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(15.2) 
 
 
An Open Label Addendum to the AMAM adult study to Assess Efficacy and 
Safety of Mirikizumab in the Induction and Maintenance of Remission in 
Adolescents (15 to <18 years of age) with Moderately to Severely Active 
Crohn’s Disease (CD) 
 
 
NCT03926130 
 
 
Approval Date: 07 Oct 2022 

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I6T-MC-AMAM(15.2) Clinical Protocol Adolescent Addendum 
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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 mirikizumab (LY3074828) unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.   
 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Addendum Title:  An Open Label Addendum to the AMAM adult study to Assess 
Efficacy and Safety of Mirikizumab in the Induction and Maintenance of Remission in 
Adolescents (15 to <18 years of age) with Moderately to Severely Active Crohn’s Disease (CD) 
Protocol Addendum Number:  I6T-MC-AMAM Adolescent Addendum (15.2)  
Compound Number:  LY3074828 
Study Phase:  3 
Short Title:  VIVID-1 Adolescent Addendum 
Sponsor Name:  Eli Lilly and Company 
Legal Registered Address:  Indianapolis, Indiana, USA 46285  
Regulatory Agency Identifier Numbers 
IND:  130052 
EudraCT:  2018-004614-18 
Approval Date:  Revised Protocol Addendum (15.2) Electronically Signed and Approved by 
Lilly on date provided below.   
Document ID:  VV-CLIN-006075 
 
 
 
 

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Protocol Addendum Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Revision 15.1 
15-Jan-2021 
Original Protocol Addendum 
08-Jun-2020  
Revision 15.2 
This revision to addendum 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 Revision: 
The rationale for this revision to the adolescent addendum (AA) are provided below: 
• Lilly is in the process of opening a mirikizumab intervention-specific appendix (I6T-MC-
AMAY [AMAY]) under the MACARONI-23 IL-23 pediatric platform master protocol 
that will enroll pediatric participants 2 to ≤18 years of age with moderately to severely 
active CD. Study AMAY provides a better option for adolescents with moderately to 
severely active CD as it allows fo
 
 Therefore, Lilly has stopped new 
patient enrollment into the AMAM AA. Patients already enrolled will continue in the 
AMAM AA until completion.  
• Due to the planned significant reduction in adolescent sample size the data for both 
induction and maintenance phases, the efficacy of mirikizumab-treated adolescent 
patients will be summarized instead of comparison with the adult placebo group and the 
adult mirikizumab group. For the adolescents that were enrolled in the study prior to 
stopping enrollment, their safety and efficacy information will be summarized. 
• Primary and secondary objectives and endpoints are revised in response to regulatory 
feedback and alignment with study AMAY.  
Overall changes, including the above, specific to certain protocol sections and a brief rationale 
are provided in the below table. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Removed the specific number of 
adolescent patients planned for 
enrollment in the study 
See rationale provided in the text 
preceding this table.   
1.3 Schedule of Activities 
 
 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
Added footnote “ad” to allow Visit 
2 assessments to be performed over 
2 days after consultation with the 
medical monitor 
 
Alignment with revised objective 
and endpoint on height 
 
Provides a contingency until 
Study AMAZ is ready to enroll at 
the patient’s clinical trial site. 
 
 
 
Alignment with Study AMAY 
 
 
Alignment with Study AMAM 
2.2.5 Preclinical and 
Clinical Studies of 
Mirikizumab 
Updated the status of studies in 
Ulcerative Colitis that are part of 
the LUCENT Phase 3 clinical 
development program for 
mirikizumab 
Updated the status for clinical 
studies in Crohn’s Disease 
Reflect most recent data 
3 Objectives and 
Endpoints 
 
 
 
 
  
 
 
  
 
 
 
 
See rationale provided in the text 
preceding this table.   
3 Objectives and 
Endpoints 
Overall revision of secondary 
objectives and endpoints 
Alignment with rationale 
provided in the text preceding 
this table and with Study AMAM 
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Section # and Name 
Description of Change 
Brief Rationale 
3 Objectives and 
Endpoints 
 
 
 
 
 
 
Details of the analyses will be 
described in the addendum SAP 
3 Objectives and 
Endpoints 
Removed tertiary/exploratory 
objectives and endpoints 
Details of the tertiary/exploratory 
objectives and endpoints will be 
described in the addendum SAP 
4.1 Overall Design 
 
 
 
 
 
 
 
 
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. 
4.2 Scientific Rationale for 
Study Design 
Revised based on changes made to 
objectives and endpoints 
See rationale provided in the text 
preceding this table.   
5.1 Exclusion Criteria 
Updated Criterion #40 to replace 
monoclonal antibodies with 
 
Clarification to state adult 
comparator and mirikizumab 
5.4 Screen Failures 
 
  
 
 
6.5.3 Corticosteroid Taper 
Added, “Investigators must contact 
the Study Medical Monitor to 
discuss any participant who does 
not
 
 
 
 
 
6.7.3.2 Management of 
Hypersensitivity, Infusion-
Related Events, Infusion 
Site Reactions, and 
Injection Site Reactions 
Modified instructions for 
nonsystemic hypersensitivity 
reactions.  
For consistency across the 
mirikizumab protocols and with 
the current Lilly standardized 
safety language. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.2 Criteria for 
Temporary Interruption 
(Withholding) of Study 
Drug 
Added wording to clarify that an 
 
 
 
 
 
. 
Clarification. 
8.1 Efficacy Assessments 
Added endpoint definitions for 
clinical response by 
 
 clinical remission 
 
Updated definition for clinical 
remission 
 
endoscopic remission endpoint of 
SES-CD ≤4 
Alignment with revised 
objectives and endpoints and with 
Study AMAY 
8.1.1 Primary Efficacy 
Assessment 
Added clinical response
 
 clinical remission 
  
 
from secondary efficacy 
assessment to primary efficacy 
assessment.  
 
Removed the description for 
clinical remission 
 
 assessment and 
moved it to secondary efficacy 
assessments 
Alignment with revised 
objectives and endpoints 
8.1.2 Secondary Efficacy 
Assessments 
 
 
from secondary efficacy 
assessment and moved to primary 
efficacy assessment 
Alignment with revised 
objectives and endpoints 
8.2.1 Growth Monitoring 
 
 
Emerging information from  
internal updates
 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.12 Depression, and 
Suicidal Ideation and 
Behavior 
 
 
 
Alignment with the Schedule of 
Activities. 
9.1 Statistical Hypotheses 
Revised coprimary endpoints 
Alignment with revised 
objectives and endpoints 
9.2 Sample Size 
Determination 
Revised the original sample size  
See rationale provided in the text 
preceding this table.   
9.4.1 General Statistical 
Considerations 
For both induction and 
maintenance phases, the efficacy of 
mirikizumab-treated adolescent 
patients will be summarized instead 
of comparison with the adult 
placebo group and the adult 
mirikizumab group  
For the adolescents that were 
enrolled in the study prior to 
stopping enrollment, their safety 
and efficacy information will be 
summarized 
9.4.1.2 Estimand 
For both induction and 
maintenance phases, the efficacy of 
mirikizumab-treated adolescent 
patients will be summarized instead 
of comparison with the adult 
placebo group and the adult 
mirikizumab group 
  
For the adolescents that were 
enrolled in the study prior to 
stopping enrollment, their safety 
and efficacy information will be 
summarized 
9.4.1.3. Missing Data 
Imputation 
Removed NRI method that may be 
used when the estimand of interest 
uses the hypothetical strategy for 
handling the intercurrent event of 
switching adult participants who do 
not achieve some type of response 
from placebo to mirikizumab 
Alignment with revised 
objectives and endpoints 
9.4.1.4 Multiple 
Comparisons/Multiplicity 
Removed “as hypothesis testing is 
only occurring for the primary 
objective”. 
 
9.4.3.1 Primary Analyses 
Added clinical response by 
 
clinical remission 
 to the 
coprimary endpoint 
Alignment with revised 
objectives and endpoints 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.3.2 Secondary 
Analyses 
 
 secondary endpoints 
description from primary analyses 
and moved it to secondary analyses 
Added endoscopic remission SES-
CD ≤4 
Alignment with revised 
objectives and endpoints 
Additional secondary analysis 
details have been removed 
These analyses of the secondary 
endpoints will be fully detailed in 
the SAP 
9.4.3.3 Tertiary 
Exploratory Analyses 
Removed reference to exploratory 
endpoints from Section 3 
Details of exploratory endpoints 
will be described in the 
addendum SAP 
9.4.4 Safety Analyses 
 
 
  
 
9.4.5 Pharmacokinetic 
/Pharmacodynamic 
Analyses   
Revised PK analyses of 
mirikizumab and relationships 
between exposure and the efficacy 
endpoints 
With reduction in sample size, the 
analysis methods needed to be 
updated. 
9.4.7.2 Subgroup 
Analyses 
Removed “Subgroup analyses for 
selected endpoints in Section 3 will 
be conducted” 
Updated to accommodate the 
reduced sample size. 
9.5 Interim Analyses 
Removed primary database lock for 
the addendum  
Updated with adolescent 
pharmacokinetic (PK) and safety 
data from Study AMAM 
Updated external data monitoring 
committee information 
See rationale provided in the text 
preceding this table.   
10.2 Appendix 2: Clinical 
Laboratory Tests 
 
 
 
 
Clarification 
11 References 
Updated Citations 
Editorial change 
Throughout 
Minor editorial changes. 
Correction 
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Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Addendum Summary of Changes Table ...........................................................................2 
Table of Contents ...........................................................................................................................8 
1. 
Protocol Addendum Summary ....................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
2. 
Introduction ...................................................................................................................21 
2.1. 
Study Rationale ...............................................................................................................21 
2.2. 
Background .....................................................................................................................21 
2.2.1. 
Disease State and Treatment Goals .................................................................................21 
2.2.2. 
Currently Available Treatments and Unmet Need ..........................................................22 
2.2.3. 
Interleukin-23 as a Therapeutic Target in Crohn’s Disease ............................................22 
2.2.4. 
IL-23p19 Blockade in Crohn’s Disease ..........................................................................23 
2.2.5. 
Preclinical and Clinical Studies of Mirikizumab ............................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................26 
3. 
Objectives and Endpoints ............................................................................................27 
4. 
Study Design ..................................................................................................................30 
4.1. 
Overall Design ................................................................................................................30 
4.2. 
Scientific Rationale for Study Design ............................................................................31 
4.3. 
Justification for Dose ......................................................................................................32 
4.4. 
End of Study Definition ..................................................................................................34 
5. 
Study Population ...........................................................................................................35 
5.1. 
Inclusion Criteria ............................................................................................................35 
5.2. 
Exclusion Criteria ...........................................................................................................39 
5.2.1. 
Rationale for Exclusion of Certain Study Candidates ....................................................44 
5.3. 
Lifestyle Considerations .................................................................................................44 
5.4. 
Screen Failures ................................................................................................................45 
5.4.1. 
Allowed Retesting of Screening Investigations ..............................................................46 
6. 
Study Intervention ........................................................................................................48 
6.1. 
Study Intervention(s) Administered................................................................................48 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................49 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding ...........................................49 
6.4. 
Study Intervention Compliance ......................................................................................49 
6.5. 
Concomitant Therapy .....................................................................................................50 
6.5.1. 
Permitted Therapy ...........................................................................................................50 
6.5.2. 
Prohibited Therapy..........................................................................................................50 
6.5.3. 
 .......................................................................................................51 
6.5.4. 
Rescue Medicine .............................................................................................................51 
6.6. 
Dose Modification ..........................................................................................................52 
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6.7. 
Intervention after the End of the Study ...........................................................................52 
6.7.1. 
Study Extension ..............................................................................................................52 
6.7.2. 
Treatment after Study Completion..................................................................................52 
6.7.3. 
Special Treatment Considerations ..................................................................................52 
6.7.3.1. 
Premedication for Infusions ...............................................................................52 
6.7.3.2. 
Management of Hypersensitivity, Infusion-Related 
Events, Infusion Site Reactions, and Injection Site 
Reactions ............................................................................................................52 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................55 
7.1. 
Discontinuation of Study Intervention ............................................................................55 
7.1.1. 
Criteria for Permanent Discontinuation of Study Drug ..................................................55 
7.1.2. 
Criteria for Temporary Interruption (Withholding) of Study Drug ................................57 
7.1.3. 
Discontinuation of Inadvertently Enrolled Participants ..................................................57 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................57 
7.3. 
Lost to Follow-up............................................................................................................58 
8. 
Study Assessments and Procedures.............................................................................59 
8.1. 
Efficacy Assessments .....................................................................................................59 
8.1.1. 
Primary Efficacy Assessment .........................................................................................60 
 
 
 
 
 
 
 
 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................61 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.3. 
Exploratory Assessments ................................................................................................63 
8.1.3.1. 
Disease Severity Index – Crohn’s Disease .........................................................63 
 
