A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active- Controlled, Treat-Through Study to Evaluate the Efficacy and Safety of Mirikizumab in Patients With Moderately to Severely Active Crohn's Disease
Phase: PHASE3
Conditions: Crohn's Disease
Sponsor: Eli Lilly and Company

 
 
 
Protocol: I6T-MC-AMAM(e) 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active- 
Controlled, Treat-Through Study to Evaluate the Efficacy and Safety of 
Mirikizumab in Patients with Moderately to Severely Active Crohn's Disease 
 
 
NCT03926130 
 
 
Approval Date: 23 Feb 2022 

CONFIDENTIAL 
 
Protocol I6T-MC-AMAM(e) 
 
LY3074828 
1 
Title Page 
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 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. 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active- 
Controlled, Treat-Through Study to Evaluate the Efficacy and Safety of Mirikizumab in Patients 
with Moderately to Severely Active Crohn's Disease 
Protocol Number:  I6T-MC-AMAM 
Amendment Number:  e 
Compound Number:  LY3074828 
Study Phase:  3 
Acronym:  VIVID-1 
Sponsor Name:  Eli Lilly and Company 
Legal Registered Address:  Indianapolis, Indiana, USA  46285  
Regulatory Agency Identifier Numbers 
IND:  130052 
EudraCT:  2018-004614-18 
Document ID:  VV-CLIN-019253 
Approval Date:  Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below. 
Approved on 23 Feb 2022 GMT

CONFIDENTIAL 
 
Protocol I6T-MC-AMAM(e) 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment d 
07-Feb-2022 
Amendment c 
01-Apr-2021 
Amendment b 
18-Dec-2020 
Amendment a 
08-Apr-2020 
Original Protocol  
25-Mar-2019 
Amendment [e] 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
The main purpose of this protocol amendment is to revise the co-primary and secondary 
objectives and endpoints in response to Food and Drug Administration (FDA) feedback. 
Changes specific to certain protocol sections and a brief rationale are provided in the below 
table. Other minor typographical corrections not affecting content have also been made in the 
document. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Updated objectives and endpoints 
Address FDA feedback 
and editorial consistency 
1.3. Schedule of 
Activities 
Removed ‘mirikizumab assay 
development’ from footnote ‘n’  
Clarification 
1.3. Schedule of 
Activities 
Revised footnote ‘o’ to indicate that 
results from the PK, immunogenicity 
(ADA) and exploratory hypersensitivity 
analyses in the event of a systemic 
allergic/hypersensitivity event will not 
be provided to the investigator 
Clarification 
1.3. Schedule of 
Activities 
Revised footnote ‘u’ for diary 
compliance check to specify 
compliance percentage threshold 
Clarification 
1.3. Schedule of 
Activities 
Added a footnote to allow Visit 2 
assessments and dosing to be 
performed over 2 days after 
consultation with the medical monitor 
Clarification  
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Section # and Name 
Description of Change 
Brief Rationale 
2.2.1. Disease State and 
Treatment Goals 
Replaced assessment by PRO to CDAI  Address FDA feedback 
2.2.5. Preclinical and 
Clinical Studies of 
Mirikizumab 
Updated the results of Studies 16T-
MC-AMAN and 16T-MC-AMAG  
Reflect most recent data 
3. Objectives and 
Endpoints 
Updated co-primary endpoints to 
include clinical response by PRO at 
Week 12, endoscopic response and 
clinical remission by CDAI at Week 52  
Address FDA feedback 
3. Objectives and 
Endpoints 
Updated the following efficacy 
assessments in major and other 
secondary objectives and endpoints,   
 clinical remission by CDAI at 
Week 12 and 52,  
 clinical response by PRO at 
Week 12,  
 clinical remission by PRO at 
Week 52  
 corticosteroid-free and either 
clinical remission by CDAI 
(removed by PRO) at Week 52 
 stability of clinical remission by 
CDAI (removed by PRO) 
Alignment to FDA 
feedback 
3. Objectives and 
Endpoints 
Added the following efficacy 
assessments in secondary objectives 
and endpoints  
 Urgency NRS at Week 12 and 
Week 52 
 urgency remission at Week 52 
 clinical response by CDAI 
(removed by PRO) at Week 4  
Alignment to FDA 
feedback 
3. Objectives and 
Endpoints 
Added footnotes defining the mITT 
population and the efficacy endpoints 
(Clinical response by PRO, Endoscopic 
response, Clinical remission by CDAI, 
Clinical remission by PRO, Clinical 
response by CDAI, Urgency remission, 
Endoscopic remission, Endoscopic 
remission SES-CD ≤4) 
Editorial consistency 
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Section # and Name 
Description of Change 
Brief Rationale 
3. Objectives and 
Endpoints 
Revised the section to remove duplicate 
objectives and endpoints 
Editorial consistency 
4.2. Scientific Rationale 
for Study Design 
Added CDAI as an endpoint used for 
the primary objective 
Alignment to FDA 
feedback 
5.1. Inclusion Criteria 
 
Inclusion criterion 9d 
Revised language for Crohn’s disease 
treatment 
Clarification 
5.1. Inclusion Criteria 
 
Inclusion criterion 11b 
Removed ‘an established’ from 
diagnosis of Gilbert’s syndrome 
Clarification 
5.2. Exclusion Criteria 
 
Inclusion criterion 17 
Removed adenoma without dysplasia 
and added colonic adenomatous polyp 
Reflect most recent data 
5.2. Exclusion Criteria 
 
Inclusion criterion 18 
Removed colonic dysplasia and added 
any adenomatous polyp, any evidence 
of dysplasia in GI tract, or presence of 
any serrated lesion 
Reflect most recent data 
6.5.3. Corticosteroid 
Taper 
Added oral corticosteroid dose initiation 
for participants not on corticosteroids at 
randomization 
Clarification 
6.5.4. Rescue Medicine 
Removed “other than oral 5 ASA 
compounds or immunomodulators” 
Correction 
7.1.1. Criteria for 
Permanent 
Discontinuation of Study 
Drug 
Removed intestinal dysplasia and added 
any colonic adenomatous polyp, any 
evidence of dysplasia in GI tract, or 
presence of any serrated lesion in safety 
considerations 
Reflect most recent data 
8.1.1. Primary Efficacy 
Assessments 
Updated co-primary endpoints with the 
changes made in Section 3 (Objectives 
and Endpoints) 
Alignment to FDA 
feedback 
8.1.1. Primary Efficacy 
Assessments 
Crohn’s Disease Activity Index (CDAI) 
description added as part of Primary 
Efficacy Assessments 
Removed CDAI description 
Alignment to co-primary 
objectives 
8.2.5 Stool Testing 
Updated C. difficile toxin testing 
Clarified intended 
collection and testing 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.6. Tuberculosis 
Testing 
Updated retesting and confirmatory 
testing for participants who have been 
assessed by the PI to have a false 
positive TB test 
Clarified intended 
collection and testing 
8.5. Pharmacokinetics 
Revised the additional samples to 
indicate that results from these samples 
in the event of a systemic 
allergic/hypersensitivity event will not 
be provided to the investigator 
Clarification  
8.5.1. Mirikizumab Assay 
Development 
Removed this section with Corgenix 
samples collection and testing including 
sample use and retention 
Clarification 
9.1. Statistical 
Hypotheses 
Revised primary hypothesis and major 
secondary hypotheses with the changes 
made in Section 3 (Objectives and 
Endpoints) 
Address FDA feedback 
9.2. Sample Size 
Determination  
Revised estimated power for the co-
primary endpoint 
Address FDA feedback 
and editorial consistency 
9.4.1. General Statistical 
Considerations 
Replaced stratification factors with 
covariates and removed region and 
95% confidence interval in Cochran-
Mantel-Haenszel chi-square test  
Removed baseline corticosteroid use 
and region from restricted maximum-
likelihood-based mixed effects model 
of repeated measures 
Added finalized graphical testing 
scheme to be provided in the SAP 
Clarification and editorial 
consistency 
9.4.1.3. Missing Data 
Imputation 
Revised selected analysis for 
participants in placebo group 
Clarification 
9.4.1.4. Multiple 
Comparisons/Multiplicity 
Added ‘mirikizumab’ to compare with 
placebo for Group 1 and to compare 
with ustekinumab for Group 2 
Added pre-specified graphical scheme 
for comparisons in Group 1 
Clarification and editorial 
consistency 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.3.1. Primary Analyses  Updated primary analyses with the 
changes made in Section 3 (Objectives 
and Endpoints) and added definitions 
for clinical response by PRO and 
clinical remission by CDAI 
Address FDA feedback 
10.2. Appendix 2: 
Clinical Laboratory Tests 
Updated C. difficile toxin testing 
Clarified intended 
collection and testing 
10.2. Appendix 2: 
Clinical Laboratory Tests 
Removed ‘serum for PK assessment 
and mirikizumab assay development’ 
from exploratory biomarker samples 
Clarified intended testing 
10.7. Appendix 7: 
Permitted Medications 
Revised language for Crohn’s disease 
treatment 
Clarification 
10.12. Appendix 12:  
Provisions for Changes in 
Study Conduct During 
Exceptional 
Circumstances 
Revised changes in study conduct 
during exceptional circumstances 
Clarification for flexibility 
outlined for study conduct 
during exceptional 
circumstances 
10.12. Appendix 12:  
Provisions for Changes in 
Study Conduct During 
Exceptional 
Circumstances 
Added the following to ‘Local 
laboratory testing option’, 
“Local collection of screening 
laboratories for eligibility may be 
collected after approval by the sponsor 
and may not be allowed in all 
circumstances.” 
Clarification for local labs 
during exceptional 
circumstances 
 
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Protocol I6T-MC-AMAM(e) 
 
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Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Amendment Summary of Changes Table .........................................................................2 
Table of Contents ...........................................................................................................................7 
1 
Protocol Summary ........................................................................................................11 
1.1 
Synopsis ..........................................................................................................................11 
1.2 
Schema ............................................................................................................................15 
1.3 
Schedule of Activities (SoA) ..........................................................................................16 
2 
Introduction ...................................................................................................................22 
2.1 
Study Rationale ...............................................................................................................22 
2.2 
Background .....................................................................................................................22 
2.2.1 
Disease State and Treatment Goals .................................................................................22 
2.2.2 
Currently Available Treatments and Unmet Need ..........................................................22 
2.2.3 
Interleukin-23 as a Therapeutic Target in Crohn’s Disease ............................................23 
2.2.4 
IL-23p19 Blockade in Crohn’s Disease ..........................................................................23 
2.2.5 
Preclinical and Clinical Studies of Mirikizumab ............................................................24 
2.3 
Benefit/Risk Assessment ................................................................................................25 
3 
Objectives and Endpoints ............................................................................................27 
4 
Study Design ..................................................................................................................34 
4.1 
Overall Design ................................................................................................................34 
4.2 
Scientific Rationale for Study Design ............................................................................35 
4.3 
Justification for Dose ......................................................................................................37 
4.4 
End of Study Definition ..................................................................................................38 
5 
Study Population ...........................................................................................................39 
5.1 
Inclusion Criteria ............................................................................................................39 
5.2 
Exclusion Criteria ...........................................................................................................44 
5.2.1 
Rationale for Exclusion of Certain Study Candidates ....................................................49 
5.3 
Lifestyle Considerations .................................................................................................49 
5.4 
Screen Failures ................................................................................................................49 
5.4.1 
Allowed Retesting of Screening Investigations ..............................................................51 
6 
Study Intervention ........................................................................................................52 
6.1 
Study Intervention(s) Administered................................................................................52 
6.2 
Preparation/Handling/Storage/Accountability ................................................................53 
6.3 
Measures to Minimize Bias:  Randomization and Blinding ...........................................53 
6.4 
Study Intervention Compliance ......................................................................................54 
6.5 
Concomitant Therapy .....................................................................................................55 
6.5.1 
Permitted Therapy ...........................................................................................................55 
6.5.2 
Prohibited Therapy..........................................................................................................55 
6.5.3 
Corticosteroid Taper .......................................................................................................56 
6.5.4 
Rescue Medicine .............................................................................................................56 
6.6 
Dose Modification ..........................................................................................................57 
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6.7 
Intervention after the End of the Study ...........................................................................57 
6.7.1 
Study Extension ..............................................................................................................57 
6.7.2 
Treatment after Study Completion..................................................................................57 
6.7.3 
Special Treatment Considerations ..................................................................................57 
6.7.3.1 
Premedication for Infusions ............................................................................................57 
6.7.3.2 
Management of Hypersensitivity, Infusion-Related Events, 
Infusion Site Reactions, and Injection Site Reactions ....................................................57 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................60 
7.1 
Discontinuation of Study Intervention ............................................................................60 
7.1.1 
Criteria for Permanent Discontinuation of Study Drug ..................................................60 
7.1.2 
Criteria for Temporary Interruption (Withholding) of Study Drug ................................62 
7.1.3 
Discontinuation of Inadvertently Enrolled Participants ..................................................63 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................63 
7.3 
Lost to Follow up ............................................................................................................63 
8 
Study Assessments and Procedures.............................................................................64 
8.1 
Efficacy Assessments .....................................................................................................64 
8.1.1 
Primary Efficacy Assessment .........................................................................................64 
8.1.1.1 
Crohn’s Disease Activity Index (CDAI) ........................................................................65 
8.1.1.2 
Simple Endoscopic Score for Crohn’s Disease (SES-CD) .............................................65 
8.1.1.3 
Endoscopy .......................................................................................................................65 
8.1.1.4 
Endoscopic Biopsies .......................................................................................................66 
8.1.2 
Secondary Efficacy Assessments ....................................................................................66 
8.1.2.1 
Patient Reported Outcomes (PROs) ...............................................................................66 
8.1.2.2 
Inflammatory Biomarkers ...............................................................................................67 
8.1.2.3 
Extraintestinal Manifestations (EIMs) ............................................................................67 
8.1.2.4 
Fistulas ............................................................................................................................68 
8.1.3 
Exploratory Assessments ................................................................................................68 
8.1.3.1 
Disease Severity Index-Crohn’s Disease (DSI-CD) .......................................................68 
 
 
8.2 
Safety Assessments .........................................................................................................68 
8.2.1 
Vital Signs .......................................................................................................................68 
8.2.2 
Physical Examinations ....................................................................................................69 
8.2.3 
Electrocardiograms .........................................................................................................69 
8.2.4 
Chest Radiography ..........................................................................................................69 
8.2.5 
Stool Testing ...................................................................................................................70 
8.2.6 
Tuberculosis Testing .......................................................................................................70 
8.2.7 
Clinical Laboratory Tests ................................................................................................73 
8.2.7.1 
Pregnancy Testing...........................................................................................................74 
8.2.7.2 
Immunogenicity Assessment ..........................................................................................74 
8.2.8 
Hepatitis B Testing .........................................................................................................75 
8.2.9 
Hepatitis C Testing .........................................................................................................76 
8.2.10 
Hepatic Safety Monitoring ..............................................................................................77 
8.2.11 
Depression, and Suicidal Ideation and Behavior ............................................................77 
8.3 
Adverse Events and Serious Adverse Events .................................................................78 
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8.3.1 
Serious Adverse Events ..................................................................................................79 
8.3.1.1 
Suspected Unexpected Serious Adverse Reactions ........................................................80 
8.3.2 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................80 
8.3.2.1 
Adverse Event Monitoring with a Systematic Questionnaire .........................................80 
8.3.3 
Follow-up of AEs and SAEs ...........................................................................................80 
8.3.4 
Regulatory Reporting Requirements for SAEs ...............................................................80 
8.3.5 
Pregnancy Reporting .......................................................................................................81 
8.3.6 
Cardiovascular and Death Events ...................................................................................81 
8.3.7 
Adverse Events of Special Interest .................................................................................81 
8.3.7.1 
Opportunistic Infections .................................................................................................81 
8.3.7.2 
Systemic Allergic Reactions and Hypersensitivity Events .............................................82 
8.3.7.3 
Injection/Infusion Site Reactions ....................................................................................82 
8.3.7.4 
Cerebro-cardiovascular Events Adjudication .................................................................82 
8.3.8 
Complaint Handling ........................................................................................................82 
8.4 
Treatment of Overdose ...................................................................................................83 
8.5 
Pharmacokinetics ............................................................................................................83 
8.6 
Pharmacodynamics .........................................................................................................83 
8.7 
Pharmacogenomics .........................................................................................................84 
8.7.1 
Whole Blood Sample for Pharmacogenetic Research ....................................................84 
8.8 
Exploratory Biomarkers ..................................................................................................84 
8.9 
Medical Resource Utilization and Health Economics ....................................................85 
9 
Statistical Considerations .............................................................................................86 
9.1 
Statistical Hypotheses .....................................................................................................86 
9.2 
Sample Size Determination ............................................................................................86 
9.3 
Populations for Analyses ................................................................................................87 
9.4 
Statistical Analyses .........................................................................................................87 
9.4.1 
General Statistical Considerations ..................................................................................87 
9.4.1.1 
Definition of Baseline .....................................................................................................88 
9.4.1.2 
Estimand .........................................................................................................................89 
9.4.1.3 
Missing Data Imputation ................................................................................................89 
9.4.1.4 
Multiple Comparisons/Multiplicity ................................................................................89 
9.4.2 
Treatment Group Comparability .....................................................................................90 
9.4.2.1 
Participant Disposition ....................................................................................................90 
9.4.2.2 
Participant Characteristics ..............................................................................................90 
9.4.2.3 
Concomitant Therapy .....................................................................................................90 
9.4.2.4 
Treatment Compliance ....................................................................................................90 
9.4.3 
Efficacy Analyses ...........................................................................................................90 
9.4.3.1 
Primary Analyses ............................................................................................................90 
9.4.3.2 
Secondary Analyses ........................................................................................................91 
9.4.3.3 
Tertiary/Exploratory Analyses ........................................................................................93 
9.4.4 
Safety Analyses ...............................................................................................................93 
9.4.5 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................94 
9.4.6 
Evaluation of Immunogenicity .......................................................................................95 
9.4.7 
Other Analyses ................................................................................................................95 
9.4.7.1 
Health Economics ...........................................................................................................95 
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9.4.7.2 
Subgroup Analyses .........................................................................................................95 
9.5 
Interim Analyses .............................................................................................................95 
10 
Supporting Documentation and Operational Considerations ..................................97 
10.1 
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................97 
10.1.1 
Regulatory and Ethical Considerations ...........................................................................97 
10.1.2 
Informed Consent Process ..............................................................................................97 
10.1.3 
Data Protection................................................................................................................98 
10.1.4 
Committees Structure......................................................................................................98 
10.1.5 
Dissemination of Clinical Study Data.............................................................................99 
10.1.6 
Data Quality Assurance ..................................................................................................99 
10.1.7 
Source Documents ........................................................................................................100 
10.1.8 
Study and Site Closure ..................................................................................................101 
10.1.8.1 Discontinuation of the Study ........................................................................................101 
10.1.8.2 Discontinuation of Study Sites .....................................................................................101 
10.1.9 
Publication Policy .........................................................................................................101 
10.2 
Appendix 2:  Clinical Laboratory Tests ........................................................................102 
10.3 
Appendix 3:  Hepatic Monitoring Tests for Treatment Emergent 
Abnormality ..................................................................................................................104 
10.4 
Appendix 4:  Risk Factors for Latent Tuberculosis Infection ......................................105 
10.5 
Appendix 5:  Examples of Infections that May Be Considered 
Opportunistic in the Setting of Biologic Therapy .........................................................106 
10.6 
Appendix 6:  Prohibited Medications ...........................................................................108 
10.7 
Appendix 7:  Permitted Medications ............................................................................110 
10.8 
Appendix 8:  Patient-Reported Outcome Instruments ..................................................111 
10.9 
Appendix 9:  Additional Information on the Columbia Suicide 
Severity Rating Scale, and Quick Inventory of Depressive 
Symptomatology (self-report).......................................................................................115 
10.10 
Appendix 10:  Definitions and Selected Abbreviations................................................116 
10.11 
Appendix 11:  Protocol Amendment History ...............................................................122 
 
 
11 
References ....................................................................................................................155 
 
 
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Protocol I6T-MC-AMAM(e) 
 
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1 Protocol Summary 
1.1 Synopsis 
Protocol Title:  A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active- 
Controlled, Treat-Through Study to Evaluate the Efficacy and Safety of Mirikizumab in 
Patients with Moderately to Severely Active Crohn's Disease 
Acronym:  VIVID-1 
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-AMAM (AMAM) is a Phase 3 clinical trial designed to 
evaluate the safety and efficacy of mirikizumab in achieving endoscopic and clinical outcomes 
up to Week 52 in participants with moderately to severely active Crohn’s disease (CD).  
Participants who have an inadequate response to, loss of response to, or are intolerant to 
corticosteroid or immunomodulator therapy for CD (termed “conventional-failed”), and those 
who have an inadequate response to, loss of response to, or are intolerant to biologic therapy for 
CD (termed “biologic-failed”) will be included in the study. 
Objectives and Endpoints 
The study primary and secondary objectives will be assessed based on the Primary Analysis Set 
as defined in Section 9.3.  
Objectives 
Endpoints 
Co-primary 
 
To evaluate the efficacy of  mirikizumab is 
superior to placebo as assessed by 
 clinical response by PRO at Week 12 
and endoscopic response at Week 52 
 clinical response by PRO at Week 12 
and clinical remission by CDAI at 
Week 52 
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and endoscopic responsed at Week 52  
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and clinical remission by CDAIe at 
Week 52 
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Objectives 
Endpoints 
Major Secondary a,b 
 
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 52 as assessed by 
 endoscopic response 
 clinical remission by CDAI 
 
 Proportion of participants achieving 
endoscopic responsed at Week 52 
 Proportion of participants achieving 
clinical remission by CDAIe at Week 52  
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 12 as assessed by  
 endoscopic response  
 endoscopic remission 
 clinical remission by CDAI 
 Urgency NRS 
 Proportion of participants achieving 
endoscopic responsed at Week 12 
 Proportion of participants achieving 
endoscopic remission SES-CD≤4 j at 
Week 12 
 Proportion of participants achieving 
clinical remission by CDAIe at Week 12 
 Change from baseline in Urgency NRS 
at Week 12 
To evaluate the efficacy of mirikizumab is 
superior to placebo as assessed by both 
clinical response by PRO at Week 12 and 
each below, individually: 
 clinical remission by PRO at Week 52 
 endoscopic remission at Week 52 
 corticosteroid-free and either clinical 
remission by CDAI or endoscopic 
remission at Week 52 
Proportion of participants achieving clinical 
response by PROc at Week 12 and each below, 
individually: 
 Clinical remission by PROf at Week 52 
 Endoscopic remission SES-CD≤4 j at 
Week 52 
 Corticosteroid-free from Week 40 to 
Week 52 and either clinical remission 
by CDAIe at Week 52 or endoscopic 
remission SES-CD≤4 j at Week 52 
 
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 52 as assessed by 
Urgency NRS 
Change from baseline in Urgency NRS at 
Week 52 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab in 
comparison to ustekinumab at Week 52 as 
assessed by 
 endoscopic response (superior) 
 endoscopic remission (superior) 
 clinical remission by CDAI (non-
inferior) 
Proportion of participants achieving 
 Endoscopic responsed at Week 52 
 Endoscopic remission SES-CD≤4 j at 
Week 52 
 Clinical remission by CDAIe at Week 
52 
Abbreviations:  AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; CS = corticosteroid; NRS = numeric 
rating scale; PRO = patient reported outcome; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = 
stool frequency. 
a 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 0.05.  The graphical multiple testing procedure described in Bretz et al. (2009, 2011) will be used. 
b The order of testing of the major secondary endpoints will be detailed in the statistical analysis plan (SAP).  
Therefore, the order of the secondary endpoints does not reflect the order of the statistical testing. 
c  Clinical response by PRO is defined as at least a 30% decrease in SF and/or AP with neither score worse than 
baseline. 
d    Endoscopic response is defined as ≥50% reduction from baseline in SES CD Total Score. 
e    Clinical remission by CDAI is defined as CDAI total score <150. 
f      Clinical remission by PRO is defined as SF≤3 and not worse than baseline (as per Bristol Stool Scale Category 6 
or 7) and AP ≤1 and no worse than baseline at Week 52. 
i   Endoscopic remission is defined as SES-CD Total Score ≤2 
j    Endoscopic remission SES-CD ≤4 is defined as SES-CD Total Score ≤4 and at least a 2-point reduction from 
baseline and no subscore >1  
Overall Design: 
Study AMAM is a Phase 3, multicenter, randomized, double-blind, double-dummy, parallel 
group, placebo and active controlled, treat-through study to evaluate the safety and efficacy of 
mirikizumab compared to placebo and ustekinumab.  The study population includes participants 
with moderately to severely active CD who have an inadequate response to, loss of response to, 
or intolerance to conventional or biologic therapy for CD. 
Disclosure Statement: 
This is a parallel, double-blinded treatment study with three groups in Period 1 and four groups 
in Period 2.   
Number of Participants: 
Approximately 1100 participants will be randomly assigned to study intervention such that 
approximately 690 participants complete the study. 
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Protocol I6T-MC-AMAM(e) 
 
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14 
Intervention Groups and Duration: 
Participants will be randomized in a 6:3:2 ratio to receive, respectively:   
 Mirikizumab 900 mg intravenously (IV) every 4 weeks (Q4W) for 3 doses, then 300 mg 
subcutaneously (SC) Q4W 
 Ustekinumab ~6 mg/kg IV for one dose, then 90 mg SC every 8 weeks 
 Placebo 
o When Period 1 concludes (Week 12), responders continue receiving placebo, and 
o Nonresponders (NR) at Week 12 will receive mirikizumab as described above. 
 
To maintain blinding, participants receive placebo in a double-dummy manner.   
The maximum total duration of study participation for each participant is 73 weeks, across the 
following study periods:   
 Screening:  up to 5 weeks 
 Intervention Period 1:  12 weeks 
 Intervention Period 2:  40 weeks 
 Post-Treatment Follow-Up:  12 to 16 weeks 
Data Monitoring Committee:  Yes  
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Protocol I6T-MC-AMAM(e) 
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1.2 Schema 
 
Abbreviations:  IV = intravenous; mg = milligram; kg = kilogram; SC = subcutaneous 
Note:  From Week 8 through Week 20, all participants receive their assigned treatment and matching placebo via both IV and SC administration.  
 
