A Phase 2, Multicenter, Randomized, Parallel-Arm, Placebo-Controlled Study of LY3074828 in Subjects With Active Crohn's Disease (SERENITY)
Phase: PHASE2
Conditions: Crohn's Disease
Sponsor: Eli Lilly and Company

Protocol I6T-MC-AMAG(b) 
 
A Phase 2, Multicenter, Randomized, Parallel-Arm, Placebo-Controlled Study of LY3074828 in 
Subjects with Active Crohn’s Disease (SERENITY) 
 
NCT02891226 
 
Approval Date: 11-July-2018 
 
 

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Protocol I6T-MC-AMAG(b)
A Phase 2, Multicenter, Randomized, Parallel-Arm, 
Placebo-Controlled Study of LY3074828 in Subjects with 
Active Crohn’s Disease (SERENITY)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
mirikizumab (LY3074828), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Mirikizumab (LY3074828)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 21 July 2016
Amendment (a) Electronically Signed and Approved by Lilly:  21 November 2017
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 11-Jul-2018 GMT

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Table of Contents
Section
Page
Protocol I6T-MC-AMAG(b) A Phase 2, Multicenter, Randomized, 
Parallel-Arm, Placebo-Controlled Study of LY3074828 in Subjects 
with Active Crohn’s Disease (SERENITY).........................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................26
3.1.
Study Rationale............................................................................................................26
3.2.
Background..................................................................................................................26
3.3.
Benefit/Risk Assessment..............................................................................................27
4.
Objectives and Endpoints..................................................................................................28
5.
Study Design.....................................................................................................................31
5.1.
Overall Design .............................................................................................................31
5.2.
Number of Participants.................................................................................................32
5.3.
End of Study Definition ...............................................................................................32
5.4.
Scientific Rationale for Study Design...........................................................................33
5.5.
Justification for Dose ...................................................................................................33
6.
Study Population...............................................................................................................35
6.1.
Inclusion Criteria..........................................................................................................35
6.2.
Exclusion Criteria ........................................................................................................37
6.3.
Lifestyle Restrictions....................................................................................................40
6.4.
Screen Failures.............................................................................................................40
7.
Treatments........................................................................................................................41
7.1.
Treatments Administered .............................................................................................41
7.1.1.
Packaging and Labeling .......................................................................................42
7.2.
Method of Treatment Assignment ................................................................................42
7.2.1.
Selection and Timing of Doses.............................................................................43
7.3.
Blinding .......................................................................................................................43
7.4.
Dosage Modification....................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Medications.............................................................................................44
7.8.
Treatment after the End of the Study............................................................................45
7.8.1.
Continued Access.................................................................................................45

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7.8.2.
Special Treatment Considerations ........................................................................45
7.8.2.1.
Premedication for Infusions............................................................................45
7.8.2.2.
Management of Hypersensitivity Events, Fever 
Associated Reactions, and Infusion/Injection Site 
Reactions........................................................................................................45
8.
Discontinuation Criteria ....................................................................................................48
8.1.
Discontinuation from Study Treatment.........................................................................48
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................48
8.1.2.
Discontinuation of Inadvertently Enrolled Subjects..............................................48
8.2.
Discontinuation from the Study....................................................................................48
8.3.
Lost to Follow-Up........................................................................................................49
9.
Study Assessments and Procedures ...................................................................................50
9.1.
Efficacy Assessments...................................................................................................50
9.1.1.
Primary Efficacy Assessments .............................................................................50
9.1.2.
Secondary Efficacy Assessments..........................................................................50
9.1.3.
Subject Diary .......................................................................................................50
9.1.4.
Endoscopy ...........................................................................................................51
9.1.5.
Other Assessments...............................................................................................52
9.1.6.
Appropriateness of Assessments ..........................................................................52
9.2.
Health Outcomes/Quality of Life..................................................................................52
9.3.
Adverse Events ............................................................................................................54
9.3.1.
Serious Adverse Events........................................................................................55
9.3.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................56
9.3.2.
Complaint Handling.............................................................................................56
9.4.
Treatment of Overdose.................................................................................................56
9.5.
Safety...........................................................................................................................56
9.5.1.
Electrocardiograms ..............................................................................................56
9.5.2.
Vital Signs ...........................................................................................................56
9.5.3.
Laboratory Tests ..................................................................................................57
9.5.4.
Other Tests...........................................................................................................57
9.5.4.1.
Chest Radiography and Tuberculosis Testing..................................................57
9.5.5.
Safety Monitoring ................................................................................................58
9.6.
Pharmacokinetics .........................................................................................................59
9.7.
Pharmacodynamics ......................................................................................................59
CCI