 
8.2. 
Safety Assessments .........................................................................................................63 
8.2.1. 
Growth Monitoring .........................................................................................................64 
8.2.2. 
Vital Signs .......................................................................................................................64 
8.2.3. 
Physical Examinations ....................................................................................................64 
8.2.4. 
Electrocardiograms .........................................................................................................65 
8.2.5. 
Chest Radiography ..........................................................................................................65 
8.2.6. 
Stool Testing ...................................................................................................................65 
8.2.7. 
Tuberculosis Testing .......................................................................................................66 
8.2.8. 
Clinical Laboratory Tests ................................................................................................69 
8.2.8.1. 
Pregnancy Testing ..............................................................................................70 
8.2.8.2. 
Immunogenicity Assessment ..............................................................................70 
8.2.9. 
Hepatitis B Testing .........................................................................................................71 
8.2.10. Hepatitis C Testing .........................................................................................................72 
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8.3. 
Adverse Events and Serious Adverse Events .................................................................74 
8.3.1. 
Serious Adverse Events ..................................................................................................74 
8.3.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................75 
8.3.2. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................75 
 
 
 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................76 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................76 
8.3.5. 
Pregnancy Reporting .......................................................................................................7  
 
 
8.3.7. 
Adverse Events of Special Interest .................................................................................77 
 
 
 
 
 
 
 
 
8.3.8. 
Complaint Handling ........................................................................................................78 
8.4. 
Treatment of Overdose ...................................................................................................78 
8.5. 
Pharmacokinetics ............................................................................................................78 
8.6. 
Pharmacodynamics .........................................................................................................79 
8.7. 
Pharmacogenomics .........................................................................................................79 
 
 
 
 
 
 
9. 
Statistical Considerations .............................................................................................81 
9.1. 
Statistical Hypotheses .....................................................................................................81 
9.2. 
Sample Size Determination ............................................................................................81 
9.3. 
Populations for Analyses ................................................................................................81 
9.4. 
Statistical Analyses .........................................................................................................81 
9.4.1. 
General Statistical Considerations ..................................................................................81 
9.4.1.1. 
Definition of Baseline ........................................................................................82 
9.4.1.2. 
Estimand .............................................................................................................82 
9.4.1.3. 
Missing Data Imputation ....................................................................................83 
9.4.1.4. 
Multiple Comparisons/Multiplicity ....................................................................83 
9.4.2. 
Treatment Group Comparability .....................................................................................83 
9.4.2.1. 
Participant Disposition .......................................................................................83 
9.4.2.2. 
Participant Characteristics ..................................................................................83 
9.4.2.3. 
Concomitant Therapy .........................................................................................84 
9.4.2.4. 
Treatment Compliance .......................................................................................84 
9.4.3. 
Efficacy Analyses ...........................................................................................................84 
9.4.3.1. 
Primary Analyses ...............................................................................................84 
9.4.3.2. 
Secondary Analyses ...........................................................................................84 
9.4.3.3. 
Tertiary Exploratory Analyses ...........................................................................85 
9.4.4. 
Safety Analyses ...............................................................................................................85 
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9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................86 
9.4.6. 
Evaluation of Immunogenicity .......................................................................................86 
9.4.7. 
Other Analyses ................................................................................................................86 
 
 
 
 
9.5. 
Interim Analyses .............................................................................................................87 
10. 
Supporting Documentation and Operational Considerations ..................................88 
10.1. 
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................88 
10.1.1. Regulatory and Ethical Considerations ...........................................................................88 
10.1.2. Informed Consent Process ..............................................................................................88 
10.1.3. Data Protection................................................................................................................89 
10.1.4. Committees Structure......................................................................................................89 
10.1.5. Dissemination of Clinical Study Data.............................................................................90 
10.1.6. Data Quality Assurance ..................................................................................................91 
10.1.7. Source Documents ..........................................................................................................92 
10.1.8. Study and Site Closure ....................................................................................................92 
10.1.8.1. 
Discontinuation of the Study ..............................................................................92 
10.1.8.2. 
Discontinuation of Study Sites ...........................................................................92 
10.1.9. Publication Policy ...........................................................................................................92 
10.2. 
Appendix 2:  Clinical Laboratory Tests ..........................................................................93 
 
 
10.4. 
Appendix 4:  Risk Factors for Latent Tuberculosis Infection ........................................96 
10.5. 
Appendix 5:  Examples of Infections that May Be Considered 
Opportunistic in the Setting of Biologic Therapy ...........................................................97 
10.6. 
Appendix 6:  Prohibited Medications .............................................................................99 
10.7. 
Appendix 7:  Permitted Medications ............................................................................101 
 
 
 
 
 
 
10.10. 
Appendix 10:  Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................106 
10.11. 
Appendix 11:  Definitions and Selected Abbreviations................................................107 
10.12. 
Appendix 12:  Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................113 
10.13. 
Appendix 13:  Protocol Amendment History ...............................................................124 
11. 
References ....................................................................................................................134 
 
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1. 
Protocol Addendum Summary 
1.1. 
Synopsis 
Protocol Addendum Title:  An Open Label Addendum to the AMAM adult study to Assess 
Efficacy and Safety of Mirikizumab in the Induction and Maintenance of Remission in 
Adolescents (15 to <18 years of age) with Moderately to Severely Active Crohn’s Disease (CD) 
Acronym:  VIVID-1 Adolescent Addendum 
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.  This addendum to Study I6T-MC-AMAM (AMAM) is a Phase 3 open 
label study to assess efficacy and safety of mirikizumab in the induction and maintenance of 
remission in adolescents (15 to <18 years of age) with moderately to severely active Crohn’s 
Disease (CD) in achieving endoscopic and clinical outcomes through Week 52 in adolescent 
patients.  Patients 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. 
Few medications have been approved for the treatment of adolescent patients with CD and the 
treatments that do exist require close monitoring for the potential of serious adverse effects.  
Thus, there is a substantial unmet need for the development, evaluation, and approval of 
efficacious, safe, and well-tolerated therapies for children and adolescents with CD.   
Overall Design: 
This study is a 52-week open-label addendum to the AMAM adult study to assess efficacy and 
safety of mirikizumab in the induction and maintenance of remission in adolescents (15 to <18 
years of age) with moderately to severely active Crohn’s disease. 
Number of Participants: 
Adolescents aged 15 to <18 years evaluable for primary analysis. 
Intervention Groups and Duration: 
Sites and adolescent participants will know that participants are receiving mirikizumab treatment 
for the full duration of the study, though the study material assigned and dispensed will be 
labeled in a blinded fashion (See Section 6.3).  During the induction period, participants will 
receive mirikizumab 900 mg by intravenous (IV) infusion at Weeks 0, 4, and 8. In the 
maintenance period, participants will receive mirikizumab 300 mg by subcutaneous (SC) 
injection every 4 weeks until Week 48.  

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The maximum total duration of study participation for each participant is 73 weeks, across the 
following study periods:   
Screening Period:  up to 5 weeks 
Intervention Periods 1 and 2: 
Induction:  12 weeks 
Maintenance:  40 weeks (Week 12 to Week 52) 
, patients may enter 3-year extension study AMAZ or enter Post-Treatment Follow-
up Period:
 
Data Monitoring Committee:  Yes  
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1.2. 
Schema 
 
Abbreviations:  IV = intravenous; mg = milligram; SC = subcutaneous. 

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1.3. 
Schedule of Activities (SoA) 
 
Screening 
Period 1: 
Induction 
Period 2: 
Maintenance 
 
UA/SVz 
Post-
Treatment 
Follow-up 
Visit Number 
V1a,b 
V2b V3c V4 V5c V6 V7 
V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETVw V997x  
V801 V802 
Week Relative to Study 
Drug Start 
Days Relative to Study 
Drug Start and Visit 
Interval Tolerance 
(Days)ad 
Informed consent/assent  
Preexisting conditions / 
Medical and vaccine 
history / Relevant surgical 
history 
Inflammatory bowel 
disease diagnosis forms 
Inclusion/Exclusion 
Criteria 
Concomitant medications 
Alcohol use  
Tobacco / Nicotine use 
Adverse events 
 
VS (T, PR, BP)d 
Heightr 
Weight 
Physical exame 
EIMs  
Fistula evaluation 
 
 
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Screening 
Period 1: 
Induction 
Period 2: 
Maintenance 
 
UA/SVz 
Post-
Treatment 
Follow-up 
Visit Number 
V1a,b 
V2b V3c V4 V5c V6 V7 
V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETVw V997x  
V801 V802 
Week Relative to Study 
Drug Start 
Days Relative to Study 
Drug Start and Visit 
Interval Tolerance 
(Days)ad 
CXRg 
 
TB Monitoringy 
 
 
Urine pregnancyi 
Serum pregnancyj 
 
 
 
Interferon-γ release assay
(or tuberculin skin test)k  
HIV testing  
HBV testing 
HBV DNAl 
HCV testingm 
 
 
PK samplen, o 
Immunogenicity (ADA) 
sampleso  
 
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Screening 
Period 1: 
Induction 
Period 2: 
Maintenance 
 
UA/SVz 
Post-
Treatment 
Follow-up 
Visit Number 
V1a,b 
V2b V3c V4 V5c V6 V7 
V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETVw V997x  
V801 V802 
Week Relative to Study 
Drug Start 
Days Relative to Study 
Drug Start and Visit 
Interval Tolerance 
(Days)ad 
 
 
  
 
 
  
 
 
Stool cultures 
C. difficile testing s 
 
 
 
Supply stool collection kitt 
  
 
 
 
 
 
 
 
 
 
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Screening 
Period 1: 
Induction 
Period 2: 
Maintenance 
 
UA/SVz 
Post-
Treatment 
Follow-up 
Visit Number 
V1a,b 
V2b V3c V4 V5c V6 V7 
V8 
V9 V10 V11 V12 V13 V14 V15 V16 V17 ETVw V997x  
V801 V802 
Week Relative to Study 
Drug Start 
Days Relative to Study 
Drug Start and Visit 
Interval Tolerance 
(Days)ad 
  
 
 
 
 
Assign to Treatment 
Dosingaa 
Abbreviations:  ADA = anti-drug antibodies (immunogenicity); 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; 
; CXR = chest X-ray; 
; 
; EIM = extraintestinal manifestation; ETV = early termination visit; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; 
 ; IP = investigational product; LV = last 
visit; N/A = not applicable; 
 
 
 SES-CD = Simple Endoscopic Score for Crohn’s Disease; T = temperature; TB = tuberculosis; 
UA/SV = Unscheduled Assessments during a Scheduled Visit; V997 = unscheduled visit; V = visit; VS = vital signs; 
 
 
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 sites have received and 
reviewed all screening laboratory test results, as well as screening endoscopy results, prior to randomization and dosing at V2.  
 
   
b 
All screening/baseline activities should be completed prior to any study drug administration unless otherwise stated. 
c 
Telephone visit. 
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d 
Sitting blood pressure and pulse rate to be obtained at approximately the same time of day 
 measurements and/or blood sampling.  When multiple assessments are 
scheduled for the same visit, the preferred order of completion is:  VS, 
 (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 node assessment.  
After screening, physical examinations include a symptom-directed evaluation as well as examination of heart, lungs, abdomen, perianal area, and visual examination of the 
skin. 
f 
 
 
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 
   
i 
Urine pregnancy test to be performed on all female patients.  Done locally and prior to dosing. 
j 
Serum pregnancy test to be performed on all female patients. 
k 
Tuberculin skin tests (TST) are to be read by a qualified professional 48 to 72 hours after placement with results noted in source documentation.   
l 
Perform only if patient result is anti-HBc+ with negative HBV DNA test at screening.  Any enrolled patient whose result is anti-HBc+ will undergo monitoring of HBV DNA 
at specified intervals.  Any patient with a positive HBV DNA test at any time must be discontinued from the study and receive appropriate follow-up medical care. 
m 
 
 
   
n 
   
o 
In the event of an systemic allergic/hypersensitivity event, blood samples will be collected f
 
 
 
 
   
p 
Sample can be obtained at any time at or after V2. 
q 
Stool samples must be collected up to 3 days before endoscopy and prior to beginning bowel prep for endoscopy
.  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 
During the study, collect height 3 times per visit at the indicated visits using a calibrated stadiometer. 
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s 
Stool culture and C. difficile must be negative at screening. 
t 
Instruct patients that the stool samples must be collected up to 3 days before endoscopy and prior to beginning bowel prep 
.   
u 
 
v 
 
 
 
 
 
 
w ETVs may occur on any day without regard to visit interval.  
 
   
x 
Unscheduled visits (V997) may be performed at the discretion of the investigator between protocol visits.  During all unscheduled visits, concomitant medications and adverse 
events 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 
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. 
z 
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). 
aa Visit procedures and assessments must be completed prior to dosing, except as noted in applicable footnotes above. 
ab   With sponsor approval, 
 
  
 
ac 
. 
ad   Visit 2 may be done over 
.
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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 patients with moderately to severely active Crohn’s disease (CD).  Patients 
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 in both adolescents and adults 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 during their 
lifetime.  Relapsing–remitting symptoms, meaning that many patients have intermittent disease 
flares that are interspersed with periods of remission, are very common in CD (Lichtenstein et al. 
2018).   
Crohn’s disease is similar in adult and pediatric/adolescent patients in terms of overall disease 
pathology and progression and potential treatment targets (Jakobson et al.  2011).  In addition, 
pediatric patients with CD are at increased risk of growth failure, retarded puberty, and reduced 
peak bone mass due to factors such as undernourishment, corticosteroid dependency, and pro-
inflammatory cytokines (Gasparetto et al. 2014).  According to both the Food and Drug 
Administration (FDA) (FDA Guidelines 2019) and European Medicines Agency (EMA) (EMA 
Guidelines 2019), these marginal differences in disease pathology between pediatric and adult 
CD should not prohibit the inclusion of adolescents with CD into trials with adults. 
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 patient-reported outcomes (PROs), including a 
reduction in stool frequency (SF) and AP.  In both clinical practice and in clinical trials, 
assessment of the response to therapeutic interventions also includes endoscopy to assess 
improvement in the endoscopic appearance of the mucosa and healing of ulcers. 