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Protocol I6T-MC-AMAM(e) 
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1.3 Schedule of Activities (SoA) 
 
Screening 
Period 1 
Period 2 
UA/SVac Post-Treatment 
Follow-up 
Visit Number 
V1a,b 
V2
b 
V3c V4 V5c V6 V7 V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETV
w 
V997
x 
 
V801 
V802 
Week Relative to Study Drug 
Start 
-5 
0 
2 
4 
6 
8 12 16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
N/A N/A 
 
LV/ETV  
+ 4 
LV/ETV 
+12/16 
Days Relative to Study Drug 
Start and Visit Interval 
Tolerance (Days)ad 
≤35 from 
V2 
1 15 
± 3 
29 
± 3 
43  
± 3 
57 
± 3 
85 
± 6 
113 
± 7 
141 
± 7 
169 
± 7 
197 
± 7 
225 
± 7 
253 
± 7 
281 
± 7 
309 
± 7 
337 
± 7 
365  
± 7 
N/A N/A 
 
 
± 10 
 
± 10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preexisting conditions / 
Medical history / Relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory bowel disease 
diagnosis forms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Alcohol use  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco/ 
Nicotine use 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Physical Evaluation 
 
VS (T, PR, BP)d 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
Opt 
 
 
Physical exame 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt  
X 
X 
EIMs  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
 
X 
X 
Fistula evaluation 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
 
X 
X 
Clinician CDAI 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECGf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Chest x-rayg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
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Protocol I6T-MC-AMAM(e) 
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Screening 
Period 1 
Period 2 
UA/SVac Post-Treatment 
Follow-up 
Visit Number 
V1a,b 
V2
b 
V3c V4 V5c V6 V7 V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETV
w 
V997
x 
 
V801 
V802 
Week Relative to Study Drug 
Start 
-5 
0 
2 
4 
6 
8 12 16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
N/A N/A 
 
LV/ETV  
+ 4 
LV/ETV 
+12/16 
Days Relative to Study Drug 
Start and Visit Interval 
Tolerance (Days)ad 
≤35 from 
V2 
1 15 
± 3 
29 
± 3 
43  
± 3 
57 
± 3 
85 
± 6 
113 
± 7 
141 
± 7 
169 
± 7 
197 
± 7 
225 
± 7 
253 
± 7 
281 
± 7 
309 
± 7 
337 
± 7 
365  
± 7 
N/A N/A 
 
 
± 10 
 
± 10 
TB Monitoringab 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Opt 
Opt 
 
 
Laboratory Tests 
 
Serum Chemistry / 
Hematology 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
Opt 
 
 
Fasting Lipid panel 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Xy 
Opt 
Opt 
 
 
FSHh (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Urine pregnancyi 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Opt 
 
X 
X 
Serum pregnancyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Interferon-γ release assay 
(or tuberculin skin testk)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
HIV testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
HBV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
HBV DNAl 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Opt 
Opt 
 
 
HCV testingm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Predose PK samplen 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
Opt 
 
 
Postdose PK samplen,o 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
 
 
PK samplen,o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Opt 
Opt 
 
X 
Immunogenicity (ADA) 
sampleso  
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Opt 
Opt 
 
X 
Serum and plasma samples 
for cytokines 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Opt 
Opt 
 
 
hsCRP 
X 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Opt 
Opt 
 
 
Serum and plasma for 
exploratory biomarkers  
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Opt 
Opt 
 
 
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Protocol I6T-MC-AMAM(e) 
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Screening 
Period 1 
Period 2 
UA/SVac Post-Treatment 
Follow-up 
Visit Number 
V1a,b 
V2
b 
V3c V4 V5c V6 V7 V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETV
w 
V997
x 
 
V801 
V802 
Week Relative to Study Drug 
Start 
-5 
0 
2 
4 
6 
8 12 16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
N/A N/A 
 
LV/ETV  
+ 4 
LV/ETV 
+12/16 
Days Relative to Study Drug 
Start and Visit Interval 
Tolerance (Days)ad 
≤35 from 
V2 
1 15 
± 3 
29 
± 3 
43  
± 3 
57 
± 3 
85 
± 6 
113 
± 7 
141 
± 7 
169 
± 7 
197 
± 7 
225 
± 7 
253 
± 7 
281 
± 7 
309 
± 7 
337 
± 7 
365  
± 7 
N/A N/A 
 
 
± 10 
 
± 10 
Blood for RNA and DNA 
(epigenetic) exploratory 
biomarkers  
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Opt 
Opt 
 
 
Blood for DNA 
pharmacogeneticsp 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Stool Samplesq 
 
Stool cultures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optr 
Opt 
 
 
C. Difficile testings 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opt 
Opt 
 
 
Fecal calprotectin  
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Opt 
Opt 
 
 
Exploratory fecal biomarkers 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Opt 
Opt 
 
 
Supply stool collection kit t  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Opt 
Opt 
 
 
Patient Diary 
 
Patient diary dispensed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary compliance checku 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Opt 
Opt 
 
 
Diary collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Questionnaires 
 
IBDQ 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
SF-36 v2 Acute 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
WPAI-CD 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
PGIC 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
FACIT-Fatigue 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
IBD-DI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QIDS-SR16 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
Opt 
Opt 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol I6T-MC-AMAM(e) 
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Screening 
Period 1 
Period 2 
UA/SVac Post-Treatment 
Follow-up 
Visit Number 
V1a,b 
V2
b 
V3c V4 V5c V6 V7 V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETV
w 
V997
x 
 
V801 
V802 
Week Relative to Study Drug 
Start 
-5 
0 
2 
4 
6 
8 12 16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
N/A N/A 
 
LV/ETV  
+ 4 
LV/ETV 
+12/16 
Days Relative to Study Drug 
Start and Visit Interval 
Tolerance (Days)ad 
≤35 from 
V2 
1 15 
± 3 
29 
± 3 
43  
± 3 
57 
± 3 
85 
± 6 
113 
± 7 
141 
± 7 
169 
± 7 
197 
± 7 
225 
± 7 
253 
± 7 
281 
± 7 
309 
± 7 
337 
± 7 
365  
± 7 
N/A N/A 
 
 
± 10 
 
± 10 
DSI-CD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endoscopy 
 
Endoscopy / SES-CD with 
biopsiesv 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Opt 
Opt 
 
 
Randomization and Dosing 
 
Randomizationz 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosingaa 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Abbreviations:  ADA = anti-drug antibodies (immunogenicity); AE = adverse event; anti-HBc+ = positive for anti-hepatitis B core antibody; AP = abdominal 
pain; BMC = bowel movement count; BP = blood pressure; CDAI = Crohn’s Disease Activity Index; CDAI-SF= Crohn’s Disease Activity Index – Stool 
Frequency; CRF = case report form; C-SSRS = Columbia-Suicide Severity Rating Scale; CXR = chest x-ray; DSI-CD= Disease Severity Index-Crohn’s 
Disease; ECG = electrocardiogram; EIM = extraintestinal manifestation; EQ-5D-5L = European Quality of Life 5–Dimension 5 Level; ETV = early 
termination visit, FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; F/U=follow-up; 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; IBD-DI =Inflammatory Bowel Disease-Disability Index; IBDQ = Inflammatory Bowel Disease Questionnaire, 
IP = investigational product; LV = last visit; N/A = not applicable; NRS = numeric rating scale; Opt = optional procedure; PGIC = Patient Global Impression 
of Change; PGRS = Patient Global Rating of Severity; PK = pharmacokinetic; PR = pulse rate; QIDS-SR16 = Quick Inventory of Depressive 
Symptomatology-Self Report (16 items); SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF-36v2 Acute = Medical Outcomes Study 36-Item Short 
Form Health Survey; T = temperature; UA/SV = Unscheduled Assessments during a Scheduled Visit; V997 = unscheduled visit; V = visit; VS = vital signs; 
WPAI-CD = Work Productivity and Activity Impairment Questionnaire Crohn’s Disease. 
a Visit 1 procedures may be conducted over more than 1 day as long as all tasks are completed within the allowable visit tolerance.  It is required that you have 
received and reviewed all of your screening laboratory test results, as well as screening endoscopy results, prior to randomization and dosing at V2.  Please 
note at least 3 business days should be allowed for receipt of laboratory test results.  Lab results can take up to 10 business days to obtain after the sample was 
received at the laboratory, and endoscopy results may take up to 5 business days after receipt of video.   
b 
All screening/baseline activities should be completed prior to any study drug administration unless otherwise stated below. 
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Protocol I6T-MC-AMAM(e) 
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c 
Telephone visit. 
d 
Sitting blood pressure and pulse rate to be obtained at approximately the same time of day as ECG measurements and/or blood sampling.  When multiple 
assessments are scheduled for the same visit, the preferred order of completion is:  Vital signs, ECG (if applicable) then blood sampling.   
e 
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be performed at screening and will include peripheral lymph 
nodes.  After screening, physical examinations include a symptom-directed evaluation as well as examination of eyes, heart, lungs, abdomen and visual 
examination of the skin. 
f 
ECG should be completed prior to any blood draw.  Participants should be supine for approximately 5 to 10 minutes before ECG collection and remain supine 
and awake during ECG collection. 
g 
Chest radiography (CXR) (posterior-anterior view interpreted and reported by a radiologist or pulmonologist) will be performed at screening unless such 
radiography has been performed within 3 months before initial screening (provided the radiographs and/or formal report are available for the investigator’s 
review).  A computed tomography (CT) scan can be performed as an alternative to the CXR based on regional standard of practice. 
h Optional, may be performed to confirm postmenopausal status. 
i 
Urine pregnancy test to be performed only on women of childbearing potential.  Done locally and prior to dosing. 
j 
Serum pregnancy test to be performed only on women of childbearing potential. 
k Participants who had a tuberculin skin test (TST) will return 48 to 72 hours after placement to have their test results read (See Section 8.2.6). 
l 
Perform only if participant HBcAB+ with negative HBV DNA test at screening.  Any enrolled participant who is HBcAB + will undergo monitoring of HBV 
DNA at specified intervals.  Any participant with a positive HBV DNA test at any time must be discontinued from the study and receive appropriate follow-
up medical care. 
m Participants 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 24 weeks after completion of a full, documented course of an approved, potentially curative antiviral therapy for HCV.   
n 
Serum for PK assessment.   
o In the event of an systemic allergic/hypersensitivity event, blood samples will be collected for PK, immunogenicity (ADA) and exploratory hypersensitivity 
analyses at the following time points:  as close as possible to:  (1) the onset of the systemic allergic/hypersensitivity event, (2) the resolution of the systemic 
allergic/Hypersensitivity Event, and (3) 30 [±3] days following the systemic allergic/hypersensitivity events and (4)12 to 16 weeks after the event.  
Exploratory hypersensitivity samples may be analyzed for markers of basophil/mast cell activation (for example, tryptase), immune complex formation (for 
example, C3 levels) and cytokine release (for example, IL-6) as appropriate for the clinical presentation.  The results will not be provided to the investigator. 
p 
Sample can be obtained at any time at or after V2. 
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Protocol I6T-MC-AMAM(e) 
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q Stool samples must be collected up to 3 days before endoscopy and prior to beginning bowel prep for endoscopy at Visits 7 and 17.  For all other visits, 
samples may be collected on the day of visit.  If stool collection is not possible on the day of the visit, the sample may be collected at home and returned to the 
site.  Additional local stool testing (for example, ova and parasites) is allowed at the investigator’s discretion.   
r 
Optional per country requirements. 
s 
Stool culture and C. difficile must be negative at screening prior to randomization. 
t 
Instruct participants that the stool samples must be collected up to 3 days before endoscopy and prior to beginning bowel prep for endoscopy at Visits 7 and 
17.  
u 
Diary compliance check of >80% for each visit (BMC, CDAI-SF with Bristol Stool Scale, CDAI-AP, CDAI well-being, Abdominal Pain NRS, Urgency 
NRS, PGRS).   
v Screening endoscopy must occur within 21 days (inclusive) of randomization.  Allow 5 business days for receipt of endoscopy results prior to randomization 
(Visit 2).  Biopsies will be taken during each endoscopy; instruction for collection will be provided in a laboratory manual.  It is recommended that the 
collection of responses to study questionnaires, administration of IP, and endoscopy (with or without sedation) be performed on separate days within visit 
window with the endoscopy preceding the study questionnaires and IP administration.  However, if logistical issues preclude this and all has to occur on same 
day, the following order of procedures must be followed:  (1) Collection of responses to questionnaires; (2) Administration of IP with protocol-specific 
observation period (at least 1 hour); (3) Performance of endoscopy with or without sedation. 
w Early Termination Visits (ETV) may occur on any day without regard to visit interval.  An endoscopy should only be performed at the ETV if the visit occurs 
at least 16 weeks after the last endoscopy.  An ETV endoscopy will not be performed during Period 1 or the post-treatment follow-up period.   
x Unscheduled visits (V997) may be performed at the discretion of the investigator between protocol visits.  During all unscheduled visits, concomitant 
medications and AEs must be completed.  Other assessments are considered optional (defined as Opt), and if performed, require documentation via the 
appropriate standard (CRF, laboratory requisition, and/or source documentation).   
y Fasting is not required for the lipid panel at an early termination visit.   
z Randomization will be timed to begin no earlier than 14 days from the start of screening procedures. 
aa Visit procedures and assessments must be completed prior to dosing, except as noted in the applicable footnotes above   
ab Participants will be assessed for risk factors for TB (Appendix 10.4).  If the participant has a risk factor(s), the investigator should conduct a thorough exam to 
evaluate for TB, including examination of peripheral lymph nodes and documentation of body temperature.  If there are relevant physical findings, an IGRA 
and CXR should be performed.  A CT scan can be performed as an alternative to the CXR based on regional standard of practice. 
ac Unscheduled assessments may be performed during a scheduled visit at the discretion of the investigator and are considered part of that protocol scheduled 
visit.  The optional assessments (defined as Opt), if performed, require documentation via the appropriate standard (CRF, laboratory requisition, and/or source 
documentation). 
ad    Visit 2 may be done over 2 days if needed, after consultation with medical monitor
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2 Introduction 
2.1 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-AMAM (AMAM) is a Phase 3 clinical trial designed to 
evaluate the safety and efficacy of mirikizumab in achieving endoscopic and clinical outcomes 
up to Week 52 in participants with moderately to severely active Crohn’s disease (CD).  
Participants who have an inadequate response to, loss of response to, or are intolerant to 
corticosteroid or immunomodulator therapy for CD (termed “conventional-failed”), and those 
who have an inadequate response to, loss of response to, or are intolerant to biologic therapy for 
CD (termed “biologic-failed”) will be included in the study. 
2.2 Background 
2.2.1 Disease State and Treatment Goals 
Crohn’s disease (CD) is a chronic disease of unknown etiology with environmental, genetic, and 
immunologic influences.  Transmural inflammation affecting any part of the gastrointestinal tract 
from the mouth to the anus, usually appearing as discontinuous lesions, are normal 
characteristics for CD (Baumgart and Sandborn 2007).  Symptoms include chronic diarrhea 
(often bloody and containing pus or mucus), abdominal pain (AP), weight loss, fever, fatigue, 
anemia, rectal bleeding, and a feeling of fullness in the abdomen.  Symptoms depend on the 
severity of the disease and location of the disease, with most patients experiencing an abscess, 
fistula, stricture or an obstruction requiring surgical intervention.  Relapsing–remitting 
symptoms, meaning that many patients have intermittent disease flares that are interspersed with 
periods of remission, is very common in CD (Lichtenstein et al. 2018).   
Treatment goals in clinical practice are control of symptoms and healing of the intestinal 
mucosa.  In clinical trials, these goals are reflected by assessing induction of response (typically 
within a 6-week to 12-week period) and maintenance of remission in the longer term (over 
52 weeks of continuous treatment) as assessed by Crohn’s Disease Activity Index (CDAI), 
including a reduction in stool frequency [SF] and AP).  In both clinical practice and in clinical 
trials, assessment of the response to therapeutic interventions includes endoscopy to assess 
improvement in the endoscopic appearance of the mucosa and healing of ulcers. 
2.2.2 Currently Available Treatments and Unmet Need 
Medications used for the treatment of CD may include aminosalicylic acid (5-ASA)–containing 
medications (sulfasalazine, mesalazine, balsalazide, olsalazine), corticosteroids or budesonide, 
immunomodulator (example:  azathioprine [AZA], 6-mercaptopurine [6-MP], and methotrexate 
[MTX]), antimicrobial therapy specific for CD and diet, and anti-tumor necrosis factor (TNF) 
agents (infliximab, adalimumab, certolizumab pegol) for treatment of CD resistant to treatment 
with corticosteroids or refractory to MTX or thiopurine therapy.  Agents targeting leukocyte 
trafficking such as vedolizumab (an anti-integrin) are currently used in patients who have failed 
other therapies.  Ustekinumab, an IL-12/23 (anti-p40) antibody, is recommended in patients who 
Approved on 23 Feb 2022 GMT

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Protocol I6T-MC-AMAM(e) 
 
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23 
have failed prior treatments with corticosteroids, immunomodulators, or anti-TNF agents.  
Adalimumab and certolizumab pegol are recommended for treatment of perianal fistulas.   
A sizable proportion of the population with moderately to severely active Crohn’s disease is 
unresponsive to, fail to tolerate, or lose response to conventional therapies or approved biologic 
therapies.  The estimated rates of clinical remission in patients failing conventional therapy range 
from approximately 20% to 50%, depending on the biologic therapy evaluated.  The estimated 
rates of clinical remission in the biologic-failure population is around 20% in all treated patients 
at 12 months (Kamm et al. 2011).  Thus, there remains considerable unmet medical need for new 
treatment options, especially therapies with novel mechanisms of action that have the potential to 
have improved efficacy and maximize the proportion of patients who achieve clinical remission 
while maintaining a reassuring safety profile. 
2.2.3 Interleukin-23 as a Therapeutic Target in Crohn’s Disease 
The contribution of IL-12 and IL-23 in driving the pathophysiology of CD have been explored in 
genetic and animal model studies.  These studies would suggest that IL-23 plays a predominant 
role in inflammatory bowel disease (IBD) and, indeed, blocking IL-23 alone may be a more 
effective strategy than blocking both IL-12 and IL-23. 
A number of observations suggest that CD is mediated by IL-12 and/or IL-23, potentially 
through the Th1 and Th17 pathways they induce (Monteleone et al. 1997; Berrebi et al. 1998; 
Parrello et al. 2000).  Moreover, the predominant role for IL-23 in CD has been suggested by 
genomics studies (Duerr et al. 2006; Barrett et al. 2008).  The role of IL-23 in driving intestinal 
inflammation has been shown in several mouse models of IBD (Hue et al. 2006; Uhlig et al. 
2006; Elson et al. 2007; Maxwell et al. 2015), and mice with a genetic deletion of the p19 
subunit of IL-23 have been shown to be protected in several models of intestinal inflammation 
(Hue et al. 2006; Kullberg et al. 2006; Yen et al. 2006). 
The relative contribution of IL-12 and IL-23 to disease pathology in IBD has been explored in 
several studies.  The results of these studies would indicate that IL-23, but not IL-12, promotes 
intestinal inflammation (Hue et al. 2006; Kullberg et al. 2006; Uhlig et al. 2006; Yen et al. 2006).  
Data from murine models of psoriasis demonstrating a protective role in dermatologic 
inflammation (Kulig et al. 2016), as well as clinical trials (Blauvelt et al. 2017; Reich et al. 
2017a), would imply that IL-12 blockade may actually be counterproductive to the control of 
intestinal inflammation.  These data suggest that the efficacy obtained with IL-12/23p40 
blockade may be through the inhibition of IL-23 and provide a strong rationale for inhibiting 
IL-23 in CD. 
2.2.4 IL-23p19 Blockade in Crohn’s Disease 
The efficacy of IL-23p19 blockade in CD has been demonstrated in recent Phase 2 studies 
evaluating the short-term efficacy and safety of two different IL-23p19 mAbs, risankizumab and 
MEDI2070 (Feagan et al. 2017, 2018; Sands et al. 2017).  These Phase 2 studies explored a 
range of doses from 200 mg to 700 mg IV given up to Q4W through up to Week 12 and provide 
information regarding the short-term dose-response profile of IL-23p19 blockade in patients with 
moderately to severely CD.  The data from these studies showed evidence of improvements in 
clinical signs and symptoms, reduction in inflammatory disease burden as evaluated by 
biomarkers, and evidence of endoscopic healing after a typical short-term induction period.  It 
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should be noted that although these studies were small, no safety signals were identified relative 
to placebo through 12 weeks of treatment, and no additional safety signals were seen in open-
label extensions of up to 52 weeks of treatment. 
2.2.5 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 SC injection of human IL-23.  Mirikizumab does not prevent IL-12 signaling in vitro. 
A number of clinical studies of mirikizumab have been completed or are currently ongoing in 
participants with psoriasis, ulcerative colitis (UC), and CD.   
Clinical studies in ulcerative colitis 
Study 16T MC AMAC (AMAC) was a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in participants with moderate-to-severe UC, for which induction and maintenance 
results are available.  In the 12-week induction period, mirikizumab demonstrated efficacy for 
both endoscopic as well as symptomatic indices as assessed by multiple measures (Sandborn et 
al. 2018).  Overall adverse event (AE) frequencies were similar for mirikizumab-treated and 
placebo-treated participants (Sandborn et al. 2018).  In the maintenance period through Week 52, 
mirikizumab demonstrated durable efficacy for both endoscopic as well as symptomatic indices:  
among participants in clinical remission at Week 12, 61.1% (Q4W) and 38.5% (every 12 weeks 
[Q12W]) remained in clinical remission at Week 52.  There were few serious adverse events 
(SAEs) and few discontinuations due to AEs over 52 weeks (D’Haens et al. 2019). 
The Phase 3 LUCENT program comprises Study 16T-MC-AMAN (AMAN), a 12-week double-
blind, placebo-controlled, Phase 3 induction study of mirikizumab in participants with moderate 
to severe UC who had failed conventional and/or biologic treatments. Mirikizumab met the 
primary endpoint of clinical remission at Week 12 compared to placebo (p<0.0001). At Week 
12, mirikizumab when compared to placebo also achieved highly statistically significant p-
values, including reduced bowel urgency, clinical response, endoscopic remission, symptomatic 
remission and improvement in endoscopic histologic inflammation. Mirikizumab also reduced 
symptoms among participants who had previously not responded to or stopped responding to 
biologic and/or JAK inhibitor therapies. The incidence of treatment-emergent AEs and SAEs 
among participants treated with mirikizumab was consistent with that of the previous Phase 2 
mirikizumab study in UC and studies with the anti-IL-23p19 antibody class. The most common 
AEs included nasopharyngitis, anemia and headache for both placebo and mirikizumab-treated 
participants (Lilly 2021). 
The Phase 3 LUCENT program also comprises of 16T-MC-AMBG (mirikizumab/placebo 
maintenance) and 16T-MC-AMAP (mirikizumab open-label extension) in participants with 
moderately to severely active UC; these studies are ongoing at the time of this writing. 
Clinical studies in Crohn’s disease 
Study 16T-MC-AMAG (AMAG) was a Phase 2, placebo-controlled, double-blind clinical trial 
of mirikizumab in participants with active CD.  Unblinded results are available from the 
completed 12-week induction period.  The primary efficacy objective is to test the hypothesis 
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that treatment with mirikizumab is superior to placebo in the proportion of participants with 
endoscopic response at Week 12, defined as a 50% reduction from baseline in Simple 
Endoscopic Score for Crohn’s Disease (SES-CD) score.   
At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance 
level of 0.1 for all mirikizumab groups compared with placebo (200 mg: 25.8%, 8/31, 95% 
confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = 
.003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–
18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and 
SC groups, respectively. Thus, mirikizumab effectively induced endoscopic response after 12 
weeks in participants with moderate-to-severe CD and demonstrated durable efficacy to Week 
52. Frequencies of AE in the mirikizumab groups were similar to PBO. Treatment with 
mirikizumab has shown clinically relevant and consistent treatment effect in reducing or 
resolving endoscopic inflammation and patient-reported symptoms in participants with 
moderately to severely active CD. Through Week 52, frequencies of treatment-emergent AEs 
were similar across all groups. Frequencies of serious AE and discontinuations due to AE 
were higher in the nonrandomized maintenance cohort. There were no deaths in any study 
period, and no malignancies or instances of veno-occlusive disease (including pulmonary 
embolism) reported in the induction or maintenance period of the study (Sands et al. 2021).  
Additional nonclinical and clinical trial data are summarized in the Investigator’s Brochure (IB). 
2.3 Benefit/Risk Assessment 
At the time of this benefit/risk assessment, mirikizumab has demonstrated efficacy in blinded, 
placebo-controlled Phase 2 studies in psoriasis (Reich et al. 2017b), UC (Sandborn et al. 2018; 
D’Haens et al. 2019) and CD.  In the Phase 2 CD study AMAG, treatment with mirikizumab has 
shown clinically relevant and consistent treatment effect in reducing or resolving endoscopic 
inflammation and patient-reported symptoms in participants with moderately to severely active 
CD.  Evaluation of unblinded safety data in ongoing studies in psoriasis, UC and CD with dose 
regimens of up to 1000 mg IV Q4W for up to 52 weeks and up to 300 mg SC Q4W for up to 104 
weeks have shown a safety profile generally consistent with the IL-23 antibody class.  Across the 
ongoing Phase 2 mirikizumab studies, immediate hypersensitivity reactions, including 2 reports 
of immediate, infusion-related hypersensitivity events consistent with anaphylaxis, have been 
reported at the onset or during IV infusion of mirikizumab.  Such reactions are considered by the 
sponsor to be related to mirikizumab and hence have been identified as adverse drug reactions 
(ADRs).  The protocol includes specific measures for reducing the incidence and for 
management of such events including management of study drug infusion rate and observation 
during and after infusion.  Consult the IB for information regarding ADRs and potential risks 
with mirikizumab. 
Given the data from the Phase 2 study in CD and data from other clinical studies completed to 
date, potential benefits to participants who receive mirikizumab while participating in Study 
AMAM may be reasonably anticipated. 
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 
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product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations—are noted in Section 8.3.7 of this protocol.  For all AESIs, including 
hypersensitivity events, the protocol and IB provide monitoring and 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 (Appendix 10.1.4).  
This independent assessment of clinical trial data will contribute to the overall ongoing 
evaluation and management of potential risks associated with mirikizumab administration. 
In summary, the efficacy and safety data from the Phase 2 CD study AMAG support the 
continued clinical development of mirikizumab as a treatment for participants with CD. 
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of mirikizumab can be found in the IB. 
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3 Objectives and Endpoints 
The study primary and secondary objectives will be assessed based on the Primary Analysis Set 
as defined in Section 9.3.  
Objectives 
Endpoints 
Co-primary 
 
To evaluate the efficacy of  mirikizumab is 
superior to placebo as assessed by 
 clinical response by PRO at Week 12 
and endoscopic response at Week 52 
 clinical response by PRO at Week 12 
and clinical remission by CDAI at 
Week 52 
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and endoscopic responsed at Week 52  
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and clinical remission by CDAIe at 
Week 52 
Major Secondary a,b 
 
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 52 as assessed by 
 endoscopic response 
 clinical remission by CDAI 
 
 Proportion of participants achieving 
endoscopic responsed at Week 52 
 Proportion of participants achieving 
clinical remission by CDAIe at Week 52  
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 12 as assessed by  
 endoscopic response  
 endoscopic remission 
 clinical remission by CDAI 
 Urgency NRS 
 Proportion of participants achieving 
endoscopic responsed at Week 12 
 Proportion of participants achieving 
endoscopic remission SES-CD≤4 j at 
Week 12 
 Proportion of participants achieving 
clinical remission by CDAIe at Week 12 
 Change from baseline in Urgency NRS 
at Week 12 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab is 
superior to placebo as assessed by both 
clinical response by PRO at Week 12 and 
each below, individually: 
 clinical remission by PRO at Week 52 
 endoscopic remission at Week 52 
 corticosteroid-free and either clinical 
remission by CDAI or endoscopic 
remission at Week 52 
Proportion of participants achieving clinical 
response by PROc at Week 12 and each below, 
individually: 
 Clinical remission by PROf at Week 52 
 Endoscopic remission SES-CD≤4 j at 
Week 52 
 Corticosteroid-free from Week 40 to 
Week 52 and either clinical remission 
by CDAIe at Week 52 or endoscopic 
remission SES-CD≤4 j at Week 52 
 
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 52 as assessed by 
Urgency NRS 
Change from baseline in Urgency NRS at 
Week 52 
To evaluate the efficacy of mirikizumab in 
comparison to ustekinumab at Week 52 as 
assessed by 
 endoscopic response (superior) 
 endoscopic remission (superior) 
 clinical remission by CDAI (non-
inferior) 
Proportion of participants achieving 
 Endoscopic responsed at Week 52 
 Endoscopic remission SES-CD≤4 j at 
Week 52 
 Clinical remission by CDAIe at Week 
52 
Other Secondary 
 
