5L):  A widely used, generic 
questionnaire that assesses health status (Herdman et al. 2011; EuroQol Group 2015).  
The questionnaire consists of 2 parts.  The first part assesses 5 dimensions (mobility, self-
care, usual activities, pain/discomfort and anxiety/depression) that have 5 possible levels 
of response (no problems, slight problems, moderate problems, severe problems, extreme 
problems).  This part of the EQ-5D can be used to generate a health state index score, 
which is often used to compute quality-adjusted life years (QALY) for utilization in 
health economic analyses.  The health state index score is calculated based on the 
responses to the 5 dimensions, providing a single value on a scale from less than 0 (where 
zero is a health state equivalent to death; negative values are valued as worse than dead) 
to 1 (perfect health), with higher scores indicating better health utility.  The second part 
of the questionnaire consists of a visual analog scale on which the patient rates their 
perceived health state from 0 (the worst health you can imagine) to 100 (the best health 
you can imagine).  Patients will record their responses to the EQ-5D 5L electronically as 
source data in the tablet device at appropriate visits.

Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Version 2:  A 
patient-reported, generic, health-related quality of life instrument originally published in 
1992 with some item wordings and response options revised in 2000 (Ware and 
Sherbourne 1992; Ware 2000).  It consists of 36 questions measuring 8 health domains:  
physical functioning, bodily pain, role limitations due to physical problems, role 
limitations due to emotional problems, general health perceptions, mental health, social 
function, and vitality.  The patient’s responses are solicited using Likert scales that vary 
in length, with 3 – 6 response options per item.  The SF-36 can be scored into the 8 health 
domains named above and two overall summary scores:  physical component summary 
(PCS) and mental component summary (MCS) scores.  The domain and summary scores 
range from 0 to 100; higher scores indicate better levels of function and/or better health.  
The SF-36 version 2 (standard version) will be used, which utilizes the recall period of 
”the past 4 weeks” (Ware and Sherbourne 1992; Maruish 2011).  Patients will record 


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their responses to the SF-36 Version 2 electronically as source data in the tablet device at 
appropriate visits.

Work Productivity and Activity Impairment Questionnaire:  Ulcerative Colitis 
(WPAI:UC):  A patient-reported instrument developed to measure the impact on work 
productivity and regular activities attributable to a specific health problem (WPAI:UC).  
It contains 6 items that measure:  1) employment status, 2) hours missed from work due 
to the specific health problem, 3) hours missed from work for other reasons, 4) hours 
actually worked, 5) degree health affected productivity while working, and 6) degree 
health affected productivity in regular unpaid activities.  Four scores are calculated from 
the responses to these 6 items:  absenteeism, presenteeism, work productivity loss, and 
activity impairment (Reilly Associates [WWW]).  Scores are calculated as impairment 
percentages (Reilly et al. 1993), with higher numbers indicating greater impairment and 
less productivity (Reilly Associates [WWW]), i.e, worse outcomes.  Patients will record 
their responses to the WPAI:UC electronically as source data in the tablet device at 
appropriate visits.


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Appendix 8.
Examples of Infections that May Be 
Considered Opportunistic in the Setting of Biologic 
Therapy


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Bacterial
Bartonellosis (disseminated disease only)
Campylobacteriosis (invasive disease only)
Legionellosis
Listeria monocytogenes (invasive disease only)
Nocardiosis
Tuberculosis
Non-tuberculous mycobacterial disease (see Section 9.4.5.3)
Salmonellosis (invasive disease only) 
Shigellosis (invasive disease only)
Vibriosis (invasive disease due to Vibrio vulnificus)
Viral
BK virus disease including polyomavirus-associated nephropathy
Cytomegalovirus disease
Hepatitis B virus reactivation
Hepatitis C virus progression
Herpes simplex (invasive disease only)
Herpes zoster (any form)
Post-transplant lymphoproliferative disorder (Epstein-Barr virus)
Progressive multifocal leukoencephalopathy (PML), John Cunningham (JC) virus [excluded from the study]
Fungal
Aspergillosis (invasive disease only)
Blastomycosis
Candidiasis (invasive disease or pharyngeal)
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Paracoccidioides infections
Penicillium marneffei
Pneumocystis jirovecii (formerly Pneumocystis carinii)
Sporothrix schenckii
Other invasive fungi: Mucormycosis (zygomycosis) (Rhizopus, Mucor and Lichtheimia), 
Scedosporium/Pseudallescheria boydii, Fusarium
Protozoan
Leishmaniasis (visceral only)
Microsporidiosis
Toxoplasmosis
Trypanosoma cruzi infection (Chagas’ disease) (disseminated disease only)
Source:  Adapted from  Winthrop et al. 2015.
This table is provided to aid the investigator in recognizing infections that may be considered 
opportunistic in the context of biologic therapy, for the purposes of Exclusion Criterion [28c].  This list is 
not exhaustive.  Investigators should use their own clinical judgement in determining if other infections 
may be considered opportunistic, for the purposes of Exclusion Criterion [28c].  
Winthrop et al. (2015) consider tuberculosis (TB) and non-TB mycobacterial disease to be opportunistic 
infections in the context of biologic therapy.  See Section 9.4.5.3 for the approach to screening for latent 
TB infection within the study.  Patients with any history of active TB are excluded from the study, 
regardless of previous or current TB treatments. 


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Appendix 9.
Prohibited Medications


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This section outlines medications that are prohibited during the treatment phase of the study, 
including discontinuation windows for prohibited medications prior to the screening endoscopy, 
if applicable.  Use of the medications listed in this appendix is allowed at the discretion of the 
investigator after a patient discontinues study drug and completes the early termination visit.


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Drug Class
Prohibited Medication Restrictions
Anti-TNF antibodies (for example, infliximab, adalimumab or 
golimumab)
Discontinue at least 8 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Anti-integrin antibodies (for example, vedolizumab)
Discontinue at least 8 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Agents depleting B or T cells (for example, rituximab, 
alemtuzumab, or visilizumab)
Discontinue at least 12 months prior to baseline; 
patients remain excluded if evidence of persistent 
targeted lymphocyte depletion at the time of 
screening endoscopy
Immunomodulatory medications, including oral cyclosporine, 
IV cyclosporine, tacrolimus, mycophenolate mofetil, 
thalidomide, or JAK inhibitors (for example, tofacitinib) 
Discontinue at least 4 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered 5-ASA therapies (enemas or 
suppositories)
Discontinue at least 2 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered investigational preparations for UC such 
as arsenic preparations
Discontinue at least 4 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered corticosteroids (enemas or suppositories)
Discontinue at least 2 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
IV corticosteroids for UC
Discontinue at least 2 weeks prior to screening 
endoscopy.  A course of IV corticosteroids for 
UC is prohibited throughout duration of study
Systemic corticosteroids for non-UC indications (oral or IV) 
Patients requiring systemic corticosteroids for 
non-UC indications are excluded.  Exceptions 
include corticosteroids to treat adrenal 
insufficiency, premedication for IP infusion, or 
locally administered corticosteroids (e.g. inhaled, 
intranasal, intra-articular, topical) (see Appendix 
10).
Oral budesonide standard formulation (that is not the oral 
budesonide extended release tablet formulation [budesonide 
MMX])
Discontinue at least 2 weeks prior to 
screening endoscopy and prohibited 
throughout duration of study.  
Any investigational therapy (biologic or nonbiologic) 
Discontinue at least 4 weeks, or 5 half-lives 
whichever is longer, prior to screening endoscopy 
and prohibited throughout duration of study
Interferon therapy
Discontinue at least 8 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Leukocyte apheresis (leukapheresis, for example, Adacolumn)
Discontinue at least 3 weeks prior to screening 
endoscopy