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2.2.2. 
Currently Available Treatments and Unmet Need 
Medications used for the treatment of CD in both adolescents and adults may include 
aminosalicylic acid (5-ASA) containing medications (sulfasalazine, mesalazine, balsalazide, 
olsalazine), corticosteroids or budesonide, immunomodulators (example:  azathioprine [AZA], 6-
mercaptopurine [6-MP], and methotrexate), antimicrobial therapy specific for CD, diet, and anti-
TNF agents (infliximab, adalimumab, certolizumab pegol) for treatment of CD resistant to 
treatment with corticosteroids or refractory to methotrexate or thiopurine therapy.  Agents 
targeting leukocyte trafficking such as vedolizumab (an anti-integrin) are currently used in 
patients who have failed other therapies.  Adult approved treatments like ustekinumab, an 
interleukin-12 (IL-12)/23 (anti-p40) antibody, are recommended in patients who have failed prior 
treatments with corticosteroids, immunomodulators, or anti-TNF agents.  Infliximab is the only 
biologic agent recommended for treatment of perianal fistulas, albeit in adult patients.  For 
adolescent patients, off-label use of adult treatments is common.   
A sizable proportion of the overall adolescent and adult population with moderately to severely 
active CD is unresponsive to, fails to tolerate, or loses response to conventional therapies or 
approved biologic therapies.  Studies have shown that up to 40% of patients show no clinical 
benefit in response to treatment with the first anti-TNF agent (Ding et al. 2015).  Further, for 
those that do respond initially, a recent meta-analysis showed, with a median follow-up of 
1-year, the incidence of secondary loss of response is 33%, with an annual risk for loss of 
response as 21% per patient-year (Qiu et al. 2017).  Compounding the primary and secondary 
loss of response data, there are currently only 2 biologics (infliximab, adalimumab) approved in 
any 1 country for use in pediatric CD (Shi and NG 2018).   
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 (Parrello et al. 2000). 
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).  
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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 2 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 intravenous (IV) given up to every 4 weeks (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 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 subcutaneous (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 
patients 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 patients 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 patients (Sandborn et al. 2018).  In the maintenance period through Week 52, 
mirikizumab demonstrated durable efficacy for both endoscopic as well as symptomatic indices:  
among patients 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 LUCENT Phase 3 clinical development program for mirikizumab includes studies 
LUCENT-1 (16T-MC-AMAN), LUCENT-2 (16T-MC-AMBG) and LUCENT-3 (16T-MC-
AMAP). 
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• 
Study 16T-MC-AMAN (AMAN) was 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 
Efficacy results 
A significantly greater proportion of participants treated with mirikizumab achieved 
clinical remission at Week 12 (Miri: 24.2%; PBO: 13.3%  [99.875%CI: 3.2, 19.1]; 
p=0.00006). Mirikizumab-treated participants achieved all key secondary endpoints 
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.  
Safety results  
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 other studies with the anti-IL-23p19 antibody class. The frequencies of treatment-
emergent AEs in mirikizumab-treated participants were similar to placebo. There were 
numerically fewer SAEs (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to 
adverse events (Miri: 15 [1.6%], PBO: 23 [7.2%]) in mirikizumab-treated participants 
compared to placebo (D’Haens et al. 2022). 
• 
Study 16T-MC-AMBG (AMBG) was a multicenter, randomized, double-blind, parallel-
arm placebo-controlled, Phase 3 maintenance study in participants who completed 
AMAN.  
Efficacy results 
A statistically higher proportion of participants met the primary endpoint of clinical 
remission at one year compared to participants who were re-randomized to placebo 
(p<0.001). All key secondary endpoints were also met (p<0.001), including significantly 
higher proportions of participants treated with mirikizumab achieving endoscopic 
remission, corticosteroid-free remission, resolution or near-resolution of bowel urgency, 
improvement in endoscopic histologic intestinal inflammation and maintenance of 
remission, and greater reduction from baseline in bowel urgency symptoms at one year 
compared to placebo.  
Safety results 
The frequency of SAEs among participants treated with mirikizumab was numerically 
lower compared to placebo, and the overall safety profile was consistent with that of the 
previous mirikizumab studies in UC and studies with the anti-IL-23p19 antibody class. 
The most common TEAEs reported among participants treated with mirikizumab were 
nasopharyngitis, arthralgia and exacerbation of ulcerative colitis (Lilly 2021). 

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• 
16T-MC-AMAP (AMAP) is a multicenter, open-label extension study to evaluate the 
long term efficacy and safety of mirikizumab in participants with moderately to severely 
active UC. This study is ongoing at the time of this writing. 
Pediatric Ulcerative Colitis Study  
Study I6T-MC-AMBU (AMBU) is an ongoing Phase 2, open-label study to evaluate the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and clinical response to mirikizumab to 
establish induction and maintenance doses to evaluate in Phase 3, in children and adolescents 
with UC, aged 2 to less than 18 years.  Study AMBU will include safety data following 
mirikizumab treatment for at least 1 year. 
Clinical Studies in Crohn’s Disease 
Study 16T-MC-AMAG (AMAG) was a Phase 2, placebo-controlled, double-blind clinical trial 
of mirikizumab in adult patients with active CD.  The primary efficacy objective was to test the 
hypothesis that treatment with mirikizumab is superior to placebo in the proportion of adult 
patients 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 TEAE 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).  
Pediatric CD Study  
• 
Study PLATFORMPBCRD3001-16T-MC-AMAY is a Phase 3, multicenter, randomized, 
platform study of p19 inhibition of the IL-23 pathway to establish efficacy in pediatric 
CD 
o Study I6T-MC-AMAY (AMAY) is an intervention-specific appendix to the 
Master protocol PLATFORMPBCRD3001-I6T-MC-AMAY and contains unique 
study elements specific for mirikizumab. 
Additional nonclinical and clinical trial data are summarized in the Investigator’s Brochure (IB). 

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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 patients 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 has 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. 
Patients ≥15 and <18 years of age and body weight >40 kg were selected for the adolescent 
addendum due to the similarity to the adult population.  Specifically, by 15 years of age patients 
will often have reached sexual maturity and a weight above 40 kg (the weight required for study 
enrollment) based on available growth chart data (Emmanuel and Bokor 2020; CDC [WWW] 
2019) and their immune systems are fully functional (Georgountzou and Papadopoulos 2017). 
The lower age of 15 years old required for study enrollment represents the onset for the peak 
age-specific incidence for CD (15 to 30 years of age for peak incidence), and thus is 
representative of the general adolescent CD population (Ananthakrishnan 2015). 
Given both the efficacy and safety data from the Phase 2 adult study in CD and data from other 
mirikizumab clinical studies completed to date, potential benefit to both adult and adolescent 
patients receiving mirikizumab in Study AMAM is 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 programs, potential risks associated with biologic immunomodulators as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations—are noted in Section 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 in both adult and adolescent 
patients 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   
Participants in the AMAM Adolescent Addendum will be assigned mirikizumab with clinical 
trial material provided to sites as blinded treatment.  This allows the use of the same test article 
in both the adult study and the adolescent addendum.  The primary and secondary efficacy 
objectives will summarize the data for open-label mirikizumab-treated adolescents and placebo-
treated adults from Study AMAM for endpoints collected in both adolescents and adults. 
Objectives 
Endpoints 
Co-Primary  
 
To evaluate the efficacy of mirikizumab as 
assessed by  
• 
Clinical response at Week 12 and 
endoscopic response at Week 52 
and  
• 
Clinical response at Week 12 and 
clinical remission at Week 52 
The proportion of patients achieving:  
• 
clinical response 
 at Week 
12 and endoscopic response by SES-
CD at Week 52  
and 
• 
clinical response 
 at Week 
12 and clinical remission 
 at 
Week 52  
Secondary  
 
To evaluate the efficacy of mirikizumab as 
assessed by 
• 
clinical response 
 
and endoscopic response at Week 52 
• 
clinical response 
 
and clinical remission by CDAI at 
Week 52 
The proportion of patients achieving:  
• 
clinical response 
 
and endoscopic response at Week 52  
• 
clinical response 
 
and clinical remission by CDAI at 
Week 52 
• 
To evaluate the efficacy of treatment 
with mirikizumab in endoscopic 
response at Week 12 
• 
Proportion of patients achieving 
endoscopic response at Week 12  
• 
To evaluate the efficacy of treatment 
with mirikizumab in endoscopic 
remission at Week 52 
• 
Proportion of patients achieving 
endoscopic remission SES-CD ≤4a at 
Week 52  
• 
 
 
• 
 
  
• 
To evaluate the efficacy of treatment 
with mirikizumab in endoscopic 
remission at Week 12 
• 
Proportion of patients achieving 
endoscopic remission SES-CD ≤4a at 
Week 12  
• 
To evaluate the efficacy of treatment 
with mirikizumab in clinical remission 
• 
Proportion of patients achieving 
clinical remission by CDAI at Week 12 
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Objectives 
Endpoints 
by CDAI 
• 
Proportion of patients achieving 
clinical remission by CDAI at Week 52 
• 
To summarize the efficacy of treatment 
with mirikizumab in clinical remission 
 
• 
Proportion of patients achieving 
clinical remission 
 
 
• 
Proportion of patients achieving 
clinical remission 
 
 
• 
To summarize the efficacy of treatment 
with mirikizumab
 
 
Mean change from baseline at Week 12 and at 
Week 52:   
• 
  
• 
  
• 
To summarize the efficacy of treatment 
with mirikizumab
 
 
Change from baseline in the following 
   
• 
 
• 
 
• 
To summarize the proportion
 
 
• 
Proportion of patients who had 
 
  
• 
Proportion of patients who had 
 
  
• 
Proportion of patients who had 
 
  
• 
To evaluate the pharmacokinetic and 
pharmacokinetic/pharmacodynamic 
relationships of mirikizumab  
• 
 
• 
 
 
• 
To summarize the change
 
 
 
• 
Change from baseline 
 
 
• 
Change from baseline 
 
 
  
• 
To summarize the change
 
  
• 
Change from baseline 
 
 
• 
Change from baseline
 
 
• 
To summarize the efficacy of treatment 
with mirikizumab in endoscopic 
• 
Proportion of patients achieving 
endoscopic remission 
 
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Objectives 
Endpoints 
 
 
 
• 
Proportion of patients achieving 
endoscopic remission 
 
 
 
 
 
 
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4. 
Study Design 
4.1. 
Overall Design 
Design Summary 
This open-label addendum to the AMAM adult study will assess efficacy and safety of 
mirikizumab in the induction and maintenance of remission in adolescents (15 to <18 years of 
age) with moderately to severely active Crohn’s Disease. See Schema in Section 1.2. 
Addendum participants with moderate-to-severe CD will be unblinded to treatment for the full 
duration of the study, though the study material assigned and dispensed has blinded labeling 
(Section 6.3).  During the induction period, participants will receive 900 mg mirikizumab by IV 
infusion doses at Weeks 0, 4, and 8.  In the maintenance period, participants will receive 300 mg 
mirikizumab by SC injection every 4 weeks until Week 48.   
Adult double-blind and double dummy placebo-treated participants will be used as the 
comparator for adolescent mirikizumab treated patients, noting: 
• When Period 1 induction dosing concludes (Week 12), placebo responders continue 
receiving placebo, and placebo nonresponders (NRs) at Week 12 will receive 
mirikizumab as described in the adult protocol.   
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. 
Participant Visit Scheme 
Study participants will undergo screening assessments, be assigned to treatment with 
investigational product, and participate
 if they do not proceed 
to the long-term extension Study AMAZ. 
Screening may be done on more than 1 day, as long as all activities are completed within 
  It is required that sites have received and reviewed all 
the screening laboratory test results, as well as screening endoscopy results, prior to treatment 
assignment and dosing at V2.  Please note that laboratory results could take
 
 
 
After screening and baseline visits, participants will receive their assigned therapy during the 
52-week 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 adolescent addendum through 
 will be given 
the option to enroll in Study AMAZ if they are eligible (Section 6.7.1). With sponsor approval, 
additional dosing at 
 may occur as needed for participants 
eligible to enroll in Study AMAZ where the clinical trial site is not yet open. Participants must 
have completed all procedures at 
 
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 from the prior dose.  Urine pregnancy test must be negative prior to study drug 
administration. Refer to study AMAZ main protocol inclusion criteria for participants moving 
into study AMAZ. 
Participants who do not meet enrollment criteria for Study AMAZ or who do not choose to 
participate in Study AMAZ will continue for 
 follow-up visits in Study AMAM.  
 