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10.
Statistical Considerations ..................................................................................................62
10.1. Sample Size Determination ..........................................................................................62
10.2. Populations for Analyses..............................................................................................62
10.3. Statistical Analyses ......................................................................................................62
10.3.1.
General Statistical Considerations ........................................................................62
10.3.1.1.
Analysis of Populations ..................................................................................63
10.3.1.2.
Missing Data Imputation ................................................................................63
10.3.1.3.
Adjustment for Multiple Comparisons ............................................................64
10.3.2.
Treatment Group Comparability...........................................................................64
10.3.2.1.
Patient Disposition..........................................................................................64
10.3.2.2.
Patient Characteristics ....................................................................................64
10.3.2.3.
Concomitant Therapy .....................................................................................64
10.3.2.4.
Treatment Compliance....................................................................................64
10.3.3.
Efficacy Analyses ................................................................................................65
10.3.3.1.
Primary Efficacy Analyses .............................................................................65
10.3.3.2.
Secondary Efficacy Analyses..........................................................................65
10.3.3.3.
Health Outcomes/Quality-of-Life Analyses ....................................................65
10.3.3.4.
Exploratory Efficacy Analyses........................................................................65
10.3.4.
Safety Analyses....................................................................................................66
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................67
10.3.6.
Other Analyses.....................................................................................................68
10.3.6.1.
Subgroup Analyses.........................................................................................68
10.3.7.
Interim Analyses..................................................................................................68
11.
References ........................................................................................................................69
12.
Appendices .......................................................................................................................71
CCI

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List of Tables
Table
Page
Table AMAG.1. Objectives and Endpoints...............................................................................28
Table AMAG.2. Margin of Safety for LY3074828 Based on Administered Dose and 
Predicted Exposure........................................................................................34
Table AMAG.3. Treatment Regimens......................................................................................41
Table AMAG.4. Permitted Concomitant Therapies for Crohn’s Disease ..................................44

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List of Figures
Figure
Page
Figure AMAG.1. Illustration of study design for Clinical Protocol I6T-MC-AMAG. ................32

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................72
Appendix 2.
Clinical Laboratory Tests...............................................................................76
Appendix 3.
Study Governance Considerations..................................................................78
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................82
Appendix 5.
Histologic Grading Indices ............................................................................83
Appendix 6.
Additional Information on Systemic Drug Administration Reactions .............84
Appendix 7.
Protocol Amendment I6T MC AMAG(b) Summary:  A Phase 2, 
Multicenter, Randomized, Parallel-Arm, Placebo-Controlled Study of 
LY3074828 in Subjects with Active Crohn’s Disease (SERENITY)..............85

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1. Synopsis
Title of Study:
A Phase 2, Multicenter, Randomized, Parallel-Arm, Placebo-Controlled Study of LY3074828 in Subjects with 
Active Crohn’s Disease
Rationale: 
Study I6T-MC-AMAG (AMAG) is a Phase 2 study designed to determine whether LY3074828, a humanized 
immunoglobulin G4 (IgG4)–variant monoclonal antibody that binds to the p19 subunit of interleukin 23 (IL-23), is 
safe and efficacious in subjects with moderate to severe Crohn’s disease.  This study will help evaluate safety and 
determine the clinical activity defined by improvement in Crohn’s disease activity measures and key 
patient-reported outcomes (PRO) measures.
Objectives/Endpoints:
Objectives
Endpoints
Primary

To test the hypothesis that treatment with LY3074828 is 
superior to placebo in the proportion of subjects with 
endoscopic response at Week 12, defined as 50% reduction 
from baseline in SES-CD Score

Proportion of subjects achieving 
endoscopic response at Week 12
Secondary 

To evaluate the safety and tolerability of treatment with 
LY3074828

To evaluate the effect of LY3074828 on the proportion of 
subjects with endoscopic response at Week 52, defined as 
50% reduction from baseline in SES-CD score

To evaluate the efficacy of treatment with LY3074828 as 
superior to placebo in  endoscopic remission (defined as an 
SES-CD score of <4 ileal-colonic or <2 for isolated ileal 
disease, and no subscore >1) at Week 12