To evaluate the efficacy of mirikizumab is 
superior to placebo at Week 12 as assessed by  
 Clinical remission by PRO 
 Clinical response by CDAI 
 Clinical response by PRO 
 Endoscopic remission SES-CD Total 
Score 0-2 
 Endoscopic response and clinical 
response by CDAI 
 Endoscopic response and clinical 
remission by CDAI 
Proportion of participants achieving 
 Clinical remission by PROf at Week 12 
 Clinical response by CDAIg at Week 12 
 Clinical response by PROc at Week 12 
 Endoscopic remissioni at Week 12 
 Endoscopic responsed and clinical 
response by CDAIg at Week 12 
 Endoscopic responsed and clinical 
remission by CDAIe at Week 12 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab is 
superior to placebo as assessed by both 
clinical response by PRO at Week 12 and 
each below, individually: 
 Urgency remission at Week 52 among 
participants with Urgency NRS ≥3 at 
baseline 
 Clinical response by CDAI at Week 
52 
 Clinical response by PRO at Week 52 
 Endoscopic remission SES-CD Total 
Score 0-2 at Week 52 
 Stability of clinical remission by 
CDAI from Week 12 to Week 52 
 Durability of endoscopic response at 
Week 12 and Week 52 
 Durability of endoscopic remission at 
Week 12 and Week 52  
 Endoscopic response and clinical 
response by CDAI at Week 52 
 Endoscopic remission and clinical 
remission by CDAI at Week 52 
 Endoscopic response and clinical 
remission by CDAI at Week 52 
Proportion of participants achieving clinical 
response by PROc at Week 12 and each below, 
individually: 
 Urgency remissionh at Week 52 in 
participants with Urgency NRS ≥3 at 
baseline 
 Clinical response by CDAIg at Week 52 
 Clinical response by PROc at Week 52 
 Endoscopic remissioni at Week 52 
 Stability of Clinical remission by 
CDAIe from Week 12 to Week 52 
 Durability of endoscopic responsed at 
Week 12 and Week 52 
 Durability of endoscopic remissionj at 
Week 12 and Week 52  
 Endoscopic response d and clinical 
response by CDAI g at Week 52 
 Endoscopic remissionj and clinical 
remission by CDAIe at Week 52 
 Endoscopic response d and clinical 
remission by CDAIe at Week 52 
To evaluate the efficacy of mirikizumab is 
superior to placebo in clinical response by 
CDAI at Week 4 
Proportion of participants achieving Clinical 
response by CDAIg at Week 4 
To evaluate the efficacy of mirikizumab is 
superior to placebo in Modified Intent-to-
Treat population (mITT) as assessed by 
 clinical response by PRO at Week 12 
and endoscopic response at Week 52 
 clinical response by PRO at Week 12 
and clinical remission by CDAI at 
Week 52 
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and endoscopic responsed at Week 52  
 Proportion of participants achieving 
clinical response by PROc at Week 12 
and clinical remission by CDAIe at 
Week 52 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab is 
superior to placebo in conventional-failed and 
biologic-failed subgroups 
 
Proportion of participants achieving  
 Endoscopic responsed at Week 12 
 Clinical remission by CDAIe at Week 
12 
Proportion of participants achieving clinical 
response by PROc at Week 12 and each below 
at Week 52, individually: 
 Endoscopic responsed 
 Endoscopic remission SES-CD≤4j  
 Clinical remission by CDAIe 
To evaluate the efficacy of mirikizumab in 
comparison to placebo in health outcomes 
and quality of life measures, symptomatic 
endpoints, inflammatory biomarkers  
Proportion of participants achieving each below 
over time 
 Clinical remission by CDAI e 
 Clinical response by CDAIg 
 Clinical remission by PROf 
 Clinical response by PROc 
Change from baseline at Week 12 and Week 52 
of each below: 
 C-reactive protein 
 Fecal calprotectin  
 FACIT-Fatigue scores  
 European Quality of Life 5-Dimensions 
5 Level (EQ-5D-5L) index  
 Work Productivity and Activity 
Impairment Questionnaire Crohn’s 
Disease (WPAI-CD) score  
 Medical Outcomes Study 36-Item Short 
Form Health Survey (SF-36) Version 2 
acute scores 
 Inflammatory Bowel Disease 
Questionnaire (IBDQ) 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab in 
comparison to placebo for other assessments 
Proportion of participants  
 had EIMs among those who had EIMs 
at baseline 
 Crohn’s related emergency room visits 
 Crohn’s related hospitalization 
 Crohn’s related surgeries 
Proportion of participants achieving clinical 
response by PROc at Week 12 and each below 
evaluated at Week 24, and at Week 52, 
individually: 
 ≥50% reduction from baseline in the 
number of draining fistulae  
 draining fistulae at baseline with closure 
of draining fistulae 
To evaluate the efficacy of mirikizumab in 
comparison to ustekinumab as assessed by 
 Endoscopic response at Week 12 
(superior) 
 Clinical remission by CDAI at 12 
(non-inferior) 
 Clinical response by CDAI at Week 
12 (non-inferior) 
 Clinical response by CDAI at Week 
52 (non-inferior) 
 Corticosteroid-free clinical remission 
by CDAI at Week 52 (non-inferior) 
 Clinical response by PRO at Week 12 
 Clinical response by PRO at Week 52 
 Clinical remission by PRO at Week 
12 
 Clinical remission by PRO at Week 
52 
Proportion of participants achieving 
 Endoscopic responsed at Week 12 
 Clinical remission by CDAIe at Week 
12 
 Clinical response by CDAIg at Week 12 
 Clinical response by CDAIg at Week 52 
 Corticosteroid-free clinical remission by 
CDAIe at Week 52 
 Clinical response by PROc at Week 12 
 Clinical response by PROc at Week 52 
 Clinical remission by PROf at Week 12 
 Clinical remission by PROf at Week 52 
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Objectives 
Endpoints 
To evaluate the efficacy of mirikizumab in 
comparison to ustekinumab in conventional-
failed and biologic-failed subgroups 
 
Proportion of participants achieving  
 Endoscopic responsed at Week 52 
 Endoscopic remission SES-CD ≤4 j at 
Week 52 
 Clinical remission by CDAIe at Week 
52 
 Endoscopic responsed at Week 12 
 Clinical remission by CDAIe at Week 
12 
To evaluate the pharmacokinetic and 
pharmacokinetic/pharmacodynamic 
relationships of mirikizumab 
 Clearance and volume of distribution of 
mirikizumab 
 Relationship between mirikizumab 
exposure and efficacy 
Tertiary/Exploratory 
 
Abbreviations:  AP = abdominal pain; CD = Crohn’s disease; CDAI=Crohn’s Disease Activity 
Index;EIM = extraintestinal manifestation; EQ-5D-5L= European Quality of Life 5–Dimension 5 Level; FACIT-
Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; IBDQ = Inflammatory Bowel Disease 
Questionnaire; NRS = numeric rating scale; PRO = patient-reported outcome; SES-CD = Simple Endoscopic 
Score for Crohn’s Disease; SF = stool frequency as per Bristol Stool Scale Category 6 or 7, SF-36v2 Acute = 
Medical Outcomes Study 36-Item Short Form Health Survey; WPAI-CD = Work Productivity and Activity 
Impairment Questionnaire Crohn’s Disease. 
Note: Modified Intent-to-Treat (mITT) Population is defined as all participants from ITT population who take at 
least one dose of study drug. 
a 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 0.05.  The graphical multiple testing procedure described in Bretz et al. (2009, 2011) will be used. 
b The order of testing of the major secondary endpoints will be detailed in the statistical analysis plan (SAP).  
Therefore, the order of the secondary endpoints does not reflect the order of the statistical testing. 
c  Clinical response by PRO is defined as at least a 30% decrease in SF and/or AP with neither score worse than 
baseline. 
d    Endoscopic response is defined as ≥50% reduction from baseline in SES CD Total Score. 
e    Clinical remission by CDAI is defined as CDAI total score <150. 
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f      Clinical remission by PRO is defined as SF≤3 and not worse than baseline (as per Bristol Stool Scale Category 6 
or 7) and AP ≤1 and no worse than baseline at Week 52. 
g  Clinical response by CDAI is defined as a decrease from baseline ≥100 and/or CDAI <150 
h   Urgency remission is defined as Urgency NRS ≤1 
i   Endoscopic remission is defined as SES-CD Total Score ≤2 
j    Endoscopic remission SES-CD ≤4 is defined as SES-CD Total Score ≤4 and at least a 2-point reduction from 
baseline and no subscore >1  
 
 
 
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4 Study Design 
4.1 Overall Design 
Design Summary 
Study AMAM is a Phase 3, multicenter, randomized, double-blind, double-dummy, parallel 
group, active- and placebo-controlled, treat-through design (see schema in Section 1.2).  Three 
intervention groups in the first period and four intervention groups in the second period will be 
studied in participants with moderate-to-severe Crohn’s disease:   
 Mirikizumab 900 mg IV Q4W for 3 doses, then 300 mg SC Q4W 
 Ustekinumab ~6 mg/kg IV for one dose, then 90 mg SC every 8 weeks 
 Placebo 
o When Period 1 concludes (Week 12), responders continue receiving placebo, and 
o NR at Week 12 will receive mirikizumab as described above. 
The total duration of the combined treatment periods is up to 52 weeks. 
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up period, is 73 weeks. 
Participants in either active group will receive placebo to match the other active group using a 
double-dummy design.  Participants in the placebo group will receive both IV and SC placebo 
administrations.   
For further details see Section 6.1 (Study Intervention Administered).   
Participant Visit Scheme 
Study participants will undergo screening assessments; double-blind treatment with 
investigational product, active comparator product, or placebo; and two post-treatment follow-up 
visits.   
Screening may be done on more than 1 day, as long as all activities are completed within 
≤35 days from the baseline visit (Visit 2).  It is recommended that at least 3 business days be 
allowed for receipt of laboratory test results before randomization and dosing at Visit 2.  
Randomization will be timed to begin no earlier than 14 days from the start of the screening 
procedures. 
After screening and baseline visits, participants will receive their assigned therapy during the 
52-week double-blind treatment period (Visits 2 to 17).  Period 1 is from Weeks 0 to 12.  
Period 2 encompasses Weeks 12 to 52.  Dosing visits are as specified in the SoA (Section 1.3). 
Participants who complete Study AMAM through Visit 17 will be given the option to enroll in 
Study AMAX if they are eligible (Section 6.7.1).  Participants who do not meet enrollment 
criteria for Study AMAX or who do not choose to participate in Study AMAX will return for 
2 post-treatment follow-up visits in Study AMAM.  The first such follow-up visit (Visit 801) will 
be 4 weeks after the last visit (LV) (LV/early termination visit [ETV] + 4 weeks).  The second 
follow-up visit (Visit 802) will be from 12 to 16 weeks after the LV (LV/ETV + 12 to 16 weeks). 
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Participants who permanently discontinue study drug early will undergo early termination 
procedures, including an ETV and the post-treatment follow-up visits (Section 7). 
Assessments and Procedures 
Assessments and procedures to be conducted in each study period are described in the SoA 
(Section 1.3), and in “Study Assessments and Procedures” (Section 8). 
Stratification 
Participants who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2.  To achieve between-group comparability, participants will be stratified to treatment 
groups based upon these factors:  a) biologic-failed status (yes/no), b) baseline corticosteroid use 
(yes/no), c) baseline SES-CD total score (<12, ≥12), d) region (North America/Europe/Other) 
and e) either baseline SF ≥7 and/or baseline AP ≥2.5 (yes/no) (Section 9.4.1).  This stratification 
will be controlled by an interactive web-response system (IWRS) (Section 6.3). 
Placebo Nonresponders (NR) 
Any participant in the placebo group who is considered a NR at Week 12 will be assigned 
blinded mirikizumab induction therapy followed by blinded mirikizumab maintenance therapy 
for the remainder of the study; doses and routes of administration will be the same as those 
described above for mirikizumab treatment groups.  Nonresponse is defined as failing to achieve 
at least a 30% decrease in SF and/or AP and be no worse than baseline. 
Placebo Responders 
Participants in the placebo group who are in clinical response at Week 12 will continue to 
receive placebo for the remainder of the study.  No rescue therapy will be provided after 
Week 12.   
4.2 Scientific Rationale for Study Design 
Study AMAM is designed to evaluate the safety and efficacy of mirikizumab in clinical 
remission and endoscopic response at Weeks 12 and 52 of treatment. 
Endpoints 
To evaluate the effect of mirikizumab on decreasing intestinal mucosa inflammation and 
symptoms of CD, the following endpoints will be used for the primary objective of Study 
AMAM:  SES-CD, Crohn’s Disease Activity Index (CDAI) and patient-reported symptoms of 
AP and SF.   
The SES-CD will be determined at baseline, Week 12, and Week 52 (or end of study for 
participants with early discontinuation) with evaluation of endoscopic response (defined as 
≥50% reduction from baseline in SES-CD total score) as a co-primary endpoint.  At the GREAT 
3 workshop, endoscopic response as a co-primary endpoint was considered clinically meaningful 
and relevant and would provide sufficient evidence of efficacy for CD trials at various time 
points.  The 50% reduction from baseline in SES-CD as a definition of endoscopic response in 
CD was ranked first by 11 of 12 participants (Vuitton et al. 2016) in a modified Delphi process 
by members of the International Organization of Inflammatory Bowel Disease.  Based on this 
consensus of gastroenterology experts, endoscopic response is considered a meaningful and 
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relevant endpoint for assessment of therapies in CD.  Additionally, the 50% cutoff point was 
shown to correlate with steroid-free remission at a later time point based on a post hoc analysis 
of the SONIC trial (Ferrante et al. 2013).  Thus, 50% improvement in the SES-CD correlates 
with long-term clinical improvement and provides a robust and meaningful assessment of 
endoscopic improvement. 
To evaluate the effect of mirikizumab on decreasing symptoms of CD, AP and SF will be 
assessed.  Qualitative patient research, clinical gastroenterological expert opinion, and a review 
of the peer-reviewed literature assert that AP and SF are the most important and clinically 
relevant symptoms associated with moderate-to-severe CD (Baumgart and Sandborn 2007; 
Khanna et al. 2015; Kim et al. 2015).  Both AP and frequent bowel movements with the 
consistency of liquid or soft stools have a significant impact on the day-to-day function and life 
of a participant with moderate-to-severe CD. 
To assess the effect of mirikizumab on SF and AP, clinical remission by PRO at Week 12 and 
Week 52 (or end-of-study for participants with early discontinuation) will be measured in Study 
AMAM.  At baseline, participants will be required to have active CD as defined by the  inclusion 
criteria (see Section 5.1). Clinical remission by PRO is as defined in Section 8.1.  Participants 
will be provided with an electronic daily diary during the study to record their signs and 
symptoms on a daily basis.   
To measure the number of liquid or very soft stools in the past 24 hours, participants will use the 
SF item of the CDAI (unweighted).  To further define “liquid or very soft stools,” participants 
will be referred to the Bristol Stool Scale Category 6 and/or 7, which provides a pictorial and 
verbal description of stool consistency and form, for example, liquid or watery stool.  To 
measure the participant’s AP, participants will be asked to record AP using the 4-point scale. 
Use of placebo comparator 
Placebo was selected as the primary comparator for Study AMAM.  The use of a placebo 
comparator is reasonable in this study, as mirikizumab can be added to preexisting background 
therapy (FDA 2011).  A week 12-timepoint was chosen for the assessment of induction efficacy 
to balance the timepoint at which substantial induction efficacy could be demonstrated against 
the longest time considered reasonable for participants to be maintained on placebo without 
receiving rescue treatment.  This timepoint falls within the study duration (from 6 week to 
12 weeks) recommended for demonstration of short-term efficacy.  As the main noninferiority 
comparison of mirikizumab to ustekinumab will be conducted at Week 52, continuation of the 
placebo group to Week 52 is warranted to provide internal evidence of assay sensitivity 
(FDA 2011 [ICH E10]) and to document the efficacy of mirikizumab in long-term treatment.  
The protocol defines conditions under which the study participants may be switched to 
mirikizumab (placebo NR [Section 4.1]) or must be discontinued.  Study participants and 
physicians may discontinue the study participation if they perceive no benefit.  These conditions 
provide for a balance between a rigorous scientific evaluation of the efficacy of mirikizumab in 
comparison to placebo and in comparison to ustekinumab and provide for appropriate 
management of each individual’s disease activity. 
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Ustekinumab as an active comparator 
Ustekinumab is approved in several countries for the treatment of CD and is included in Study 
AMAM as an active comparator for comparisons with mirikizumab.  The ustekinumab dosages 
selected for this study were found to be safe and effective in the pivotal Phase 3 studies of 
ustekinumab in participants with CD (Feagan et al. 2016; Stelara USPI) and are included in both 
the FDA and EMA labels (Stelara SmPC).  In Study AMAM, participants enrolled in the 
ustekinumab group will receive a single IV induction dose of approximately 6 mg/kg (based on 
the weight tiers described in labeling), which is the approved induction dose for participants with 
CD.  From Week 8, these participants will receive a maintenance dose regimen of 90 mg SC 
Q8W.  Of note, the ustekinumab Q8W regimen was chosen for the maintenance dose regimen as 
opposed to the Q12W regimen as it more dependably demonstrated efficacy across a range of 
clinical endpoints, especially with more stringent measures of efficacy such as sustained 
remission and steroid free-remission, in the pivotal ustekinumab CD maintenance study (Feagan 
et al. 2016).  Additionally, only the 90 mg Q8W dosing regimen demonstrated significant effects 
on endoscopic endpoints, with the 90 mg Q12W dose not appreciably differing from placebo.  
The 90 mg Q8W regimen would therefore provide the fairest comparison for testing the 
superiority of mirikizumab to ustekinumab, especially as regards the important outcomes of 
endoscopic response and remission. 
4.3 Justification for Dose 
The mirikizumab 900 mg IV Q4W induction and 300 mg SC Q4W maintenance dose regimens 
selected for this study were based primarily on analyses of interim pharmacokinetics (PK), 
safety, and efficacy data from the Phase 2 Study AMAG, safety data from other clinical studies 
evaluating mirikizumab, and nonclinical safety data. 
Safety Considerations 
The safety data collected for mirikizumab in completed and ongoing clinical studies and in 
nonclinical toxicology studies support the proposed dose regimen.  As noted in Section 2.3, in 
the Phase 2 Study AMAG, the incidences of SAEs and TEAEs were similar between placebo and 
mirikizumab treatment groups, with no dose relationship noted in the first 12 weeks (Period 1).  
In Period 2 (Weeks 12 to 52), comparative data are limited.  The incidence of overall TEAEs 
was similar across all mirikizumab dose groups and were generally mild to moderate in severity.  
Patients exposed to 1000 mg mirikizumab IV had a higher number of SAEs, including 2 reports 
of immediate, infusion-related hypersensitivity events consistent with anaphylaxis.  For IV dose 
administration, mitigation measures that include slowing the infusion rate, and monitoring during 
and after drug infusion have been implemented.  There were no deaths during Study AMAG.  As 
noted in Section 2.3, for all AESIs, including hypersensitivity events, the protocol and IB 
provide monitoring and management guidance to the investigator. 
Single IV doses of up to 600 mg were evaluated in Study AMAA (healthy participants and 
participants with psoriasis) and up to 2400 mg in Study I6T-JE-AMAD (AMAD) (healthy 
participants).  No dose-related safety or tolerability issues were observed in either study.  
Evaluation of the unblinded safety data available to date in the ongoing Phase 2 study in 
participants with psoriasis (Study AMAF) and of the unblinded safety data available to date in 
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the ongoing Phase 2 study of mirikizumab in participants with UC (Study AMAC) has not 
revealed a safety concern that differs from the safety findings noted above for Study AMAG. 
The nonclinical safety profile of mirikizumab supports the proposed dose regimens in this study 
on the basis of the no-observed-adverse-effect levels (NOAELs) established in studies in 
monkeys.  
 
 
 
Considerations of Efficacy and Exposure–Response Relationships 
Significant efficacy of mirikizumab relative to placebo was observed in the 600 mg and 1000 mg 
IV Q4W treatment groups in Study AMAG based on the Week 12 endoscopic response endpoint, 
with the highest rates observed in the 1000 mg treatment group.  Significant efficacy relative to 
placebo was also observed at Week 12 for the PRO remission endpoints and indicated 
near-maximal efficacy between the 600 mg and 1000 mg doses.   
A model-based analysis of the relationship between individual subject mirikizumab systemic 
exposures and Week 12 endoscopic response revealed a significant relationship, with higher 
mirikizumab exposures associated with higher rates of endoscopic response.  The proposed 
900 mg IV induction dose is expected to produce near-maximal effect based on this exposure-
response analysis
 
 
 
  
In the Week 12 to Week 52 maintenance period of Study AMAG, the mirikizumab dose 
regimens that were evaluated ranged from 300 mg SC Q4W to 1000 mg IV Q4W. 
 
  The Week 52 endoscopic response 
 across the 
maintenance treatment groups were similar and did not appear to have any relationship to dose or 
mirikizumab exposure within any of the doses and range of exposures evaluated in Study 
AMAG. 
 
 
 
 
4.4 End of Study Definition 
The end of the study is defined as the date of the LV or last scheduled procedure shown in the 
SoA (Section 1.3) for the last participant participating in this global study. 
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5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
5.1 Inclusion Criteria 
Participants with CD are eligible for enrollment only if they meet all of the following criteria 
during screening, unless otherwise specified below. 
Informed Consent 
[1] 
have given written informed consent approved by the Ethical Review Board (ERB) 
governing the site. 
Participant Characteristics 
[2] 
are male or female participants ≥18 and ≤80 years of age at the time of initial screening. 
[2a] 
male participants: 
no male contraception required except in compliance with specific local 
government study requirements, 
[2b] 
female participants: 
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. 
i. Two effective methods of contraception (such as male or female condoms 
with spermicide, diaphragms with spermicide, or cervical sponges) will be 
used.  The participant may choose to use a double barrier method of 
contraception.  Barrier protection methods without concomitant use of a 
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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 40 years of age with an intact uterus, not on hormone 
therapy, who has had either 
 cessation of menses for at least 1 year without an alternative medical 
cause  
 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] 
have venous access sufficient to allow blood sampling and IV administration as per the 
protocol. 
Disease-Specific Inclusion Criteria 
[4] 
have had a diagnosis of CD or fistulizing CD established at least 3 months prior to 
enrollment confirmed by clinical, endoscopic, and histological criteria.   
Note:  A histopathology report supporting the diagnosis of CD must be available in the 
source documents prior to randomization, in order to satisfy this inclusion criterion.  If a 
histopathology report supporting the diagnosis of CD is not available in the source 
documents prior to randomization, the investigator can obtain additional biopsies for this 
purpose at the screening endoscopy (sent to the local histopathology laboratory). 
[5] 
have moderately to severely active CD as defined by unweighted daily average SF ≥4 
(loose and watery stools defined as Bristol Stool Scale Category 6 or 7) AND/OR 
unweighted daily average AP ≥2 at baseline (Visit 2). 
[6] 
have a centrally read SES-CD score ≥7 for participants with ileal-colonic or ≥4 for 
participants with isolated ileal disease within 21 days before randomization.  
Note:  Enrollment of participants meeting the below criterion will be limited to 
approximately 10% of total enrollment:  Participants with a SES-CD score ≥3 and <7 
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(SES-CD <4 for participants with isolated ileal disease) and presence of at least one large 
ulcer (in the ileum, colon, or both) that results in a minimum score of 2 for the 
component of “size of ulcers” and a minimum score of 1 for the component of “ulcerated 
surface.”  
[7] 
Participants with a family history of colorectal cancer, personal history of increased 
colorectal cancer risk, age >50 years, or other known risk factor must be up-to date on 
colorectal cancer surveillance per local guidelines.  If not, this documentation of negative 
colorectal cancer surveillance may be performed according to local guidelines during 
screening. 
Prior Medication Failure Criteria 
[8] 
Participants must have an inadequate response to, loss of response to, or intolerance to at 
least 1 of the medications described in Inclusion Criterion [8a] OR [8b].  For the relevant 
medication specified in these criteria, documentation of dose, frequency, route of 
administration, and duration of the qualifying failure is required. 
[8a] 
Conventional-failed participants:  Participants 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 disease, defined as signs and/or symptoms of 
active CD despite 
: 
- oral prednisone (or equivalent) at doses of at least 
, or 
- 
  
o corticosteroid-dependent disease: 
a. defined as an inability to reduce corticosteroids below the equivalent 
of prednisone
 
 
b. 
 of completing a course of corticosteroids; or 
o history of intolerance of corticosteroids (which includes evidence of a 
side-effect sufficiently serious as to precluding continued treatment with 
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 
 