 
Participants who permanently discontinue study drug early will undergo early termination 
procedures, including an ETV and the post-treatment follow-up visits (Section 7.1). 
Assessments and Procedures 
Assessments and procedures to be conducted in each study period are described in the Schedule 
of Activities (Section 1.3) and in “Study Assessments and Procedures” (Section 8). 
Adolescent Responders/Nonresponders within the AMAM Addendum 
All adolescent participants consented in the addendum, irrespective of response status or age 
during their enrollment in the trial, will proceed from the induction period at 
 
. 
Adult Placebo Nonresponders within the AMAM Adult Trial   
Any participant in the adult placebo group who is considered NR at Week 12 will be assigned 
blinded mirikizumab induction therapy followed by blinded maintenance therapy for the 
remainder of the study; doses and routes of administration will be the same as those described 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. 
Adult Placebo Responders within the AMAM Adult Trial 
Participants in the adult 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 
The AMAM adolescent addendum (AA) is designed to evaluate the safety and efficacy of 
mirikizumab in the induction and maintenance of remission in adolescent patients (15 to <18 
years of age) with moderately to severely active CD. 
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 AA:  SES-CD 
 
The SES-CD will be determined at baseline, Week 12, and Week 52 (or end of study for patients 
with early discontinuation) with evaluation of endoscopic response (defined as ≥50% reduction 
from baseline in SES-CD total score) as a coprimary endpoint.  At the GREAT 3 Workshop, 
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endoscopic response as a coprimary endpoint was considered clinically meaningful and relevant 
and would provide sufficient evidence of efficacy for CD trials at various time points (FDA 
Workshop).  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 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. 
 
  
Use of Adult Placebo Comparator 
The control arm in this addendum is placebo-treated adult patients from study AMAM (main 
study).   
The extrapolation approach from adults to pediatric patients with CD is scientifically justified 
and is based on: 
• similar disease progression based on shared pathobiology and similar response to 
intervention between adults and children (Turner et al. 2016), and 
• 
   
A Week 12 timepoint for the addendum was chosen to match that of the adult protocol.  This 
timepoint falls within the study duration (from 6 week to 12 weeks) recommended for 
demonstration of short-term efficacy. Week 52 assessments will document the efficacy of 
mirikizumab in long-term treatment.   
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
 
Pharmacokinetic Considerations 
Previous evaluations of therapeutic antibodies in pediatric subjects indicate that the primary 
factor that influences PK is body weight rather than age (Dirks and Meibohm 2010).  The adult 
Phase 2 Study AMAG enrolled subjects who had baseline body weights ranging from 35.5 to 
125 kg, with a median of 71.6 kg.  Population PK analyses of the AMAG data were used to 
understand the relationship between body weight and clearance and body weight and volume of 
distribution. 
These analyses indicate that compared to the median adult body weight, subjects with a body 
weight of 
 would typically be expected to have a clearance 
 and a volume 
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of distribution 
. 
 
 
 The magnitude of these impacts is small relative to the overall random 
interpatient variability in clearance and volume of distribution.  
 
 
  These results indicate that, for body 
weights included in this trial, weight does not have a clinically relevant impact on the PK of 
mirikizumab. 
Based on the above observations in adults and PK data analyses, IV doses of up to 1000 mg that 
produced exposures higher than those produced with 
 
 
 
 
 
 
 
relationship could be expected across adult and pediatric CD populations. 
Therefore, the available efficacy and nonclinical and clinical safety data support th
 
It is expected that the 
 
predicted exposures similar to that of adults. 
Safety Considerations 
The safety data collected for mirikizumab in completed and ongoing clinical studies and in 
nonclinical toxicology studies support the proposed dose regimen.  Details of the clinical studies 
are outlined in Section 2.2.5. 
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 patients 
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with psoriasis (Study AMAF) and of the unblinded safety data available to date in the ongoing 
Phase 2 study of mirikizumab in patients 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 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 adolescent addendum study is defined as the date of the last visit or last scheduled 
procedure shown in the SoA (Section 1.3) for the last patient 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] 
the investigator, or a person designated by the investigator, will obtain written informed 
consent approved by the Ethical Review Board (ERB) from each study participant or the 
participant's parent/legal guardian and the subject’s assent, when applicable, before any 
study-specific activity is performed.  The investigator will retain the original copy of each 
participant's signed consent/assent document. 
Patient Characteristics 
[2] 
are male or female patients 15 to <18 years of age weighing >40 kgs with moderate to 
severely active CD as defined in points 5 and 6 below at the time of initial 
screening/consent.   
 
[2a] 
male patients: 
no male contraception required except in compliance with specific local 
government study requirements. 
[2b] 
female patients: 
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 
postovulation methods), declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception. 
OR 

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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 
. 
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 
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: 
infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as Mullerian agenesis. 
[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, or surgical, 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 symptoms of inflammation 
attributable to CD evaluated
 
   
[6] 
have signs of inflammation attributable to CD defined as a centrally read SES-CD score 
 
 
[7] 
Participants with a family history of colorectal cancer, personal history of increased 
colorectal cancer risk, 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 
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[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 patients:  Patients who have an inadequate response to, loss 
of response to, or are intolerant to at least 1 of the following medications: 
• 
corticosteroids 
o 
corticosteroid-refractory disease, defined as signs and/or symptoms 
of active CD despite a minimum of 
: 
 oral prednisone (or equivalent) at doses of at least 
, or 
 
.  
o 
corticosteroid-dependent disease, defined as: 
an inability to reduce corticosteroids below the equivalent of 
prednisone
 
 
 of completing a course of corticosteroids. 
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 at 
 
 oral AZA 
 
 
 oral AZA or 6-MP within a therapeutic range as judged by thioguanine 
metabolite testing, or 
 a combination of a thiopurine and allopurinol within a therapeutic 
range as judged by thioguanine metabolite testing. 
o 
history of intolerance to at least 1 immunomodulator (including but 
not limited to nausea/vomiting, 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 used for the treatment of 
CD. 
Discontinuation despite clinical benefit does not qualify as having failed or being 
intolerant to CD conventional therapy. 
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[8b] 
Biologic-failed patients:  Participants who have an inadequate response to, loss 
of response to, or are intolerant to a 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 or above 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 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 a 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. 
CD Medication Dose Stabilization Criteria 
[9] 
are on stable doses of the following permitted drugs (see Appendix 10.7): 
[9a] 
oral 5-ASA therapy: 
 
. 
[9b] 
oral corticosteroid therapy (prednisone ≤30 mg/day or equivalent, or budesonide 
9 mg/day):  
 
[9c] 
AZA, 6-MP, or MTX: 
 
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[9d] 
CD-specific antibiotics:  
 
 
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 control of the participant (example:  sudden death in family, 
sudden staff changes, broken equipment), rescreening or assessing potential assignment 
to treatment (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: 
, 
[11b] Chemistry: 
 
 
Retesting within the screening period is allowed for hematology and chemistry; see 
Section 5.4. 
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). 
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[12b] currently have or are suspected to have an abscess.  Recent cutaneous and perianal 
abscesses are not exclusionary if drained and adequately treated at least 
 
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 
, or any kind of intra-abdominal surgery 
within 
 (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
 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 adenoma without dysplasia that has not been removed.  Once 
completely removed, the patient is eligible for study. 
[18] 
have any evidence of colonic dysplasia. 
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 
. 
[19b] 5-ASA enemas or 5-ASA suppositories 
 
 
[19c] immunomodulatory medications, including oral cyclosporine, IV cyclosporine, 
tacrolimus, mycophenolate mofetil, thalidomide, or Janus kinase inhibitors 
 
 
• 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) 
. 
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[19e] anti-integrin antibodies (for example, vedolizumab) 
 
. 
[19f] agents that deplete B or T cells (for example, rituximab, alemtuzumab, or 
visilizumab) 
  Patients remain excluded if 
there is evidence of persistent targeted lymphocyte depletion at the time of 
screening endoscopy. 
[19g] any investigational nonbiologic therapy 
 
 
[19h] any investigational biologic therapy 
 
 
[19i] 
leukocyte apheresis (leukapheresis, for example, Adacolumn) 
 
 
[19j] 
interferon therapy 
 
[19k] natalizumab 
 
[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 (e.g., 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.   
Note:  Participants who have received up to the IV induction dose and 1 SC dose of 
anti-IL 12/23p40 antibodies (e.g., ustekinumab), may be enrolled.  However, these 
participants must have discontinued treatment for a nonclinical reason (e.g., change of 
insurance) and discontinued at least 16 weeks prior to screening endoscopy.  Enrollment 
of participants meeting this criterion will be limited to approximately 10% of total 
enrollment. 
[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 history of active TB, without documented appropriate treatment by the 
World Health Organization (WHO) and/or Centers for Disease Control (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 8.2.7). 
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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 8.2.7. 
[24] 
have received a Bacillus Calmette-Guerin (BCG) vaccination 
 or 
received live attenuated vaccine(s) 
 of screening or intend to receive such 
during the study. 
[25] 
have human immunodeficiency virus infection/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 8.2.9). 
[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 8.2.10). 
Note:  Participants with a previous HCV infection that has been successfully treated with 
antiviral therapy are not excluded (see Section 8.2.10). 
[28] 
have tested positive for C. difficile toxin or for other intestinal pathogens within 
 
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 
 prior to screening endoscopy.  (See Section 8.2.6). 
[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 
 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. 
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Participants with an opportunistic infection or chronic, recurrent infection (within 
the last 
) 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, i
 
 
[31] 
have evidence of active/infectious herpes zoster infection
 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. 
[36] 
have previously completed or discontinued from this study or any other study 
investigating mirikizumab.  This criterion does not apply to patients undergoing 
rescreening procedures. 
[37] 
have had extra-abdominal surgery and have not recovered fully following surgery, 
including complete wound healing, before screening. 
[38] 
 
 
 
 
 
 
 
 
 
 
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[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
 
 for the duration of Study AMAM, or unable to 
complete other study procedures. 
Note:  In situations out of control of the participant (example:  sudden death in family, 
sudden staff changes, broken equipment), rescreening or assessing potential assignment 
to treatment (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 
 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. 
[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 (CBD) 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 sex.   
Participants from 15 to <18 years of age at the time of screening will be eligible to be included in 
this study.   
5.3. 
Lifestyle Considerations 
Study participants should be instructed not to donate blood or blood products during the study 
and for 
 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). 
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5.4. 
Screen Failures 
Allowed Rescreening of Participants After Initial Screen Failure 
 
   
For the reasons above, participants 
 
   
Participants who have failed screening because of Exclusion Criterion [23c] (if treated for LTBI 
for at least 
 and compliant with LTBI therapy while on study) may be rescreened 1 time.  
See Section 8.2.7. 
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 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 8.2.6 and 
Section 5.4.1).  The start of rescreening is when the screen failure was first noted.  The interval 
between rescreenings should be at least 
, unless a shorter interval has been agreed with 
the study’s medical monitor.  Each time rescreening is performed the participant, parent/guardian 
must sign a new informed consent form (ICF) and will be assigned a new identification number. 
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The interval between rescreening should be at least 
 after time/date of screen failure for 
participants because 
   
Participants who screen fail because they are unable to complete their endoscopy 
 
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 investigator’s 
judgment the patient has risk factors and/or signs and symptoms of illness.  Participants may 
undergo repeat rescreening sooner than 
 between screen failure and rescreening. 
Disallowed Rescreening of Participants After Initial Screen Failure 
  
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:  
 
 
  
Stool testing:  if there is a technical difficulty in performing or reporting the C. difficile or stool 
culture assays (see Section 8.2.6). 
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 8.2.7 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). 
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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 (Induction), SC injection (Maintenance) 
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 blinded solution vial containing mirikizumab, with study-specific labels.   
o 
 
   
• Single-use blinded solution pre-filled syringe containing mirikizumab.   
o 
   
o 
   
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 
blinded labels. 
Preparation and Administration 
Mirikizumab 900 mg will be administered intravenously every 4 weeks at Weeks 0, 4, and 8, 
then 300 mg subcutaneously every 4 weeks starting Week 12 until Week 48.  Investigational 
product will be administered at the site by 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 
 after IV dosing, according to investigator practice or local standard of care. 
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 patient’s electronic case report 
form (eCRF). 
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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 
Treatment Assignment  
Treatment will be dispensed using an interactive web-response system (IWRS) as blinded study 
material.  There will be no randomization, all adolescent patients will be assigned to 
mirikizumab.   
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. 