To evaluate the effect of LY3074828 on the proportion of 
subjects with endoscopic remission (defined as an SES-CD 
score of <4 ileal-colonic or <2 for isolated ileal disease, 
and no subscore >1) at Week 52

To evaluate the efficacy of treatment with LY3074828 as 
superior to placebo in PRO remission (defined as SF ≤2.5 
and AP ≤1) at Week 12

To evaluate the effect of LY3074828 on the proportion of 
subjects with PRO remission (defined as SF ≤2.5 and AP 
≤1) at Week 52

To evaluate the effect of LY3074828 on health 
outcomes/quality-of-life measures (including:  PGRS 
score, PGRC score, IBDQ score, SF-36 score, and 
FACIT-Fatigue) at Weeks 12 and 52

To characterize the PK of LY3074828

AEs and discontinuation rates; mean 
change vital signs; laboratory values

Proportion of subjects achieving 
endoscopic response at Week 52

Proportion of subjects achieving 
endoscopic remission at Week 12  

Proportion of subjects achieving 
endoscopic remission at Week 52  

Proportion of subjects achieving 
PRO remission at Week 12

Proportion of subjects achieving 
PRO remission at Week 52

The mean change from baseline for 
PGRS score, IBDQ score,
FACIT-Fatigue, and SF-36, and the 
mean PGRC at Weeks 12 and 52

Clearance and volume of distribution

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Abbreviations:  AE = adverse event; AP = abdominal pain; FACIT-Fatigue = Functional Assessment of Chronic 
Illness Therapy–Fatigue; IBDQ = Inflammatory Bowel Disease Questionnaire; PGRC = Patient’s Global Rating 
of Change; PGRS = Patient’s Global Rating of Severity; PK = pharmacokinetics; PRO = patient-reported 
outcomes; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF-36 = Medical 
Outcomes Study 36-Item Short Form Health Survey.
Summary of Study Design:  
Study AMAG is a multicenter, randomized, parallel-arm, placebo-controlled trial in which approximately 
180 subjects will be randomized.  All subjects in the study will have had loss of response or intolerance to 
conventional medication used to treat Crohn’s disease.  
Study Periods:
Screening (Approximately 4 Weeks): Subjects will be evaluated for study eligibility ≤28 days before the baseline 
visit.
Period 1 (Weeks 0 to 12):  A 12-week dosing period is designed to evaluate the efficacy and safety of LY3074828 
administered intravenously (IV) at Weeks 0, 4, 8.  At baseline, subjects will be randomized with a 2:1:1:2 allocation 
across the 4 treatment arms (1000, 600, 200 mg LY3074828, and placebo) and stratified on the basis of previous 
exposure to biologic therapy for treatment of Crohn’s disease.
Period 2 (Weeks 12 to 52): Patients will receive both intravenous (IV) and subcutaneous (SC) dosing to maintain 
blinding from Weeks 12 through 48.  All patients who received LY3074828 treatment in Period 1 and who achieved 
an improvement in their Simple Endoscopic Score for Crohn’s Disease (SES-CD) score from baseline at Week 12 
(determined by the central reader) will be randomized evenly to either (i) continue Period 1 treatment assignment 
(IV LY3074828 1000 mg, 600 mg, or 200 mg every 4 weeks [Q4W]) with placebo administered subcutaneously 
Q4W OR (ii) IV placebo Q4W with SC LY3074828 300 mg Q4W.
All patients who received LY3074828 treatment in Period 1 and who did not achieve an improvement from baseline 
SES-CD score at Week 12 will receive IV LY3074828 1000 mg and SC placebo Q4W.
All patients who received placebo in Period 1 will receive IV LY3074828 1000 mg and SC placebo Q4W. 
Randomization will be stratified based on endoscopic response (i.e. achieving a 50% reduction in SES-CD score 
from baseline).

Period 3 (Weeks 52 to 104):  All subjects having clinical benefit per investigator and continuing on study 
treatment may proceed to Period 3 and receive 300 mg SC LY3074828 Q4W open-label starting at Week 52 
through Week 104. Patients not receiving clinical benefit at Week 52 will discontinue treatment and will enter 
the Follow-Up period.
Follow-Up (Weeks 104 to 120):  At Week 104, subjects will stop treatment and be followed for safety for an 
additional 16 weeks.
Number of Subjects:
Approximately 180 subjects will be randomized.