 
 oral AZA 
 
or 
 oral AZA or 6-MP within a therapeutic range as judged by thioguanine 
metabolite testing, or 
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 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, AP, 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 approved for the 
treatment of CD. 
Discontinuation despite clinical benefit does not qualify as having failed or being 
intolerant to CD conventional therapy. 
[8b] 
Biologic-failed participants:  Participants who have an inadequate response to, 
loss of response to, or are intolerant to an approved biologic therapy for CD (such 
as anti-TNF antibodies or anti-integrin antibodies).  Investigators must be able 
to document an adequate history of induction and/or maintenance dose use.  
Participants 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 
 Loss of response:  Recurrence of signs and symptoms of active disease 
following prior clinical benefit during treatment with approved maintenance 
dosing, 
OR 
 Intolerance:  History of intolerance to infliximab, adalimumab, certolizumab 
pegol, vedolizumab, natalizumab, or other approved biologics (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). 
Discontinuation despite clinical benefit does not qualify as having failed or being         
intolerant to CD biologic therapy. 
Participants previously exposed to approved 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. 
Participants previously exposed to investigational therapies for the treatment of CD must 
still meet Inclusion Criteria [8a] OR [8b]. 
Participants who meet both Inclusion Criteria [8a] and [8b] will be considered to be 
“biologic-failed” for the purpose of this study. 
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CD Medication Dose Stabilization Criteria 
[9] 
are on stable doses of the following permitted drugs (see Appendix 10.7): 
[9a] 
oral 5-aminosalicylic (ASA) therapy:  if the prescribed dose has been stable for at 
least 2 weeks prior to the screening endoscopy. 
[9b] 
oral corticosteroid therapy (prednisone 
 or equivalent, or budesonide 
:  if the prescribed dose has been stable for at least 2 weeks before the 
screening endoscopy. 
[9c] 
AZA, 6-MP, or MTX:  if these immunomodulators have been prescribed at a 
stable dose for at least 8 weeks before the screening endoscopy. 
[9d] 
 Antibiotics being used specifically for the treatment of CD:  if the prescribed 
dose has been stable 4 weeks prior to baseline (Visit 2) or stopped treatment at 
least 3 weeks prior to screening endoscopy. 
Study Procedure Inclusion Criteria 
[10] 
are willing and able to complete the scheduled study assessments, including endoscopy 
and daily diary entry. 
Note:  In situations out of the control of the participant (example:  Sudden death in 
family, sudden staff changes, or broken equipment), rescreening or assessing potential 
randomization (whichever applies) may be allowed ONLY if prior approval from the 
medical monitor is obtained. 
[11] 
have clinically acceptable central laboratory test results at screening, as assessed by the 
investigator, including: 
[11a] Hematology: 
 absolute neutrophil count ≥1.5 × 109/L (≥1.5 × 103/L or ≥1.5 GI/L) 
 platelet count ≥100 × 109/L (≥100 × 103/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 (≥0.50 × 103/L or ≥0.50 GI/L), and  
 total white blood cell count ≥3.0 × 109/L (≥3.0 × 103/L or ≥3.0 GI/L) 
[11b] Chemistry: 
 serum creatinine ≤2 × upper limit of normal (ULN) 
 total bilirubin level (TBL) ≤1.5 × ULN  
 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2 × ULN, 
and 
 alkaline phosphatase (ALP) ≤1.5 × ULN 
Participants with diagnosis of Gilbert’s syndrome (requires source documentation 
showing isolated unconjugated hyperbilirubinemia, with no evidence of hemolysis) 
can be included with bilirubin levels ≤3 × ULN. 
Retesting within the screening period is allowed for hematology and chemistry; see 
Section 5.4. 
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5.2 Exclusion Criteria 
Participants will be excluded from study enrollment if they meet any of the following criteria 
within the screening period, unless otherwise specified below.   
For rescreening activities within the screening period, see Section 5.4. 
Gastrointestinal Exclusion Criteria 
[12] 
are participants who: 
[12a] have a current diagnosis of UC or inflammatory bowel disease-unclassified 
(formerly known as indeterminate colitis). 
 [12b] currently have or are suspected to have an abscess.  Recent cutaneous and perianal 
abscesses are not exclusionary if drained, adequately treated and resolved at least 
3 weeks prior to baseline or 8 weeks prior to baseline for intra-abdominal 
abscesses, provided that there is no anticipated need for any further surgery.   
[13] 
have a stoma, ileoanal pouch or ostomy. 
[14] 
have had a bowel resection within 6 months, or any kind of intra-abdominal surgery 
within 3 months of baseline (Visit 2). 
[15] 
have complications of CD such as symptomatic strictures or stenosis, short bowel 
syndrome, or any other manifestation that:  
 might be anticipated to require surgery within 6 months after screening,  
OR 
 could preclude the use of the SES-CD, CDAI, or PRO to assess response to therapy,  
OR 
 would possibly confound the ability to assess the effect of treatment. 
Adenoma, Dysplasia, and Gastrointestinal Cancer Exclusion Criteria 
[16] 
have any history or current evidence of cancer of the gastrointestinal tract.   
[17] 
have any current sporadic colonic adenomatous polypa ≤10 mm that has not been 
removed.  Once completely removed, the participant may be eligible for the study provided the 
local histology report confirms no or low-grade dysplasia and absence of malignancy.  
a pedunculated or sessile polypoid, with a dome-shaped and symmetric contour, smooth surface, and well-
delineated border occurred in the non-colitic area 
 [18] 
have any adenomatous polyp (including sporadic) >10 mm, any evidence of dysplasia 
(low-grade* or high grade) in GI tract, or presence of any serrated lesion (with or without 
dysplasia). 
*Note: except for low grade sporadic colonic adenomatous polyp a ≤10 mm once 
completely removed (per [17] above) 
a pedunculated or sessile polypoid, with a dome-shaped and symmetric contour, smooth surface, and well-
delineated border which occurred in the non-colitic area 
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Criteria for Discontinuing Prohibited Medications 
[19] 
have received any of the following for treatment of CD within the time frames specified 
below:   
[19a] corticosteroid enemas, corticosteroid suppositories 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 within 
4 weeks prior to the screening endoscopy. 
 AZA, 6-MP, and MTX are allowed at stable doses (Appendix 10.7). 
 Other immunomodulatory medications should be discussed with the sponsor 
prior to screening. 
[19d] anti-TNF antibodies (for example, infliximab, adalimumab, or certolizumab 
pegol) within 4 weeks prior to screening endoscopy. 
[19e] anti-integrin antibodies (for example, vedolizumab) within 4 weeks prior to 
screening endoscopy. 
[19f] agents that deplete B or T cells (for example, rituximab, alemtuzumab, or 
visilizumab) within 12 months of baseline (Visit 2).  Participants 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. 
[19k] natalizumab within 12 months prior to screening endoscopy. 
[20] 
have ever received 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] 
Subjects who discontinued an anti-IL 12/23p40 antibody (for example, ustekinumab) due 
to primary nonresponse or secondary loss of response or intolerance OR who received 
more than the IV induction dose and 1 SC dose are not eligible.   
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[22] 
require systemic corticosteroids for non-CD conditions (except corticosteroids to treat 
adrenal insufficiency). 
Infectious Disease Exclusion Criteria 
[23] 
are participants who 
[23a] have evidence of active tuberculosis (TB), or 
[23b] have a past history of active TB, without documented appropriate treatment by the 
World Health Organization (WHO) and/or the Centers for Disease Control and 
Prevention (CDC), or 
[23c] are diagnosed with latent tuberculosis infection (LTBI) at screening and/or have a 
past history of LTBI and have not started a course of an appropriate TB 
prophylaxis regimen (Section 8.2.6). 
Participants diagnosed with LTBI at screening and/or history of LTBI without 
appropriate treatment (aligned with WHO/CDC guidance in place at the time of 
treatment) may be allowed to rescreen and may be eligible for the study, provided they 
fulfill all the criteria described in Section 8.2.6. 
[24] 
have received a Bacillus Calmette-Guérin (BCG) vaccination within 12 months or 
received live attenuated vaccine(s) within 3 months of screening or intend to receive such 
during the study. 
[25] 
have human immunodeficiency virus/acquired immune deficiency syndrome 
(HIV/AIDS). 
[26] 
have acute or chronic hepatitis B infection; or test positive for hepatitis B virus (HBV) at 
screening, which is defined as: 
 positive for hepatitis B surface antigen (HBsAg+) 
OR 
 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 8.2.8). 
[27] 
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 8.2.9). 
Note:  Participants with a previous HCV infection that has been successfully treated with 
anti-viral therapy are not excluded (see Section 8.2.9). 
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[28] 
have tested positive for C. difficile toxin or for other intestinal pathogens within 30 days 
of screening endoscopy or test positive at screening for C. difficile toxin or for other 
intestinal pathogens.  Participants with a confirmed diagnosis of cytomegalovirus-
associated colitis should have adequate treatment and resolution of symptoms at least 3 
months prior to screening endoscopy (See Section 8.2.5). 
[29] 
have serious, opportunistic, or chronic/recurring extraintestinal infections.  Participants 
may be eligible for entry into the study if they have been adequately treated and off 
antibiotics for 30 days without recurrence of symptoms prior to screening.  Such 
extraintestinal infections include but are not limited to the following: 
[29a] infections requiring IV antibiotics. 
[29b] infections requiring hospitalization. 
[29c] infections that are considered “opportunistic” (see Appendix 10.5). 
[29d] chronic, recurrent infections (for example, osteomyelitis, recurring cellulitis).  
Participants with only recurrent, mild, and uncomplicated orolabial and/or genital 
herpes may be discussed with the medical monitor to determine the relevance of 
this infection for entry into the study, 
Participants with an opportunistic infection or chronic, recurrent infection (within 
the last 60 days prior to Visit 2) should be discussed on a case-by-case basis with the 
medical monitor. 
[30] 
have a current or recent acute, active nonserious extraintestinal infection for which signs 
and/or symptoms are present or treatment, if indicated, is not yet complete 2 weeks prior 
to screening. 
[31] 
have evidence of active/infectious herpes zoster infection ≤8 weeks prior to screening.  
Herpes zoster infections remain active until all vesicles are dry and crusted over. 
General Exclusion Criteria 
[32] 
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, 
b) cervical carcinoma in situ that has been adequately treated with no evidence of 
recurrence within the 3 years prior to baseline (Visit 2). 
[33] 
are investigator site personnel directly affiliated with this study or are immediate families 
of such personnel.  Immediate family is defined as a spouse, parent, child, or sibling, 
whether biological or legally adopted. 
[34] 
are Lilly employees or employees of third-party organizations involved with the study. 
[35] 
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. 
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[36] 
have previously completed or discontinued from this study or any other study 
investigating mirikizumab.  This criterion does not apply to participants undergoing 
rescreening procedures. 
[37] 
have had extra-abdominal surgery and have not recovered fully following surgery, 
including complete wound healing, before screening. 
[38] 
have 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 (Visit 1) prior to dosing at Visit 2; 
OR 
marked yes to suicide behaviors questions during the screening period (Visit 1) prior to 
dosing at Visit 2 
AND 
the ideation or behavior occurred within the past month. 
[39] 
have an unstable or uncontrolled illness, including but not limited to cerebro-
cardiovascular, respiratory, gastrointestinal (excluding CD), hepatic, renal, endocrine, 
hematologic, or neurological disorders that would potentially affect participant safety 
within the study or confound efficacy assessment. 
[40] 
have a known hypersensitivity to any component of mirikizumab or ustekinumab  
[41] 
have a solid organ transplant or hematopoietic stem cell transplantation. 
[42] 
are unwilling or unable to comply with the use of a data collection device to directly 
record data from the participant daily for the duration of Study AMAM, or unable to 
complete other study procedures.   
Note:  In situations out of the control of the participant (example:  Sudden death in 
family, sudden staff changes, or broken equipment), rescreening or assessing potential 
randomization (whichever applies) may be allowed ONLY if prior approval from the 
medical monitor is obtained. 
[43] 
are unsuitable for inclusion in the study in the opinion of the investigator or sponsor for 
any reason that may compromise the participant’s safety or confound data interpretation. 
[44] 
are pregnant, breastfeeding, or women who are planning pregnancy while enrolled in the 
study, or within 20 weeks after receiving the last dose of study drug. 
[45] 
have current or history of alcohol dependence and/or illicit drug abuse within the last 
year. 
[46] 
have abnormal 12-lead electrocardiogram (ECG) that, in the opinion of the investigator 
or sponsor, increases the risks associated with participating in the study. 
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[47] 
requires parenteral nutrition delivered by central vein and/or central venous catheter for 
venous access or receives enteral feeding as the primary source of their diet with limited 
oral intake.   
[48] 
participants who use marijuana (both recreational and medicinal uses [including 
cannabidiol oil]).  Marijuana use must be stopped prior to screening and is prohibited for 
the duration of the study. 
5.2.1 Rationale for Exclusion of Certain Study Candidates 
Both male and female participants are allowed to participate in this study.  Participants will not 
be excluded on the basis of gender.   
Participants from ≥18 and ≤80 years of age at the time of screening will be eligible to be 
included in this study.  Participants >80 years of age at screening will not be allowed in the study 
for the following reasons.  The extent of CD is more limited in the elderly than in the adult 
population.  Colonic involvement is more common than ileal involvement.  Elderly CD 
participants have a longer postoperative stay and a higher in-hospital mortality rate (Sturm et al. 
2017). 
5.3 Lifestyle Considerations 
Study participants should be instructed not to donate blood or blood products during the study 
and for 20 weeks following their last dose.   
To participate in the study, participants must agree to the contraception, reproduction, and 
breastfeeding criteria detailed in study entry criteria (Section 5.1 and Section 5.2). 
5.4 Screen Failures 
Allowed rescreening of participants after initial screen failure 
Participants who have failed screening because of the following entry criteria may be rescreened 
when the reason for screen failure has resolved:   
 [4] 
 [5] 
 [6] 
 [8] 
 [9] 
 [10] only in situations out of control of the participant and after medical review and 
approval 
 [11] 
 [12b] (once adequately treated) 
 [14] 
 [17] (once polyps are removed)  
 [19a] to [19j] 
 [22] Rescreening is only allowed if a participant is no longer receiving steroids and has 
met washout criteria. 
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 [24] 
 [28] (See rescreening allowances below) 
 [29] to [32] 
 [37] 
 [42] only in situations out of control of participant and after medical review and approval 
 [43] situation related to participant’s safety or data interpretation resolves 
 [44], [47] 
 [48] Participant must agree to stop marijuana use prior to screening and throughout 
participation in the study.   
For the reasons above, participants may be rescreened up to 3 times (unless specified otherwise), 
for a maximum total of 3 rescreens; however, the maximum number of endoscopies should never 
exceed 3 (even if separated by more than 8 weeks) including the initial endoscopy and  
2 rescreens 
Participants who have failed screening because of Exclusion Criterion [23c] (if treated for LTBI 
for at least 4 weeks and compliant with LTBI therapy while on study) may be rescreened 1 time.  
See Section 8.2.6. 
Participants who have failed screening because of Exclusion Criterion [28] may be rescreened 
1 time for C. difficile stool toxin.  Additionally, a participant may be rescreened 1 time for stool 
culture or ova parasite.  In either situation, participant rescreening should only occur after the 
reason for screen failure has been resolved.  It is recommended that the investigator confirms the 
participant has a negative C. difficile stool toxin/stool culture/stool ova parasite (as applicable) 
before performing additional rescreening investigations (see also Section 8.2.5 and 
Section 5.4.1). 
The interval between rescreenings starts when the screen failure was first noted and 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 participant must sign a new informed consent form (ICF) and 
will be assigned a new identification number. 
The interval between rescreening should be at least 8 weeks after time/date of screen failure for 
participants who screen failed because of Criterion [6].   
Participants who screen fail because they are unable to complete their endoscopy prior to Visit 2 
may undergo repeat rescreening sooner than 4 weeks between screen failure and rescreening. 
Participants rescreening sooner than 4 weeks for the inability to complete endoscopy, or who are 
allowed by the study’s medical monitor to rescreen within less than 4 weeks, will not be required 
to undergo repeat TB testing; chest X-ray (CXR) or computed tomography (CT); HIV, HBV, and 
HCV testing; stool cultures; and C. difficile testing if these were normal or negative during 
screening.  These tests should be repeated if, based on the principal investigator’s judgment, the 
participant has risk factors and/or signs and symptoms of illness.   
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Disallowed rescreening of participants after initial screen failure 
Participants who have failed screening because of the following criteria may not be rescreened:   
 [10] with the exception noted above  
 [12a]  
 [13] 
 [15] 
 [16] 
 [18] 
 [20] and [21], 
 [23a] and [23b] (if evidence of active TB or past history of active TB)  
 [25] to [27] 
 [33] to [36] 
 [38] to [41] 
 [42] with the exception noted above  
 [45] 
 [46]   
5.4.1 Allowed Retesting of Screening Investigations 
Retesting of screening investigations within a screening period (without a requirement for screen 
failure and rescreening) is allowed as described below.  The following screening investigations 
may be retested 1 time 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, taking into account test-retest variability.   
 Stool testing:  if there is a technical difficulty in performing or reporting the C. difficile or 
stool culture assays (see Section 8.2.5). 
 Retesting or confirmatory testing with an interferon-γ release assay (IGRA):  for 
example, QuantiFERON®-TB Gold or T-SPOT® assay, in selected participants as part 
of screening for LTBI (see Section 8.2.6 for details).   
 Endoscopy:  where the endoscopist is unable to adequately visualize the mucosa (for 
example, due to poor bowel preparation, technical issues with equipment) or where the 
central readers are unable to determine the centrally read SES-CD score (for example, 
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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6 Study Intervention 
Study intervention is defined as any investigational intervention, marketed product, placebo, or 
medical device intended to be administered to a study participant according to the study protocol. 
6.1 Study Intervention(s) Administered 
The study interventions used in this study are 
 Mirikizumab administered by IV infusion or SC injection  
 Ustekinumab administered by IV infusion or SC injection 
 Placebo administered by IV infusion or SC injection 
The doses and routes of administration reflect the multi-part study design (Section 4.1).   
A double-dummy design is used to preserve the study blinding. 
Packaging and Labeling 
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 intervention will be supplied as: 
 Single-use solution vial containing mirikizumab, ustekinumab, or placebo with 
study-specific labels.   
 
 
 
   
 Single-use solution prefilled syringe containing mirikizumab, ustekinumab, or placebo.   
 
 
 
 
 
 
Vials and syringes will be supplied in cartons, with the appropriate quantity specific to the 
planned dispensing schedule.  Investigational product will be provided with study-specific labels. 
Preparation and Administration 
The first dose of investigational product will be prepared at the site by unblinded pharmacists or 
other trained and qualified personnel as designated by the investigator.  Subsequent doses of 
investigational product will not require an unblinded pharmacist. 
Investigational product will be administered at the site by blinded nurse, pharmacist, or other 
trained and qualified personnel as designated by the investigator. 
Sites must have resuscitation equipment, emergency medications, and appropriately trained staff 
available during the infusion and monitoring period.  All participants should be monitored for 
1 hour or longer after IV dosing, according to investigator practice or local standard of care.  
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Intravenous infusions must be completed prior to administration of SC injections.  Subcutaneous 
injections may be given during the IV observation period. 
Detailed instructions for investigational product administration, including infusion rate and SC 
injections, will be provided separately by the sponsor. 
Time of Doses 
The actual time of all dose administrations will be recorded in the participant’s electronic case 
report form (eCRF). 
Investigator Responsibilities 
The investigator or his or her designee is responsible for the following, in addition to the 
responsibilities listed in Section 6.2: 
 explaining the correct use of the investigational interventions 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. 
6.2 Preparation/Handling/Storage/Accountability 
The investigator or his or 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 (interventions) will be supplied in accordance with current GMP and 
will be supplied with lot numbers, expiry dates, and certificates of analysis, as applicable. 
6.3 Measures to Minimize Bias:  Randomization and Blinding 
Randomization 
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an IWRS.   
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The stratification for randomization, as described in Section 9.4.1 and Section 4.1, will be 
controlled by IWRS.   
Blinding 
This is a double-blind study.  All treatments are blinded.  To maintain the blind, placebo will be 
administered as appropriate, either by IV, SC, or both.  All study assessments will be done by 
study personnel who are blinded to the participant’s treatment assignment.   
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 participant’s well-being requires knowledge of the participant’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 participant’s treatment assignment is warranted for medical management of the event.  The 
participant safety must always be the first consideration in making such a determination.  If a 
participant’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 participant is unblinded, the 
participant must be discontinued from the study drug and must complete the ETV and post-
treatment follow-up visits (Section 7.1).  In cases where there are ethical reasons to have the 
participant continue on the study drug, the investigator must obtain specific approval from the 
sponsor or designee for the participant continue. 
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. 
A limited number of preidentified individuals may gain access to unblinded data, as specified in 
the unblinding plan, prior to the database lock, in order to initiate the final population 
PK/pharmacodynamic (PD) model development processes for analyses.  Information which 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 statistical analysis plan (SAP) or a separate unblinding plan document. 
See also provisions for ongoing safety monitoring as described in Section 8.2. 
6.4 Study Intervention 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 participants 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 participant before randomization.   
In particular, the investigator is responsible for ensuring that study participants receive adequate 
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 the importance of complete bowel prep prior to colonoscopies 
 how to evaluate their CD symptoms and to record them on the eDiary, and 
 the importance of being compliant with the daily eDiary recording. 
If a participant is noncompliant with study procedures and/or investigational product 
administration, the investigator should assess the participant to determine the reason for 
noncompliance and educate and/or manage the participant as appropriate to improve compliance. 
If, in consultation with Lilly or its designee, the noncompliance is deemed to be significant or if 
further noncompliance occurs, the participant may be discontinued.  See Section 7.1.1 for 
treatment noncompliance leading to permanent discontinuation from study drug. 
6.5 Concomitant Therapy 
Recording of information about concomitant medications 
All concomitant medications, including endoscopy preparation medications taken during the 
study, must be recorded on the Concomitant Medication eCRF.  This includes concomitant 
medications for CD as well as underlying conditions or diseases, and for AEs.   
Use of concomitant medications during the study 
All participants are encouraged to maintain their usual medication regimens for concomitant 
conditions or diseases throughout the study unless those medications are specifically prohibited 
(Appendix 10.6). 
6.5.1 Permitted Therapy 
Participants taking permitted CD concomitant medications are to keep doses stable unless 
modifications are needed due to AEs or for appropriate medical management. 
 
 Instructions regarding guidance for use are detailed in 
Appendix 10.7.  
6.5.2 Prohibited Therapy 
Use of such medications should not be withheld if, in the opinion of the investigator, failure to 
prescribe them would compromise participant safety.  Participants who require a prohibited 
medication should be discontinued from study drug as described in Section 7.1.1 and should 
complete an ETV and post-treatment follow-up visits as described in the SoA (Section 1.3).  
Some exceptions, IV corticosteroid, systemic corticosteroids for non-CD indications, and 
marijuana, may result in discontinuation; consult your medical monitor prior to discontinuing the 
participant (see Appendix 10.6). 
If a concomitant medication is needed to treat an AE or for appropriate medical management, the 
investigator should base decisions on the participant and clinical factors, considering the list of 
prohibited medication. 
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Vaccinations 
Use of BCG vaccination is prohibited throughout the duration of the study and for 12 months 
after discontinuation of study drug.   
Use of live, attenuated vaccines are prohibited during the study and for 3 months after 
discontinuation of study drug.  
Use of nonlive (killed, inactivated, subunit, and RNA-based) vaccinations are allowed; however, 
their efficacy with concomitant mirikizumab is unknown.   
For more information 
The list of prohibited medications is provided in Appendix 10.6. 
The list of permitted medications with dose stabilization guidance is provided in Appendix 10.7. 
6.5.3 Corticosteroid Taper 
Participants who achieve clinical response (clinical response by PRO [Section 8.1]) 
 
 
 
 
 
 
For participants who cannot tolerate the corticosteroid taper without recurrence of clinical 
symptoms, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5.4 Rescue Medicine 
As noted in Section 6.5, participants who require a prohibited medication as described above to 
treat their CD should be discontinued from study drug as described in Section 7.1.1 and should 
complete an ETV and post-treatment follow-up visits as described in the SoA (Section 1.3). 
Participants assigned to active study drug 
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This study does not include rescue therapy for participants who are assigned to active study drug.   
Participants assigned to placebo 
Participants in the placebo group who are NR at Week 12 will be treated as described in the 
Overall Design (Section 4.1). 
6.6 Dose Modification 
Dose modification of study drug is not permitted in this study. 
6.7 Intervention after the End of the Study 
6.7.1 Study Extension 
Participants who complete Study AMAM through Visit 17 will be assessed for eligibility to enter 
Study AMAX.  If a participant does not meet enrollment criteria for Study AMAX or does not 
opt to continue into Study AMAX, he or she will be asked to complete the post-treatment follow-
up period, as described in the SoA (Section 1.3), which will complete his or her study 
participation. 
6.7.2 Treatment after Study Completion 
Mirikizumab and ustekinumab will not be made available to study participants after conclusion 
of the study; however, participants who are eligible may choose to participate in Study AMAX 
(Section 6.7.1). 
6.7.3 Special Treatment Considerations 
6.7.3.1 Premedication for Infusions 
Premedication for the study drug infusions or injections is not planned.  Any premedication for 
infusions or injections should be discussed with the medical monitor.  Any premedication given 
will be documented as a concomitant therapy (Section 6.5). 
6.7.3.2 Management of Hypersensitivity, Infusion-Related Events, Infusion Site Reactions, 
and Injection Site Reactions 
During and after study drug administration, participants should be closely monitored for signs or 
symptoms of AEs, including hypersensitivity events, other infusion-related events, and infusion 
or injection site reactions.  See Section 8.3.7.2 for more information about blood sampling and 
data collection. 
Hypersensitivity events 
If a participant experiences a systemic hypersensitivity reaction involving two or more organ 
systems (that is, mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems), during 
or up to 6 hours after an infusion of study drug, the following guidance should be followed:   
 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). 
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 After the participant’s stabilization, blood samples should be obtained as described in the 
SoA (Section 1.3). 
 The participant should be monitored until resolution or stabilization of the symptoms, as 
clinically appropriate.   
 Study drug should be discontinued (Section 7.1.1).  The participant should undergo an 
ETV and post-treatment follow-up procedures after study drug discontinuation. 
For nonsystemic hypersensitivity reactions involving a single organ system, all of the above 
should be followed, except the participant may be allowed to continue in the study. Continuation 
of a participant in the clinical study based on the investigator’s assessment of the event must be 
discussed and agreed upon with the medical monitor. If it is agreed the participant can continue, 
premedication prior to subsequent study drug administration may be considered, if judged by the 
investigator to be appropriate for the individual participant. 
Other infusion-related events 
If a participant experiences a reaction consisting of headache, rigors and/or temperature >38°C 
(in the absence of signs or symptoms of a systemic hypersensitivity reaction), during or up to 
6 hours after an infusion of study drug, the following guidance should be followed: 
 The study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, non-steroidal anti-inflammatory drugs, antipyretics, or 
antihistamines).   
 Blood samples for anti-drug antibodies (ADA) and PK analysis should be obtained as 
described in the SoA (Section 1.3).   
 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 the investigator’s discretion, and considering the risk/benefit of 
readministration. 
 Premedication prior to subsequent study drug administration may be considered, if 
judged by the investigator to be appropriate for the individual participant.   
 If the participant develops systemic hypersensitivity symptoms or signs, he or she should 
be managed as described above for a systemic hypersensitivity reaction.  The participant 
should remain in observation, as is clinically appropriate for the participant’s symptoms. 
Injection site reactions or infusion site reactions 
If a participant experiences an injection site reaction or an infusion site reaction, such as pain, 
erythema, urticaria, pruritus, or angioedema localized to the SC injection or infusion site (in the 
absence of systemic hypersensitivity signs or symptoms), the following guidance should be 
followed: 
 The participant should be instructed to contact the study site to report any symptoms 
experienced following a SC injection or an infusion site reaction.   
 If the participant develops systemic hypersensitivity symptoms, he or she should be 
managed as described above for a systemic hypersensitivity reaction.   
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 Premedication prior to subsequent study drug administration may be considered as 
appropriate for the individual participant.   
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7 Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
These sections describe reasons for 
 permanent or temporary discontinuation of study drug, or 
 participant’s discontinuation (withdrawal) from the study. 
Discontinuation of the study as a whole or of particular study sites is described in 
Appendix 10.1.8. 
7.1 Discontinuation of Study Intervention 
Study drug may be permanently discontinued or temporarily withheld during the study.   
Participants who permanently discontinue study drug early will undergo early termination 
procedures, which include 
 an ETV and, 
 post-treatment follow-up visits (Visit 801 and Visit 802). 
The investigator will complete any AE reporting and necessary follow-up (Section 8.3). 
7.1.1 
Criteria for Permanent Discontinuation of Study Drug 
Possible reasons leading to permanent discontinuation of study drug include, but are not limited 
to: 
Subject Decision 
 The participant requests to discontinue the study drug. 
Disease Worsening 
 The participant requires treatment with a specified prohibited CD medication 
(Appendix 10.6). 
 The participant undergoes surgery for CD (with the exception of drainage of a perianal or 
other cutaneous abscess or seton placement). 
Safety Considerations 
 The participant has a diagnosis of any of the following during the study: 
o cancer other than squamous cell or basal cell carcinoma of the skin 
o any colonic adenomatous polyp (including sporadic) >10 mm, any evidence of 
dysplasia (low-grade* or high grade) in GI tract, or presence of any serrated 
lesion (with or without dysplasia).  
*Note: except for low grade sporadic colonic adenomatous polyp a ≤10 mm once 
completely removed. 
a pedunculated or sessile polypoid, with a dome-shaped and symmetric contour, smooth surface, 
and well-delineated border which occurred in the non-colitic area 
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o active TB (Section 8.2.6) 
o HIV/AIDS 
o hepatitis B or development of detectable HBV DNA (Section 8.2.8). 
o hepatitis C or development of detectable HCV RNA (Section 8.2.9). 
 The participant has a systemic hypersensitivity event or anaphylaxis to mirikizumab 
(Section 6.7.3.2).  Study drug should be discontinued after a systemic hypersensitivity 
event or anaphylaxis. 
 The participant has absolute lymphocyte count <0.5 x 103/μL after retesting (see 
Section 7.1.2). 
 The participant becomes pregnant.  Pregnant participants will not undergo an endoscopy 
at the ETV (Section 8.1.1.3). 
 Noncompliance with LTBI treatment (see Section 8.2.6). 
 The participant has an AE or SAE which, in the opinion of the investigator or sponsor, 
would preclude the participant from continuing to receive study drug. 
 It is recommended that the participant be assessed by an appropriately trained 
professional to assist in deciding whether the participant is to be discontinued if: 
o The participant 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 
o The participant reports suicidal ideation or suicidal behaviors during the study. 
Hepatic Event or Liver Test Abnormality 
 Participants who are discontinued from study drug because of a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via the hepatic eCRF 
packet. 
Discontinuation of study drug because of abnormal liver tests should be considered by 
the investigator when a participant meets one of the following conditions after 
consultation with the medical monitor (see Section 8.2.10): 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and TBL >2 × ULN or international normalized 
ratio (INR) >1.5 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
o alkaline phosphatase (ALP) >3 × ULN 
o ALP >2.5 × ULN and TBL >2 × ULN 
o ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, 
right quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%). 
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Other Reasons 
 Unblinding:  If an investigator, site personnel performing assessments, or participant is 
unblinded, the participant must be discontinued from the study drug and continue to 
post-treatment follow-up.  In cases where there are ethical reasons to have the participant 
continue on study drug, the investigator must obtain specific approval from the sponsor 
or designee for the participant to continue. 
 Treatment noncompliance:  participant missed 
 of study drug 
(Section 6.4). 
Participants discontinuing from the study drug prematurely for any reason will complete AE and 
other follow-up procedures as specified in Section 1.3 (Schedule of Activities), Section 8.2 
(Safety Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events), including 
ETV and post-treatment follow-up visits (Visit 801 and Visit 802). 
7.1.2 Criteria for Temporary Interruption (Withholding) of Study Drug 
Cases that may merit temporary withholding of study drug should be discussed with the medical 
monitor.  The medical monitor, in consultation with the investigator, will determine when it is 
appropriate to recommence study drug. 
Some possible reasons for temporarily withholding study drug include, but are not limited to: 
 The participant develops a clinically important intestinal or extraintestinal infection 
(including LTBI) during the study (see Section 5.2). 
 The participant requires major surgery.  Administration of study drug may be restarted 
only after adequate wound healing. 
 The participant develops a confirmed absolute neutrophil count <1 x 109/L (<1 x 103/μL 
or <1 GI/L (2 consecutive assessments below this threshold). 
 Participants who develop an absolute lymphocyte count <500 cells/μL (<0.5 × 103/μL or 
<0.50 GI/L) will be retested approximately every 2 weeks for up to 8 weeks unless the 
lymphocyte count becomes ≥0.5 × 103/μL or ≥0.50 GI/L.  
o Azathioprine, methotrexate, or 6-mercaptopurine must be discontinued, if 
applicable, after the first retest confirming absolute lymphocyte count 
<0.5 × 103/L (2nd assessment below threshold), and the next dose of study 
drug held. The participant must be retested in approximately 2 weeks. 
o The third retest (4th assessment below threshold) should occur prior to the next 
monthly dosing and if still below <0.5 × 103/L, the next dose of study drug 
should also be held.  The participant must be retested in approximately 
2 weeks.   
o After the fourth retest (fifth assessment below threshold), the participant may 
be permanently discontinued. Consult your medical monitor.  White blood cell 
and lymphocyte counts will be followed for these participants until they return 
to an acceptable level. 
  The participant has laboratory abnormalities that may lead investigator to hold the study 
drug until resolution of the abnormalities.  
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7.1.3 Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, the participant should be discontinued from study drug unless there 
are extenuating circumstances that make it medically necessary for the participant to continue on 
study drug.  If the investigator and the sponsor agree that it is medically appropriate to continue, 
the investigator must obtain documented approval from the sponsor to allow the inadvertently 
enrolled participant to continue in the study.  Participants who are discontinued from study drug 
will complete AE and other follow-up as specified in Section 1.3 (Schedule of Activities), 
Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events), 
including ETV and post-treatment follow-up visits (Visit 801 and Visit 802). 
7.2 Participant Discontinuation/Withdrawal from the Study 
Participants will be discontinued (withdrawn) from the study in the following circumstances:   
 enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study 
 participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP) 
 investigator decision 
o the investigator decides that the participant should be discontinued from 
the study 
 subject decision 
o the participant requests to be withdrawn from the study. 
Participants discontinuing from the study prematurely for any reason should have AE and other 
safety follow-up specified for the ETV.  See Section 1.3 (Schedule of Activities), Section 8.2 
(Safety Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events). 
7.3 Lost to Follow up 
A participant 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 participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
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8 Study Assessments and Procedures 
Study procedures and their timing, including tolerance limits for timing, are listed in the SoA 
(Section 1.3).  Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
The disease activity measurements are used in clinical practice and CD clinical trials.   
The safety parameters in this study are routine elements of clinical health assessment and 
Phase 3 drug development.   
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study drug. 
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. 
8.1 Efficacy Assessments 
The following table defines efficacy endpoints used in this study.   
Endpoint 
Definition 
Endoscopic response  
≥50% reduction from baseline in SES-CD total score 
Endoscopic remission SES-CD ≤4 
SES-CD Total Score ≤4 and at least a 2-point reduction versus baseline and 
no subscore >1 
Endoscopic remission SES-CD 0-2 
SES-CD Total Score ≤2 
Clinical remission by PRO 
unweighted daily average SF ≤3 (number of liquid or very soft stools [as 
taken from the Crohn’s Disease Activity Index, CDAI], defined using the 
Bristol Stool Scale Category 6 or 7 [Lewis and Heaton 1997], that is, liquid 
or watery stools) and the unweighted daily average AP ≤1 (AP [4-point 
scale:  0=none, 1=mild, 2=moderate, 3=severe]) and both SF and AP no 
worse than baseline 
Clinical response by PRO 
as at least a 30% decrease in SF and/or AP and neither score worse than 
baseline 
Clinical remission by CDAI 
CDAI score <150 
Clinical response by CDAI 
A reduction in CDAI score by ≥100 points compared to baseline and/or 
being in clinical remission by CDAI 
Abbreviations:  AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; PRO = patient-reported outcome; 
SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency. 
 