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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 
training on and appropriate understanding of: 
• 
the importance of complete bowel prep prior to colonoscopies, 
• 
how to evaluate their CD symptoms 
 
and 
• 
 
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 patient 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, pre-SC topical 
preparations, or devices used 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. 
 
nstructions 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 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). 
 
consult your medical monitor prior to discontinuing the participant. 
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Vaccinations 
During the screening period, the investigator must review the study participant’s vaccine record 
to confirm required vaccinations are up to date.  If nonlive vaccination is needed, it should be 
performed during the screening period prior to the first dose of study drug.  Use of BCG 
vaccination is prohibited throughout the duration of the study and for 
 after 
discontinuation of study drug.   
Use of live, attenuated vaccines is prohibited
 
  
Use of nonlive (killed, inactivated, subunit and RNA-based) vaccinations is allowed; 
 
   
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 (Section 8.1) and who are currently on corticosteroids 
 
 
 
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 other than oral 5-ASA 
compounds or immunomodulators as described above to treat their CD should be discontinued 
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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). 
, as all patients are assigned to active study drug.   
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 Adolescent Addendum through 
 will be 
assessed for eligibility to enter Study AMAZ.  If a participant does not meet enrollment criteria 
for Study AMAZ or does not opt to continue into Study AMAZ, he or she will be asked to 
complete the post-treatment follow-up period, as described in the Schedule of Activities 
(Section 1.3), which will complete his or her study participation.  At Week 52, patients may enter 
3-year extension study or enter post-treatment follow-up 
.   
6.7.2. 
Treatment after Study Completion 
Mirikizumab will not be made available to study participants after conclusion of the study; 
however, participants who are eligible may choose to participate in Study AMAZ 
(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 2 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, 
antihistamine, 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 patient 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, nonsteroidal anti-inflammatory drugs (NSAIDS), antipyretics, 
or antihistamines).   
• Blood samples for antidrug 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: 
• 
ETV and, 
• 
post-treatment follow-up visits 
 
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/Legal Guardian Decision 
The participant or legal guardian requests to discontinue the study drug. 
Disease Worsening 
• 
The participant requires treatment with a prohibited CD medication (Appendix 10.6). 
• 
The participant undergoes surgery for active CD (with the exception of drainage of an 
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 intestinal dysplasia. 
o active TB (Section 8.2.7). 
o HIV/AIDS. 
o hepatitis B or development of detectable HBV DNA (Section 8.2.9). 
o hepatitis C or development of detectable HCV RNA (Section 8.2.10). 
• 
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. 
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• 
The participant has absolute lymphocyte count 
 
 
• 
The participant becomes pregnant.  Pregnant participants will not undergo an endoscopy 
at the ETV (Section 8.1.1.2). 
• 
Noncompliance with LTBI treatment (see Section 8.2.7). 
• 
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: 
Other Reasons 
• 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 
 
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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 
 
   
• Patients who develop an absolute lymphocyte
 
 
   
 
 
   
 
 
  
 
 
 
• The participant has laboratory abnormalities that may lead investigator to hold the 
study drug until resolution of the abnormalities. 
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 (V801 and V802). 
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 
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• 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 
• Legal guardian decision  
o the legal guardian requests the participant 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 
 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 
with ≥ 2 point reduction 
SES-CD Total Score ≤4 and at least a 2-point reduction versus baseline 
and no subscore >1 
Endoscopic remission SES-CD 0 to 2 
SES-CD Total Score ≤2 
Clinical remission by PRO 
 
 
 
 
 
Clinical response by PRO 
 
 
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 
Clinical remission by 
 
 
 
Clinical response by 
 
 
 
  
 
Clinical response by
 
 
  
 
Clinical remission by 
 
 
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Abbreviations:  AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; 
 
; PRO = patient-reported outcome; SES-CD = Simple Endoscopic Score for Crohn’s Disease; 
 
 
8.1.1. 
Primary Efficacy Assessment 
The coprimary endpoint is clinical response by 
 
 
 
  
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 patient endoscopic examination.  The SES-CD is discussed further in 
Section 8.1.1.1. 
Refer to Sections 8.1.1.2 and 8.1.1.3 for more information on Endoscopy and Endoscopic 
Biopsies. 
 
 
8.1.1.1. 
Simple Endoscopic Score for Crohn’s Disease 
The Simple Endoscopic Score for Crohn’s Disease (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. 
8.1.1.2. 
Endoscopy 
An endoscopy will be performed on all patients during screening, prior to randomization.  The 
endoscopy report and histopathology report (if biopsies sent to the local histopathology 
laboratory for histology confirmation for eligibility requirements) must be available in the source 
documents.  Prior to performing the screening endoscopy, investigators should ensure that 
patients have clinically acceptable central laboratory test results.  Stool culture and C. difficile 
must be negative at screening prior to randomization. 
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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 patient, 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 patient becomes pregnant during the study, no additional endoscopies will be performed. 
8.1.1.3. 
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 patient 
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. 
Clinical Remission by PRO 
 
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8.1.2.2. 
Crohn’s Disease Activity Index 
Crohn’s Disease Activity Index 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]).  Patient 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 (Crohn’s Disease Activity Index – Stool Frequency [CDAI-SF], 
Crohn’s Disease Activity Index – Abdominal Pain [CDAI-AP], and Crohn’s Disease Activity 
Index – Well-Being [CDAI-well-being]). 
8.1.2.3. 
Patient Reported Outcomes 
The following PROs will be collected:   
 
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 
 
 
See Appendix 10.8 for details on the above PROs. 
8.1.2.4. 
Inflammatory Biomarkers 
High-sensitivity C-Reactive Protein 
High-sensitivity C-reactive protein (hsCRP) is an acute phase protein expressed by hepatocytes 
in response to inflammatory cytokines, particularly IL-6, TNF, and IL-1β (Sands 2015).  
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High-sensitivity CRP will be obtained at time points described in the Schedule of Activities 
(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 Schedule of Activities (Section 1.3).  Investigators will 
be blinded to fecal calprotectin results. 
8.1.2.5. 
Extraintestinal Manifestations 
Review of extraintestinal manifestations (EIMs) will be performed at the time points described in 
the Schedule of Activities (Section 1.3).  Extraintestinal manifestations include ankylosing 
spondylitis, anal fissure, fistula or abscess, other fistulae, arthralgia, arthritis, cholelithiasis, 
erythema nodosum, nephrolithiasis, aphthous stomatitis, primary sclerosing cholangitis, 
pyoderma gangrenosum, sacroiliitis, iritis/uveitis, and thrombosis (deep vein/portal vein). 
8.1.2.6. 
Fistulas  
Additional data on bowel fistulas will be collected on an eCRF at the time points described in the 
Schedule of Activities (Section 1.3).   
8.1.3. 
Exploratory Assessments 
Exploratory endpoints will be defined in the statistical analysis plan (SAP).   
8.1.3.1. 
Disease Severity Index – Crohn’s Disease 
The Disease Severity Index – Crohn’s Disease (DSI-CD) is a clinician reported 16-item 
measurement scored by reviewing patient 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:   
• 
Height 
• 
Weight  
• 
Vital signs 
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• 
ECG (if applicable) 
• 
Blood sampling 
Adverse event collection should occur before the collection of the 
 
 
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 AESI are noted in Section 8.3.7. 
Safety Monitoring 
The sponsor will periodically review evolving aggregate safety data within the study by 
appropriate methods.   
8.2.1. 
Growth Monitoring 
  
 
 
 
 
 
   
8.2.2. 
Vital Signs 
Measurements of vital signs (body temperature, blood pressure collected with appropriately sized 
cuff, and pulse rate) will be conducted at the study visits specified in the SoA (Section 1.3). 
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. 
8.2.3. 
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, 1 complete physical examination (excluding pelvic, rectal, and breast 
examinations) will be performed and will include an assessment of peripheral lymph nodes. 
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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 8.2.7). 
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. 
8.2.4. 
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. 
Evaluation of ECGs should be performed by appropriately trained personnel with experience in 
reading pediatric ECGs.  Electrocardiograms will be read locally by a health care professional 
trained in the reading of pediatric ECGs. 
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. 
8.2.5. 
Chest Radiography 
A posterior-anterior (PA) 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. 
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. 
8.2.6. 
Stool Testing 
Stool Culture 
A stool sample for culture will be obtained at screening.  In order to be assigned to treatment, 
participants must have a negative stool culture from which no enteric pathogens are isolated.   

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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 repeat central C. difficile toxin lab is negative (a local test may be completed prior 
to repeat central test) 
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 toxin will be obtained at screening.  This assay tests for the 
presence of C. difficile toxin protein, followed by a confirmatory test for C. difficile toxin gene 
expression in the stool sample.  In order to be assigned to treatment, participants must have a 
negative test result.   
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 condition has been met: 
• the participant has been adequately treated, and repeat central C. difficile toxin lab 
is negative (a local test may be completed prior to repeat central test) 
Participants who have been adequately treated for C. difficile with fecal microbial transplantation 
or IV immunoglobulin therapy can be rescreened once for the study. 
8.2.7. 
Tuberculosis Testing 
Initial Screening 
All participants will be screened for active TB and LTBI.   
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 8.2.2 and Section 8.2.3, 
• CXR or CT, as described in Section 8.2.5, and 
• a test to assess immune response to mycobacterial antigens (unless patient has a 
history of a positive IGRA): 
o IGRA (for example, QuantiFERON-TB Gold or T-SPOT.TB), or 
o Tuberculin skin test (TST, also called a purified protein derivative [PPD] or 
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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 patients who have received a BCG vaccination.  In 
countries where the TST is available and is preferred (in the judgment of the investigator) as an 
alternative screening test for LTBI, that test may be used instead of an IGRA for appropriate 
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.  
There must be a minimum of 2 weeks between initial TST and 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, (CDC 2016) or 
(WHO 2018), with documentation of having completed the appropriate TB 
prophylaxis regimen, 
• no evidence of reactivation of LTBI, and 
• have no evidence of hepatotoxicity (ALT and AST levels must remain ≤2 × AA 
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 
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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.  Patients with 2 indeterminate 
QuantiFERON-TB Gold assays or 2 borderline T-SPOT assays will require a TST test and CXR; 
if both are negative, the participant may enroll. 
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.   
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 
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.  

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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 patient 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. 
8.2.8. 
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. 
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 8.1.2.4), Lilly or 
its designee will provide the investigator with the results of laboratory tests analyzed by a central 
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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. 
8.2.8.1. 
Pregnancy Testing 
Pregnancy testing is to be performed on all female patients.  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 at designated scheduled visits through 
Week 52.  The urine pregnancy test must be “negative” prior to administration of study drug at 
each 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.   
8.2.8.2. 
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:   
• 
 
• 
 
 
To aid interpretation of these results, 
 
 
 
 
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.
 
 
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Sample Retention 
Samples will be retained for a maximum of 
 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 
 will be destroyed. 
8.2.9. 
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 anti-hepatitis B core antibody (anti-HBc), followed by a test for HBV 
DNA in patients who are HBsAg-, anti-HBc+. 
Exclusion Based on HBV Serology and HBV DNA Testing 
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 
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 × AA 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 IP, 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 
consolidation has been completed and after discussion with medical monitor.   
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If HBV DNA is detected during the study, the investigator should consider using 1 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. 
8.2.10. 
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 times AA 
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, 
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.   
 
 
 
 
 
 
   
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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. 
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 

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• 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 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the 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 
information.  Participants with a serious hepatic AE should have additional data collected using 
the hepatic eCRF packet (see Section 8.2.11). 
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 guidance 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 guidance. 
8.3.2. 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events that begin before the first dose of study drug but after signing of the ICF will be 
recorded on the AE 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 
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reasonably possibly related to the study treatment or study participation, the investigator must 
promptly notify Lilly. 
 
 
   
 
 
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 
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 
 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. 
8.3.6. 
Cardiovascular and Death Events 
Cardiovascular AEs and other events leading to death are collected as described in Section 8.3 
and its subsections.  See also Section 8.3.7.4. 
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8.3.7. 
Adverse Events of Special Interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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 2 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 patients and/or caregivers about the symptoms and signs of 
hypersensitivity events and provide instructions on dealing with these events.   
For recommendations on the management and follow-up of hypersensitivity events, see 
Section 6.7.3.2. 
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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. 
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. 
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 
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designated by the sponsor.  Serum concentrations of mirikizumab will be determined using a 
validated enzyme-linked immunosorbent assay.  It is not intended that samples collected from 
placebo-treated patients will be analyzed. 
Additional Samples 
A maximum of 
 
 
  In the case of systemic 
allergic/hypersensitivity reactions (Section 8.3.7.2), additional blood samples will be obtained, as 
described in the SoA. 
Sample Retention 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a 
 following last participant visit for the study. 
8.6. 
Pharmacodynamics 
See Section 8.8 for biomarkers. 
8.7. 
Pharmacogenomics 
 
 
 
 
 
 
 
 
 
 
 
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 
 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards (IRBs) impose shorter time limits.  
 
 
 
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8.8. 
Exploratory Biomarkers 
 
 
 
 
 
 
 
 
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 
 
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 efficacy objective is to summarize the efficacy of treatment of open-label 
mirikizumab in adolescents and placebo in adults from Study AMAM with regards to the 
coprimary endpoints of the rates of clinical response by 
 endoscopic 
response at 
 clinical response 
 and clinical remission
 
. 
9.2. 
Sample Size Determination 
The original sample size to be enrolled was at least 50 evaluable adolescent participants assigned 
to study intervention to provide 
 to detect a difference between mirikizumab-treated 
adolescents and placebo-treated adults for the coprimary endpoint of clinical remission by PRO 
and endoscopic response when comparing the corresponding 95% confidence intervals (CIs).  
Due to a change in the pediatric program, enrollment in this addendum has been stopped.
 