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Statistical Analysis:
The primary endpoint is Week 12 endoscopic response rate (defined as a 50% reduction in SES-CD).  For 
endoscopic response, the assumed LY3074828 and placebo rates are 35% and 15%, respectively. 
Treatment comparisons of the primary endpoint and other categorical efficacy variables will be conducted using a 
logistic regression analysis with treatment, geographic region, and prior biologic Crohn’s disease therapy use 
(yes/no) in the model.  Unless otherwise specified, efficacy and health outcomes analyses will be conducted on the 
intent-to-treat population (ITT).

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2. Schedule of Activities
Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
Obtain Informed 
Consent
X
Physical 
Examination 
X
X
X
One complete physical examination (excluding 
pelvic, rectal, and breast examinations) will be 
performed at screening.  All physical examinations 
throughout the study should include a 
symptom-directed evaluation as well as 
examination of heart, lungs, and abdomen, and 
visual examination of the skin.
Height
X
Weight
X
X
X
X
X
X
X
According to standard medical practice.
Vital Signs (BP and 
HR) at all marked 
visits; body temp. 
only at V1 and V2, 
unless clinically 
indicated
X
X
X
X
X
Sitting BP and pulse, to be obtained at 
approximately the same time as ECG measurements 
or blood sampling.  When multiple assessments are 
scheduled for the same time point, the order of 
completion should be as follows:  ECG, vital signs, 
and then blood sampling.  
Preexisting 
Conditions
X
Adverse Events
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X

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Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
Randomization
X
Dosing
X
X
X
CDAI
X
X
X
X
X
X
X
Patient-reported items of CDAI (Q1–Q3) will be 
recorded daily (see Section 9.1.3).  
Clinician-reported items of CDAI (Q4–Q8) will be 
recorded at every visit (see Section 9.1.3).
X
X
X
X
X
X
X
BMC
X
X
X
X
X
X
X
Subjects will record BMC daily (as measured by 
subject diary; see Section 9.1.3).
Colonoscopy/
SES-CD
X
X
Screening colonoscopy must occur within 14 days 
of baseline, and should occur no fewer than within 
5 days of baseline.  Biopsies will be taken during 
all colonoscopy time points; instruction for 
collection will be provided in a laboratory manual. 
PGRC
X
X
PGRS
X
X
X
X
X
X
X
Subjects will record daily (as measured by subject 
diary; see Section 9.1.3).
IBDQ
X
X
X
X
SF-36 
X
X
X
X
FACIT-Fatigue
X
X
X
X
QIDS-SR16
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI

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Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
X
X
X
Chest Radiography 
(CXR)
X
Chest radiography (see Section 9.5.4.1) 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).
PPD, T-SPOT®, or 
QuantiFERON-TB 
Gold 
X
Subjects will return 2 to 3 days after Visit 1 to read 
their PPD test results.
ECG
X
X
X
This should be completed prior to any study dose 
administration or blood draw.  Subjects should be 
supine for approximately 5 to 10 minutes before 
ECG collection and remain supine but awake 
during ECG collection.
Serum Chemistry/ 
Hematology
X
X
Xb
X
Xb
X
X
Unscheduled blood chemistry and hematology 
panels may be performed at the discretion of the 
investigator.
Urinalysis
X
X
X
X
X
FSH
X
FSH test is to be performed at screening for women 
who have had spontaneous amenorrhea for 6 to 12 
months to confirm lack of child-bearing potential.
Serum Pregnancy 
Test
X
To be performed only on women of child-bearing 
potential.
CCI

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Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
Urine Pregnancy 
Test
X
X
X
To be performed only on women of child-bearing 
potential.
HIV, HBV, HCV 
Testing
X
HBV PCR
X
X
Perform only if subject was HBcAb+ with negative 
HBV PCR test at screening.
Any enrolled subject who is HBcAb+ will undergo 
monitoring of HBV PCR at specified intervals.  
Any subject with a positive HBV PCR test at any 
time must be discontinued from the study and 
receive appropriate follow-up medical care, 
including consideration for antiviral therapy.
LY3074828 PK 
Samples
Pre-dose and 
end of 
infusion
X
Pre-dose 
& end of 
infusion
X
Pre-dose 
& end of 
infusion
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be collected.
See Section 7.8.2.2.
Immunogenicity 
Samples
X
X
X
X
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be collected.
See Section 7.8.2.2.
hsCRP
X
X
X
X
CCI