8.1.1 Primary Efficacy Assessment 
The co-primary endpoints (mirikizumab versus placebo) are:  
 Proportion of participants achieving clinical response by PRO at Week 12 and 
endoscopic response at Week 52; and  
 Proportion of participants achieving clinical response by PRO at Week 12 and clinical 
remission by CDAI at Week 52. 
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Clinical Response by PRO 
Clinical Response by PRO is defined in the table in Section 8.1. 
The PROs used for the co-primary endpoint are:  SF per Bristol Stool Scale Category 6 or 7, and 
AP based on the 0-3 scale of CDAI (Section 4.2).  Refer to Appendix 10.8 for more information 
on PROs. 
Endoscopic Response 
Endoscopic response is based on the SES-CD score (Vuitton et al. 2016) and is defined in the 
table in Section 8.1. 
The SES-CD tool will be utilized by central readers to evaluate the endoscopy video that is 
collected during the participant endoscopic examination.  The SES-CD is discussed further in 
Section 8.1.1.1. 
Refer to Sections 8.1.1.3 and 8.1.1.4 for more information on Endoscopy and Endoscopic 
Biopsies. 
Clinical Remission by CDAI 
Clinical remission by CDAI is defined in the table in Section 8.1. 
The CDAI is discussed further in Section 8.1.1.1. 
8.1.1.1 Crohn’s Disease Activity Index (CDAI) 
The CDAI is an 8-item disease activity measure comprised of a composite of 3 patient-reported 
and 5 physician-reported/laboratory items (physical signs and a laboratory parameter 
[hematocrit]).  Participant responses are summed over a 7-day period and all items are 
subsequently weighted, yielding a total score range of 0 to 600 points.  See Appendix 10.8 for 
additional descriptions of PROs (CDAI-Stool Frequency [CDAI-SF], CDAI-Abdominal Pain 
[CDAI-AP], and CDAI-Well-Being). 
8.1.1.2 Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
The SES-CD (Daperno et al. 2004) is an endoscopic scoring system for CD based on 4 
endoscopic variables (presence and size of ulcers, proportion of surface covered by ulcers, 
proportion of surface affected by disease, and presence and severity of stenosis), which are 
assessed in 5 ileocolonic bowel segments (ileum; right, transverse, and left colon; and rectum).  
Each of the 4 endoscopic variables is scored from 0 to 3:  presence and size of ulcers 
(none = score 0; diameter 0.1 cm to 0.5 cm = score 1; 0.5 cm to 2 cm = score 2; >2 cm = score 
3); extent of ulcerated surface (none = 0; <10% = 1; 10% to 30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50% to 75% = 2; >75% = 3); and presence and type of 
narrowing (none = 0; single, can be passed = 1; multiple, can be passed = 2; cannot be 
passed = 3).  The grand total is obtained as the sum of all endoscopic scores across all bowel 
segments.  Scores range from 0 to 56, with higher scores indicating more severe disease. 
8.1.1.3 Endoscopy 
An endoscopy will be performed on all participants during screening, prior to randomization.  
The endoscopy report and histopathology report (if biopsies sent to the local histopathology 
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laboratory) must be available in the source documents.  Prior to performing the screening 
endoscopy, investigators should ensure that participants have clinically acceptable central 
laboratory test results.  Stool culture and C. difficile must be negative at screening prior to 
randomization. 
To ensure quality data and standardization, endoscopy will be performed locally at clinical sites 
per the study schedules and using the same endoscopist throughout the trial wherever possible.  
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.   
During the study, the SES-CD will be determined by central readers blinded to study treatment, 
to determine study eligibility and endoscopic efficacy evaluation.  A detailed imaging review 
charter from the central reading laboratory will outline the endoscopic procedures, video 
recordings, and equipment to be used for video capture and transmission of endoscopic  
recordings.  For each participant, video recording of the entire endoscopic procedure will be 
performed using a storage medium provided by the sponsor or designee.  The endoscopic 
recordings will be read centrally in a blinded manner by qualified gastroenterologists according 
to the image review charter.   
If a participant becomes pregnant during the study, no additional endoscopies will be performed. 
8.1.1.4 Endoscopic Biopsies 
Biopsies will be collected during the endoscopy procedure.  Biopsies will be used for the 
assessment of exploratory biomarkers where permitted (Section 8.8) and to support assessment 
of the histopathology endpoints (Section 8.1.3.2).  The biopsy samples will be sent to the central 
study laboratory for processing.  To ensure quality data and standardization, bowel tissue 
histopathologic scoring will be performed by blinded central readers.  The details of biopsy 
sample collection will be provided in both the imaging manual and laboratory manual.  A 
detailed endoscopy and histopathology charter will outline the procedures to be used for secure 
specimen transfer, processing, slide preparation and digitization of slides for histopathologic 
scoring.  These results will not be made available to study sites during the study. 
At the scheduled endoscopies, additional biopsies may be taken as clinically indicated for 
participant management.  These specimens will be sent to a local laboratory.  Any clinically 
significant findings must be recorded as an AE on the eCRF. 
8.1.2 Secondary Efficacy Assessments 
8.1.2.1 Patient Reported Outcomes (PROs) 
The following PROs will be collected:   
 Via patient eDiary 
o bowel movement count (BMC) 
o CDAI-SF 
▪ Note:  Bristol Stool Scale is used as a reference to complete CDAI-SF. 
o CDAI-AP 
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o CDAI-Well-Being 
o Abdominal Pain numeric rating scale (NRS) 
o Urgency NRS 
o Patient Global Rating of Severity (PGRS) 
 Via tablet device 
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
o Inflammatory Bowel Disease Questionnaire (IBDQ) 
o European Quality of Life 5-Dimension 5 Level (EQ-5D-5L) 
o Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) version 
2, Acute 
o Work Productivity and Activity Impairment Questionnaire – Crohn’s Disease 
(WPAI-CD) 
o Inflammatory Bowel Disease – Disability Index (IBD-DI) 
o Patient Global Impression of Change (PGIC) 
As noted in Section 6.4, the investigator is responsible for ensuring that study participants 
receive adequate training on, and have appropriate understanding of, how to evaluate their CD 
symptoms and to record them on the eDiary. 
See Appendix 10.8 for details on the above PROs. 
8.1.2.2 Inflammatory Biomarkers 
High-sensitivity C-Reactive Protein (hsCRP) 
High-sensitivity C-reactive protein is an acute phase protein expressed by hepatocytes in 
response to inflammatory cytokines, particularly IL-6, TNF, and IL-1β (Sands 2015).  
High-sensitivity C-reactive protein will be obtained at time points described in the SoA (Section 
1.3).  Investigators will be blinded to hsCRP 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 calprotectin 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 SoA (Section 1.3).  Investigators will be blinded to fecal 
calprotectin results. 
8.1.2.3 Extraintestinal Manifestations (EIMs) 
Review of EIMs will be performed at the time points described in the SoA (Section 1.3).  
Extraintestinal manifestations include ankylosing spondylitis, anal fissure, fistula or abscess, 
other fistulae, arthritis/arthralgia, cholelithiasis, erythema nodosum, nephrolithiasis, aphthous 
stomatitis, primary sclerosing cholangitis, pyoderma gangrenosum, sacroiliitis, iritis/uveitis, and 
thrombosis (deep vein/portal vein). 
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8.1.2.4 Fistulas  
Additional data on bowel fistulas will be collected on an eCRF at the time points described in the 
SoA (Section 1.3).   
8.1.3 Exploratory Assessments 
Other exploratory endpoints will be defined in the SAP.   
8.1.3.1 Disease Severity Index-Crohn’s Disease (DSI-CD) 
The DSI-CD is a clinician’s reported 16-item measurement scored by reviewing participant 
symptoms, physical assessment, labs, medications, physical activity, and pain.  Scores range 
from 0 to 100, with a higher score indicating worse disease severity. 
This assessment will only be performed at screening.   
 
 
   
8.2 Safety Assessments 
Visits and order of safety assessments 
Safety assessments occur at visits specified in the SoA (Section 1.3).  When multiple 
assessments are scheduled for the same visit, the preferred order of completion is:   
 
vital signs first, 
 
ECG (if applicable), and then 
 
blood sampling last. 
Adverse event collection should occur before the collection of the C-SSRS or QIDS-SR16 
(Section 8.2.11 and Section 8.3.2.1). 
Data collection and reporting 
The AE data collection and reporting requirements are described in Section 8.3.  The additional 
requirements for collection of data regarding AESIs are noted in Section 8.3.7. 
Safety monitoring 
The sponsor 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 DMC (Appendix 10.1.4) or by the sponsor, through its 
Internal Review Committee (IRC) process. 
8.2.1 Vital Signs 
Measurements of vital signs (body temperature, blood pressure, and pulse rate) will be conducted 
at the study visits specified in the SoA (Section 1.3). 
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Sitting blood pressure and pulse rate should be measured after the participant 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 participant receives the first dose of study drug should be reported to Lilly or 
its designee as an AE via eCRF. 
8.2.2 Physical Examinations 
Physical examinations are mandated and will be performed as specified in the SoA (Section 1.3).  
Physical examinations 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. 
At screening, one complete physical examination (excluding pelvic, rectal, and breast 
examinations) will be performed and will include an assessment of peripheral lymph nodes. 
After screening, physical examinations should include a symptom-directed evaluation as well as 
examination of eyes, heart, lungs, abdomen, and visual examination of the skin.  For participants 
with a risk factor, a thorough exam to evaluate for TB will be performed (Section 8.2.6). 
Any clinically significant findings from physical examination that result in a diagnosis and that 
occur after the participant receives the first dose of study drug should be reported to Lilly or its 
designee as an AE via eCRF. 
8.2.3 Electrocardiograms 
Electrocardiograms (12-lead) will be conducted at the study visits specified in the SoA 
(Section 1.3). 
Electrocardiograms should be completed prior to any blood draw.  Participants should be supine 
for approximately 5 to 10 minutes before ECG collection and should remain supine and awake 
during ECG collection. 
Electrocardiograms will be read locally. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
participant receives the first dose of study drug should be reported to Lilly or its designee as an 
AE via eCRF. 
8.2.4 Chest Radiography 
A posterior-anterior CXR, interpreted and reported by a radiologist or pulmonologist, will be 
obtained at screening, as specified in the SoA (Section 1.3).  A lateral CXR can also be obtained 
if, in the opinion of the investigator, a lateral view is indicated.   
Participants need not have a CXR at screening if, based on the judgement of the investigator, all 
the following conditions are met: 
 the CXR was performed within 3 months before initial screening, and 
 documentation of the CXR, read by a qualified radiologist or pulmonologist, is sufficient 
for TB evaluation according to local standard of care. 
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A CT scan can be performed as an alternative to the CXR based on regional standard of practice.   
For all participants, CXR films or images or a radiology report must be available to the 
investigator for review. 
Certain findings from CXR may be consistent with a condition that excludes a participant from 
the study; see Section 5.2. 
8.2.5 Stool Testing 
Stool Culture 
A stool sample for culture will be obtained at screening.  In order to be randomized, participants 
must have a negative stool culture from which no enteric pathogens are isolated.   
Retesting is allowed within the screening period if there is a technical difficulty in performing or 
reporting the stool culture assay, as stated in Section 5.4.1.   
Participants who have a “positive” stool culture result can be rescreened once, as stated in 
Section 5.4, provided that the following conditions have been met: 
 the participant has been adequately treated, and 
o if antibiotics were prescribed, participant has been off antibiotics for 30 days, or 
o if antibiotics were not prescribed, 30 days or more has elapsed since resolution of 
acute symptoms and signs associated with the underlying intestinal infection. 
Additional local stool culture/testing is allowed at the investigator’s discretion. 
Participants with a positive stool culture result are excluded from the study (see Section 5.2). 
C. difficile Toxin 
A stool sample for C. difficile testing (including C. difficile toxin A and B, GDH with reflex to 
PCR testing as needed) will be obtained at screening.   
Participants with a positive test for C. difficile are excluded from the study (Section 5.2). 
Retesting is allowed within the screening period if there is a technical difficulty in performing or 
reporting the C. difficile result, as stated in Section 5.4.1. 
Participants who test positive at screening for C. difficile can be rescreened once, as stated in 
Section 5.4, provided that the following conditions have been met: 
 the participant has been adequately treated, and 
 the participant has been off antibiotics for 30 days. 
Participants who have been adequately treated for C. difficile with fecal microbial transplantation 
or IV immunoglobulin therapy can be rescreened once for the study, 30 days after completing 
their therapy.   
8.2.6 Tuberculosis Testing 
Initial screening 
All participants will be screened for active TB and LTBI.   
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Screening for LTBI will include the following: 
 Thorough medical and social history to determine risk factors for TB infection over 
lifetime, symptoms or signs of active TB, and physical examination, including body 
temperature measurement and assessment of peripheral lymph nodes, as described in 
Section 8.2.1 and Section 8.2.2. 
 CXR or CT, as described in Section 8.2.4, and 
 A test to assess immune response to mycobacterial antigens (unless participant has a 
history of a positive IGRA): 
o Interferon-γ release assay (IGRA; for example, 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.  Interferon-γ release assay is 
also the preferred screening test for LTBI in participants 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 
participants. 
Participants 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 ≥5 mm in diameter 
is interpreted as positive for the purpose of this study, regardless of BCG vaccination history. 
Participants 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 CXR or 
CT, may be rescreened once, as indicated in Section 5.4. 
Participants may be enrolled in the study if they are treated for LTBI and meet the following 
requirements: 
 no history of risk of re-exposure since their treatments were completed, 
 have received at least 4 weeks of appropriate ongoing prophylactic therapy for LTBI, 
based on national or international guidelines, for example, the CDC (CDC 2016) or the 
WHO (WHO 2018), with documentation of having completed the appropriate TB 
prophylaxis regimen, 
 no evidence of reactivation of LTBI, and 
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 have no evidence of hepatotoxicity (ALT and AST levels must remain ≤2 × ULN) upon 
retesting of serum ALT and AST levels before randomization). 
Such participants must meet all other inclusion and exclusion criteria for participation, and also 
must continue and complete appropriate LTBI therapy during the course of the study to remain 
eligible to participate. 
Retesting and confirmatory testing 
One retest is allowed for participants with an “indeterminate” QuantiFERON-TB Gold assay or 
“borderline” T-SPOT assay, as stated in Section 5.4.1.  Participants 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 participants 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, as detailed in Appendix 10.4.   
Participants who have been assessed by the PI to have a false positive TB test and meet the 
criteria to allow a retest must have confirmatory testing performed by an IGRA (QTF or T-
SPOT).  The TST should not be used for confirmatory testing. 
If the confirmatory test is positive, the participants will be excluded from the study unless he or 
she completes at least 4 weeks of appropriate therapy for LTBI, based on national or 
international guidelines (as defined above) and has no evidence of hepatotoxicity (ALT and AST 
levels must remain ≤2 × ULN) upon retesting of serum ALT and AST levels after at least 
4 weeks of LTBI treatment.  Such participants 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.   
Participants with a negative TST or IGRA can be retested with an IGRA where, in the judgement 
of the investigator, the initial test result may be a false negative, for example, due to a technical 
difficulty in administering the TST or due to concomitant immunosuppressant therapy. 
Monitoring for TB during the study 
For all participants, monitoring for TB is to be continuous throughout the study.  Every 3 months, 
the participants will be assessed for risk factors for TB (Appendix 10.4).  If the participant has a 
risk factor, the investigator should conduct a thorough exam to evaluate for TB, including 
examination of peripheral lymph nodes and documentation of body temperature.  If the 
participant has a risk factor(s), the investigator should conduct a thorough exam to evaluate for 
TB, including examination of peripheral lymph nodes and documentation of body temperature.  
If there are relevant physical findings, an IGRA and CXR or CT should be performed.   
Diagnosis of LTBI during the study 
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Participants diagnosed with LTBI during the study must be temporarily discontinued from study 
drug (Section 7.1.2).  If treatment for LTBI is considered to be appropriate, the participant 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 ≤2 × ULN) upon retesting of serum ALT and AST levels after at least 4 weeks of 
LTBI treatment.  Such participants may then resume study drug and must continue with and 
complete a full course of treatment for LTBI in order to continue on the study drug.  
Noncompliance with LTBI treatment during the study is a reason for permanent discontinuation 
from study drug (Section 7.1.1). 
Household contact 
Throughout the study, participants who have had household contact with a person with active TB 
must be evaluated for TB infection. 
Prior treatment for LTBI 
Participants who have a documented history of completing an appropriate TB prophylaxis 
regimen with no history of risk of re-exposure since their treatments were completed and no 
evidence of active TB are eligible to participate in the study.  These participants should not 
undergo TST or IGRA testing unless advised to do so based on local guidelines. 
Active TB  
Participants with a past history of active TB, without documented treatment by WHO and/or 
CDC criteria are excluded from the study (Section 5.2). 
Participants diagnosed with active TB at screening will be excluded (Section 5.2) and should be 
referred by the investigator for appropriate TB treatment and follow-up. 
If a participant is diagnosed with active TB during the study, the study drug will be permanently 
discontinued (Section 7.1.1), and the participant will undergo an ETV and then enter the post-
treatment follow-up period.  The participant should also be referred by the investigator for 
appropriate TB treatment and follow-up. 
8.2.7 Clinical Laboratory Tests 
Visits and times 
The clinical laboratory tests listed in Appendix 10.2 will be conducted at the study visits 
specified in the SoA (Section 1.3). 
Retesting is allowed during the screening period (see Section 5.4.1). 
Additional clinical laboratory tests, including local tests, may be performed at any time during 
the study as determined necessary by the investigator for immediate participant management or 
safety or as required by local regulations.   
Except where otherwise stated (for example, for postdosing PK sample), samples for laboratory 
tests should be collected prior to dosing. 
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Central and local Testing 
Unless noted as locally performed (for example, urine pregnancy tests), clinical laboratory tests 
will be sent to a central laboratory for testing. 
Provision of laboratory test results 
With the exception of laboratory test results that may unblind the study (Section 8.1.2.2), Lilly or 
its designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor. 
Investigator responsibilities 
Investigators or their designees are expected to review laboratory reports in a timely manner 
throughout the study. 
Investigators must document their review of each laboratory safety report. 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the participant receives the first dose of study drug should be reported to Lilly or its 
designee as an AE via eCRF. 
8.2.7.1 Pregnancy Testing 
Pregnancy testing is to be performed on all women unless they meet the criteria describing 
women not of childbearing potential, as outlined Section 5.1.  Participants who are pregnant will 
be discontinued from the study (Section 7.1.1). 
Visits and times 
Serum pregnancy test will be done at screening only, and results will be confirmed by the central 
laboratory.   
Urine pregnancy testing will be performed locally during designated scheduled visits through 
Week 52.  The urine pregnancy test must be “negative” within 24 hours prior to each 
administration of study drug at every study visit. 
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 Section 5.1.  Follicle-stimulating hormone can be optionally 
obtained during screening, at the discretion of the investigator.  Follicle-stimulating hormone can 
also be optionally obtained during the study to determine postmenopausal status (see Section 1.3).   
8.2.7.2 Immunogenicity Assessment 
Visits and times 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against mirikizumab.   
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 Predose samples will be obtained per the SoA. 
 The actual date and time (24-hour clock time) of each sample collection will be recorded. 
To aid interpretation of these results, a predose blood sample for PK analysis will be collected at 
the same time points. 
In the event of a systemic allergic/hypersensitivity reaction (Section 8.3.7.2), additional blood 
samples will be obtained as specified in the SoA (Section 1.3). 
Sample collection, handling, and use 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of mirikizumab at a laboratory approved by the sponsor.  Samples may be further evaluated for 
antibodies that neutralize the activity of mirikizumab. 
Sample retention 
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor.  The 
duration allows the sponsor to respond to future regulatory requests related to mirikizumab.  Any 
samples remaining after 15 years will be destroyed. 
8.2.8 Hepatitis B Testing 
HBV screening and interpretation 
Participants with acute or chronic hepatitis B infection are excluded from the study (see 
Section 5.2). 
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 
participants who are HBsAg-, anti-HBc+. 
Exclusion based on HBV serology and HBV DNA testing 
Participants with the following screening test results will be excluded from the study 
(Section 5.2). 
 HBsAg+, irrespective of anti-HBc result, or 
 HBsAg-, anti-HBc+ with detectable HBV DNA 
Participants potentially allowed into the study, based on HBV serology and HBV DNA testing 
Participants with the following screening test results may be eligible for inclusion, provided they 
meet the other study entry criteria: 
 HBsAg-, anti-HBc- 
 HBsAg-, anti-HBc+ with no HBV DNA detected. 
Management of participants with the following HBV serology at baseline:  HBsAg-, anti-HBc+, 
HBV DNA not detected 
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Randomized participants with the following serological pattern at screening will undergo 
HBV DNA monitoring as described in the SoA (Section 1.3): 
 HBsAg-, anti-HBc+, with no HBV DNA detected. 
In addition, if such participants experience an elevated ALT or AST level >3 × ULN during the 
study, they must have an HBV DNA test and be managed appropriately based on the results of 
that test. 
Management of participants with detectable HBV DNA during the study 
If HBV DNA is detected during the study, the study drug will be discontinued, and the 
participant will have an ETV; the participant will then enter the post-treatment follow-up period 
(Section 7.1).  Prior to discontinuing investigational product, the sponsor recommends that a 
hepatologist (or a physician with expertise in viral hepatitis) is consulted and that it is determined 
whether it is appropriate to start antiviral therapy prior to discontinuation of IP or any 
immunosuppressant or immunomodulatory therapy.  However, study drug should not be 
administered until this consultation has been completed and after discussion with the Medical 
Monitor.  Such participants 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 AE: 
 “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. 
8.2.9 Hepatitis C Testing 
Participants with current hepatitis C infection are excluded from the study (see Section 5.2). 
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.  Participants with a 
positive HCV antibody test and detectable HCV RNA will be excluded from the study 
(Section 5.2). 
Participants who test negative for HCV antibody will not be tested for HCV RNA and may be 
eligible for inclusion in the study. 
Participants who have spontaneously cleared hepatitis C infection, defined as  
 a positive HCV antibody test and 
 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 participant with a history of hepatitis C infection who develops elevated ALT >3 × ULN 
within the study will be tested for HCV RNA. 
Participants 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, 
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provided they have no detectable HCV RNA at screening.  Sustained virologic response is 
defined as an undetectable HCV RNA level 24 weeks after completion of a full, documented 
course of an approved, potentially curative antiviral therapy for HCV. 
If a participant is diagnosed with hepatitis C during the study (detectable HCV RNA), the study 
drug will be discontinued, and the participant will have an ETV; the participant will then enter 
the post-treatment follow-up period (Section 7.1).  Such participants should also receive 
appropriate follow-up medical care.  
8.2.10 Hepatic Safety Monitoring 
If a study participant experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated 
TBL ≥2 × ULN, liver testing (described in Appendix 10.3) 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 participant experiences an ALT or AST >3 × ULN and TBL >2 × ULN or INR >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:   
 elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests 
 elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s 
syndrome)  
 elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests 
 participant discontinued from treatment due to a hepatic event or abnormality 
of liver tests 
 hepatic event considered to be a SAE 
 participant with a history of HCV infection develops elevated ALT >3 × ULN.  
Participant will be tested for HCV RNA. 
 participant experiences an ALT or AST >3 × ULN and TBL >2 × ULN or INR >1.5.  
The study medical monitor should be consulted as soon as possible for further 
guidance. 
8.2.11 Depression, and Suicidal Ideation and Behavior 
Suicide-related events (behavior and/or ideations) will be assessed at screening with the 
administration of the C-SSRS. 
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Depressive symptomology will be assessed with the QIDS-SR16 at the visits specified in the 
SoA (Section 1.3). 
These assessments are described below, and further information is provided in Appendix 10.9. 
Columbia Suicide Severity Rating Scale:  The C-SSRS (CUIMC 2016) is a scale that 
captures the occurrence, severity, and frequency of suicidal ideation and/or behavior 
during the assessment period.  The scale includes suggested questions to solicit the type 
of information needed to determine if suicidal ideation and/or behavior occurred.  The 
C-SSRS is administered by an appropriately trained healthcare professional.  Participant 
data for the C-SSRS will be recorded 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 
(APA 2013).  Participants will record their responses to the QIDS-SR16 electronically as 
source data in the tablet device. 
See Section 8.3.2.1 for information about AE collection relative to collection of the C-SSRS or 
QIDS-SR16. 
See Section 7.1.1 for information regarding discontinuation of study drug for participants who 
have suicidal ideation or suicidal behaviors. 
8.3 Adverse Events and Serious Adverse Events 
Investigators are responsible for monitoring the safety of participants 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 participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study.  The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise 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 participant’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 
CD, 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. 
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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 participant’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. 
Care will be taken not to introduce bias when detecting AEs or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences (see Section 8.3.2.1). 
8.3.1 Serious Adverse Events 
An SAE is any AE from this study that results in one of the following outcomes: 
 death 
 initial or prolonged inpatient hospitalization 
 a life-threatening experience (that is, immediate risk of dying) 
 persistent or significant disability/incapacity 
 congenital anomaly/birth defect 
 important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
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 participant 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 8.3.2) 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 
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information.  Participants with a serious hepatic AE should have additional data collected using 
the hepatic eCRF packet (see Section 8.2.10). 
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. 
8.3.1.1 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 Code of Federal Regulations (CFR) 312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs.  Lilly has procedures that will be 
followed for the identification, recording, and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances. 
8.3.2 Time Period and Frequency for Collecting AE and SAE Information 
AEs that begin before the first dose of study drug but after signing of the ICF will be recorded on 
the Adverse Event eCRF. 
Investigators are not obligated to actively seek AEs or SAEs in participants once the participant 
has discontinued and/or completed the study (the participant disposition eCRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and the investigator considers the event 
reasonably possibly related to the study treatment or study participation, the investigator must 
promptly notify Lilly. 
8.3.2.1 Adverse Event Monitoring with a Systematic Questionnaire 
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.  However, if an event is serious 
or leads to discontinuation, the event should be included on the AE form, and the process for 
reporting SAEs, if applicable, should be followed. 
8.3.3 Follow-up of AEs and SAEs 
The investigator responsibility for follow-up of AEs sand SAEs is described in Section 8.3.  
8.3.4 Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE as stated in Section 8.3 and 
Section 8.3.2 is essential so that legal obligations and ethical responsibilities towards the safety 
of participants and the safety of a study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
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the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review and 
then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 Pregnancy Reporting 
For all pregnancies in female participants and female partners of male participants, details will 
be collected (via the procedures outlined in Section 8.3) for pregnancies that begin at any point 
after the start of study drug and until at least 20 weeks after the participant’s last dose of study 
drug. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 8.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sites should collect additional details and data regarding AESIs, as instructed on the applicable 
eCRFs. 
8.3.7.1 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).  See Appendix 10.5 for more information. 
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8.3.7.2 Systemic Allergic Reactions and Hypersensitivity Events 
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include but are not limited to: 
 Skin rash 
 Pruritus (itching) 
 Dyspnea 
 Urticarial (hives) 
 Angioedema (for example, swelling of the lips and/or tongue) 
 Hypotension 
 Anaphylactic reaction 
Participants with clinical manifestations of systemic allergic/hypersensitivity reactions should be 
treated per local standard of care.  Additional data describing each symptom should be provided 
to the sponsor in the eCRF. 
In case of a systemic hypersensitivity reaction involving two or more organ systems (that is, 
mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems), additional blood 
samples for laboratory testing should be collected at the times specified in the SOA (Section 1.3).  
The lab results are provided to the sponsor via the central laboratory.   
Site personnel should educate participants 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 6.7.3.2. 
8.3.7.3 Injection/Infusion Site Reactions 
Symptoms of a local injection/infusion site reaction may include erythema, induration, pain, 
pruritus, and edema at the site of the injection/infusion.  If an injection/infusion site event is 
reported, the AE will be recorded, and additional data will be provided to the sponsor in the 
eCRF.   
For recommendations on the management and follow-up of injection site or infusion site events, 
see Section 6.7.3.2. 
8.3.7.4 Cerebro-cardiovascular Events Adjudication 
Potential cerebro-cardiovascular events will be identified by the investigative site or by a 
medical review conducted by the sponsor or designee.  Additional data about each identified 
potential event should be provided to the sponsor via specific event adjudication forms.  A 
blinded external Clinical Event Committee will adjudicate the events in a consistent and 
unbiased manner.   
8.3.8 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. 
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Participants will be instructed to contact the investigator as soon as possible if the participant has 
a complaint or problem with the investigational product so that the situation can be assessed. 
8.4 Treatment of Overdose 
In case of suspected overdose, participants should be monitored for any signs or symptoms of 
adverse reactions or effects, and hematology, chemistry, vital signs, and oxygen saturation 
should be monitored; supportive care should be provided as necessary.  The medical monitor and 
sponsor must be informed as soon as possible when an overdose has been identified, and all AEs 
associated with the overdose will be recorded in the eCRF.  There is no known antidote for 
mirikizumab or ustekinumab. 
8.5 Pharmacokinetics 
Visits and times 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the serum concentrations of mirikizumab. 
 