 
All participants enrolled will be assigned to mirikizumab. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined. 
Intent-to-Treat (ITT) Population 
All enrolled patients, even if the participant does not receive treatment, 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 assigned. 
Modified Intent-to-Treat (mITT) Population 
All patients from ITT who take at least 1 dose of study drug.   
Safety Population 
Same as mITT Population. 
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.  
SAS (Version 9.2 or higher, SAS Institute, Cary, NC, USA) will be used for the statistical 
analysis. 
Unless otherwise specified, efficacy analyses will be conducted on the mITT population, and 
safety analyses will be conducted on the safety population as described in Section 9.3. 
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Statistical analyses will include the following 3 participant cohorts: 
1. Mirikizumab-treated adolescents:  Adolescent participants in the addendum, ages 15 to 
less than 18 years old, assigned mirikizumab treatment as specified in Section 4.1. 
2. Placebo-treated adults:  Adult participants from Study AMAM, ages 18 years and up, 
assigned placebo treatment as described in Section 4.1. 
3. Mirikizumab-treated adults:  Adult participants from Study AMAM, ages 18 years and 
up, assigned mirikizumab treatment as described in Section 4.1. 
For both induction and maintenance phases, the efficacy of mirikizumab-treated adolescent 
patients will be summarized alongside the adult placebo group and the adult mirikizumab group. 
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.   
Full details of all a priori specified analyses for the amendment will be provided in a separate 
SAP, specific to the amendment.  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 
amendment.  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 visit.  The centrally read baseline SES-CD score from the 
screening endoscopy is considered the baseline for endoscopic response and endoscopic 
remission. 
 
 
 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 prior to 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. 
9.4.1.2. 
Estimand 
The estimand (ICH 2019) is documented as follows: 
The addendum will compare adolescents (15 to <18 years of age) receiving mirikizumab to 
adults on placebo in individuals with moderately to severely active CD.  The specific treatment 
regimen is explained in Section 6.1.  The study population is described in more detail in 
“Populations for Analysis” (Section 9.3) and the inclusion/exclusion criteria (Sections 5.1 and 
5.2). 
The primary summary of interest will include descriptive summary of adolescents assigned to the 
mirikizumab group and adults assigned to the placebo and mirikizumab groups separately for the 
 as described in 
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Section 9.4.1.  Additional information concerning the primary and secondary objectives is 
included in Section 3.   
Patients will be considered nonresponders if they discontinue treatment, increase mandatory 
stable medications, have a disease related surgery, or take prohibited medications prior to the 
time point of interest (composite approach).  The nonresponder imputation (NRI) method will be 
used as the primary method of accounting for intercurrent events as summarized in “Missing 
Data Imputation” (Section 9.4.1.3). 
Additional details will be provided in the SAP.   
9.4.1.3. 
Missing Data Imputation 
The missing data methods described will be used to address the intercurrent event strategies 
proposed for this study.  Analysis of categorical efficacy and health outcomes variables will use 
a 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).   
The NRI method may be used to address missingness when the estimand of interest uses the 
composite strategy for handling intercurrent events.  In this strategy, participants with any of the 
intercurrent events stated above are defined to have failed study intervention for all subsequent 
timepoints.   
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 
No multiplicity adjustment is planned for this trial. 
9.4.2. 
Treatment Group Comparability 
9.4.2.1. 
Participant Disposition 
The number of enrolled participants (that is, participants in the ITT population) will be 
summarized.  Frequency counts and percentages of all participants who are enrolled 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. 
9.4.2.2. 
Participant Characteristics 
Demographic and baseline characteristics will be summarized descriptively; no testing will be 
performed for baseline characteristics.  For continuous measures, summary statistics will include 

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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 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 addendum SAP. 
9.4.3. 
Efficacy Analyses 
Primary and secondary analyses will be based on the mITT population as defined in Section 9.3. 
9.4.3.1. 
Primary Analyses 
Primary Endpoint: 
The coprimary endpoint is comprised of 2 separate endpoints in the proportion of participants 
achieving: 
• clinical response 
 at Week 12 and endoscopic response by SES-CD at 
Week 52 
• clinical response 
 at Week 12 and clinical remission 
 at 
Week 52 
Refer to Section 8.1 for definitions of the following endpoints: 
• 
 
• Endoscopic response  
• 
 
Primary analyses will include descriptive summary of the clinical response 
 
 endoscopic response as described in Section 9.4.1. for mirikizumab-
treated adolescents, adults assigned to the placebo group, and adults assigned to the mirikizumab 
group from Study AMAM. 
9.4.3.2. 
Secondary Analyses 
Secondary Endpoints 
Refer to Section 8.1 for definitions of the following endpoints: 
• 
Clinical remission by PRO  
• 
Clinical remission by CDAI  
• 
Endoscopic remission SES-CD ≤4  
• 
Clinical remission
  
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Confidence intervals for all secondary endpoints will also be provided for adolescents assigned 
to mirikizumab and adults assigned to placebo treatment and are not intended to correspond to a 
statistical hypothesis test. 
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. 
9.4.3.3. 
Tertiary Exploratory Analyses 
Details of the analyses of exploratory endpoints, as well as any additional exploratory analyses 
will be described in the addendum SAP. 
9.4.4. 
Safety Analyses 
Safety will be assessed by evaluating the following:  including, but not limited to, exposure, 
AEs, laboratory analytes, vital signs, growth and development (assessment of puberty), patient 
characteristics, and AESIs (Section 8.3.7). 
Duration of exposure to therapy during the treatment periods will be calculated for each 
participant and summarized.   
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 (LLT) 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.   
In an overview table, the number and percentage of patients with at least 1 TEAE, SAE, fatal 
SAE, or discontinuation from study treatment due to an AE will be summarized.  Treatment-
emergent adverse events (all and by maximum severity), SAEs including deaths, and AEs that 
lead to treatment discontinuation will be summarized and analyzed by MedDRA system organ 
class (SOC) 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.  Other data, including development, body weight, 
and height data, will be summarized.  Weight, height, and BMI data will be merged to the CDC 
standard growth data by age and sex to compare subjects’ growth with the standard.  Other 
measures related to growth (e.g., occipital circumference measurement) will be evaluated.  
Further analyses may be performed as deemed necessary.  Potential AESIs will be identified by 1 
or more standardized MedDRA queries (SMQs) by a Lilly-defined MedDRA PT listing based 
upon the review of the most current MedDRA version, or by treatment-emergent relevant 
laboratory changes.  Definitions of the AESIs and associated analyses will be described in the 
addendum SAP. 
This study also includes assessment of tolerability and acceptability 
 
 through the summarization of AEs reported as injection site 
reactions and pain, as well as treatment discontinuations as defined in the SAP. Reports of 
 will include the assessment of severity (mild, moderate, or severe).  Data from 
these assessments will be reviewed regularly throughout the study by the medical team as part of 
the trial level safety reviews, as well as presented to our external steering committee 
approximately twice a year for their independent evaluation. 
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Categorical and continuous safety parameters will be analyzed as described in Section 9.4.1.  All 
safety analyses will be fully detailed in the addendum SAP. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Analyses of the PK of mirikizumab and relationships between exposure and the efficacy 
endpoints will be conducted. 
The PK of mirikizumab will be characterized using graphical evaluations.  The observed serum 
concentration data will be overlaid to the PK profile of adult patients with CD at the same dose 
for a comparison.  
 
 
 
   
Population PK modeling and model-based analysis for exposure response relationship may be 
conducted if deemed appropriate.  Data from this study may be combined with other study data, 
if appropriate, for the modeling analysis.   
9.4.6. 
Evaluation of Immunogenicity 
Frequencies and percentages will be tabulated for the following: 
• 
 
• 
 
  
 
 
 
 
 
 
dditional details will be provided in the addendum SAP. 
9.4.7. 
Other Analyses 
 
 
 
 
 
9.4.7.2. 
Subgroup Analyses 
Subgroup analyses may be conducted for the coprimary and selected secondary endpoints.  
Subgroups to be evaluated may include sex, age, body weight, race, ethnicity, geographic region, 
baseline SES-CD category, baseline AP/SF category, corticosteroid use at baseline, duration of 
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disease, and disease location.  A detailed description of the subgroup variables and analyses will 
be provided in the addendum SAP.   
This study is not powered for subgroup analyses; therefore, all subgroup analyses will be treated 
as exploratory. 
Analyses specifically requested by regulatory agencies will be identified as appropriate. 
9.5. 
Interim Analyses 
Adolescent pharmacokinetic (PK) and safety data from Study AMAM will be needed to inform 
dosing decisions for other pediatric mirikizumab trials.  To accomplish this, a snapshot of the PK 
and safety data (including AEs, labs, and vital signs) will be taken of the adolescent patients 
when approximately 
.  If the adolescent PK 
exposure models are inconsistent with previous adult PK exposure models, a second PK snapshot 
may be performed if more information is needed to sufficiently determine drug exposure in 
adolescent patients.  The timing of the second snapshot will be based on how much information 
is still needed after the first snapshot.  Additional details on the analysis are found in the 
PK/pharmacodynamic (PD) analysis plan.  
A DMC consisting of members external to Lilly will be established for interim safety monitoring 
across all the sponsor’s Phase 3 studies in patients with CD, as well as a specific Pediatric IBD 
DMC, also composed of members external to Lilly.  See Appendix 10.1.4 for more information.   
Unblinding details can found in the unblinding plan.  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. 
• Reporting cases of suspected child abuse and/or neglect according to local 
medical association (e.g., [American Academy of Pediatrics (AAP)] or health 
department guidelines]. 
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.   

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Participants or their legally authorized representative defined as parent/legal guardian 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 (HIPAA) 
requirements, where applicable; and the IRB/IEC or study center. 
The medical record must include a statement that legally authorized representative (parent/legal 
guardian) consent and adolescent assent (if deemed appropriate by local ethics review) was 
obtained before the participant was enrolled in the study and the date the written consent was 
obtained.  The medical record should also describe how the clinical investigator determined that 
the person signing the ICF was the participant’s legally authorized representative (parent/legal 
guardian).  The authorized person obtaining the informed consent must also sign the ICF(s). 
Participants and their legally authorized representative (parent/legal guardian) must be re-
consented and re-assented to the most current version of the ICF(s) during their participation in 
the study. 
Minor participants must be reconsented if they reach the age of majority during the course of the 
study, in order to continue participating. 
A copy of the ICF(s) must be provided to the participant or the participant’s parent/legal 
guardian.  A copy of the ICF(s) is kept on file.   
Participants who are rescreened are required to sign a new ICF.  A copy of the ICF(s) must be 
provided to the participant or the participant’s parent/legal guardian.  Obtain informed consent 
for continued participation from pediatric participants once a child reaches the age of legal 
consent. 
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 
 
 
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 5 members, including a physician with expertise in gastroenterology, 
pediatrics, and a statistician.   
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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 patients 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 internal 
review committee (IRC), which is independent from the study team, to review the 
recommendation according to standard Lilly policy.  Study sites will receive information about 
interim results ONLY if it is required for the safety of their patients. 
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 (CRFs), 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. 

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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 
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. 
 
 
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. 
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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. 
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 
 
 
 
 
 
Other Testsa 
Hepatitis B core antibodyb,d 
Hepatitis B surface antigenb,d   
 
HBV DNAb,e 
Other Tests (Local)  
Hepatitis C antibodyb,d,f 
Pregnancy test (urineg) 
HCV RNAb,d,f 
T-SPOTd or TSTd 
HIVb,d 
 
Pregnancy test (serumb,d) 
 
 
QuantiFERON-TB Gold testd  
 
 
 
 
 
 
 
 
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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 
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Bacterial 
 
Bartonellosis (disseminated disease only) 
 
Campylobacteriosis (invasive disease only) 
 
Legionellosis 
 
Listeriosis (invasive disease only) 
 
Nocardiosis 
 
Tuberculosis 
 
Nontuberculous 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) 
Anti-integrin antibodies: 
 
 
    natalizumab 
Agents depleting B or T cells (for example, rituximab, 
alemtuzumab, or visilizumab) 
Immunomodulatory medications, including oral cyclosporine, 
IV cyclosporine, tacrolimus, mycophenolate mofetil 
thalidomide, or JAK inhibitors  
Rectally administered 5-ASA therapies (enemas or 
suppositories) 
Rectally administered corticosteroids (enemas or suppositories) 
IV corticosteroids 
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Drug Class 
Guidance for Use 
Systemic corticosteroids for non-CD indications (oral or IV)  
Any biologic investigational therapy  
Any nonbiologic investigational therapy 
Interferon therapy 
Leukocyte apheresis (leukapheresis, for example, Adacolumn) 
Anti-IL-23p19 antibodies (for example, risankizumab 
[BI-655066], brazikumab [MEDI-2070], guselkumab 
[CNTO1959], tildrakizumab [MK-3222]) for any indication, 
including investigational use 
Anti-IL 12/23p40 antibodies (for example, ustekinumab) 
Bacillus Calmette-Guerin (BCG) and live attenuated vaccines  
Medicinal and recreational marijuana (includes CDB oil) 
Abbreviations:  5-ASA = 5-aminosalicylic acid; CBD = cannabidiol; CD = Crohn’s disease; IL = interleukin; 
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) 
Oral corticosteroids (prednisone ≤30 mg/day or 
equivalent, or budesonide 9 mg/day) 
Corticosteroids for non-CD indications:  
corticosteroids to treat adrenal insufficiency, as 
premedication for investigational product infusion, or 
locally administered corticosteroids (e.g., 
inhaled, intranasal, intra-articular, topical) 
Immunomodulators (for example, AZA, 6-MP, or 
methotrexate) 
CD-specific antibiotics (for example:  rifaximin, 
Cipro) 
Antidiarrheals (for example, loperamide, 
diphenoxylate with atropine) 
Non-live (killed, inactivated subunit and RNA-based) 
vaccines 
Homeopathic and alternative treatments 
Abbreviations:  5-ASA = 5-aminosalicylic acid; 6-MP = 6-mercaptopurine; AZA = azathioprine; CD = Crohn’s 
disease; IV = intravenous; RNA = ribonucleic acid. 
 