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Drug Class
Prohibited Medication Restrictions
Anti-IL12p40 antibodies (for example, ustekinumab [Stelara®]) 
or anti-IL-23p19 antibodies (for example, risankizumab [BI-
655066], brazikumab [MEDI-2070], guselkumab 
[CNTO1959], tildrakizumab [MK-3222]) for any indication, 
including investigational use
Patients with any previous exposure not eligible 
to be enrolled
Bacillus Calmette-Guerin (BCG) vaccine
Last vaccination (if any) given at least 12 months 
prior to baseline.  BCG vaccination prohibited 
throughout the duration of the study and for 12 
months after discontinuation of study drug.
Live attenuated vaccines
Last vaccination (if any) given at least 3 months 
prior to baseline.  Live attenuated vaccines are 
prohibited throughout the duration of the study 
and for 3 months after discontinuation of study 
drug.
Abbreviations:  5-ASA = 5-aminosalicyclic acid; IV = intravenous; IP = investigational product; JAK = Janus 
Kinase; TNF= tumor necrosis factor; UC = ulcerative colitis.


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Appendix 10. Permitted Medications with Dose Stabilization


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Drug Class
Dose Stabilization Guidance
Oral 5-ASAs, for example, mesalamine, 
balsalazide, olsalazine and sulfasalazine
(for UC)
May continue during study with stable dose encouraged.
Oral corticosteroids for UC (prednisone 
≤20 mg/day or equivalent, budesonide 
MMX 9 mg/day, or beclomethasone 
dipropionate [gastro-resistant prolonged-
release tablet] 5 mg/day)
Prescribed dose must have been stable for at least 2 weeks before 
screening endoscopy and to remain stable for duration of study.
Corticosteroids for non-UC indications: 
corticosteroids to treat adrenal 
insufficiency, as premedication for IP 
infusion, or locally administered 
corticosteroids (e.g. inhaled, intranasal, 
intra-articular, topical).
May continue corticosteroids to treat adrenal insufficiency or locally 
administered corticosteroids during study with stable dose 
encouraged.  Single doses of oral or IV corticosteroids as 
premedication to IP administration are allowed in patients with prior 
IP or other previous biologic injection reactions.
Immunomodulators (for example, AZA, 
6-MP or methotrexate)
Prescribed at stable dose for at least 8 weeks before screening 
endoscopy; doses should remain stable throughout study unless 
medication is discontinued due to a toxicity related to the medication.  
Antidiarrheals (for example, loperamide, 
diphenoxylate with atropine)
May continue during study with stable doses encouraged.
Low-dose or baby aspirin (75 to 162.5 mg)
Daily use for cardiovascular prophylaxis permitted.
Non-live (killed, inactivated or subunit) 
vaccines
Allowed during the study.  The efficacy of non-live vaccinations with 
concomitant mirikizumab treatment is unknown.
Abbreviations:  5-ASA = 5-aminosalicyclic acid; 6-MP = 6-mercaptopurine; AZA = azathioprine; IV = intravenous; 
IP = investigational product; UC = ulcerative colitis.


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Appendix 11. Additional Information on Systemic Drug 
Administration Reactions


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A systemic drug administration reaction is defined if any of the following symptoms is present, 
in the absence of other plausible and more likely etiology, per investigator judgment: 

Generalized urticaria or pruritus

Angioedema at a location other than the injection site

Throat tightness

Difficulty swallowing/talking

Stridor

Chest tightness/dyspnea

Wheeze/bronchospasm

Hypoxemia

“Sense of impending doom”

Hypotension (systolic blood pressure change > 20 mmHg from baseline)

Syncope

Collapse

Vomiting 

Abdominal pain

Diarrhea

Bladder/Bowel incontinence


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Appendix 12. Additional Information on the Columbia 
Suicide Severity Rating Scale, and Quick Inventory of 
Depressive Symptomatology (self report)


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Columbia Suicide Severity Rating Scale
The C-SSRS was developed by the National Institute of Mental Health Treatment of Adolescent 
Suicide Attempters trial group for the purpose of being a counterpart to the Columbia 
Classification Algorithm of Suicide Assessment categorization of suicidal events.  For this study, 
the scale has been adapted (with permission from the scale authors) to include only the portion of 
the scale that captures the occurrence of the 11 preferred ideation and behavior categories.  
Quick Inventory of Depressive Symptomatology—Self-Report (16 Items)
For the QIDS-SR16, a patient is asked to consider each statement as it relates to the way they 
have felt for the past 7 days.  There is a 4-point scale for each item ranging from 0 to 3.  The 
16 items corresponding to 9 depression domains are summed to give a single score ranging from 
0 to 27, with higher scores denoting greater symptom severity.  The domains assessed by the 
instrument include:  (1) sad mood, (2) concentration, (3) self-criticism, (4) suicidal ideation, 
(5) interest, (6) energy/fatigue, (7) sleep disturbance (initial, middle, and late insomnia or 
hypersomnia), (8) decrease/increase in appetite/weight, and (9) psychomotor 
agitation/retardation. Patients will record their responses to the QIDS-SR16 electronically as 
source data in the tablet device at appropriate visits.