 
 
 
 
 
Collection, handling, and storage of samples 
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
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 participants will be analyzed. 
Additional samples 
A maximum of 3 additional samples for exploratory analyses such as bioanalytical method 
development or validation exercises may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  In the case of systemic 
allergic/hypersensitivity reactions (Section 8.3.7.2), additional blood samples will be obtained, as 
described in the SoA.  The results will not be provided to the investigator. 
Blinding 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel. 
Sample retention 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last participant visit for the study. 
8.6 Pharmacodynamics 
See Section 8.8 for biomarkers. 
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8.7 Pharmacogenomics 
8.7.1 Whole Blood Sample for Pharmacogenetic Research 
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow. 
Sample use 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to mirikizumab and 
to investigate genetic variants thought to play a role in CD, the biology of IL-23, immune 
responses, and responses to cytokines.  Assessment of variable response may include evaluation 
of AEs or differences in efficacy. 
The genetic markers on the immunochip (Illumina Infinium® ImmunoArray-24 v2.0BeadChip 
[WWW]) may be tested.  These are genetic markers that are related to the biology of 
inflammatory and autoimmune disease. 
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Sample retention 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards impose shorter time limits.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of mirikizumab or after mirikizumab 
becomes commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section. 
8.8 Exploratory Biomarkers 
Serum, plasma, whole blood RNA, whole blood for epigenetics, fecal matter, and gastrointestinal 
tissue samples for biomarker research will be collected at the visits and times specified in the 
SoA (Section 1.3) where local regulations allow. 
Sample use 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements. 
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Samples will be used for research on the drug target, CD disease process, variable response to 
mirikizumab, pathways associated with CD, mechanism of action of mirikizumab, and/or 
research method or in validating diagnostic tools or assays related to CD or the study drug. 
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Sample retention 
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of mirikizumab or after mirikizumab becomes commercially available. 
8.9 Medical Resource Utilization and Health Economics 
Sites should provide information regarding healthcare visits, including hospitalizations and 
surgeries for CD, as instructed on the eCRF. 
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9 Statistical Considerations 
9.1 Statistical Hypotheses 
The primary hypothesis that will be tested in this study is that mirikizumab is superior to placebo 
in the Primary Analysis Set on below co-primary endpoint. 
 Clinical response by PRO at Week 12 and endoscopic response at Week 52 
 Clinical response by PRO at Week 12 and clinical remission by CDAI at Week 52 
Major secondary hypotheses are that mirikizumab is superior to placebo with regards to 
 Endoscopic response at Week 52 
 Clinical remission by CDAI at Week 52 
 Clinical response by PRO at Week 12 and clinical remission by PRO at Week 52 
 Endoscopic response at Week 12   
 Clinical remission by CDAI at Week 12  
 Clinical response by PRO at Week 12 and endoscopic remission SES-CD ≤4 at Week 52  
 Clinical response by PRO at Week 12 and either clinical remission by CDAI at Week 52 
or endoscopic remission SES-CD ≤4 at Week 52 who were also corticosteroid-free from 
Week 40 to Week 52 
 Endoscopic remission SES-CD ≤4 at Week 12 
 Change from baseline in Urgency NRS at Week 12 and Week 52  
Additional major secondary hypotheses are that mirikizumab is superior to ustekinumab with 
regards to: 
 endoscopic response at Week 52   
 endoscopic remission SES-CD ≤4 at Week 52.   
Another major secondary hypothesis is that mirikizumab is noninferior to ustekinumab at Week 
52 with regards to clinical remission by CDAI. 
9.2 Sample Size Determination 
Approximately 3000 participants may be screened to achieve a total of approximately 1100 
participants randomly assigned to study intervention.  Based on a 6:3:2 randomization ratio, 
approximately 600 participants will be randomized to mirikizumab, 300 participants to 
ustekinumab, and 200 participants to placebo. 
Approximately 90% of randomized participants are expected to meet the Primary Analysis Set 
definition as described in Section 9.3. A sample size of 990 participants (540 participants in 
mirikizumab and 180 participants in placebo) provides >90% power to demonstrate that 
mirikizumab is superior to placebo for the co-primary endpoint of (1) clinical response by PRO 
at Week 12 and clinical remission by CDAI at Week 52 and (2) clinical response by PRO at 
Week 12 and endoscopic response at Week 52. This estimated power is based on a 2-sided chi-
square test with alpha = 0.005 and the assumed treatment response rates of the co-primary 
endpoint are 33% for mirikizumab and 10% for placebo.  
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The sample size based on the  Primary Analysis Set also provides >90% power to demonstrate 
that mirikizumab is superior to ustekinumab for endoscopic response at Week 52.  This 
calculation is based on a 2-sided chi-square test with alpha = 0.045 and assuming a difference of 
at least 16% between mirikizumab and ustekinumab in endoscopic response at Week 52. 
Blinded sample-size re-estimation may be performed before the last participant has been enrolled 
in the study.  For this re-estimation, response rates using blinded data will be evaluated and 
compared with the assumed response rates..  The sample size from the study is estimated to be 
between a minimum sample size, 1100 participants, and a predefined, maximum sample size 
upto 1210 participants.  If the re-estimated sample size is smaller than the planned minimum 
sample size, the study may enroll to the recalculated sample size.  If the re-estimated sample size 
is larger than the planned minimum sample size, the team will decide whether to increase the 
sample size, up to a predefined maximum, or to accept the re-assessed reduced power reduction 
in power. 
9.3 Populations for Analyses 
For purposes of analysis, the following populations are defined. 
Intent-to-Treat (ITT) Population 
The ITT Population is defined as all randomized participants, even if the participant does not 
receive the correct treatment, or otherwise does not follow the protocol.  Participants will be 
analyzed according to the treatment to which they were randomized. 
Modified Intent-to-Treat (mITT) Population 
All participants from ITT population who take at least one dose of study drug.   
Primary Analysis Set 
All participants from mITT population who have baseline SES-CD ≥7 (or ≥4 for isolated ileal 
disease). 
Safety Population  
Same as mITT. 
9.4 Statistical Analyses 
9.4.1 General Statistical Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee.  A detailed 
SAP describing the statistical methodologies will be developed by the sponsor or its designee.   
Unless otherwise specified, efficacy analyses will be conducted on the Primary Analysis Set. 
Selected efficacy analysis may also be conducted on the mITT population. Safety analyses will 
be conducted on the safety population. Definitions are described in Section 9.3. 
When reported, descriptive statistics will include the number of participants; mean, standard 
deviation, median, minimum, and maximum for continuous measures; and frequency counts and 
percentages for categorical measures. 
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Treatment comparisons of categorical efficacy measures between mirikizumab versus placebo, 
and mirikizumab versus ustekinumab will be made using the Cochran-Mantel-Haenszel (CMH) 
chi-square test with the following covariates:  biologic-failed status (yes/no), baseline SES-CD 
total score (<12, ≥12),  and either baseline SF ≥7 and/or baseline AP ≥2.5 (yes/no).  The CMH 
chi-square p-value will be provided.  The percentages, difference in percentages, and  CI of the 
difference in percentages will be reported.   
When evaluating continuous measures over time, a restricted maximum-likelihood-based mixed 
effects model of repeated measures (MMRM) will be used.  The model will include treatment, 
biologic-failed status (yes/no), baseline SES-CD total score (<12, ≥12),  and either baseline SF 
≥7 and/or baseline AP ≥2.5 (yes/no), visit, and treatment by visit interaction as fixed categorical 
effects and, if a baseline score for the measure is available, baseline score and baseline score by 
visit interaction as fixed continuous effects.  An unstructured covariance structure will be used to 
model the between- and within-subject errors.  If this analysis fails to converge, 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 
degrees of freedom.  Type III sums of squares for the least squares means will be used for the 
statistical comparison; CI will also be reported.  Contrasts will be set up within the model to test 
treatment groups at specific time points of interest. 
Fisher’s exact test will be used for categorical safety data (example, AEs) for between treatment 
group comparisons.  Continuous safety variables (example, laboratory variables) will be 
analyzed by an analysis of covariance with treatment and baseline value in the model.   
All tests for the co-primary and major secondary endpoints will be conducted under the 
multiplicity-controlled framework described in Section 9.4.1.4.  For other secondary endpoints, 
superiority comparisons will be tested at a 2-sided alpha level of 0.05 and noninferiority 
comparisons will be tested at a 1-sided alpha level of 0.025.  Full details of all apriori specified 
analyses and finalized graphical testing scheme will be provided in the SAP.  Any change to the 
data analysis methods described in the protocol will require an amendment ONLY if it changes a 
principal feature of the protocol.  Any other change to the data analysis methods described in the 
protocol, and the justification for making the change, will be described in the clinical study 
report.  Additional exploratory analyses of the data will be conducted as deemed appropriate. 
9.4.1.1 Definition of Baseline 
Visit 2 (Week 0) is the baseline randomization visit.  The centrally read baseline SES-CD score 
from the screening endoscopy is considered the baseline for endoscopic response and endoscopic 
remission.  Daily diary entries obtained prior to Visit 2 are also considered baseline for clinical 
remission by PRO, clinical response by PRO, CDAI clinical remission, and CDAI clinical 
response.  For other efficacy, and health outcome assessments, baseline is defined as the last 
nonmissing assessment recorded on or prior to the date of Visit 2 (Week 0), unless otherwise 
specified.  For safety assessments, the baseline period is defined as the start of screening and 
ends at the first dose of study treatment at Visit 2, unless otherwise specified.  Based on the type 
of safety analysis, the baseline period or the last nonmissing assessment during the baseline 
period will be used for baseline.  Baseline definitions for safety assessments will be described in 
the SAP by analysis type. 
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9.4.1.2 Estimand 
The estimand (ICH 2017) associated with each endpoint/analysis is documented in the following 
places: 
 The population of interest is described in the inclusion/exclusion criteria (Section 5.1 and 
Section 5.2) and in “Populations for Analyses” (Section 9.3) 
 The endpoints and variables are listed in Objectives and Endpoints (Section 3) 
 The handling of intercurrent events is summarized in “Missing Data Imputation” 
(Section 9.4.1.3) 
 Population summary measures are described in “General Statistical Considerations” 
(Section 9.4.1) 
Additional details will be provided in the SAP.   
9.4.1.3 Missing Data Imputation 
Analysis of categorical efficacy and health outcomes variables will use a nonresponder 
imputation (NRI) method for missing data.  A participant will be considered NR for the 
NRI-based analysis if he or she:   
 does not achieve the endpoint(s) being analyzed, 
 has missing data at time point of interest that results in non-assessment of an endpoint(s) 
at the time point of interest, 
 discontinues treatment prior to time point of interest, 
 
specified changes in concomitant CD medications (to be detailed in the SAP).  
In selected analyses, participants in the placebo group who begin treatment with mirikizumab at 
Week 12, due to not achieving clinical response by PRO, will be considered NR for all visits 
subsequent to Week 12 for NRI-based analyses on categorical endpoints at Week 52. Details will 
be provided in the SAP. 
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. 
Sensitivity analyses, including additional methods of handling missing data or analyzing the data 
that may be required to satisfy regulatory needs will be specified in the SAP.   
9.4.1.4 Multiple Comparisons/Multiplicity 
For testing the primary and major secondary hypotheses, a prespecified graphical scheme 
(Bretz et al. 2009, 2011) will be implemented to control the overall Type I error rate (FWER) at 
a 2-sided alpha level of 0.05 as described below: 
Two groups including co-primary and major secondary hypotheses will be used.  Group 1 will 
include the co-primary endpoint and all major secondary endpoints that involve comparisons of 
mirikizumab versus placebo, and Group 2 will include all major secondary endpoints that 
involve comparisons of mirikizumab versus ustekinumab.  Within each group, the graphical 
scheme will control the FWER at a prespecified level.  For Group 1, a FWER at 0.005 will be 
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used.  If all comparisons in Group 1 are achieved, following the pre-specified graphical scheme, 
testing will proceed to Group 2 with a FWER at 0.05.  If one or more hypotheses in Group 1 are 
failed to be rejected, following the pre-specified graphical scheme,  testing will proceed to Group 
2 with a FWER at 0.045.  The graphical approach is a closed testing procedure; hence, it strongly 
controls the FWER across all endpoints (Alosh et al. 2014). 
9.4.2 Treatment Group Comparability 
9.4.2.1 
Participant Disposition 
The number of randomized participants (that is, participants in ITT) will be summarized by 
treatment group.  Frequency counts and percentages of all participants who are randomized and 
complete the study or who discontinue the study or treatment intervention early will be 
presented.  Reasons for early discontinuation of the study drug or of the study will be 
summarized. 
A detailed description of participant disposition will be provided at the end of the study.   
9.4.2.2 
Participant Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group; 
no testing will be performed for baseline characteristics.  For continuous measures, summary 
statistics will include sample size, mean, standard deviation, median, minimum, and maximum.  
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. 
9.4.2.3 
Concomitant Therapy 
Concomitant therapy will be collected at each visit, and the reported term will be classified by 
the WHO drug dictionary.  A summary of preferred names of concomitant medication by 
treatment group will be generated for the mITT population. 
9.4.2.4 
Treatment Compliance 
Deviations from the prescribed dosage regimen (as described in Section 6.4) will be described in 
a patient listing.  Additional details will be described in the SAP. 
9.4.3 Efficacy Analyses 
Primary and secondary analyses will be based on the Primary Analysis Set (defined in 
Section 9.3). 
9.4.3.1 
Primary Analyses 
The co-primary endpoint is comprised of two separate endpoints: 
 the proportion of participants achieving clinical response by PRO at Week 12 and 
endoscopic response at Week 52, and 
 the proportion of participants achieving clinical response by PRO at Week 12 and clinical 
remission by CDAI at Week 52. 
Endoscopic response is defined as ≥50% improvement from baseline in SES-CD total score 
where the SES-CD total score will be calculated as the sum of its 5 subscores:  ileum; right 
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colon, transverse colon, left colon; and rectum.  If at least one subscore is non-missing, missing 
subscores will be imputed with a zero value when deriving the SES-CD total score.  Endoscopies 
performed for Week 52 that occur up to a maximum of 14 days after the Week 52 visit date but 
before any additional dosing will be used for the analysis of Week 52. 
Clinical response by PRO is defined as ≥ 30% decrease in SF and/or AP and neither score worse 
than baseline. AP average and SF average will be calculated from daily electronic diary data by 
averaging the most recent 7 days (possibly nonconsecutive) in the 12 days prior to the day of the 
visit, after removing the day(s) of the endoscopy prep, the day of endoscopy procedure, and the 2 
days following the endoscopy procedure.  If less than 4 days of data are available, the value for 
AP average or SF average will be set to missing.   
Clinical remission by CDAI is defined as the total CDAI score <150. CDAI total score will be 
calculated as the sum of 3 participants reported and 5 physician reported/laboratory items. 
Participant responses are collected from daily electronic diary data and calculated as described 
for Clinical response by PRO per visit.  
Primary analyses will use the CMH chi-square test to compare mirikizumab to placebo as 
described in Section 9.4.1. The co-primary endpoint will also be conducted for mITT population 
as a secondary analysis. 
9.4.3.2 
Secondary Analyses 
The CMH test, as described for primary analyses, will be used to analyze categorical secondary 
endpoints.  The previously described MMRM model will be used to analyze continuous 
secondary endpoints.  
Additional analyses of the secondary efficacy and health outcome endpoints may be considered 
and will be fully detailed in the SAP.  Additional endpoints may be prespecified in the SAP. 
Noninferiority Analysis 
To assess noninferiority of mirikizumab to ustekinumab, the lower bound of the 2-sided 95% CI 
of the difference in proportions between mirikizumab and ustekinumab response will be 
compared to the noninferiority margin.  The CMH test, as described for primary analyses, will be 
used to estimate the CI for difference between ustekinumab and mirikizumab proportions.  To 
establish that mirikizumab is noninferior to ustekinumab, the upper bound for the ustekinumab 
minus mirikizumab proportions must be less than the prespecified noninferiority margin. 
Justification of Noninferiority Margin 
There is no universally accepted value for what is considered to be a clinically unimportant 
difference between 2 treatments based on CDAI remission.  Global regulatory guidance 
(EMA 2005 and FDA 2016 guidelines) indicate that selection of the noninferiority margin is 
based upon a combination of statistical and clinical grounds. 
The data from two induction studies (UNITI-1 and UNITI-2) followed by a single maintenance 
study (IM-UNITI) were used to demonstrate the efficacy of ustekinumab versus placebo in 
CDAI remission.  Participants who were randomized to ustekinumab in UNITI-1 or UNITI-2 and 
who achieved CDAI response at Week 8 were eligible to enroll in the randomized placebo-
withdrawal portion of IM-UNITI as the primary population.  All placebo participants and 
participants who did not achieve clinical response at Week 8 after being dosed with ustekinumab 
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were eligible to enroll in the nonrandomized portion of IM-UNITI.  These participants received 
ustekinumab at Week 8 and were assessed for CDAI response at Week 16.  Those who achieved 
CDAI response at Week 16 were eligible to continue dosing with ustekinumab while the 
participants who did not achieve clinical response were discontinued (Feagan et al. 2016). 
For Study AMAM, the CDAI remission rate for ustekinumab 90 mg Q8W at Week 52 will be 
estimated as below: 
Prob (CDAI Remission at Week 52) = Prob (Week 52 CDAI Remission |Week 8 CDAI 
Response) * Prob (Week 8 CDAI Response) + Prob (Week 52 CDAI Remission |^CDAI 
Response at Week 8) * Prob (^Week 8 CDAI Response). 
The following table shows the CDAI response rates at Week 8 for the 6 mg/kg ustekinumab 
group: 
Induction Study 
CDAI Response at Week 8  
CDAI Nonresponse at Week 8 
UNITI 1 
94/249 (37.8%) 
155/249 (62.2%) 
UNITI 2 
121/209 (57.9%) 
88/209 (42.1%) 
Overall  
215/458 (46.9%) 
243/458 (53.1%) 
Note:  Values in the table are n/N (%) where:  n = number of participants achieving a response; N = total number of 
patients in category.  Data based on nonresponder imputation. 
Source:  Feagan et al. 2016. 
 