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CDAI-SF/Bristol Stool Scale (Reference to Types 6 
and 7) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
The following are descriptions of additional PRO instruments for this study, 
 
(listed in order of administration): 
 
 
 
 
 
 
CDAI- (SF, AP, and general well-being):  CDAI is an 8-item disease activity measure that 
includes 3 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 = lightly under par, 2 = poor, 3 = very poor, 4 = terrible).  Patients will be provided with an 
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eDiary tool during screening to record information daily pertaining to their abdominal pain, 
frequency of liquid or very soft stools, and well-being. 
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, patients will be referred to the Bristol Stool Scale Category 6 
and/or 7, that is liquid or watery stool.  Patients will be provided with an eDiary tool during 
screening to record information daily pertaining to their frequency/count of liquid or very soft 
stools. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.10. 
Appendix 10:  Contraceptive Guidance and Collection of Pregnancy 
Information 
 
Females who are infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as Mullerian agenesis 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Collection of Pregnancy Information 
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10.11. Appendix 11:  Definitions and Selected Abbreviations 
Term 
Definition 
5-ASA 
aminosalicylic acid 
6-MP 
6-mercaptopurine 
AA 
age adjusted 
AAULN 
age-adjusted upper limit of normal 
ADA 
anti-drug antibodies 
ADR 
adverse drug reactions 
AE 
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
AESI 
adverse 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.   
AIDS 
acquired immune deficiency syndrome 
ALP 
alkaline phosphate 
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-Guerin 
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. 
Cavg 
average concentration 
CBD 
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Term 
Definition 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CDAI-AP 
Crohn’s Disease Activity Index-Abdominal Pain 
CDAI-SF 
Crohn’s Disease Activity Index-Stool Frequency 
CDAI-well-being 
Crohn’s Disease Activity Index-Well-Being 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CI 
confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
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. 
CRF 
case report form 
 
 
CT 
computed tomography 
CXR 
chest X-ray 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
 
 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
 
 
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. 
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Term 
Definition 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ERB 
ethical review board 
ETV 
early termination visit 
GCP 
good clinical practice 
GMP 
good manufacturing practices 
HBsAg 
hepatitis b surface antigen 
HBsAg+ 
positive for hepatitis b surface antigen 
HBsAg- 
negative for hepatitis b surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
 
 
 
 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Conference for Harmonisation 
IEC 
Independent Ethics Committee 
IGRA 
interferon—γ release assay 
IL-12 
interleukin-12 
IL-23 
interleukin-23 
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. 
INR 
international normalized ratio 
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. 
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Term 
Definition 
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.” 
IRB 
Institutional Review Boards/Investigational Review boards 
ITT 
intent-to-treat 
IV 
intravenous 
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 
mITT 
modified intent-to-treat 
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 
 
 
 
 
 
 
PK 
pharmacokinetics 
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Term 
Definition 
PRO 
patient-reported outcomes 
PT 
preferred term 
 
 
 
 
 
 
 
 
 
 
SAC 
statistical analysis center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.   
SES-CD  
Simple Endoscopic Score for Crohn’s Disease 
SF 
stool frequency 
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 
SUSARs 
suspected unexpected serious adverse reactions 
TB 
tuberculosis 
TBL 
total bilirubin level 
TE-ADA+ 
treatment-emergent anti-drug antibodies 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. 
TST 
tuberculin skin test 
UC 
ulcerative colitis 
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Term 
Definition 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
 
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10.12. Appendix 12:  Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
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 
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. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  After approval by local Ethical Review 
Boards, regulatory bodies, and any other relevant local authorities, implementation of these 
exceptional circumstance changes will not typically require additional notification to these 
groups, unless they have specific conditions in which notification is required.  To protect the 
safety of study participants, urgent changes may be implemented before approval but need to be 
reported as soon as possible.  All approvals must be retained in the study records.   
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants.  
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.   
Informed consent 
Additional consent from the participant and legal guardian will be obtained, if required, for: 
• 
participation in remote visits, as defined in Section “Remote visits,” 
• 
a change in the method of study intervention administration,   
• 
alternate delivery of study intervention and ancillary supplies, and 
• 
provision of their personal or medical information required prior to implementation of 
these activities.   
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.  Further, the flexibilities outlined may not be available in each site 
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The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Regardless of the type of remote visits implemented, the protocol requirements regarding 
the reporting of AEs, SAEs, and product complaints remain unchanged.  Furthermore, 
every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Telemedicine:  
Telephone or technology-assisted virtual visits, or both, are acceptable to complete 
appropriate assessments.  Assessments to be completed in this manner include, but are 
not limited to:  
• 
Concomitant medication reviews  
• 
Tobacco/nicotine use 
• 
AE reviews 
• 
 
• 
Questionnaire administration  
o 
 
 
• 
Product complaint (if applicable) 
• 
Verification of negative pregnancy test (if applicable) 
• 
Status/observation of self-administration/caregiver administration of IP where applicable 
Mobile healthcare:  
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor.  Procedures performed at 
such visits include, but are not limited to:  
• 
Informed consent  
• 
Concomitant medication reviews 
• 
Tobacco/nicotine use 
• 
Adverse event collection 
• 
Vital signs (temperature, pulse rate, blood pressure), weight 
• 
Laboratory assessments (including stool collections)   
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• 
  
• 
Questionnaire administration (Must be collected by site via Telemedicine, see section 
above) 
• 
Dosing (SC only) 
• 
 
• 
Delivery of required ancillary supplies 
 
 
• 
Urine pregnancy test (as applicable) 
The below may be performed by qualified personnel approved by the sponsor:  
• 
Physical exam  
• 
EIMs  
• 
Fistula evaluation  
• 
Clinician CDAI 
 
• 
TB Monitoring 
Other alternative locations:   
The sponsor should be made aware of temporary site relocations as soon as possible.  Alternate 
locations for study conduct must be approved for appropriateness considering participant privacy 
and participant/site staff safety.    
• 
Study visits or assessments may be done at an alternate location under exceptional 
circumstances, if allowed by local authorities.  Procedures that may be done at an alternate 
location in exceptional circumstances, are:  Temporary Site Relocation:  In instances where 
temporary relocation to another facility is required, sites may continue to perform all procedures 
as feasible.  This will include utilizing alternate endoscopy suites and performing central 
laboratory collection, infusion of investigational agent, or subcutaneous injection of 
investigational agent by a trained healthcare professional.   
• 
Alternate facilities for central laboratory collection:  Where available, participants may 
utilize laboratory facilities affiliated with the studies central laboratory vendor to conduct testing 
closer to their home.   
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing.  However, central 
laboratory testing must be retained for: 
 
 
 
.  The 
local laboratory must be qualified in accordance with applicable local regulations. 
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• 
Investigators must document their review of each laboratory safety report and retain in 
the source documentation.  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. 
• 
Laboratory testing may be performed centrally or locally based on logistics related 
sample stability and feasibility to collect at alternate location.  Local laboratory collections will 
be used for immediate patient management and safety but will not be included in the data for 
analysis. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions.  These actions may 
include:   
• 
asking the participant/legal guardian to go to the site and receive study supplies from site 
staff without completion of a full study visit,  
• 
asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf,  
• 
arranging delivery of study supplies, and 
• 
working with the sponsor to determine how study intervention that is typically 
administered on site will be administered to the participant; for example, during a mobile 
healthcare visit, at an alternate location such as an infusion center, 
 
. 
o Dosing can proceed only if central or local safety labs have been performed 
 (or within a shorter timeframe for participants with previous 
abnormal lab results, as medically indicated) prior to dosing, and lab results do 
not require study drug discontinuation or temporary interruption.   
o For participants who have had abnormal laboratory values at a prior lab 
collection, the investigator may ask the participant to have local or central labs 
obtained to confirm that protocol requirements for IP administration are met. 
o Any clinically significant laboratory abnormality should be discussed with the 
medical monitor before at-home administration can proceed. 
These requirements must be met before action is taken: 
• 
Alternate delivery of study intervention should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity.  The existing protocol 
requirements for product accountability remain unchanged, including verification of participant’s 
receipt of study supplies. 
• 
When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the shipping 
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process to ensure accountability and product quality (that is, storage conditions maintained and 
intact packaging upon receipt). 
• 
Instructions may be provided to the participant or designee on the final disposition of any 
unused or completed study supplies. 
In addition, if study intervention will be administered to the participant during a mobile 
healthcare visit or at an alternate location, these additional requirements must be met:  
• 
Only authorized study personnel may supply, prepare, or administer study intervention. 
• 
If IV administration occurs at an alternate location, resuscitation equipment, emergency 
medications, and appropriately trained staff must be available during the infusion and monitoring 
period.  All participants should be monitored for 
 or longer after IV dosing, according to 
investigator practice or local standard of care.   
• 
Adherence to the detailed instructions for IP administration, including infusion rate and 
SC injections provided by the sponsor must continue to be followed.  Maintaining accurate 
records of study drug dispensing and collection.  Site staff will document the IP package 
numbers that are dispensed 
 
. 
o 
 
o 
 
  
• 
 
• 
 
 
Concomitant Therapy 
Steroid Tapering:  The PI should use clinical judgement of the benefit/risk of tapering for each 
individual subject and consider Gastrointestinal Society guidance, to determine if corticosteroid 
dosage adjustment is indicated for their participants during the exceptional circumstances.  If the 
investigator believes steroid tapering is in the best interest of the participant,
 
.   
Use of prohibited medications in exceptional circumstances may not result in discontinuation.  
Please consult your medical monitor. 
Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at the screening visit are valid for a maximum of 
  The following rules will be 
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applied for active, nonrandomized participants whose participation in the study must be paused 
due to exceptional circumstances: 
• 
Due to exceptional circumstances, a maximum of 
 can be allowed from the time 
of the endoscopy to the time of the randomization 
 
 
. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay in the source 
documentation. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent/legal guardian consent and document this confirmation in 
the source documentation. 
• 
No extensions of greater than 
 from endoscopy to randomization and/or a total 
screening window of greater than 
 will be allowed.  If either or both 
timeframes are exceeded:  The participant must be discontinued because of screening 
interruption due to an exceptional circumstance.  This is documented as a screen failure in the 
CRF.  This screen fail is allowed in addition to the main protocol screen fail.  The participant can 
reconsent and be rescreened as a new participant.  The screening procedures per the usual SoA 
should be followed, starting at the screening visit to ensure participant eligibility by the 
randomization visit.  Prior to rescreening, the PI should feel confident that the exceptional 
circumstance will no longer prohibit collection of assessments and procedures per protocol.  The 
medical monitor may be consulted if needed regarding the decision to move forward with 
rescreening. 
Adjustments to Visit Windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA.  To maximize the possibility that these visits can be conducted 
as on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor.  
This minimizes missing data and preserves the intended conduct of the study. 
IP dosing: 
There are no plans for an increase in number of IP doses or increase in exposure to IP.   
In order for IP to be administered, the following must be done at a minimum and in compliance 
with the protocol requirements:  
• 
Urine pregnancy test complete with negative result 
• 
Review of AEs 
• 
Review of concomitant medications 
• 
Review of previous labs obtained 
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• 
Safety labs must have been obtained and reviewed 
.  
Collections may utilize either local or central labs. 
• 
Follow the protocol regarding administration of IP, including temporary holding of IP for 
safety issues as per protocol 
There must be a minimum of 
 between IP doses.   
The following describes the allowed adjustments to visit windows.  See Table 1 for additional 
details.   
Visits 1 through 10, Visits 12, 14, 16, and 17  
• 
We will allow the visit window to extend to the beginning of the next window.  If the 
participant visit exceeds the extended window, the visit procedures and dosing must occur at the 
earliest opportunity.  
.   
• 
Timeframes for future participant visits must be adjusted to bring the participant back 
into compliance with the protocol defined visit windows.   
• 
Study drug dosing must occur at least 
 apart and a urine pregnancy test (if 
applicable) must be obtained prior to IP administration.   
• 
See Visits 7 and 17 below for further details. 
• 
The overall length of exposure will not be extended for this trial. 
Visits 11, 13, and 15 
• 
Per protocol, dosing visits occur every 
.  We will allow the visit window to 
extend to the beginning of the next window.   
• 
If the participant visit exceeds the extended visit window, the visit procedures and dosing 
will be considered missed, and the participant will proceed to the next visit.   
• 
Study drug dosing must occur at least 
 apart, and a urine pregnancy test (if 
applicable) must be obtained prior to IP administration. 
• 
The overall length of exposure will not be extended for this trial. 
• 
NOTE:  Per protocol, participants who miss 
 doses must be considered for 
early termination.   
Visit 7  
Endoscopy, study assessments, and nonresponder evaluation 
Visit 7 procedures should occur within the extended window if possible. 
• 
 