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Appendix 13. Protocol Amendment I6T-MC-AMAN(a)
Summary A Phase 3, Multicenter, Randomized, Double-
Blind, Parallel, Placebo-Controlled Induction Study of 
Mirikizumab in Conventional-Failed and Biologic-Failed 
Patients with Moderately to Severely Active Ulcerative 
Colitis
LUCENT 1
Overview
Protocol I6T-MC-AMAN, A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, 
Placebo-Controlled Induction Study of Mirikizumab in Conventional-Failed and Biologic-Failed 
Patients with Moderately to Severely Active Ulcerative Colitis LUCENT 1 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 described in the 
following table:
Amendment Summary for Protocol I6T-MC-AMAN Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 1 Synopsis, 
Objectives/Endpoints:  
Added, modified or deleted major 
secondary and other secondary 
objectives and endpoints 
Match Section 4 Objectives and 
Endpoints
Section 1 Synopsis, Statistical 
Analysis
Updated power calculations 
Match Section 10 Statistical 
Considerations
Section 2 Table AMAN.1. Schedule 
of Activities
Updated window for V5
Allow more time for V5
Section 2 Table AMAN.1. Schedule 
of Activities, Explain UC remission 
stool frequency question to patient 
Added task to schedule of activities 
to explain UC remission stool 
frequency question to patient 
Added this task to ensure patient’s 
proper understanding of the UC 
remission question
Section 2 Table AMAN.1. Schedule 
of Activities, FSH
Added that FSH is optional in 
women to confirm nonchild-bearing 
potential
Clarification of the patient for whom 
FSH should be performed
Section 2 Table AMAN.1. Schedule 
of Activities, PK Assessment
samples and ADA Assessment
Clarified that patients with potential 
hypersensitivity or infusion-related 
event should have sample taken as 
soon as possible after event occurs 
and at 4 and 12 to 16 weeks after the 
event.
Clarification to be consistent with 
management of hypersensitivity and 
infusion-related event section 
Section 2 Table AMAN.1. Schedule 
of Activities, C. difficile testing
C. difficile testing added to V5, ETV 
and UV
Allow additional testing for 
detection 
Section 2 Table AMAN.1. Schedule 
of Activities, Endoscopy with 
biopsies
Added clarification to refer to 
Section 9.1.1.3 of the protocol for 
specification of what endoscopic 
Clarification of Table AMAN.1. 
Schedule of Activities comment for 
Endoscopy with biopsies


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Section # and Name
Description of Change
Brief Rationale
procedure can be performed when.  
Section 2 Table AMAN.1. Schedule 
of Activities, PGRC
Removed PGRC at V1
Corrected error in original protocol 
since this assessment is not 
applicable at baseline 
Section 2 Table AMAN.1. Schedule 
of Activities
Added a description of “normal” SF 
Clarification of definition of normal 
stool frequency for the modified 
Mayo score to patients entering the 
study  
Section 2 Table AMAN.1. Schedule 
of Activities
Added footnotes and abbreviations
Clarification of acronyms and 
procedures 
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Added major secondary objective 
and endpoint of bowel movement 
urgency and removed from other 
secondary objective and endpoint list
Modified endpoint to assess 
improvement in urgency. Published 
literature shows that improvement in 
urgency is a clinically meaningful 
endpoint and supports urgency as 
one of the most bothersome 
symptoms experienced by patients 
with UC. Therefore, this endpoint 
has been moved from an other 
secondary endpoint to a major 
secondary endpoint.
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Other secondary objectives and 
endpoints clarified
Histologic remission alone will no 
longer define mucosal healing. The 
objective has been modified to 
reflect the clarification of mucosal 
healing and location of definition 
clarified throughout the protocol 
amendment. 
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Other secondary objectives and 
endpoints clarified 
Clarified the definition of 
symptomatic response
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Other secondary objectives and 
endpoints added 
Included UCEIS endoscopic 
remission; the UCEIS is considered 
to be an important endpoint 
assessing endoscopic disease 
activity.  The central reading of 
endoscopies has included this 
assessment from the onset of the 
study.  We are now adding it as an 
other secondary endpoint.
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Other secondary objectives and 
endpoints added
Modified definition of the mucosal 
healing endpoint to align with 
current scientific literature, recent 
UC clinical trials, and regulatory 
guidance. New definition includes 
histologic remission plus endoscopic 
remission.   
Section 4 Objectives and Endpoints, 
Table AMAN.2.
Other secondary objectives and 
endpoints added
Fatigue is a common symptom for 
patients with active disease. Added 
Fatigue endpoint to assess 
improvement in Fatigue. Published 
literature support fatigue as an 


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Section # and Name
Description of Change
Brief Rationale
important symptom experienced by 
patients with UC. Therefore, this 
endpoint has been added as an other 
secondary endpoint 
Section 6.1 Inclusion Criteria, 
Disease-Specific Inclusion Criteria
Added language that patients with 
rectal sparing on baseline endoscopy 
must have documentation of rectal 
involvement on a prior endoscopy 
and histopathology report to confirm
UC diagnosis.
Additional clarification to confirm 
UC diagnosis.
Section 6.1 Inclusion Criteria, 
Disease-Specific Inclusion Criteria
Changed entry criteria requiring 
endoscopy to be performed within 
14 rather than 10 days before 
baseline
To accommodate the time for central 
reading and scoring of endoscopy, 
the time from screening endoscopy 
to randomization was extended to 14 
days. This change does not impact 
the baseline endoscopic evaluation. 
Section 6.1 Inclusion Criteria, 
Disease-Specific Inclusion Criteria
Modified wording: “have evidence 
of UC extending beyond the rectum 
(more proximal to the rectosigmoid 
junction)…” 
Editorial change  
Section 6.1 Inclusion Criteria, Prior 
Medication Failure Criteria
Prednisone-equivalent language 
clarified in Inclusion Criterion 8(a): 
oral corticosteroid excluding 
budesonide MMX and 
beclomethasone dipropionate gastro-
resistant prolonged-release tablet”
Clarification added to the 
corticosteroid conventional therapy 
failure inclusion criterion excluding 
budesonide MMX and 
beclomethasone dipropionate gastro-
resistant prolonged-release tablet as 
these 2 medicines are orally 
available steroids with high first-
pass metabolism, leading to limited 
systemic exposure. These 
preparations are approved or 
commonly used for the treatment of 
mild-moderate UC in some 
countries. Prior failure of these 
therapies does not qualify as 
conventional therapy failure.
Section 6.1 Inclusion Criteria, 
Biologic-failed patients
Clarified that the medication used to 
qualify the patient for entry into this 
category must be approved for the 
treatment of UC, deleting reference 
to the country of use at the time of 
use
Clarified language regarding 
approved therapies
Section 6.1 Inclusion Criteria, Study 
Procedure Inclusion Criteria
Removed assessment required by 
investigator due to the lab thresholds 
already described in Inclusion 
Criterion 11 
Clarification of assessment
Section 6.2 Exclusion Criteria, 
Gastrointestinal Exclusion Criteria
Exclusion criteria clarified that  
patients who  have had extensive 
colonic surgery for UC or for other 
reasons are excluded
Clarification of exclusion criteria
Section 6.2 Exclusion Criteria, 
Criteria clarified from 
Clarification of exclusion criteria