CDAI Remission rates for Week 52 are estimated as follows: 
1. Probability of CDAI Remission at Week 52 for the 90 mg q8w treatment group for 
participants achieving CDAI Response at Week 8 was 68/128 (53.1%). 
2. Probability of CDAI Remission at Week 52 for the 90 mg Q8W treatment group for 
participants not achieving CDAI Response at Week 8 is estimated as 126/467 (27.0%).  
This probability assumes that participants who received ustekinumab at both weeks 0 and 
8 and did not achieve CDAI response at Week 8 and at Week 16 did not achieve CDAI 
remission at Week 52 
Based on the above, the expected CDAI Remission rate at Week 52 for the 90 mg Q8W 
treatment group is 39.2% with 95% CI (34.6, 43.9).   
CDAI remission rates for participants who were randomized to placebo and continued in placebo 
during maintenance are not available at Week 52 in IM-UNITI.  However, CDAI response and 
CDAI remission rates from Week 2 through Week 26 were shown to be stable with a slow 
decrease (approximately 5%) from Week 8 to Week 26 in PRECISE 1 (Sandborn et al. 2007).  
Assuming that CDAI remission rates in placebo participants have a similar decrease of 
approximately 5% between Week 8 and Week 52, CDAI remission at Week 52 for the placebo 
group will be 12.3% (6.8%, 17.9%) based on the summary below.   
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The following table shows the CDAI remission rates for the placebo group at Week 8: 
Induction Study 
CDAI Remission at Week 8 
UNITI-1 
18/247 (7.3%) 
UNITI-2 
41/209 (19.6%) 
Overall  
59/456 (12.9%) 
Values in the table are n/N (%) where:  n = number of participants achieving a response; N = total number of 
participants in category.  Data based on nonresponder imputation.   
Source:  Feagan et al. 2016. 
Based on these rates, the expected treatment effect for ustekinumab 6 mg/kg followed by 90 mg 
Q8W versus placebo at Week 52 in a treat-through study is 26.9% with 95% CI (19.5, 34.6).  CIs 
were estimated based on bootstrap re-sampling. 
Using the fixed 95%/95% margin method, a 10% NI margin represents clinical judgement about 
the amount of the active control effect that must be retained.  Assuming that Study AMAM will 
have similar proportions of biologic-failed and conventional-failed participants as those observed 
in the UNITI program and that the constancy assumption holds, the proposed NI margin is 
expected to preserve 50% of the expected ustekinumab effect in CDAI remission at Week 52 in a 
treat-through study.  If the lower 97.5% lower bound of the CI for the difference between 
mirikizumab and ustekinumab is greater than -10%, it would rule out a loss of more than half of 
the benefit expected for ustekinumab for CDAI remission at Week 52.   
Since a placebo group will be included in study AMAM, assay sensitivity as well as the 
constancy assumption will be checked by comparing ustekinumab to placebo for CDAI 
remission at Week 52.  Study AMAM is adequately powered (>90%) to detect a difference 
between ustekinumab and placebo in CDAI remission at Week 52 (with treatment rates of 12% 
for placebo and 29% for ustekinumab) based on a chi-square test using 2-sided alpha of 0.05. 
9.4.3.3 
Tertiary/Exploratory Analyses 
The proportion of participants in response to histologic endpoints at Week 12 and Week 52 will 
be compared across treatment groups.  Analysis details are specified in the SAP.  Additional 
analyses of exploratory health outcome endpoints may be considered and will be fully detailed in 
the SAP. 
9.4.4 Safety Analyses 
Safety will be assessed by evaluating exposure, AEs, laboratory analytes, vital signs, and AESIs 
(Section 8.3.7). 
Duration of exposure to therapy during the treatment periods will be calculated for each 
participant and summarized by treatment group.   
The AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA).  A TEAE is defined as an event that first occurred or worsened in severity after 
baseline.  The MedDRA Lowest Level Term will be used in the treatment-emergent 
computation.  If a participant reports the occurrence of a particular event more than once, the 
most severe of those events will be included in the summary tables of TEAEs.   
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In an overview table, the number and percentage of participants with at least 1 TEAE, SAE, fatal 
SAE, or discontinuation from study treatment due to an AE will be summarized by treatment.  
TEAEs (all and by maximum severity), SAEs including deaths, AEs that lead to treatment 
discontinuation will be summarized and analyzed by MedDRA System Organ Class and 
Preferred Term (PT) or by PT alone.   
Laboratory and vital signs measurements will be summarized using boxplot displays and 
treatment emergent shifts to low/high tables. 
Potential AESIs will be identified by one or more standardized MedDRA queries by a Lilly-
defined MedDRA PT listing based upon the review of the most current MedDRA version, or by 
treatment-emergent relevant laboratory changes.  Definitions of the AESIs and associated 
analyses will be described in the SAP. 
Categorical and continuous safety parameters will be analyzed as described in Section 9.4.1.  All 
safety analyses will be fully detailed in the SAP. 
9.4.5 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 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 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 change in SES-CD score, PRO2 score, and CDAI score versus 
exposure of mirikizumab at Weeks 12 and 52.  For this purpose, PRO2 score is defined as a 
2-item index comprised of the SF and AP items from the CDAI; the total PRO2 comprises the 
average daily scores over 7 days and is weighted using the CDAI multiplication factors for SF 
and AP items.  Measures of exposure may include population PK estimated average 
concentrations (Cavg), or estimated or observed trough concentrations.  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 
the efficacy endpoints.  These models may be used to evaluate participant factors that may 
impact the relationship between exposure and the probability of achieving the endpoint.  
Longitudinal exposure-response models for SF and AP 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. 
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9.4.6 Evaluation of Immunogenicity 
Frequencies and percentages will be tabulated for the following: 
 participants with preexisting ADA, and 
 participants who are treatment-emergent ADA positive (TE-ADA+) to mirikizumab.   
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA).  The frequency of neutralizing antibodies may also be 
tabulated in TE-ADA+ participants. 
The relationship between the presence of antibodies and their relationship to PK parameters, 
safety, and efficacy, may be assessed.  Additional details will be provided in the SAP. 
9.4.7 Other Analyses 
9.4.7.1 
Health Economics 
The health outcome and quality of life measures including Urgency NRS, FACIT-Fatigue,  
EQ-5D-5L, WPAI-CD, SF-36, and IBDQ will be analyzed using methods described for 
continuous data as described for efficacy measures in Section 9.4.1. 
9.4.7.2 
Subgroup Analyses 
Subgroup analyses for selected endpoints specified in Section 3 will be conducted.  Additional 
subgroup analyses will be conducted for the co-primary and selected secondary endpoints.  
Subgroups to be evaluated may include gender, age, body weight, race, ethnicity, geographic 
region, baseline SES-CD category, baseline AP/SF category, corticosteroid use at baseline, 
duration of disease, and disease location.  A detailed description of the subgroup variables and 
analyses will be provided in the SAP.   
This study is not powered for subgroup analyses; therefore, all subgroup analyses will be treated 
as exploratory. 
9.5 Interim Analyses 
A primary database lock is planned after all participants complete the Week 52 visit or the ETV.  
The analysis based on data from the primary database lock will be conducted by the sponsor or a 
designee and no multiplicity adjustment will be implemented.  The final database lock will occur 
after all participants complete the study, including safety follow-up. 
A DMC consisting of members external to Lilly will be established for interim safety monitoring 
across all the sponsor’s Phase 3 studies in participants with CD.  See Appendix 10.1.4 for more 
information. 
A limited number of preidentified Lilly employees or their designees who are not in direct 
contact with clinical sites may gain access to unblinded data, as specified in the unblinding plan 
prior to the Week 52 database lock in order to initiate the PK/PD model development process for 
the final analysis.  Information that may unblind the study during the analyses will not be shared 
with study sites or the blinded study team until the primary database lock has occurred.  
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Unblinding details can found in the unblinding plan.  PK/PD analysis details can be found in the 
Population PK/PD Analysis Plan. 
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10 Supporting Documentation and Operational Considerations 
10.1 
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 Applicable International Council for Harmonisation (ICH) GCP Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments and addenda, ICF(s), IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
After reading the protocol, each principal investigator will sign the separate protocol signature 
page and send a copy of the signed page to a Lilly representative. 
10.1.2 Informed Consent Process 
The investigator or his or her representative will explain the nature of the study to the participant 
or his or her legally authorized representative, explain the risks and benefits of participating in 
the study, and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.   
Participants or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50; local regulations; ICH guidelines; 
Health Insurance Portability and Accountability Act requirements, where applicable; and the 
IRB/IEC or study center. 
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The medical record must include a statement that written informed consent was obtained before 
the participant participated in any study procedure or received the investigational intervention.  
The statement must include the date on which the written consent was obtained.  The authorized 
person obtaining the informed consent must also sign the ICF(s). 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.  A copy of the ICF(s) is kept on file.   
Participants who are rescreened are required to sign a new ICF. 
10.1.3 Data Protection 
Participants will be assigned a unique identifier by the investigator.  Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.4 Committees Structure 
Cerebro-Cardiovascular Adjudication Committee 
The role of the committee is described in Section 8.3.7.4. 
Data Monitoring Committee 
A DMC consisting of members external to Lilly will be established.  The purpose of the DMC is 
to conduct periodic monitoring of clinical trial data for the Phase 3 CD program.  The DMC will 
consist of a minimum of 3 members, including physicians with expertise in adult 
gastroenterology, pediatric gastroenterology and a statistician.   
No member of the DMC will 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.  The SAC members 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 a DMC charter. 
The DMC is authorized to evaluate unblinded interim efficacy and safety analyses.  In addition, 
the DMC may request key efficacy data to put safety observations into context and to assess a 
reasonable benefit/risk profile for ongoing participants in the study.  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 IRC, 
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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 participants. 
10.1.5 Dissemination of Clinical Study Data 
Report Preparation 
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 
Public Access to Reports and Data 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data.  Data are available to 
request 6 months after the indication studied has been approved in the US and EU and after 
primary publication acceptance, whichever is later.  No expiration date of data requests is 
currently set once they are made available.  Access is provided after a proposal has been 
approved by an independent review committee identified for this purpose and after receipt of a 
signed data sharing agreement.  Data and documents, including the study protocol, SAP, clinical 
study report, blank or annotated case report forms, will be provided in a secure data sharing 
environment for up to 2 years per proposal.  For details on submitting a request, see the 
instructions provided at www.clinicalstudydatarequest.com. 
Publications 
For policies on publications, see Section 10.1.9. 
10.1.6 Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
 provide instructional material to the study sites, as appropriate 
 provide 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. 
 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 verify data reported to detect potential errors  
In addition, Lilly or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
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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. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.   
An electronic data capture system (EDC) will be used in this study for the collection of eCRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the eCRF. 
Additionally, clinical outcome assessment (COA) data (questionnaires) will be collected by the 
investigator site personnel, via a paper source document and will be transcribed by the 
investigator site personnel into the EDC system. 
Additionally, electronic clinical outcome assessment (eCOA) data (questionnaires, self-reported 
diary data, etc.) will be directly recorded by the participant and investigator site personnel, into 
an instrument (for example, hand-held smart phone or tablet).  The eCOA data will serve as the 
source documentation and the investigator does not maintain a separate, written or electronic 
record of these data. 
Data collected via the sponsor-provided data capture systems will be stored at third parties.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
10.1.7 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on the 
study.  Also, current medical records must be available. 
What constitutes source data is described in Section 10.1.6. 
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10.1.8 Study and Site Closure 
10.1.8.1 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. 
10.1.8.2 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. 
10.1.9 Publication Policy 
The publication policy is described in the letters of agreement between the sponsor and the 
investigators and institutions. 
 
 
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10.2 Appendix 2:  Clinical Laboratory Tests 
 
Clinical Laboratory Tests 
Hematology a,b 
Clinical Chemistry a,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 
Urinalysis a,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 Tests a 
Microscopic examination of sediment 
Hepatitis B core antibody b,d 
 
Hepatitis B surface antigen b,d   
Other Tests (Local)  
HBV DNA b,e 
Pregnancy test (urine g) 
Hepatitis C antibody b,d,f 
T-SPOT d or TST d 
HCV RNA b,d,f 
 
HIV b,d 
 
Pregnancy test (serum b,d) 
 
FSHb 
 
Exploratory Biomarker Samples a 
 
Exploratory samples (serum, plasma, 
whole blood, RNA, tissue RNA, and 
fecal sample) 
QuantiFERON-TB Gold test d  
Pharmacogenomic sample 
Immunogenicity testing (ADA) 
Serum mirikizumab concentration (PK) 
C-reactive protein, high-sensitivity (hsCRP) 
Clostridium difficile b,h (Toxin A and B, GDH, with reflex Toxin PCR) 
Stool Culture b,h 
Fecal calprotectin 
Tryptase i 
Complements (C3, C4) i 
Cytokine panel i 
 
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Abbreviations:  ADA = Anti-drug antibodies (immunogenicity testing); FSH = follicle-stimulating hormone; 
HBV = hepatitis B virus; HIV = human immunodeficiency virus; TST = tuberculin skin test. 
a Assayed by Lilly-designated laboratory. 
b Results will be confirmed by the central laboratory at the time of initial testing. 
c For the fasting lipid profile, participants should not eat or drink anything except water for 12 hours prior to test. 
d At screening and as described in the SoA (Section 1.3).  QuantiFERON-TB Gold test can be assayed locally or 
by Lilly-designated laboratory.  TST and T-Spot are performed locally.  
e Hepatitis B DNA testing will be performed in participants 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 Test required only at screening to determine the participant’s eligibility for the study but may be performed at 
investigator discretion throughout the study.  Stool sample will be used for Clostridium difficile and stool culture.   
i 
In the event of systemic allergic/hypersensitivity events, along with ADA and PK. 
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10.3 Appendix 3:  Hepatic Monitoring Tests for Treatment Emergent 
Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the medical monitor of Lilly or its 
designee. 
These tests will be performed at a Lilly-designated laboratory. 
Hepatic Monitoring Tests 
Hepatic Hematology 
Haptoglobin 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulation 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologies a 
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 = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
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10.4 Appendix 4:  Risk Factors for Latent Tuberculosis Infection 
 
Risk Factors for Latent Tuberculosis Infection (LTBI) 
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 2015 
 
 
 
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10.5 Appendix 5:  Examples of Infections that May Be Considered 
Opportunistic in the Setting of Biologic Therapy 
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 criteria.  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 criteria.  Winthrop 
et al. (2015) consider TB and non-TB mycobacterial disease to be opportunistic infections in the 
context of biologic therapy. 
 
 
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Bacterial 
 
Bartonellosis (disseminated disease only) 
 
Campylobacteriosis (invasive disease only) 
 
Legionellosis 
 
Listeriosis (invasive disease only) 
 
Nocardiosis 
 
Tuberculosis 
 
Non-tuberculous mycobacterial disease  
 
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  
Fungal 
 
Aspergillosis (invasive disease only) 
 
Blastomycosis 
 
Candidiasis (invasive disease or oropharyngeal, esophageal.  Not isolated lingual) 
 
Coccidioidomycosis 
 
Cryptococcosis 
 
Histoplasmosis 
 
Paracoccidioides infections 
 
Penicilliosis 
 
Pneumocystosis 
 
Sporotrichosis 
 
Other invasive molds:  Mucormycosis (zygomycosis) (Rhizopus, Mucor, and Lichtheimia), 
Scedosporium/Pseudallescheria boydii, Fusarium 
Parasites 
 
Leishmaniasis (visceral only) 
 
Strongyloidosis (hyperinfection syndrome or disseminated disease) 
 
Microsporidiosis 
 
Toxoplasmosis 
 
Trypanosoma cruzi infection (Chagas’ disease progression) (disseminated disease only) 
 
Cryptosporidiosis (chronic disease only) 
 
Source:  Adapted from Winthrop et al. 2015.   
 
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10.6 Appendix 6:  Prohibited Medications 
This section outlines medications that are prohibited during the treatment phase of the study and 
during 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 participant 
discontinues study drug and completes the ETV. 
 
Drug Class 
Guidance for Use 
Anti-TNF antibodies (for example, infliximab, adalimumab, or 
certolizumab pegol) 
Discontinue at least 4 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study. 
Anti-integrin antibodies: 
 
    Natalizumab 
Discontinue at least 12 months prior to screening 
endoscopy and prohibited throughout duration of 
study. 
    Other anti-integrin antibodies (for example, vedolizumab) 
Discontinue at least 4 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.  
Participants remain excluded if there is 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  
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 corticosteroids (enemas or suppositories) 
Discontinue at least 2 weeks prior to screening 
endoscopy and prohibited throughout duration of 
study. 
IV corticosteroids 
Discontinue at least 2 weeks prior to screening 
endoscopy.  A course of IV corticosteroids is 
prohibited throughout duration of study, except 
for use as premedication for infusion or for short-
term treatment of acute non-CD events (for 
example, allergic reactions).  Intravenous 
corticosteroids used for CD may result in 
discontinuation; therefore, consult your medical 
monitor. 
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Drug Class 
Guidance for Use 
Systemic corticosteroids for non-CD indications (oral or 
parenteral)  
From Week 0 to Week 12, initiation or 
adjustment of systemic corticosteroids is 
prohibited. 
From Week 12 through Week 52, participants 
may transiently initiate or increase doses (that is, 
for <4 weeks) of corticosteroids for reasons other 
than loss of response to treatment for Crohn’s 
disease (for example, stress doses of 
corticosteroids for surgery, asthma, and allergic 
reaction).  Locally administered corticosteroids 
(for example, inhaled, intranasal, intra-articular, 
or topical) are allowed.  Systemic corticosteroid 
use is allowed for adrenocortical insufficiency. 
Any biologic investigational therapy  
Discontinue at least 8 weeks, or 5 half-lives 
whichever is longer, prior to screening endoscopy 
and prohibited throughout duration of study. 
Any nonbiologic investigational therapy 
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. 
Anti-IL-23p19 antibodies (for example, risankizumab 
[BI-655066], brazikumab [MEDI-2070], guselkumab 
[CNTO1959], tildrakizumab [MK-3222]) for any indication, 
including investigational use 
Participants with any previous exposure are 
excluded from the study. 
Anti-IL 12/23p40 antibodies (for example, ustekinumab) 
Participants meeting protocol criteria (See 
Exclusion Criteria [21]) must have discontinued 
Anti-IL 12/23p40 antibodies at least 16 weeks 
prior to screening endoscopy.  
Bacillus Calmette-Guérin (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. 
Medicinal and recreational marijuana (includes CBD Oil)  
Must be stopped prior to screening.  Marijuana 
use is prohibited for the duration of the study.  If 
use is identified during the trial, it may result in 
discontinuation; consult your medical monitor. 
Abbreviations:  5-ASA = 5-aminosalicyclic acid; CBD = cannabidiol; CD = Crohn’s disease; IV = intravenous; 
JAK = Janus kinase; TNF= tumor necrosis factor. 
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10.7 Appendix 7:  Permitted Medications  
 
Drug Class 
Guidance for Use 
Oral 5-ASAs (for example, mesalamine, balsalazide, 
olsalazine) 
Prescribed dose must have been stable for at least 2 weeks 
before screening endoscopy; doses should remain stable 
throughout the study unless medication is discontinued due 
to a toxicity related to the medication.   
Oral corticosteroids (prednisone 
 or 
equivalent, or budesonide 
) 
Prescribed dose must have been stable for at least 2 weeks 
before screening endoscopy and should remain stable until 
Week 12.  After Week 12, see Section 6.5.3. 
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.   
Antibiotics being used specifically for the treatment of 
Crohn’s disease (for example:  rifaximin, Cipro) 
May continue if the prescribed dose has been stable 
4 weeks prior to baseline 
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. 
Nonlive (killed, inactivated, subunit, and RNA-based) 
vaccines 
Allowed during the study.  The efficacy of nonlive 
vaccinations with concomitant mirikizumab treatment is 
unknown. 
Abbreviations:  5-ASA = 5-aminosalicyclic acid; 6-MP = 6-mercaptopurine; AZA = azathioprine. 
 
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10.8 Appendix 8:  Patient-Reported Outcome Instruments 
This appendix describes PRO instruments used in this study.  For the physician items of the 
CDAI and other clinician efficacy assessments, see Section 8.1. 
 
Daily Diary (eDiary) 
Tablet Device 
BMC 
QIDS-SR16 a 
CDAI-SF/Bristol Stool Scale 
(Reference to Types 6 & 7) 
FACIT-Fatigue 
CDAI-AP 
IBDQ 
CDAI well-being 
EQ-5D-5L 
Abdominal Pain NRS 
SF-36 v2 Acute 
Urgency NRS 
WPAI-CD 
PGRS 
IBD-DI 
 
PGIC 
Abbreviations:  AP = abdominal pain; BMC = bowel movement count; CDAI = Crohn’s Disease Activity Index; 
EQ-5D-5L = European Quality of Life 5-Dimension 5 Level; FACIT = Functional Assessment of Chronic Illness 
Therapy-Fatigue; IBD-DI = Inflammatory Bowel Disease-Disability Index; IBDQ = Inflammatory Bowel 
Disease Questionnaire; NRS = numeric rating scale; PGRS = Patient Global Rating of Severity; PGIC = Patient 
Global Impression of Change; QIDS-SR16 = Quick Inventory of Depressive Symptomatology—Self-Report (16 
Items); SF = stool frequency; SF-36 v2 = Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) 
Version 2; WPAI-CD = Work Productivity and Activity Impairment Questionnaire — Crohn’s Disease. 
a QIDS-SR16 is described in Section 8.2.11 and Appendix 10.9. 
 
The following are descriptions of additional PRO instruments for this study, using Patient eDiary 
(listed in order of administration). 
Bowel Movement Count (BMC):  A single item that measures “stool frequency in the past 
24 hours.”  Participants are asked to count each toilet visit during which any amount of stool was 
passed.  A separate bowel movement is counted if little time has passed since leaving the toilet 
and the participant returned and passed stool again.  If stool was passed before making it to the 
toilet (an accident) that is also counted as a bowel movement.  Participants will be provided with 
an electronic diary tool during screening to record information daily pertaining to their SF. 
Crohn’s Disease Activity Index (CDAI)-(SF:  stool frequency, AP:  abdominal pain and 
general well-being):  CDAI is an 8-item disease activity measure that includes three patient 
reported items:  AP (4-point scale:  0=none, 1=mild, 2=moderate, 3=severe); SF (number of 
liquid or very soft stools); and general well-being (0=generally well, 1=slightly under par, 
2=poor, 3=very poor, 4=terrible).  Participants will be provided with an electronic diary tool 
during screening to record information daily pertaining to their AP, frequency of liquid or very 
soft stools, and well-being. 
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Bristol Stool Scale (used as a reference for CDAI-SF):  The Bristol Stool Scale provides a 
pictorial and verbal description of stool consistency and form ranging from Type 1 (Hard 
Lumps) to Type 7 (Watery/liquid).  To further define “liquid or very soft stools,” when 
responding to the CDAI SF item, participants will be referred to the Bristol Stool Scale Category 
6 and/or 7, that is liquid or watery stool.  Participants will be provided with an electronic diary 
tool during screening to record information daily pertaining to their frequency/count of liquid or 
very soft stools. 
Abdominal Pain Numeric Rating Scale (NRS):  A single item that measures the “worst level 
of abdominal pain in the past 24 hours” using an 11-point NRS ranging from 0 (no pain) to 10 
(pain as bad as you can imagine).  Participants will be provided with an electronic diary tool 
during screening to record information daily pertaining to their worst AP experience. 
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).  Participants will be provided with an electronic diary 
tool during screening to record information daily pertaining to their severity of urgency. 
Patient Global Rating of Severity (PGRS):  The PGRS is a 1-item patient-rated questionnaire 
designed to assess the participants’ 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 participant 
has no symptoms (that is, “none”) and a score of 6 indicates that the participant’s symptom(s) are 
“very severe.”  Participants will be provided with an electronic diary tool during screening to 
record information daily pertaining to their disease experience. 
The following are descriptions of additional PRO instruments for this study, using the Tablet 
Device at visits. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) (version 4):  
FACIT-Fatigue is a 13-item instrument developed to measure fatigue in chronic illness 
participants.  Total score ranges from zero to 52 based on a rating of 5-point Likert scale.  
Participants will record their responses to the FACIT-Fatigue 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 participants’ 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.  Participants 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-5L 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 
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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 
participant rates their perceived health state from 0 (the worst health you can imagine) to 100 
(the best health you can imagine).  Participants 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, Acute:  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 participant’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 (acute version) will be used, which utilizes 
the recall period of “the past week” (Ware and Sherbourne 1992; Ware 2000; Maruish 2011).  
Participants will record 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:  Crohn’s Disease (WPAI-CD):  
A patient-reported instrument developed to measure the impact on work productivity and regular 
activities attributable to a specific health problem (WPAI-CD).  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]); that is, worse 
outcomes.  Participants will record their responses to the WPAI-CD electronically as source data 
in the tablet device at appropriate visits. 
Inflammatory Bowel Disease-Disability Index (IBD-DI):  A 15-item patient reported 
questionnaire developed to measure IBD-related disability by reviewing the participant’s 
symptoms, mood and overall well-being over the past 7 days.  Total scores range from 0 to 100, 
with higher scores representing greater levels of IBD-related disability.  Participants will record 
their responses to the IBD-DI electronically as source data in the tablet device at the appropriate 
visit. 
Patient Global Impression of Change (PGIC):  The PGIC scale is a patient-rated instrument 
designed to assess the participants’ rating of symptom severity.  Responses are graded on a 7-
point Likert scale in which a score of 1 indicates that the participant’s symptom(s) is “very much 
better,” a score of 4 indicates that the participant’s symptom has experienced “no change,” and a 
score of 7 indicates that the participant’s symptom(s) is “very much worse.”  Participants will 
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record their response to the PGIC electronically as source data in the tablet device at appropriate 
visit.
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10.9 Appendix 9:  Additional Information on the Columbia Suicide Severity 
Rating Scale, and Quick Inventory of Depressive Symptomatology (self-
report) 
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 participant is asked to consider each statement as it relates to the way he 
or she has 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. 
 
 
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10.10 
Appendix 10:  Definitions and Selected Abbreviations 
Term 
Definition 
ADA 
anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
adverse event:  Any untoward medical occurrence in a participant 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 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 the 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 population.  
ALT 
alanine aminotransferase 
Anti-HBc 
anti-hepatitis B core antibody 
Anti-HBc+ 
positive for anti-hepatitis B core antibody 
AP 
abdominal pain 
AST 
aspartate aminotransferase 
AZA 
azathioprine 
BCG 
Bacillus Calmette-Guérin 
blinding 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the 
participants are aware of the treatment received. 
BMC 
bowel movement count 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CDAI-AP 
CDAI-Abdominal Pain 
CDAI-SF 
CDAI-Stool Frequency 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
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Term 
Definition 
CIOMS 
Council for International Organizations of Medical Sciences 
CMH 
Cochran-Mantel-Haenszel 
COA/eCOA 
clinical outcome assessment/electronic clinical outcome assessment 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
Compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements 
CT 
computed tomography 
CXR 
chest x-ray 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DSI-CD 
Disease Severity Index-Crohn’s Disease 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIM 
extraintestinal manifestation 
enroll 
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been randomized and assigned to a treatment. 
Enter 
Participants 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-Dimensions 5 Level 
ERB 
Ethical Review Board 
ETV 
early termination visit 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FSH 
follicle-stimulating hormone 
FWER 
overall Type I error rate 
GCP 
good clinical practice 
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Term 
Definition 
GMP 
good manufacturing practices 
HBsAG 
hepatitis B surface antigen 
HBsAG+/- 
positive/negative for hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV/AIDS 
human immunodeficiency virus/acquired immune deficiency syndrome 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
IBD-DI 
Inflammatory Bowel Disease-Disability Index 
ICF 
informed consent form 
ICH 
International Conference for Harmonisation 
IEC 
Independent Ethics Committee 
IgG4 
immunoglobulin G4 
IGRA 
interferon-γ release assay 
IL 
interleukin 
INR 
international normalized ratio 
informed consent 
A process by which a participant 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 participant’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. 
Intervention 
See “study intervention.” 
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.  See “study intervention.” 
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Term 
Definition 
IRB 
Institutional Review Board 
IRC 
Internal Review Committee 
ITT/mITT 
intent-to-treat/modified intent-to-treat 
IV 
intravenous(ly) 
IWRS 
interactive web-response system 
LTBI 
latent tuberculosis infection 
LV 
last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
medical monitor 
The sponsor’s designated medical monitor for the study 
MMRM 
mixed effects model of repeated measures 
MTX 
methotrexate 
NOAEL 
no-observed-adverse-effect level 
NR 
nonresponder, or nonresponse 
NRI 
nonresponder imputation 
NRS 
numeric rating scale 
patient 
See “participant” when used in the context of clinical studies. 
Participant 
Equivalent to “subject”:  an individual who participates in a clinical trial, either as 
recipient of an investigational medicinal product or as a control 
PD 
pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PGRS 
Patient Global Rating of Severity 
PK 
pharmacokinetics 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
PT 
Preferred Term 
QIDS-SR16 
Quick Inventory of Depressive Symptomatology – Self Report (16 items) 
Q12W 
every 12 weeks 
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Term 
Definition 
Q4W 
every 4 weeks 
RNA 
ribonucleic acid 
SAC 
Statistical Analysis Center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SF 
stool frequency 
SF-36 
Medical Outcomes Study 36-Item Short Form Health Survey 
SoA 
Schedule of Activities 
study drug 
See “study intervention” 
study intervention 
Any investigational intervention, marketed product, placebo, or medical device 
intended to be administered to a study participant according to the study protocol 
SUSAR 
suspected unexpected serious adverse reaction 
TB 
tuberculosis 
TBL 
total bilirubin level 
TE-ADA+ 
treatment-emergent ADA positive 
TEAE 
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
TNF 
tumor necrosis factor 
TST 
tuberculin skin test 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WPAI-CD 
Work Productivity and Activity Impairment Questionnaire Crohn’s Disease 
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Term 
Definition 
5-ASA 
aminosalicylic acid 
6-MP 
6-mercaptopurine 
 
 
 
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10.11 
Appendix 11:  Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]  
This amendment is considered to be Overall Rationale for the Amendment: 
The overall changes and rationale for the changes made to this protocol were to provide more 
clarity to specific sections or items, to better fit the protocol to the clinical reality and to correct 
errors.   
The plan for a blinded sample size re-estimation before the last participant has been enrolled in 
the study has been added to compare the blinded response rates with the assumed response rates 
and allow for a potential sample size adjustment. 
The following global changes in terminology or corrected errors were made throughout the 
protocol for clarification and consistency:   
 Corrected “>50% reduction” to “≥50% reduction” for the Endoscopic Response definition 
throughout document to correct a preexisting error.   
 Terminology of “deep response” was deleted as this is not a standardized definition and 
was replaced by the factual description “endoscopic response and clinical response by 
PRO.”  
 Terminology of “deep remission” was deleted as this is not a standardized definition and 
was replaced by the factual description “endoscopic remission and clinical remission by 
PRO.” 
 Terminology of “SES-CD response” or “SES-CD remission” was replaced by “endoscopic 
response” and “endoscopic remission.” 
Other minor typographical corrections and clarifications or semantic changes not affecting 
content have also been made in the document. 
Changes specific to certain protocol sections and a brief rationale are provided in the below 
table. 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
 Screening Period was prolonged by 1 
week (from 4 to 5 weeks), resulting in a 
maximum total study duration of 73 
weeks (previously 72 weeks) 
Improve feasibility to 
complete all 
assessments within a 
clinically acceptable 
interval 
Section 1.2 Schema 
 Schema adjusted to reflect the prolonged 
screening period from 4 to 5 weeks  
Consistency 
 
Section 1.3 Schedule 
of Activities 
 Changes reflecting the extended 
Screening Period  
 Added more details to footnotes t (stool 
collection) and v (endoscopy) 
 Added footnote to existing TB 
Monitoring during the study  
 Added optional unscheduled visit for 
QIDS-SR16 collection and reflected in 
footnote 
Clarifications for 
accuracy 
 
 
 
 
Fit to clinical reality 
 
Section 3 Objectives 
and Endpoints 
 Added Other Secondary for efficacy of 
mirikizumab compared to placebo in 
clinical response by CDAI 
 Added Other Secondary for efficacy of 
mirikizumab compared to placebo in 
both endoscopic response and clinical 
remission by PRO  
 Added FACIT-Fatigue score to the list of 
health outcomes/quality of life 
endpoints 
Update for consistency 
with approved SAP 
 
 
Section 4.1 Overall 
Design 
 Timing of follow-up visits Visit 801 & 
Visit 802 are defined relative to “last 
visit,” not “last dose” 
Clarify original content 
Section 5.1 Inclusion 
Criteria & 5.2 
Exclusion Criteria 
 Criteria 2b:  women not of childbearing 
potential.  Minimal required age 
relative to definition B, of 
postmenopausal women was adjusted 
from 50 to 40 years  
 Criteria 6:  broadened window between 
endoscopy result and randomization 
from 14 days to 21 days  
 Criteria 9b:  Allowed stable 
corticosteroid dose at entry changed 
from ≤20mg/day to ≤30mg/day 
Reflect most recent 
internal safety 
guidance 
 
Accommodate clinical 
reality and/or clarify 
original content 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
 Criteria 10:  note added to specify that if, 
out of control of the participant, certain 
assessments could not be completed in 
the specified timelines, Medical to 
assess potential randomization or 
rescreening (whichever applies) 
 Criteria 12:  divided into chronic 
conditions vs an infection that allows 
for treatment and rescreening 
 Criteria 14:  removed extra abdominal 
surgery 
 Criteria 21:  noted that short-term prior 
exposure to ustekinumab is permitted if 
specific conditions are met  
 Criteria 42:  noted that exclusion does 
not apply in situations out of control of 
the participant 
 Criteria 47:  newly added criteria relative 
to total parenteral nutrition delivery 
 
 
 
Correction of error 
 
Accommodate clinical 
reality and/or clarify 
original content 
Section 5.4 Screen 
Failures 
 Clarified rescreening criteria for 
Inclusion Criteria 4, 5, 6, 10, and 42 
 Clarified that participants who screen fail 
because of inability to complete their 
endoscopy in time may not need to 
repeat certain specific assessments 
when rescreening 
Clarify original content 
Section 6.5 
Concomitant therapy 
 Additional clarifications have been 
added relative to permitted vs 
prohibited therapy 
Clarify original content 
Section 8.2.8 
Hepatitis B Testing 
 Clarified IP discontinuation criteria 
relative to HBV DNA  
Reflect clinical 
practice  
Section 8.2.11, 
Depression, and 
Suicidal Ideation and 
Behavior 
 Relative to the HCP assessing the 
removal of requirement of 1 
year of patient care/clinical experience 
Clarify original content 
Section 9.2, Sample 
Size Determination 
 Added additional considerations relative 
to sample size 
Clarify original content 
Section 9.4.1 General 
Statistical 
Considerations 
 Removed the treatment comparisons of 
ustekinumab vs placebo  
Clarify original content 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.3.1 
Primary Analysis 
 Clarified the analysis window for the 
endoscopic measure at Week 52  
Clarify original content 
Section 9.4.3.3 
Tertiary/Exploratory 
Analyses 
 Clarified histologic endpoints at Week 
12 and Week 52  
Clarify original content 
Section 9.5 Interim 
Analyses 
  Language for the planned PK interim 
analysis already included in Section 6.3 
has been added to Section 9.5  
Clarify original content 
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Amendment [b]  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
The primary rationale for this amendment is the addition of Appendix 12:  Provisions for 
Changes in Study Conduct During Exceptional Circumstances.  The changes to procedures 
described in this appendix are temporary measures intended to be used only during specific time 
periods as directed by the sponsor in partnership with the investigator.  Exceptional 
circumstances are rare events that may cause disruptions to the conduct of the study.  Examples 
include pandemics or natural disasters.  These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Other minor typographical corrections and clarifications or semantic changes not affecting 
content have also been made in the document. 
Changes specific to certain protocol sections and a brief rationale are provided in the below 
table. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities  Added timepoints for various 
evaluation criteria to allow for 
additional optional data collection at 
Visit 997 or for unscheduled 
assessments during a scheduled visit 
(UA/SV). 
 Updated to reflect all 
assessments that may be 
collected at the 
discretion of the 
investigator at scheduled 
or unscheduled visits. 
 