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Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
Stool Samples
X
X
X
X
Xd
Supply Stool 
Collection Kit 
X
Patients need to collect stool samples up to 3 days 
prior to beginning bowel prep for endoscopy at V7 
and V18.
CCI
CCI

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Period 2 [V8–V18] Schedule of Activities
Visit Number:
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Comments
Week Relative to 
Study Drug Start
12-13
16
20
24
28
32
36
40
44
48
52
All activities should be completed prior to any 
study dose administration unless otherwise stated 
below.
Day with Visit 
Tolerance Interval
86-92
113
5
141
5
169 
5
197  
5
225  
5
253 
5
281 
5
309 
5
337 
5
365 
5
Physical 
Examination 
X
X
X
All physical examinations throughout the study 
should include a symptom-directed evaluation as 
well as examination of heart, lungs, and 
abdomen, and visual examination of the skin.
Weight
X
X
X
X
X
X
X
X
X
X
X
According to standard medical practice.
Randomization
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (BP and 
HR) at all marked 
visits; body temp. 
only at V1 and V2, 
unless clinically 
indicated
X
X
X
Sitting BP and pulse, to be obtained at 
approximately the same time as ECG 
measurements or blood sampling.  When multiple 
assessments are scheduled for the same time 
point, the order of completion should be as 
follows:  ECG, vital signs, and then blood 
sampling.  
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
Week 52 dosing begins dosing for Period 3 and is 
open label.
Colonoscopy/
SES-CD
X
Week 52 colonoscopy may occur within 12 days 
of the Week 52 visit but must occur 3 days prior 
to the visit to determine centrally read SES-CD 
score.  Biopsies will be taken during all 
colonoscopy time points; instruction for 
collection will be provided in a laboratory 
manual.

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Period 2 [V8–V18] Schedule of Activities
Visit Number:
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Comments
Week Relative to 
Study Drug Start
12-13
16
20
24
28
32
36
40
44
48
52
All activities should be completed prior to any 
study dose administration unless otherwise stated 
below.
Day with Visit 
Tolerance Interval
86-92
113
5
141
5
169 
5
197  
5
225  
5
253 
5
281 
5
309 
5
337 
5
365 
5
CDAI 
X
X
X
X
X
X
X
X
X
X
Patient-reported items of CDAI (Q1–Q3) will be 
recorded daily (see Section 9.1.3).  
Clinician-reported items of CDAI (Q4–Q8) will 
be recorded at every visit (see Section 9.1.3).
X
X
X
X
X
X
X
X
X
X
BMC
X
X
X
X
X
X
X
X
X
X
Subjects will record BMC daily (as measured by 
subject diary; see Section 9.1.3).
PGRC
X
X
X
X
X
PGRS
X
X
X
X
X
X
X
X
X
X
Subjects will record daily (as measured by 
subject diary; see Section 9.1.3).
IBDQ
X
X
X
X
X
SF-36
X
X
X
X
X
FACIT-Fatigue
X
X
X
X
X
QIDS-SR16
X
ECG
X
ECG should be completed prior to any study dose 
administration or blood draw.  Subjects should be 
supine for approximately 5 to 10 minutes before 
ECG collection and remain supine but awake 
during ECG collection.
Serum Chemistry/ 
Hematology
X
X
X
X
X
X
X
X
X
X
Unscheduled blood chemistry and hematology 
panels may be performed at the discretion of the 
investigator.
LY3074828 PK 
Samples
X
X
X
X
X
X
X
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be 
collected. See Section 7.8.2.2.
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LY3074828
Period 2 [V8–V18] Schedule of Activities
Visit Number:
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Comments
Week Relative to 
Study Drug Start
12-13
16
20
24
28
32
36
40
44
48
52
All activities should be completed prior to any 
study dose administration unless otherwise stated 
below.
Day with Visit 
Tolerance Interval
86-92
113
5
141
5
169 
5
197  
5
225  
5
253 
5
281 
5
309 
5
337 
5
365 
5
Immunogenicity 
Samples
X
X
X
X
X
Urinalysis
X
X
X
hsCRP
X
X
X
X
X
HBV PCR
X
X
X
Perform only if subject was HBcAb+ with 
negative HBV PCR test at screening.
Any enrolled subject who is HBcAb+ will 
undergo monitoring of HBV PCR at specified 
intervals.  Any subject with a positive HBV PCR 
test at any time must be discontinued from the 
study and receive appropriate follow-up medical 
care, including consideration for antiviral 
therapy.
Urine Pregnancy 
Test
X
X
X
X
X
X
X
X
X
X
X
To be performed only on women of child-bearing 
potential.
X
X
Stool Samples
X
X
X
Xd
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I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Period 2 [V8–V18] Schedule of Activities
Visit Number:
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Comments
Week Relative to 
Study Drug Start
12-13
16
20
24
28
32
36
40
44
48
52
All activities should be completed prior to any 
study dose administration unless otherwise stated 
below.
Day with Visit 
Tolerance Interval
86-92
113
5
141
5
169 
5
197  
5
225  
5
253 
5
281 
5
309 
5
337 
5
365 
5
Supply Stool 
Collection Kit
X
Patients need to collect stool samples up to 3 days 
prior to beginning bowel prep for endoscopy at 
V7 and V18.