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Section # and Name
Description of Change
Brief Rationale
Criteria for Prohibited Medications 
‘Discontinuing Prohibited 
Medications’ to ‘Prohibited 
Medications”
Section 6.2 Exclusion Criteria, 
Criteria for Prohibited Medications
Oral budesonide standard 
formulation added to Exclusion 
Criterion 19(a).
Clarification of exclusion criterion
Section 6.2 Exclusion Criteria, 
Infectious Disease Exclusion 
Criteria
Deleted ‘toxin’ from C. difficile in 
Exclusion Criterion 27
Clarification of what constitutes a C. 
difficile infection 
Section 6.2 Exclusion Criteria, 
Infectious Disease Exclusion 
Criteria
Modified wording for extraintestinal 
infection criteria deleting redundant 
phrase 
Editorial change
Section 6.2 Exclusion Criteria, 
Infectious Disease Exclusion 
Criteria
Changed: “patients with nonserious 
extraintestinal infections not 
adequately treated prior to 
screening” from “must have been 
adequately treated prior to 
screening”  
Editorial change 
Section 6.2 Exclusion Criteria, 
General Exclusion Criteria
Added C-SSRS to Exclusion 
Criterion 37
Editorial change
Section 6.4 Screen Failure
Changed to: “stool for C. difficile
stool toxin/stool culture/stool ova 
and parasites”
Clarified screen failure criteria 
related to C. difficile infection 
Section 7.7 Concomitant Therapy
Deleted text to align with other 
sections of the protocol. 
Since all permitted UC concomitant 
medications have to remain at stable 
doses throughout the trial, deleted 
reference to corticosteroids since 
tapering of corticosteroids occurs in 
the maintenance study. In addition, 
removed discussion of treatment 
failure since treatment failure is 
defined in other sections of the 
protocol.
Section 7.8.3.2 Management of 
Hypersensitivity, Infusion Related 
Events, and Infusion Site Reactions
Added “These samples will also be 
used for tryptase, complement 
(C3/C4), and cytokine panel assays.”
Additional assessments added to 
better understand the possible 
etiology if a drug hypersensitivity 
event is observed, including markers 
of basophil/mast cell activation (i.e. 
tryptase), immune complex 
formation (i.e. C3/C4 levels) and 
cytokine release (i.e., cytokine 
panel). No additional blood would 
be required for this sample 
collection. 
Section 7.8.3.2 Management of 
Hypersensitivity, Infusion Related 
Events, and Infusion Site Reactions
Under “Other Infusion-Related 
Events and Infusion Site Reactions” 
clarified reaction consisting of 
headache, rigors and/or temperature 
>38°C
Clarification of criteria for other 
infusion related events 
Section 7.8.3.2 Management of 
Hypersensitivity, Infusion Related 
Added “These samples will also be 
used for tryptase, complement 
Additional assessments added to 
better understand the possible 


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Section # and Name
Description of Change
Brief Rationale
Events, and Infusion Site Reactions 
(C3/C4), and cytokine panel assays.”
etiology if a drug hypersensitivity 
event is observed, including markers 
of basophil/mast cell activation (i.e. 
tryptase), immune complex 
formation (i.e. C3/C4 levels) and 
cytokine release (i.e., cytokine 
panel). No additional blood would 
be required for this sample 
collection. 
8.1.1. Permanent Discontinuation 
from Study Treatment, Safety 
Criteria for Study Drug 
Discontinuation
The patient requiring a 
proctocolectomy or partial 
colectomy during the study was 
added to safety criteria for drug 
discontinuation
Clarification of safety criteria for 
drug discontinuation
Table 9.1. Efficacy Assessments, 
Table AMAN.4.
Term “Mucosal Healing” deleted 
from Histologic remission endpoint 
definition
Clarification of term “histologic 
remission”
Table 9.1. Efficacy Assessments, 
Table AMAN.4.
“Mucosal Healing” endpoint 
definition  added to table
Clarification to be consistent with 
Section 4 Objectives and Endpoints
Table 9.1. Efficacy Assessments, 
Table AMAN.4.
“Histologic Response” endpoint 
definition removed 
Since there is no histologic response 
endpoint in Section 4, this definition 
is not needed and therefore was 
removed. 
Table 9.1. Efficacy Assessments, 
Table AMAN.4.
Footnote under Table AMAN.4 has 
been deleted
Clarification to be consistent with 
Section 4 Objectives and Endpoints
Table 9.1. Efficacy Assessments, 
Table AMAN.4.
Term ‘bowel movement urgency 
improvement” added to endpoint 
definition table
Now included as a major secondary 
endpoint because of unmet patient 
needs and the symptom being one of 
the most meaningful and important 
symptoms from patient perspective
9.1.1.2. Mayo Score
Deleted from SF Subscore and 
expanded to its own sub-section: 
Normal SF for that patient is based 
on reported SF when the patient was 
in remission or reported SF before
initial onset of signs and symptoms 
of UC.  
Sentence moved to new description 
of Normal SF and to provide 
additional detail regarding the 
definition
Section 9.1.1.3. Endoscopy
Window changed for a flexible 
sigmoidoscopy or colonoscopy to be 
performed from within 10 days to 14 
days prior to randomization  
This change was made to be 
consistent with changes in Section 
6.1
Section 9.1.1.3. Endoscopy, 3.
Added extent of disease 
clarification. Added clarification that 
patients with rectal sparing on 
baseline endoscopy must have 
documentation of rectal involvement 
on a prior endoscopy
This change was made to be 
consistent with changes in Section 
6.1 
Section 9.1.1.3. Endoscopy
Wording added to clarify when 
colonoscopy can be performed 
instead of flexible sigmoidoscopy in 
the judgement of the investigator 
Clarification of when to discuss with 
medical monitor the need for 
colonoscopy vs. flexible 
sigmoidoscopy to assure appropriate 




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Section # and Name
Description of Change
Brief Rationale
10.1. Sample Size Determination
Power calculations in study 
population updated to be consistent 
with current population.  Rates for 
clinical remission changed from 
“maintaining” to “achieving”. 
Power calculations in study updated 
to reflect changes in the assumed 
proportion of biologic- and 
conventional-failed patients. 
Editorial changes made
Section 10.3.1.1.Missing Data 
Imputation
Deleted “or take rescue medication 
prior to the time point of interest”
Modifications made to align with 
other recent UC clinical trials and to 
clarify that patients who require 
treatment with rescue medication 
should be discontinued from the trial 
as described in Section 8.1.1 of the 
protocol. Therefore, imputing such 
patients as nonresponders will be 
performed because the data will be 
missing.
Section 11. References
References added
Editorial change
Appendix 1. Abbreviations and 
Definitions
Term added
Editorial Change
Appendix 2. Clinical Laboratory 
Tests
Other tests along with their 
associated footnotes added; one 
footnote deleted
Clarification of procedures. Updates 
made to align with Section 7.8.3.2 
Management of Hypersensitivity, 
Infusion Related Events, and 
Infusion Site Reactions of the 
protocol 
Appendix 3. Section 3.1.7. Final 
Report Signature
Deleted that the investigator with 
most enrolled patients will be 
selected by the study team to act as 
the CSR coordinating investigator
This change reflects that the 
selection of CSR coordinating 
investigator is not dependent on 
number of patients enrolled. 
Appendix 6. Mayo Scoring System 
for the Assessment of Ulcerative 
Colitis Activity
Note added to table for stool 
frequency
Definition of normal stool frequency 
when in remission from UC to align 
with Section 9.1.1.2 of the protocol
Appendix 7. Patient Reported 
Outcome Instruments
Replaced language in definition of 
Abdominal Pain Numeric Rating 
Scale (NRS) and Fatigue NRS   
Clarification of definitions of ranges
Appendix 9 Prohibited Medications
Term “washout periods” has been 
replaced with “discontinuation 
windows for prohibited 
medications”
Clarification of discontinuation 
windows for prohibited medications 
Appendix 9. Prohibited Medications
Replaced table heading category 
“Conditions for Washout” with 
“Prohibited Medication 
Restrictions”
Clarification of discontinuation 
windows for prohibited medications
Appendix 9. Prohibited Medications
Added rectally administered 
investigational preparations for UC 
and restrictions 
Arsenic and other therapies were 
added because it was recognized that 
there are other treatments for UC in 
certain countries that need to be 
considered as prohibited 
medications. 
Appendix 9. Prohibited Medications
Added “for UC” to IV 
corticosteroids category
Clarification of  restrictions for IV 
corticosteroid use for UC vs. non 