 
 
• 
Sites should remind patients to
. 
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Nonresponder evaluation: 
 slate information should continue to be collected in order to review response status 
to assess corticosteroid tapering timing. 
• 
Sites will still need to enter Visit 7 date (Week 12) on the slate.  The date of Visit 7 can 
be entered in the slate prior to the next visit, regardless of when the next visit occurs, if needed.   
Visit 17 
Visit 17 procedures should occur within the extended window if possible. 
• 
 
 
 
 
 
• 
 
Post-treatment Follow-up Visits 801 and 802 
• 
Visit 801:  Visit window may be extended up to
 
 
• 
Visit 802:  Visit window may be extended up to 
 
 
  If additional time is required, a discussion with the sponsor should take place. 
Documentation 
Changes to study conduct will be documented: 
• 
Sites will identify and document the details of how participants, visit types, and 
conducted activities were affected by exceptional circumstances.  Dispensing/shipment records 
of study intervention and relevant communications, including delegation, should be filed with 
site study records. 
• 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.   
The table below describes the mitigations to allow for expanded visit windows during 
exceptional circumstances.  See the section Adjustments to Visit Windows for further details.  
There must be a minimum of 
 between study drug doses. 
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Table 1 
Extended Visit Windows for Exceptional Circumstances 
Study Visit 
(Week)a 
Protocol 
Specified  
Day 
Protocol 
Specified Visit 
Interval 
Tolerance 
Mitigation 
Extension of Visit 
Interval Tolerance 
Mitigation 
Study Day 
Rangeb 
Endoscopy Evaluation  
Other Assessments 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
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Study Visit 
(Week)a 
Protocol 
Specified  
Day 
Protocol 
Specified Visit 
Interval 
Tolerance 
Mitigation 
Extension of Visit 
Interval Tolerance 
Mitigation 
Study Day 
Rangeb 
Endoscopy Evaluation  
Other Assessments 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
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Study Visit 
(Week)a 
Protocol 
Specified  
Day 
Protocol 
Specified Visit 
Interval 
Tolerance 
Mitigation 
Extension of Visit 
Interval Tolerance 
Mitigation 
Study Day 
Rangeb 
Endoscopy Evaluation  
Other Assessments 
801 
802 CCI
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10.13. Appendix 13:  Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 15.1:  15-Jan-2021 
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 
1.2 Schema 
 
Updated Schema. 
 
Dosing information was 
added. 
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). 
 
Changed Visit 5 to a phone visit. 
 
 
 
 
 
 
 
 
Updated list of abbreviations. 
 
Updated to reflect all 
assessments that may be 
collected at the discretion 
of the investigator at 
scheduled or unscheduled 
visits. 
 
Aim to avoid risk of an 
unnecessary visit to the 
site during the coronavirus 
disease 2019 pandemic, 
and as participants do not 
receive study drug at 
Visit 5, on-site 
assessments are not 
required. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Footnote g:  Modified text. 
 
 
 
 
Footnote k: Modified text. 
 
 
 
 
 
 
Footnote q:  Modified text. 
 
 
 
 
Footnote x:  Modified text. 
 
 
 
 
Footnote y:  Modified text. 
 
 
 
 
 
Footnote z:  Modified text. 
 
 
 
 
Footnote aa:  Added. 
 
Computed tomography 
(CT) scan can be 
performed as an alternative 
to the chest x-ray (CXR). 
 
Tuberculin skin tests 
(TST) are to be read by a 
qualified professional 48 
to -72 hours after 
placement with results 
noted in source 
documentation. 
 
Clarified collection of 
stool sample prior to 
endoscopy and visits 
where endoscopy is not 
scheduled to be performed. 
 
Optional testing may be 
performed during 
unscheduled visits at the 
discretion of the 
investigator. 
 
Clarification that CT scan 
can be performed as an 
alternative to the CXR 
based on regional standard 
of practice. 
 
Unscheduled assessments 
may be performed at the 
discretion of the 
investigator. 
 
For consistency with adult 
protocol. 
2.2.5 Preclinical and 
Clinical Studies of 
Mirikizumab 
 
Updated text describing clinical 
studies in Crohn’s disease. 
 
For consistency with adult 
protocol. 
2.3 
Benefit/Risk 
Assessment 
 
Reworded the information on 
selection criteria with respect to 
age and weight. 
 
Updated additional text. 
 
Reworded text to improve 
clarity. 
 
 
For consistency with adult 
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Section # and Name 
Description of Change 
Brief Rationale 
3.  Objectives and 
endpoints 
 
Additional and updated secondary 
endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised objective regarding 
safety and tolerability of 
mirikizumab treatment from 
evaluation of to description of. 
 
Revised endpoint regarding 
tolerability and acceptability of 
SC injection volumes to indicate 
that it is descriptive. 
 
For all:  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For both, clarification. 
4.1 Overall Design 
 
Modified text to note that placebo 
nonresponders (NRs) are used as 
the comparator. 
 
To align with statistical 
analysis plan (SAP). 
4.3 Justification for Dose 
 
Revised information on safety 
considerations to reflect current 
information from completed and 
ongoing clinical studies.   
 
To reflect the safety data 
collected from AMAG, 
AMAA, AMAD, AMAF, 
and AMAC studies. 
5.1 Inclusion Criteria 
 
Criterion [8a]:  Updated text 
 
Improved clarity relative 
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Section # and Name 
Description of Change 
Brief Rationale 
relative to conventional-failure: 
prior budesonide use, dose change 
for methotrexate (MTX) – from 
25 mg to at least 15 mg, and oral 
MTX use. 
to prior budesonide and 
MTX use. 
5.2 Exclusion Criteria 
 
Criterion [19e]: 
 
 
   
 
Criterion [19j]:  Updated text 
relative to discontinuing 
interferon therapy from prior to 
baseline endoscopy to screening 
endoscopy. 
 
Criterion [21]:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criterion [22]:  Removed text 
allowing oral and intravenous 
(IV) corticosteroids as 
premedication in patients with 
prior investigational product or 
other previous biologic injection 
reactions from criterion for 
discontinuing prohibited 
medications. 
 
Criterion [47]:  Updated text 
regarding delivery of parenteral 
nutrition. 
 
 
For consistency with 
pediatric program. 
 
For consistency with adult 
protocol language. 
 
 
 
 
For consistency with adult 
protocol language. 
 
 
 
 
Timeframe extended to 
to rule out 
participants not responding 
to ustekinumab. 
 
 
 
For consistency with adult 
protocol language. 
 
 
 
 
 
 
 
Parenteral and enteral 
nutrition as primary source 
of diet is excluded due to 
potential to confound 
efficacy assessments. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 
Criterion [48]: 
 
 
 
(Prohibited Medications) 
accordingly. 
 
 
 
 
 
 
 
 
5.4 Screen Failures 
 
Removed restriction of only 
1 rescreening permitted for entry 
Criteria [4], [5], and [6]. 
 
 
 
 
 
Criterion [22]:  Specified that 
rescreening is allowed if a 
participant is no longer receiving 
steroids and has met washout 
criteria. 
 
 
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. 
 
Added Criterion [43].  
 
Added Criterion [48] to list of 
entry criteria with allowance for 
rescreening provided participant 
 
 
Updated text to specify 
assessments that will not be 
repeated at rescreening for 
patients who screen fail due to 
inability to complete endoscopy 
prior to Visit 2.   
 
Criteria [4], [5], and [6]:  
To permit flexibility for 
multiple rescreening.  
Crohn’s disease (CD) 
activity can change over 
time; thus, participants 
may qualify upon 
rescreening. 
 
Criterion [22]:  Improve 
clarity.   
 
 
 
 
Criterion [28]:  Added for 
consistency and clarity per 
questions that have come 
up in live AMAM trial 
regarding ova parasite. 
 
 
 
Added for consistency 
with adult protocol. 
 
Criterion [48]:  
 
 
 
Participants may avoid 
CT, human 
immunodeficiency virus 
(HIV), hepatitis B virus 
(HBV), and hepatitis C 
virus (HCV) retest within 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
Modified text disallowing 
rescreening:   
Now allow rescreening for 
Criteria [22] and [43]. 
Disallow rescreening for 
Criterion [21]. 
a 
 timeframe 
provided there are no risk 
factors or signs/symptoms.  
 
 
Non-CD treatment can 
change. 
 
Added for consistency 
with adult protocol. 
6.5.1 Permitted Therapy 
 
Renamed from Concomitant 
Therapy to Permitted Therapy 
added text to include dose 
stabilization 
 for 
corticosteroids. 
 
Correction/clarification. 
6.5.2 Prohibited Therapy 
 
Added exceptions to prohibited 
CD medications, 
 
 
  
 
 
 
Allow more flexibility to 
prevent unnecessary 
discontinuation. 
7.1.1 Criteria for 
Permanent 
Discontinuation of Study 
Drug 
 
 
 
 
Correct prior inadvertent 
errors in original protocol.   
7.1.2 Criteria for 
Temporary Interruption 
(Withholding) of Study 
Drug 
 
 
 
   
 
Improve clarity and 
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.   
 
Clarification/correction. 
8.1.2.3 Patient Reported 
Outcomes 
 
 
 
 
Correction to be consistent 
with Section 10.8. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.5 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 Stool testing 
 
Modified the conditions for 
rescreening of participants who 
have a “positive” stool culture 
result: 
Added that repeat central C. difficile 
toxin lab should be negative. 
Removed
 
 or 
since resolution of acute symptoms 
and signs.  
 
For all, to simplify 
criteria. 
8.2.7 Tuberculosis 
Testing 
 
Clarified that CT scan can be 
performed as an alternative to the 
CXR. 
 
Revised text to remove that 
patients with 2 indeterminate 
QuantiFERON-TB Gold assays 
or 2 borderline T-SPOT assays 
will be excluded, and added that 
if the TST test and CXR are both 
negative, the participant may 
enroll. 
 
For both, clarification and 
consistency with 
Section 8.2.5. 
8.2.8.1 Pregnancy 
Testing 
 
Revised text to replace women 
with female patients, and deleted 
women of childbearing potential.   
 
Align with the adolescent 
study population.   
8.2.8.2 Immunogenicity 
Assessment 
 
 
 
 
Gives more freedom; 
aligns with current/future 
analysis approach. 
8.3.5 Pregnancy 
Reporting 
 
Pregnancy details will be 
collected through 
 
 
Clarification/correction. 
8.7.1 Whole Blood 
Sample for 
Pharmacogenetic 
Research 
 
 
 
 
Clarification/correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
[WWW]) that may be tested. 
8.8 Exploratory 
Biomarkers 
 
Modified the section title. 
 
Improve accuracy. 
9.2 Sample Size 
Determination 
 
Updated wording on sample size. 
 
Clarification/correction. 
9.4.1.2 Estimand 
 
Deleted and reworded text 
because adolescent patients will 
not be randomized to placebo and 
updated composite approach 
when patients will be considered 
nonresponders. 
 
Correcting an error in the 
original document. 
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. 
 
Added text relative to handling of 
concomitant CD medications and 
noted specifics will be provided in 
the SAP. 
 
Revision to plan for 
missing data imputation. 
 
 
 
 
Revision to plan for 
missing data imputation. 
9.4.6 Evaluation of 
Immunogenicity 
 
 
 
 
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 
nonexploratory 
biomarkers. 
Section 10.6 Appendix 6:  
Prohibited Medications 
 
Revised heading for Column 2 of 
table. 
 
 
 
 
Added text to include information 
on IV corticosteroid used for CD 
that may result in discontinuation. 
 
Revised guidance for use of 
systemic corticosteroids for 
 
For consistency with adult 
protocol. 
 
For consistency with adult 
protocol. 
 
 
 
Allow medical discretion 
to prevent unnecessary 
discontinuation. 
 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
non-CD indications. 
 
Added information about any 
nonbiologic investigational 
therapy. 
 
Revised text regarding anti-IL-
23p19 antibodies. 
 
 
 
 
 
 
 
 
Updated abbreviations list.   
 
 
Clarification. 
 
 
 
 
For consistency with adult 
protocol. 
 
 
 
 
 
 
 
 
To include new additions. 
Section 10.7 Appendix 7:  
Permitted Medications  
 
Revised table title and revised 
table column header for 
Column 2. 
 
Revised guidance for use for oral 
aminosalicylic acids (5-ASAs) 
and CD-specific antibiotics, oral 
corticosteroid stabilization, and 
updated type of permitted 
vaccines. 
 
To align with development 
program. 
 
 
For consistency with adult 
protocol. 
Section 10.10 Appendix 
10  Contraceptive 
Guidance and Collection 
of Pregnancy Information 
 
Revised text. 
 
Clarification. 
Section 10.11 
Appendix 11:  
Definitions and Selected 
Abbreviations 
 
Updated the list. 
 
To include new additions. 
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. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
 
Minor typographical corrections, 
clarifications, or semantic 
changes. 
 
Changes do not affect 
content. 
 

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