I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Period 3 [V19–V31] Schedule of Activities
Visit Number:
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30
V31
Comments
Week Relative to 
Study Drug Start
56
60
64
68
72
76
80
84
88
92
96
100
104
All activities should be completed 
prior to any study drug 
administration unless otherwise 
stated below.
Day with Visit 
Tolerance Interval
393
5
421 
5
449
5
477 
5
505
5
533
5
561 
5
589
5
617
5
645
5
673
5
701
5
729
5
Physical Examination 
X
X
X
X
X
All physical examinations 
throughout the study should include 
a symptom-directed evaluation as 
well as examination of heart, lungs, 
and abdomen, and visual 
examination of the skin.
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
According to standard medical 
practice.
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (BP and 
HR) at all marked 
visits; body temp. 
only at V1 and V2, 
unless clinically 
indicated
X
X
X
X
Sitting BP and pulse, to be obtained 
at approximately the same time as 
ECG measurements or blood 
sampling.  When multiple 
assessments are scheduled for the 
same time point, the order of 
completion should be as follows:  
ECG, vital signs, and then blood 
sampling.  
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
X

I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Period 3 [V19–V31] Schedule of Activities
Visit Number:
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30
V31
Comments
Week Relative to 
Study Drug Start
56
60
64
68
72
76
80
84
88
92
96
100
104
All activities should be completed 
prior to any study drug 
administration unless otherwise 
stated below.
Day with Visit 
Tolerance Interval
393
5
421 
5
449
5
477 
5
505
5
533
5
561 
5
589
5
617
5
645
5
673
5
701
5
729
5
CDAI 
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient-reported items of CDAI 
(Q1–Q3) will be recorded daily.  
Clinician-reported items of CDAI 
(Q4–Q8) will be recorded at every 
visit (see Section 9.1.3).
X
X
X
X
X
X
X
X
X
X
X
X
X
BMC
X
X
X
X`
X
X
X
X
X
X
X
X
X
Subjects will record BMC daily (as 
measured by subject diary; see 
Section 9.1.3).
PGRC
X
X
X
X
PGRS
X
X
X
X
X
X
X
X
X
X
X
X
X
Subjects will record daily (as 
measured by subject diary; see 
Section 9.1.3).
IBDQ
X
X
X
X
SF-36
X
X
X
X
FACIT-Fatigue
X
X
X
X
QIDS-SR16
X
ECG
X
ECG should be completed prior to 
any study dose administration or 
blood draw.  Subjects should be 
supine for approximately 5 to 
10 minutes before ECG collection 
and remain supine but awake 
during ECG collection.
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Period 3 [V19–V31] Schedule of Activities
Visit Number:
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30
V31
Comments
Week Relative to 
Study Drug Start
56
60
64
68
72
76
80
84
88
92
96
100
104
All activities should be completed 
prior to any study drug 
administration unless otherwise 
stated below.
Day with Visit 
Tolerance Interval
393
5
421 
5
449
5
477 
5
505
5
533
5
561 
5
589
5
617
5
645
5
673
5
701
5
729
5
Serum Chemistry/ 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Unscheduled blood chemistry and 
hematology panels may be 
performed at the discretion of the 
investigator.
LY3074828 PK 
Samples
X
X
X
X
X
X
Additional immunogenicity, PK, 
and hypersensitivity markers 
samples may be collected. See 
Section 7.8.2.2.
Immunogenicity 
Samples
X
X
X
X
X
X
Urinalysis
X
X
X
X
hsCRP
X
X
HBV PCR
X
X
X
X
Only if HBcAb+ with negative 
HBV PCR test at screening.
Any enrolled subject who is 
HBcAb+ will undergo monitoring 
of HBV PCR.  Any subject with a 
positive HBV PCR test at any time 
must be discontinued from the 
study and receive appropriate 
follow-up medical care, including 
consideration for antiviral therapy.