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Section # and Name
Description of Change
Brief Rationale
UC indication. 
Appendix 9. Prohibited Medications
Added that patients requiring 
systemic corticosteroids for non-UC 
indications are “excluded.” Added 
“Exceptions include: premedication 
for IP infusion or locally” 
Added allowance for single limited 
dose for study drug administration 
premedication.  This would be a 
single limited dose that would not be 
expected to affect efficacy. Other 
minor editorial changes were made. 
Appendix 10. Permitted Medications 
with Dose Stabilization
Added sulfasalazine as another oral 
5-ASA example 
Clarification of drug class
Appendix 10. Permitted Medications 
with Dose Stabilization
Added to Drug Class: oral 
corticosteroids “for UC” indications 
clarification
Clarified that oral corticosteroids are 
allowed for UC indication 
Appendix 10. Permitted Medications 
with Dose Stabilization
Added beclomethasone dipropionate 
[gastro-resistant prolonged-release 
tablet] 5 mg/day
Based on wide use of this 
corticosteroid in certain countries, 
this medication was added as a 
permitted medication during the 
study along with prednisone or 
equivalent or budesonide MMX. 
Appendix 10. Permitted Medications 
with Dose Stabilization
Added to Drug Class: 
“corticosteroids for non-UC 
indications” that are allowed. 
Added clarification to reinforce the 
exception to the prohibited 
concomitant medications 


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1.
Synopsis
Objectives/Endpoints
Objectives
Endpoints
Major Secondarya

To evaluate the efficacy of treatment with 
mirikizumab compared to placebo in inducing 
bowel movement urgency improvement at 
Week 12 in patients with bowel urgency 
symptoms at baseline

The proportion of patients with bowel movement 
urgency improvement at Week 12 as defined in the 
study statistical analysis plan (SAP)
Other Secondary (continued)

To evaluate histologic remission (mucosal
healing) between mirikizumab and placebo at 
Week 12

Proportion of patients in histologic remission, as 
defined in the histopathology charter SAP

To evaluate the time to symptomatic 
response

Time to symptomatic response, defined as at least 
a 30% decrease from baseline in the composite 
clinical endpoint of the sum of SF and RB subscores

To evaluate the effect of mirikizumab 
compared to placebo on changes in the 
urgency numeric rating scale (NRS) at Week 
12
Change from baseline in: 

Urgency NRS at Week 12

To evaluate the efficacy of mirikizumab 
compared to placebo in Ulcerative Colitis 
Endoscopic Index of Severity (UCEIS) 
endoscopic remission at Week 12

The proportion of patients with a UCEIS score 
of ≤1 at Week 12

To evaluate the efficacy of mirikizumab 
compared to placebo in mucosal healing at 
Week 12

The proportion of patients with mucosal healing at 
Week 12, defined as achieving both:  
o Histologic remission, as described in the 
histopathology charter SAP, and
o Endoscopic remission, defined as ES = 0 or 1 
(excluding friability)

To evaluate the efficacy of mirikizumab 
compared to placebo on changes in fatigue at 
Week 12.

Change from baseline in Fatigue NRS scores at 
Week 12. 


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1.
Synopsis 
Statistical Analysis 
(1) The randomized study population will include approximately 5060% biologic-failed patients 
and approximately 5040% conventional-failed patients.  
(2) The predicted clinical remission rates at Week 12 for mirikizumab versus placebo are 
expected to be 21.6 23% versus 6.9 7.8% (biologic-failed patients:  16% versus 3.5%; 
conventional-failed patients:  30% versus 12%).
The primary endpoint of this study is ato test the hypothesis that mirikizumab is superior to 
placebo in inducing clinical remission at Week 12 in patients with moderately to severely active 
UC.  Given the assumptions described above, a sample size of 1160 patients are expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this 
endpoint, as assessed usingbased on a chi-square test with a 2-sided significance level of 
0.00125.  
Patients who complete Study AMAN may be eligible to participate in Study AMBG, a 40-week 
maintenance study.  One endpoint of interest in The primary objective of Study AMBG is to test 
the hypothesis that mirikizumab is superior to placebo in maintaining achieving clinical 
remission at Week 40 of Study AMBG (Week 52 of continuous therapy) amongst patients 
induced into clinical remissionresponse with mirikizumab at Week 12 of Study AMAN.  A 
sample size of 1160 patients in Study AMAN is predicted to ensure that there will be a sufficient 
number of biologic-failed patients in clinical remission at Week 12 of Study AMAN who will 
enter Study AMBG.,  This is expected to provide in order to achieve an approximately 980% 
power to demonstrate that mirikizumab is superior to placebo in achieving this the primary
endpoint in Study AMBG, as assessed based on using a chi-square test with a 2-sided 
significance level of 0.05.  
2.
Schedule of Activites 
Table AMAN.1.
Schedule of Activities 
Visit 5:  85 ± 4 7
Procedure added to V0:  Explain UC remission stool frequency question to patient; Notes: 
Investigator or site staff should explain the purpose of UC remission question in the TrialSlate 
(tablet) device before the patient answers the question to ensure accurate data capture. Errors in 
response cannot be corrected once response is saved and confirmed by the patient.
Procedure:  FSH (optional in women to confirm nonchild-bearing potential)e
PK Assessment:  Patients with potential hypersensitivity or infusion-related event should have 
sample taken as soon as possible after event occurs,
ADA Assessment:  Patients with potential hypersensitivity or infusion-related event should have 
sample taken as soon as possible after event occurs