 Changed Visit 5 to a phone visit; 
removed requirements for vital signs, 
physical exam, extraintestinal 
manifestation (EIMs), fistula 
evaluation, Crohn’s Disease Activity 
Index (CDAI), and serum chemistry 
and hematology. 
 Aim to avoid risk of an 
unnecessary visit to the 
site during the 
COVID-19 pandemic, 
and as participants do 
not receive study drug at 
Visit 5, on-site 
assessments are not 
required. 
 
 Updated list of abbreviations. 
 To reflect changes to 
table 
 
 Footnote g:  Modified text. 
 Computed tomography 
(CT) scan can be 
performed as an 
alternative to the chest 
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Section # and Name 
Description of Change 
Brief Rationale 
x-ray (CXR). 
 
 Footnote q:  Modified text. 
 Clarified collection of 
stool sample prior to 
endoscopy, and visits 
where endoscopy is not 
scheduled to be 
performed. 
 
 Footnote x:  Modified text. 
 Optional testing may be 
performed during 
unscheduled visits at the 
discretion of the 
investigator. 
 
 Footnote aa:  Modified text. 
 Clarification 
 
 Footnote ab:  Modified text. 
 Clarification that CT 
scan can be performed 
as an alternative to the 
CXR based on regional 
standard of practice. 
 
 Footnote ac:  Added. 
 UA/SVs may be 
performed at the 
discretion of the 
investigator. 
2.2.2 Currently Available 
Treatments and Unmet 
Need 
 Reworded the information on clinical 
remission. 
 Reordered text to 
improve clarity and 
readability. 
4.3 Justification for Dose 
 Change to NOAEL number to align 
with adolescent addendum. 
 Correction of error 
5.1 Inclusion Criteria 
 Criterion [8]:  Updated text relative 
to conventional-failure and prior 
budesonide use. 
 Improved clarity relative 
to prior budesonide use. 
 
 Criterion [10]:  Revised note to 
account for when participants are not 
able to complete study assessments 
due to situations beyond their 
control. 
 Consistency with other 
criteria. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
 Criterion [12]:  Removed short 
bowel syndrome from criterion. 
 Criterion [15]:  Replaced short gut 
syndrome with short bowel 
syndrome.  
 Avoid redundancy and 
improve clarity of 
Criteria [12] and [15] 
relative to management 
of patients with short 
bowel syndrome. 
 
 Criterion [21]:  Lengthened required 
timeframe between last dose of 
anti-interleukin (IL) 12/23p40 
antibodies and screening endoscopy 
from at least 8 weeks to at least 
16 weeks, and updated Appendix 6 
(Prohibited Medications) 
accordingly. 
 Timeframe extended to 
16 weeks to rule out 
participants not 
responding to 
ustekinumab. 
 
 Criterion [42]:   Revised note to 
account for when participants are not 
able to complete study assessments 
due to situations beyond their 
control. 
 Consistency with other 
criteria. 
 
 
 Criterion [47]:  Updated text 
regarding delivery of parenteral 
nutrition. 
 Parenteral and enteral 
nutrition as primary 
source of diet is 
excluded due to 
potential to confound 
efficacy assessments. 
 
 Criterion [48]:  Added new criterion 
on prohibited marijuana use and 
updated Appendix 6 (Prohibited 
Medications) accordingly. 
 Avoid potential impact 
on protocol assessments 
as cannabinoids have 
shown a potential role in 
inflammation and 
mucosal permeability of 
the gastrointestinal tract.  
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Section # and Name 
Description of Change 
Brief Rationale 
5.4 Screen Failures 
 Removed restriction of only 
1 rescreening permitted for entry 
Criteria [4], [5], and [6]. 
 Criteria [4], [5], and [6]:  
Crohn’s disease (CD) 
activity can change over 
time; thus, participants 
may qualify upon 
rescreening. 
 
 Criterion [22]:  Specified that 
rescreening is allowed if a participant 
is no longer receiving steroids and 
has met washout criteria. 
 Criterion [22]:  Improve 
clarity. 
 
 Added Criterion [28] to list of entry 
criteria with allowance for 
rescreening and updated text to 
include that rescreening may be 
permitted once for C. difficile and 
once for stool culture or ova parasite. 
 Criterion [28]:  Correct 
prior inadvertent 
omission and improve 
clarity. 
 
 Moved Criteron (43) from Screening 
not allowed. 
 Criterion [43] revised to 
allowed rescreen if 
patient situation changes 
over time. 
 
 Added Criterion [48] to list of entry 
criteria with allowance for 
rescreening provided participant is 
no longer using marijuana at the time 
of rescreening. 
 Criterion [48]:  Added 
due to addition of 
exclusion criteria for 
marijuana (see above). 
 
 Updated text to specify assessments 
will not repeated at rescreening for 
patients who screen fail due to 
inability to complete endoscopy prior 
to Visit 2. 
 Participants may avoid 
CT, human 
immunodeficiency virus 
(HIV), hepatitis B virus 
(HBV), and hepatitis C 
virus (HCV) retest 
within a 4-week 
timeframe provided 
there are no risk factors 
or signs/symptoms 
 
 Modified text disallowing 
rescreening:  Now allow rescreening 
for Criterion [22]. 
 Non-CD treatment can 
change. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 Added that a total maximum of  
3 rescreens are permissible. 
 Only 3 total endoscopies are 
permissible.  
 Correction of error. 
 
 Provide additional 
information relative to 
rescreen. 
6.1 Study Intervention(s) 
Administered 
 Modified text stating that 
intravenous (IV) infusions must be 
completed prior to administration of 
subcutaneous (SC) injections. 
 Provide clearer 
distinction between 
hypersensitivity, 
infusion-related events, 
and events related to SC 
dosing. 
6.5 Concomitant Therapy  Renumbered from 6.5.1 to 6.5.   
 Correction/Clarification. 
6.5.1 Permitted Therapy 
 Added as third level heading; 
modified text to permit dose 
adjustments to concomitant CD 
medications for appropriate medical 
management, and added in-text 
reference for information on 
corticosteroid tapering. 
 Correction/Clarification. 
6.5.2 Prohibited Therapy 
 Added exceptions to prohibited CD 
medications, IV corticosteroid and 
marijuana use, that may result in 
discontinuation.  Clarified that RNA-
based vaccines are permitted. 
 Allow medical 
discretion to prevent 
unnecessary 
discontinuation. 
6.5.3 Corticosteroid Taper  Removed text prohibiting initiation 
of corticosteroid unless there is a 
medical necessity. 
 Clarification. 
7.1.1 Criteria for 
Permanent 
Discontinuation of Study 
Drug 
 Revised Disease Worsening, bullet 1 
to require treatment with a specified 
prohibited CD medication 
  Clarification. 
 
 Revised Disease Worsening, bullet 2 
to include exception of drainage of a 
perianal or other cutaneous abscess 
or seton placement. 
 Clarification. 
7.1.2 Criteria for 
Temporary Interruption 
 Revised text for patients who 
develop decreased absolute 
 Improve clarity and 
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Section # and Name 
Description of Change 
Brief Rationale 
(Withholding) of Study 
Drug 
lymphocyte count.  
readability.  
7.2 Participant 
Discontinuation/ 
Withdrawal from the 
Study 
 Removed text related to participant 
requiring prohibited medications. 
 Redundant.  
8.1.1.3 Endoscopic 
Biopsies 
 Revised text referencing source of 
details of biopsy sample collection.  
 Correction/Clarification. 
8.2.4 Chest Radiography 
 Clarified that a CT scan can be 
performed as an alternative to the 
CXR based on regional standard of 
practice.   
 Clarification.  
8.2.6 Tuberculosis 
Testing 
 Clarified that CT scan can be 
performed as an alternative to the 
CXR. 
 Clarification and 
consistency with 
Section 8.2.4. 
8.5 Pharmacokinetics 
 Deleted “Other PK samples on or 
after
 
 
 
 Corrected to align with 
intended collection and 
SoA 
8.2.7.2 Immunogenicity 
Assessment 
 Revised wording regarding the 
frequency of the tabulation of 
neutralizing antibodies. 
 Align with analysis 
approach. 
8.8 Exploratory 
Biomarkers 
 Modified the section title. 
 Improve accuracy. 
9.2 Sample Size 
Determination 
 Updated wording. 
 Improve clarity.   
9.4.1.3 Missing Data 
Imputation 
 Deleted bullets regarding status of 
mandatory stable medication use and 
taking of prohibited medications in 
defining a participant as a 
nonresponder. 
 Revision to plan for 
missing data imputation. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 Added text relative to handling of 
concomitant medications and noted 
specifics will be provided in the 
statistical analysis plan (SAP). 
 As noted. 
9.4.6 Evaluation of 
Immunogenicity 
 Revised wording regarding the 
frequency of the tabulation of 
neutralizing antibodies. 
 Clarification of sentence 
to align with analysis 
approach. 
Section 10.2 Appendix 2:  
Clinical Laboratory Tests 
 Updated information on exploratory 
biomarker storage samples. 
 Separate exploratory 
biomarkers from 
non-exploratory 
biomarkers. 
Section 10.6 Appendix 6:  
Prohibited Medications 
 Revised column heading to table for 
Column 2. 
 Clarification. 
 
 Added text to include information on 
IV corticosteroid used for CD that 
may result in discontinuation. 
 Allow medical 
discretion to prevent 
unnecessary 
discontinuation.  
Aligned with Exclusion 
Criteria [19g] and [19h]. 
 
 
 Changed requirement for 
discontinuing of anti-IL 12/23p40 
antibodies (ustekinumab) prior to 
screening endoscopy from 8 weeks 
to 16 weeks. 
 Corrected discrepancy 
related to biologic and 
nonbiologic washout 
periods. 
 Timeframe extended to 
16 weeks to rule out 
participants not 
responding to 
ustekinumab. 
 
 Revised text to clarify that systemic 
corticosteroid use is allowed for 
adrenal insufficiency. 
 Clarification. 
 
 Changed requirement for 
discontinuing of biologic 
investigational therapy prior to 
screening endoscopy from 4 weeks 
to 8 weeks. 
 Aligned with Exclusion 
Criteria [19g] and [19h]. 
 
 Added information about any 
 Corrected discrepancy 
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Section # and Name 
Description of Change 
Brief Rationale 
nonbiologic investigational therapy. 
related to biologic and 
nonbiologic washout 
periods. 
 
 Added text to include information on 
prohibited marijuana use. 
 Avoid potential impact 
on protocol assessments 
as cannabinoids have 
shown a potential role in 
inflammation and 
mucosal permeability of 
the gastrointestinal tract. 
Section 10.7 Appendix 7:  
Permitted Medications  
 Renamed section and revised table 
column header. 
 Revised guidance for use for oral 
corticosteroid stabilization and 
updated type of permitted vaccines. 
 To align with 
development program. 
 Clarification. 
Section 10.10 
Appendix 10:  Definitions 
and Selected 
Abbreviations 
 Updated the list. 
 To include new 
additions. 
Section 10.11 
Appendix 11:  Protocol 
Amendment History 
 Updated with information from prior 
protocol amendment (a). 
 To provide continuity of 
recorded updates. 
Section 10.12 
Appendix 12:  Provisions 
for Changes in Study 
Conduct During 
Exceptional 
Circumstances 
 Added appendix. 
 Provides for temporary 
changes to procedures 
intended to be used only 
during specific time 
periods as directed by 
the sponsor in 
partnership with the 
investigator. 
Throughout 
 Minor editorial changes. 
 Corrections  
 
 
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Amendment [c]   
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
Published literature suggests that appropriate endoscopic disease measuring cutoffs in clinical 
trials are those that account for the presence of a minimal degree of ulceration reflecting 
moderate to severely active disease, rather than a higher degree of overall inflammation (Vuitton 
et al. 2016). Completed and ongoing clinical trials evaluating biologic treatment effect 
(adalimumab, ustekinumab, risankizumab, and guselkumab) in participants with moderately to 
severely active Crohn’s Disease (CD) have enrolled all or up to 10% of the total population with 
a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of ≥3. Therefore, inclusion criterion 6 
has been updated to allow up to 10% of the participant population with SES-CD score of ≥3 with 
the provision that ulceration be present as a component of this total score (presence of at least 
one large ulcer [in the ileum, colon, or both] that results in a minimum score of 2 for the 
component of “size of ulcers” and a minimum score of 1 for the component of “ulcerated 
surface”). The purpose of inclusion of this subset is to increase understanding of these patients 
and their response to treatment. The analysis population in which the primary and key secondary 
endpoints will be evaluated does not change; this patient population remains defined by SES CD 
of ≥7, as per the original protocol. 
The below table summarizes overall protocol changes, specific to certain protocol sections, 
together with a brief rationale. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added above table “The study primary 
and secondary objectives will be 
assessed based on the Primary Analysis 
Set as defined in Section 9.3.” 
Alignment with Section 3. 
1.3 Schedule of Activities Removed Self-Harm Supplement Form 
and Self-Harm Follow-Up Form. 
Removed “with the exception of 
screening” from Footnote q. 
Information currently 
collected via safety 
reporting provides 
sufficient information on 
self-harm cases. 
Correction. 
3 Objectives and 
Endpoints 
Added above table “The study primary 
and secondary objectives will be 
assessed based on the Primary Analysis 
Set as defined in Section 9.3.” 
Added an Other Secondary objective 
and Endpoint to evaluate endoscopic 
response and clinical remission.   
Clarification. 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
4.2 Scientific Rationale 
for Study Design 
Removed definition for active CD; 
specified that definition is provided in 
the inclusion criteria.   
Adapted to more concise 
language. 
5.1 Inclusion Criteria 
Updated Criterion 6 to allow for 
enrollment of a subset of participants 
with a SES-CD score ≥3 and <7 (for 
patients with isolated ileal disease SES-
CD ≥3 and <4) and presence of at least 
one large ulcer (in the ileum, colon, or 
both) that results in a minimum score of 
2 for the component of “size of ulcers” 
and a minimum score of 1 for the 
component of “ulcerated surface”. 
Rationale provided in the 
text preceding this table.  
 
 
 
 
Modified Criterion 40 to specify 
ustekinumab instead of “monoclonal 
antibodies”. 
Clarification. 
5.4 Screen Failures 
Removed interval requirement for 
rescreening for Criterion 5.  
Modified text “Participants who screen 
fail because they are unable to complete 
their endoscopy prior to Visit 2 may 
undergo repeat rescreening sooner than 
4 weeks between screen failure and 
rescreening. Participants rescreening 
sooner than 4 weeks for the inability to 
complete endoscopy, or who are 
allowed by the study’s medical monitor 
to rescreen within less than 4 weeks, 
will not be required to undergo 
repeat…”. 
Variability of PRO 
measures. 
Added flexibility to avoid 
unnecessary repetition of 
certain tests within short 
timeframe. 
6.5.3 Corticosteroid Taper Added “Investigators must contact the 
Study Medical Monitor to discuss any 
participant who does not initiate CS 
tapering upon achieving clinical 
response.” 
Tapering is mandatory 
unless medically 
unfeasible, in which case 
discussion with the 
medical monitor is 
required. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.7.3.2 Management of 
Hypersensitivity, 
Infusion-Related Events, 
Infusion Site Reactions, 
and Injection Site 
Reactions 
Modified instructions for nonsystemic 
hypersensitivity reactions.  
Clarification.   
7.1.2 Criteria for 
Temporary Interruption 
(Withholding) of Study 
Drug 
Added text back (erroneously removed 
in Amendment b) for participants who 
develop decreased absolute neutrophil 
count, and corrected unit for 
lymphocyte count. 
Correction of errors. 
8.2.11 Depression, and 
Suicidal Ideation and 
Behavior 
Removed text related to the Self-Harm 
Supplement Form and Self-Harm 
“Follow-Up” Form. 
Alignment with the 
Schedule of Activities. 
9.1 Statistical Hypotheses Added population description to the 
primary statistical hypothesis. 
Clarification: added detail. 
9.2 Sample Size 
Determination 
Added the analysis population to 
sample size determination. 
Clarification. 
9.3 Populations for 
Analyses 
Added definition for the Primary 
Analysis Set. 
Clarification.  
9.4.1 General Statistical 
Considerations 
Removed text specifying the SAS 
version to be used for statistical 
analysis. 
Defined population to be used in 
analyses. 
Correction: analysis is not 
limited to using SAS only. 
 
Clarification:  added detail. 
9.4.1.3 Missing Data 
Imputation 
Modified text “…For placebo 
participants who begin treatment with 
mirikizumab at Week 12, participants 
who discontinue study treatment early, 
and participants who change specified 
concomitant CD medications increase 
mandatory stable medications or take 
prohibited medications, the data 
collected after any of these events occur 
will be censored in the primary 
analysis…” 
Correction: alignment with 
modifications made in 
Amendment b. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.3 Efficacy Analyses 
Moved first sentence (regarding both 
primary and secondary analyses 
populations) of following subsection 
(9.4.3.1) to parent subsection (9.4.3). 
Organization. 
9.4.3.1 Primary Analyses 
Added statement that the co-primary 
endpoint will be evaluated in the mITT 
population as a secondary analysis. 
Alignment with Section 3. 
9.4.7.1 Health Economics Added “FACIT-Fatigue.” 
Correction. 
9.4.7.2 Subgroup 
Analyses 
Removed statement that analyses 
requested by regulatory agencies will 
be labeled as appropriate. 
Correction. 
Throughout 
Minor editorial changes. 
Corrections. 
 
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Amendment [d]    
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Overall Rationale for the Amendment: 
The main purpose of this protocol amendment is to revise the co-primary and secondary 
objectives and endpoints in response to Food and Drug Administration (FDA) feedback. 
Changes specific to certain protocol sections and a brief rationale are provided in the below 
table. Other minor typographical corrections not affecting content have also been made in the 
document. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Updated objectives and endpoints 
Address FDA feedback 
and editorial consistency 
1.3. Schedule of 
Activities 
Revised footnote ‘o’ to indicate that 
results from the PK, immunogenicity 
(ADA) and exploratory hypersensitivity 
analyses in the event of a systemic 
allergic/hypersensitivity event will not 
be provided to the investigator 
Clarification 
1.3. Schedule of 
Activities 
Revised footnote ‘u’ for diary 
compliance check to specify 
compliance percentage threshold 
Clarification 
1.3. Schedule of 
Activities 
Added a footnote to allow Visit 2 
assessments and dosing to be 
performed over 2 days after 
consultation with the medical monitor 
Clarification  
2.2.1. Disease State and 
Treatment Goals 
Replaced assessment by PRO to CDAI  Address FDA feedback 
2.2.5. Preclinical and 
Clinical Studies of 
Mirikizumab 
Updated the results of Studies 16T-
MC-AMAN and 16T-MC-AMAG  
Reflect most recent data 
3. Objectives and 
Endpoints 
Updated co-primary endpoints to 
include clinical response by PRO at 
Week 12, endoscopic response and 
clinical remission by CDAI at Week 52  
Address FDA feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
3. Objectives and 
Endpoints 
Updated the following efficacy 
assessments in major and other 
secondary objectives and endpoints,   
 clinical remission by CDAI at 
Week 12 and 52,  
 clinical response by PRO at 
Week 12,  
 clinical remission by PRO at 
Week 52  
 corticosteroid-free and either 
clinical remission by CDAI 
(removed by PRO) at Week 52 
 stability of clinical remission by 
CDAI (removed by PRO) 
Alignment to FDA 
feedback 
3. Objectives and 
Endpoints 
Added the following efficacy 
assessments in secondary objectives 
and endpoints  
 Urgency NRS at Week 12 and 
Week 52 
 urgency remission at Week 52 
 clinical response by CDAI 
(removed by PRO) at Week 4  
Alignment to FDA 
feedback 
3. Objectives and 
Endpoints 
Added footnotes defining the mITT 
population and the efficacy endpoints 
(Clinical response by PRO, Endoscopic 
response, Clinical remission by CDAI, 
Clinical remission by PRO, Clinical 
response by CDAI, Urgency remission, 
Endoscopic remission, Endoscopic 
remission SES-CD ≤4) 
Editorial consistency 
3. Objectives and 
Endpoints 
Revised the section to remove duplicate 
objectives and endpoints 
Editorial consistency 
4.2. Scientific Rationale 
for Study Design 
Added CDAI as an endpoint used for 
the primary objective 
Alignment to FDA 
feedback 
5.1. Inclusion Criteria 
 
Inclusion criterion 9d 
Revised language for Crohn’s disease 
treatment 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
 
Inclusion criterion 11b 
Removed ‘an established’ from 
diagnosis of Gilbert’s syndrome 
Clarification 
5.2. Exclusion Criteria 
 
Inclusion criterion 17 
Removed adenoma without dysplasia 
and added colonic adenomatous polyp 
Reflect most recent data 
5.2. Exclusion Criteria 
 
Inclusion criterion 18 
Removed colonic dysplasia and added 
dysplasia in GI tract or presence of any 
serrated lesion 
Reflect most recent data 
6.5.3. Corticosteroid 
Taper 
Added oral corticosteroid dose initiation 
for participants not on corticosteroids at 
randomization 
Clarification 
6.5.4. Rescue Medicine 
Removed “other than oral 5 ASA 
compounds or immunomodulators” 
Correction 
7.1.1. Criteria for 
Permanent 
Discontinuation of Study 
Drug 
Removed intestinal dysplasia and added 
dysplasia in GI tract or presence of any 
serrated lesion in safety considerations 
Reflect most recent data 
8.1.1. Primary Efficacy 
Assessments 
Updated co-primary endpoints with the 
changes made in Section 3 (Objectives 
and Endpoints) 
Alignment to FDA 
feedback 
8.1.1. Primary Efficacy 
Assessments 
Crohn’s Disease Activity Index (CDAI) 
description added as part of Primary 
Efficacy Assessments 
Removed CDAI description 
Alignment to co-primary 
objectives 
8.2.5 Stool Testing 
Updated C. difficile toxin testing 
Clarified intended 
collection and testing 
8.2.6. Tuberculosis 
Testing 
Updated retesting and confirmatory 
testing for participants who have been 
assessed by the PI to have a false 
positive TB test 
Clarified intended 
collection and testing 
8.5. Pharmacokinetics 
Revised the additional samples to 
indicate that results from these samples 
in the event of a systemic 
allergic/hypersensitivity event will not 
be provided to the investigator 
Clarification  
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Section # and Name 
Description of Change 
Brief Rationale 
9.1. Statistical 
Hypotheses 
Revised primary hypothesis and major 
secondary hypotheses with the changes 
made in Section 3 (Objectives and 
Endpoints) 
Address FDA feedback 
9.2. Sample Size 
Determination  
Revised estimated power for the co-
primary endpoint 
Address FDA feedback 
and editorial consistency 
9.4.1. General Statistical 
Considerations 
Replaced stratification factors with 
covariates and removed region and 
95% confidence interval in Cochran-
Mantel-Haenszel chi-square test  
Removed baseline corticosteroid use 
and region from restricted maximum-
likelihood-based mixed effects model 
of repeated measures 
Added finalized graphical testing 
scheme to be provided in the SAP 
Clarification and editorial 
consistency 
9.4.1.3. Missing Data 
Imputation 
Revised selected analysis for 
participants in placebo group 
Clarification 
9.4.1.4. Multiple 
Comparisons/Multiplicity 
Added ‘mirikizumab’ to compare with 
placebo for Group 1 and to compare 
with ustekinumab for Group 2 
Added pre-specified graphical scheme 
for comparisons in Group 1 
Clarification and editorial 
consistency 
9.4.3.1. Primary Analyses  Updated primary analyses with the 
changes made in Section 3 (Objectives 
and Endpoints) and added definitions 
for clinical response by PRO and 
clinical remission by CDAI 
Address FDA feedback 
10.2. Appendix 2: 
Clinical Laboratory Tests 
Updated C. difficile toxin testing 
Clarified intended 
collection and testing 
10.7. Appendix 7: 
Permitted Medications 
Revised language for Crohn’s disease 
treatment 
Clarification 
10.12. Appendix 12:  
Provisions for Changes in 
Study Conduct During 
Exceptional 
Circumstances 
Revised changes in study conduct 
during exceptional circumstances 
Clarification for flexibility 
outlined for study conduct 
during exceptional 
circumstances 
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Section # and Name 
Description of Change 
Brief Rationale 
10.12. Appendix 12:  
Provisions for Changes in 
Study Conduct During 
Exceptional 
Circumstances 
Added the following to ‘Local 
laboratory testing option’, 
“Local collection of screening 
laboratories for eligibility may be 
collected after approval by the sponsor 
and may not be allowed in all 
circumstances.” 
Clarification for local labs 
during exceptional 
circumstances 
 
 
 
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Approved on 23 Feb 2022 GMT

CONFIDENTIAL  
Protocol I6T-MC-AMAM(e) 
 
LY3074828 
159 
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Approved on 23 Feb 2022 GMT

Signature Page for VV-CLIN-019253 v1.0
Signature Page for VV-CLIN-019253 v1.0
Approval
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23-Feb-2022 14:33:22 GMT+0000
Approval
23-Feb-2022 20:35:08 GMT+0000
Approved on 23 Feb 2022 GMT
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PPD