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C. Difficile Testing:  visits added to V5, ETV, and V997
Endoscopy with biopsies:  Screening endoscopy within 1014 days of V1. Please refer to Section 
9.1.1.3 for procedure clarification.
PGRC:  V1 visit deleted
Abbreviations:  DNA = deoxyribonucleic acid; RB = rectal bleeding; SF = stool frequency;
Footnotes:
f
Clostridium difficile tests at V5 and ETV may be performed for patients who do not move into Study AMBG.
g Clostridium difficile test at UV may be performed if visit is due to worsening SF and/or RB.
4.
Objectives and Endpoints 
See Section 1 Synopsis Objective(s)/Endpoints above
6.1.
Inclusion Criteria
Disease-Specific Inclusion Criteria
[4.] have had an established diagnosis of UC of ≥3 months in duration before 
baseline (Week 0), which includes endoscopic evidence of UC and a 
histopathology report that supports a diagnosis of UC (see Section 9.1.1.3).  
Supportive endoscopy and histopathology reports must be available in the 
source documents.  Patients with rectal sparing on baseline endoscopy must 
have documentation of rectal involvement on a prior endoscopy and 
histopathology report to confirm UC diagnosis.
[5.] have moderately to severely active UC as defined by a modified Mayo 
score (MMS) of 4 to 9 with an endoscopic subscore (ES) ≥2, with endoscopy 
performed within 1014 days before baseline.
[6.] have evidence of UC extending proximal to the rectum (distal to the 
rectosigmoid junction, which lies approximately 10 15 cm from anal margin).
have evidence of UC extending beyond the rectum (more proximal to the 
rectosigmoid junction).  The rectosigmoid junction lies approximately 10 to 
15 cm from the anal margin.
6.1.
Inclusion Criteria
Prior Medication Failure Criteria
[8a.] Conventional-failed patients:  Patients who have an inadequate response 
to, loss of response to, or are intolerant to at least one of the following 
medications: 

corticosteroids
o
corticosteroid-refractory colitis, defined as signs and/or symptoms of 
active UC despite oral prednisone (or equivalent oral corticosteroid 
excluding budesonide MMX and beclomethasone dipropionate gastro-
resistant prolonged-release tablet) at doses of at least 30 mg/day for a 
minimum of 2 weeks; or


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[8b.] Biologic-failed patients:  Patients who have an inadequate response to, loss 
of response to, or are intolerant to biologic therapy for UC (such as anti-
TNF antibodies or anti-integrin antibodies) or to janus kinase (JAK) 
inhibitors (such as tofacitinib).  The medication used to qualify the patient 
for entry into this category must be approved for the treatment of UC. in the 
country of use, at the time of use.  Investigators must be able to document 
an adequate clinical trial of the medication.  Patients should fulfill 1 of 
the following criteria:  

Inadequate response:  Signs and symptoms of persistently active disease 
despite induction treatment at the approved induction dosing that was indicated 
in the product label at the time of use, or
6.1.
Inclusion Criteria
Study Procedure Inclusion Criteria
[11.] have clinically acceptable central laboratory test results at screening 
(retesting is allowed for hematology and chemistry), as assessed by the 
investigator, including:
6.2.
Exclusion Criteria
Gastrointestinal Exclusion Criteria:
[14.] previous bowel resection or intestinal or intra-abdominal surgery:  

have had extensive colonic surgery for UC or for other reasons (for example, 
subtotal colectomy), or are likely to require surgery for the treatment of UC 
during the study.  Patients who have had limited colonic surgery for UC (for 
example, segmental colonic resection) may be allowed in the study, if this does 
not affect the assessment of efficacy.  Discussion with the sponsor should occur 
prior to screening of such patients.  
6.2.
Exclusion Criteria
Criteria for DiscontinuingProhibited Medications
[19a.] corticosteroid enemas, corticosteroid suppositories, oral budesonide standard 
formulation, or a course of IV corticosteroids within 2 weeks prior to 
screening endoscopy.
6.2.
Exclusion Criteria
Infectious Disease Exclusion Criteria
[27.] had Clostridium difficile or other intestinal infection within 30 days of screening 
endoscopy, or test positive at screening for C. difficile toxin or for other intestinal 
pathogens.  


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   [28.] patients with serious, opportunistic or chronic/recurring extraintestinal 
infections  should be adequately treated and off antibiotics for 30 days without 
recurrence of symptoms prior to screening, .  Serious extraintestinal infections 
include but are including but not limited to the following:·
[29.] Patients with nonserious extraintestinal infections must have beennot 
adequately treated prior to screening.  
6.2.
Exclusion Criteria
General Exclusion Criteria:
[37.] presence of significant uncontrolled neuropsychiatric disorder or judged at 
risk of suicide in the opinion of the investigator; 
OR
marked yes to C-SSRS suicide behaviors questions during the screening period prior to 
dosing at Visit 1;
6.4.
Screen Failures
Patients who have failed screening because of Exclusion Criterion [27] may be rescreened once 
when the reason for screen failure has resolved.  It is recommended that the investigator confirms 
the patient has a negative stool for C. difficile stool toxin/stool culture/stool ova and parasites (as 
applicable) before performing additional rescreening investigations (see Section 9.4.5.7).
7.7.
Concomitant Therapy
Patients taking permitted UC concomitant medications other than oral corticosteroids, are to 
keep doses stable unless modifications are needed due to AEs and follow the instructions 
regarding dose stabilization as detailed in Appendix 10.  Administration of prohibited UC 
medications, approved or investigational, constitutes treatment failure.  Use of such medications 
should not be withheld if, in the opinion of the investigator, failure to prescribe them would 
compromise patient safety.  Patients who require a prohibited medication to treat their UC (see 
Appendix 9) need to be discontinued from study drug and complete an ETV and posttreatment 
follow-up visits. 
7.8.3.2.
Management of Hypersensitivity, Infusion Related Events, and Infusion Site 
Reactions
Hypersensitivity Events

After patient’s stabilization, an ADA and PK sample should be collected; additional 
samples should be obtained 4 and 12 to 16 weeks after the event.  These samples will also 
be used for tryptase, complement (C3/C4), and cytokine panel assays.
Other Infusion-Related Events and Infusion Site Reactions
If a patient experiences a reaction consisting of headache, rigors and/or temperature >38°C (in 
the absence of other signs or symptoms of a systemic hypersensitivity reaction), 




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9.1.1.3.
Endoscopy 
Endoscopy will be used to determine the Mayo ES at screening and Week 12 (or ETV).  Site and 
blinded central reading of endoscopies will be used to determine ES.
A flexible sigmoidoscopy or colonoscopy will be performed on all patients during screening, 
within 1014 days prior to randomization.  
3. Patients who do not have the report of a completed, full colonoscopy available in source 
documents to establish extent of the disease.  Patients with rectal sparing on baseline endoscopy 
must have documentation of rectal involvement on a prior endoscopy.
4. Where, in the opinion of the investigator, a colonoscopy is indicated at screening, for example, 
to confirm that a recent removal of an adenomatous polyp is complete prior to randomization.  
If a patient already has up-to-date surveillance for dysplasia and/or up-to-date screening for 
colorectal cancer, the endoscopy report and histopathology report (if applicable) used to support 
this must be available in the source documents, in order to satisfy Inclusion Criterion [7].
Patients who undergo colonoscopy at screening do not require a separate flexible sigmoidoscopy
in the same screening period.
At Week 12 (or ETV), patients will undergo a flexible sigmoidoscopy is recommended for all 
patients.  Colonoscopy can be performed instead of flexible sigmoidoscopy at Week 12 for 
clinically indicated reasons in the judgement of the investigator and after discussion with the 
medical monitor as appropriate.  The endoscopy report and histopathology report (if biopsies are 
sent to the local histopathology laboratory) must be available in the source documents.  Patients 
who undergo a flexible sigmoidoscopy at an ETV will  not  undergo  additional endoscopies 
within the study.  Patients who discontinue the study drug because of pregnancy will not
undergo a flexible sigmoidoscopy at their ETV.
If a patient undergoes early termination soon after screening endoscopy, the need for ETV 
endoscopy should be discussed with the medical monitor.
9.1.2.1.
Major Secondary Endpoints
The major secondary endpoints are as follows:

Clinical response at Week 12 in the biologic-failed population.

Bowel movement urgency improvement at Week 12.
9.1.2.1.1.
Patient Reported Outcome Instruments
The Urgency Numeric Rating Scale (NRS) (see Appendix 7 for description) is a patient-reported 
outcome (PRO) instrument collected using a patient eDiary.  The Urgency NRS will be used to 
determine the secondary endpoint for bowel movement urgency improvement.


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9.1.2.2.1.
Physician Reported Instrument
The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a physician-reported instrument 
for measuring the endoscopic disease activity of UC on flexible sigmoidoscopy or colonoscopy, 
that includes 3 descriptors of vascular pattern, bleeding, and erosions/ulcerations (Arai et al. 
2016; Ikeya et al. 2016; Tontini et al. 2014).  Only blinded central reading of endoscopies will be 
used to determine the UCEIS score for each endoscopy.
9.1.2.2.2.
Patient Reported Outcome Instruments 
The following are additional PRO instruments collected using a patient eDiary.  Please see 
Appendix 7 for additional descriptions

Abdominal Pain Numeric Rating Scale (NRS)

Fatigue NRS

Urgency NRS
9.1.3.1.1.
Patient Reported Outcome Instruments 
In addition to stool frequency and rectal bleeding discussed in Section 9.1.1.2, and abdominal 
pain and urgency discussed in Section 9.1.2.2.1, fatigue is measured using an 11-point NRS, 
where ‘0’ = “No Symptom” and ‘10’ = “Symptom as bad as I could imagine”.  The diary also 
includes items that asks the patient to report stool consistency, the frequency of night-time stools, 
fatigue, and overall disease severity.
The following exploratory endpoints will be assessed daily via the electronic diary tool:

Patient’s Global Rating of Severity (PGRS)

Fatigue NRS
9.4.4. Immunogenicity Assessments
In the event of a drug hypersensitivity event (immediate or nonimmediate), additional samples 
for ADA and PK will be collected as close to the onset of the event as possible and at 4 and 12 to 
16 weeks after the event.  These samples will also be used for tryptase, complement (C3/C4), 
and cytokine panel assays. 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 should 
be recorded.  
9.4.5.3.
Tuberculosis Screening
Interpretation of Screening Tests for LTBI 
Patients with a diagnosis of LTBI, based on a positive IGRA test result or a positive TST 
response, and no evidence of active TB on medical history, physical examination and chest x-
ray, may be rescreened once and enrolled if they are treated for LTBI and meet the following 
requirements (as well as all other study entry criteria):

have received at least 4 weeks of appropriate ongoing prophylactic therapy for LTBI, 
based on national or international guidelines, for example the United States Centers for 


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Disease Control and Prevention guidance (CDC [WWW]) for the United States or the 
World Health Organization guidance for the treatment of LTBI for all countries outside 
of the United States (WHO LTBI [WWW])
9.4.5.7.
Stool Testing
C. difficile Toxin

A stool sample for C. difficile toxin will be obtained at screening.  This assay tests for the 
presence of C. difficile toxin protein, followed by a confirmatory test for C. difficile toxin 
gene expression in the stool sample.  

Patients should test negative must have a “negative” test for C. difficile stool toxin (C. 
difficile EIA)in order to be randomized (Exclusion Criterion 27).  Re-testing is allowed 
within the same screening period if there is a technical difficulty in performing or 
reporting the C. difficile toxin assays, or if in the judgement of the investigator, the 
patient’s symptoms or signs are not consistent with C. difficile infection.

Patients who test positive at screening for C. difficile can be re-screened once for the 
study, provided that they have been adequately treated and off antibiotics for 30 days.  
Patients who have been adequately treated for C. difficile with fecal microbial 
transplantation or IV immunoglobulin therapy can be re-screened once for the study, 30 
days after completing their therapy.  Testing for A C. difficile stool toxin assay should be 
repeated prior to re-screening, as a “negative” result is required prior to randomization.  
9.5.
Pharmacokinetics
 
 
 These samples will be retained at a facility selected by 
Lilly or its designee for a maximum of 15 years after the last patient visit for the study, or for a 
shorter period if local regulations and/or ERBs/investigational review boards impose shorter time 
limits.
10.1.
Sample Size Determination
The power calculations for this study assume the following:  
(1) The randomized study population will include approximately 6050% biologic-failed patients 
and approximately 4050% conventional-failed patients.  
(2) The predicted clinical remission rates at Week 12 for mirikizumab versus placebo are 
expected to be 21.623% versus 6.97.8% (biologic-failed patients:  16% versus 3.5%; 
conventional-failed patients:  30% versus 12%).
The primary endpoint of this study is a test the hypothesis that mirikizumab is superior to 
placebo in inducing clinical remission at Week 12 in patients with moderately to severely active 
UC.  Given the assumptions described above, a sample size of 1160 patients are expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this 
CCI


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endpoint, based on as assessed using a chi-square test with a 2-sided significance level of 
0.00125.  
Patients who complete Study AMAN may be eligible to participate in Study AMBG, a 40-week 
maintenance study.  One The primary objective of endpoint of interest in Study AMBG is to test 
the hypothesis that mirikizumab is superior to placebo in maintaining achieving clinical 
remission at Week 40 of Study AMBG (Week 52 of continuous therapy) amongst patients 
induced into clinical remission response with mirikizumab at Week 12 of Study AMAN.  A 
sample size of 1160 patients in Study AMAN is predicted to ensure that there will beprovide a 
sufficient number of biologic-failed patients in clinical remission at Week 12 of Study AMAN 
who will enter Study AMBG. , in order to achieve an approximately 80% This is expected to 
provide >90% power to demonstrate that mirikizumab is superior to placebo in achieving this the 
primary endpoint in Study AMBG, as assessed using based on a chi-square test with a 2-sided 
significance level of 0.05.  
10.3.1.1.
Missing Data Imputation

Nonresponder imputation (NRI):  For analysis of categorical efficacy and health 
outcomes variables, missing data will be imputed using an NRI method.  Patients will be 
considered nonresponders for the NRI analysis if they do not meet the categorical 
efficacy criteria or have missing clinical efficacy data at a time point of interest or take 
rescue medication prior to the time point of interest.
11.
References
Arai M, Naganuma M, Sugimoto S, Kiyohara H, Ono K, Mori K, Saigusa K, Nanki K, 
Mutaguchi M, Mizuno S, Bessho R, Nakazato Y, Hosoe N, Matsuoka K, Inoue N, Ogata H, 
Iwao Y, Kanai T. The Ulcerative Colitis Endoscopic Index of Severity is useful to predict 
medium- to long-term prognosis in ulcerative colitis patients with clinical remission. J Crohns 
Colitis. 2016;10:1303-1309.
Ikeya K, Hanai H, Sugimoto K, Osawa S, Kawasaki S, Iida T, Maruyama Y, Watanabe F. The 
ulcerative colitis endoscopic index of severity more accurately reﬂects clinical outcomes and 
long-term prognosis than the Mayo endoscopic score. J Crohns Colitis. 2016;10:286-295.
Tontini GE, Bisschops R, Neumann H. Endoscopic scoring systems for inﬂammatory bowel 
disease: Pros and cons. Expert Rev Gastroenterol Hepatol. 2014;8:543-554. 
Appendix 1.
Abbreviations
UCEIS         Ulcerative Colitis Endoscopic Index of Severity
Appendix 2.
Clinical Laboratory Tests
Other testsa
Tryptasei
Complement (C3/C4)i
Cytokine paneli


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Abbreviations:  ADA = anti-drug antibody; ETV = early termination visit; RB = rectal bleeding; SF = stool 
frequency; UV = unscheduled visit; V = visit.
h
Test required only at screening (Visit 0) to determine eligibility of patient for the study.  Visit 0 stool sample will 
be used for Clostridium difficile and biomarker testing.  
h
Clostridium difficile tests at V5 and ETV may be performed for patients who do not move into Study AMBG. 
Clostridium difficile test at UV may be performed if visit is due to to worsening SF and/or RB.
i
Test performed only in the event of systemic allergic/hypersensitivity events, along with ADA and PK.
Appendix 3.1.7.
Final Report Signature
The investigator with the most enrolled patients will serve as the CSR coordinating investigator 
will be selected by the study team.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the CSR coordinating investigator.
Appendix 6.
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Note:
Stool frequency reports the number of stools in a 24-hour period, relative to the normal number of stools for that 
patient.  The reference “normal” stool frequency for that patient will be recorded electronically at the screening visit.  
The Normal SF (stool frequency) refers to when the patient was in remission or, if the patient has never achieved 
remission, the reported stool frequency before initial onset of signs and symptoms of ulcerative colitis.  Remission 
refers to a period of time since being diagnosed with ulcerative colitis when the patient is not experiencing any signs 
or symptoms relating to ulcerative colitis.  This period of time may last a few weeks or a few months or may even 
last several years.  The patient will record this electronically as source data in the tablet device at the screening study 
visit.
Appendix 7.
Patient-Reported Outcome Instruments
Abdominal Pain NRS: A single item that measures the “worst abdominal pain in the past 24 
hours” using an 11-point NRS ranging from 0 (no pain) to 10 (pain as bad as can imagineworst 
possible pain).  
Fatigue NRS:  The Fatigue NRS is a single item that measures the “worst fatigue (weariness, 
tiredness) in the past 24 hours” using an 11-point NRS ranging from 0 (no fatigue) to 10 (fatigue 
as bad as you can imagine).
Appendix 9.
Prohibited Medications 
This section outlines medications that are prohibited during the treatment phase of the study, 
including discontinuation windows for prohibited medications washout periods prior to the 
screening endoscopy, if applicable.  Use of the medications listed in this appendix is allowed at 
the discretion of the investigator after a patient discontinues study drug and completes the early 
termination visit.


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Drug Class
Prohibited Medication RestrictionsConditions 
for Washout
Anti-TNF antibodies (for example, infliximab, adalimumab or 
golimumab)
Discontinue at least 8 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Anti-integrin antibodies (for example, vedolizumab)
Discontinue at least 8 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Agents depleting B or T cells (for example, rituximab, 
alemtuzumab, or visilizumab)
Discontinue at least 12 months prior to baseline; 
patients remain excluded if evidence of persistent 
targeted lymphocyte depletion at the time of 
screening endoscopy
Immunomodulatory medications, including oral cyclosporine, 
IV cyclosporine, tacrolimus, mycophenolate mofetil, 
thalidomide, or JAK inhibitors (for example, tofacitinib) 
Discontinue at least 4 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered 5-ASA therapies (enemas or 
suppositories)
Discontinue at least 2 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered investigational preparations for UC such 
as arsenic preparations
Discontinue at least 4 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
Rectally administered corticosteroids (enemas or suppositories)
Discontinue at least 2 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study
IV corticosteroids for UC
Discontinue at least 2 weeks prior to screening 
endoscopy.  A course of IV corticosteroids for 
UC is prohibited throughout duration of study
Systemic corticosteroids for non-UC indications (oral or IV) 
Patients requiring systemic corticosteroids for 
non-UC indications are excluded. (except 
Exceptions include corticosteroids to treat adrenal 
insufficiency, premedication for IP infusion, or
are excluded.  locally administered corticosteroids 
(e.g. inhaled, intranasal, intra-articular, topical)are 
allowed (see Appendix 10).
Abbreviations:  5-ASA = 5-aminosalicyclic acid; IV = intravenous; IP = investigational product; JAK = Janus 
Kinase; TNF= tumor necrosis factor; UC = ulcerative colitis.


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Appendix 10. Permitted Medications with Dose Stabilization
Drug Class
Dose Stabilization Guidance
Oral 5-ASAs, for example, mesalamine, 
balsalazide, olsalazine (and sulfasalazine 
for UC) (for example, mesalamine, 
balsalazide, olsalazine)
May continue during study with stable dose encouraged. 
Oral corticosteroids for UC (prednisone 
≤20 mg/day or equivalent, or budesonide 
MMX 9 mg/day, or beclomethasone 
dipropionate [gastro-resistant prolonged-
release tablet] 5 mg/day)
Prescribed dose must have been stable for at least 2 weeks before 
screening endoscopy and to remain stable for duration of study.
Corticosteroids for non-UC indications: 
corticosteroids to treat adrenal 
insufficiency, as premedication for IP 
infusion, or locally administered
corticosteroids (e.g. inhaled, intranasal, 
intra-articular, topical).
May continue corticosteroids to treat adrenal insufficiency or locally 
administered corticosteroids during study with stable dose 
encouraged.  Single doses of oral or IV corticosteroids as 
premedication to IP administration are allowed in patients with prior 
IP or other previous biologic injection reactions.
Abbreviations:  5-ASA = 5-aminosalicyclic acid; 6-MP = 6-mercaptopurine; AZA = azathioprine; IV = intravenous; 
IP = investigational product; UC = ulcerative colitis.


Leo Document ID = 657a2d1f-dff5-4018-af92-df993c3649f2
Approver: 
Approval Date & Time: 12-Sep-2019 15:59:27 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Sep-2019 20:01:36 GMT
Signature meaning: Approved
PPD
PPD