Urine Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X
X
X
To be performed only on women of 
child-bearing potential.
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LY3074828
Period 3 [V19–V31] Schedule of Activities
Visit Number:
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30
V31
Comments
Week Relative to 
Study Drug Start
56
60
64
68
72
76
80
84
88
92
96
100
104
All activities should be completed 
prior to any study drug 
administration unless otherwise 
stated below.
Day with Visit 
Tolerance Interval
393
5
421 
5
449
5
477 
5
505
5
533
5
561 
5
589
5
617
5
645
5
673
5
701
5
729
5
X
X
Stool Samples
X
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LY3074828
Unscheduled Visit / Follow-Up Period
Visit Number:
UVc
V801
V802
V803
V804/ETa
Comments
Week Relative to Study Drug Start
N/A
108
112
116
120
Visit Tolerance Interval (days)
N/A
757 5
785 5
813 5
841 5
Physical Examination 
X
X
All physical examinations throughout the study should include 
a symptom-directed evaluation as well as examination of heart, 
lungs, and abdomen, and visual examination of the skin.
Weight
X
X
X
X
According to standard medical practice.
Concomitant Medications
X
X
X
X
X
Adverse Events
X
X
X
X
X
Vital Signs (BP and HR), body temp. 
only at V1 and V2, unless clinically 
indicated
X
X
X
X
X
Sitting BP and pulse, to be obtained at approximately the same 
time as ECG measurements or blood sampling.  When multiple 
assessments are scheduled for the same time point, the order of 
completion should be as follows:  ECG, vital signs, and then 
blood sampling.
ECG
X
Subjects should be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during 
ECG collection.
Colonoscopy/ SES-CD
Xa
Performed only at early termination visit if the visit occurs 16 
weeks after last colonoscopy. For patients who discontinue 
treatment but continue in the study perform colonoscopy 
within 4 weeks of last dose of study drug.  Colonoscopy/SES-
CD is not to be performed at Period 1, Period 3 or Visit 804.
LY3074828 PK Samples
X
X
X
X
Additional immunogenicity, PK, and hypersensitivity markers 
samples may be collected. See Section 7.8.2.2.
Immunogenicity Samples
X
X
X
X
Additional immunogenicity, PK, and hypersensitivity markers 
samples may be collected. See Section 7.8.2.2.
CDAI
X
X
X
X
Patient-reported items of CDAI (Q1–Q3) will be recorded 
daily (see Section 9.1.3).  Clinician-reported items of CDAI 
(Q4–Q8) will be recorded at every visit (see Section 9.1.3).
X
BMC
X
IBDQ
X
SF-36
X
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I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
FACIT-Fatigue
X
QIDS-SR16
X
Serum Chemistry/Hematology
Xb
X
X
X
X
Unscheduled blood chemistry panel or other tests may be 
performed at the discretion of the investigator.  Complete 
blood count will be performed an unscheduled visit to obtain 
hematocrit value needed for CDAI.
Urinalysis
X
X
Urine Pregnancy Test
X
To be performed only on women of child-bearing potential.  
Abbreviations:  BMC = bowel movement count; BP = blood pressure; C diff = Clostridium difficile; CBC = complete blood count; CDAI = Crohn’s Disease 
Activity Index;
; CXR = chest X-ray; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ET = Early 
Termination; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy–Fatigue; FSH = follicle-stimulating hormone; HBcAb = anti-hepatitis B 
core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; HR = heart rate; IBDQ = Inflammatory Bowel Disease Questionnaire;
 
 NRS = Numeric Rating Scale; PCR = polymerase 
chain reaction; PK = pharmacokinetic; PGRC = Patient’s Global Rating of Change; PGRS = Patient’s Global Rating of Severity; PPD = purified protein 
derivative; Q = Question; QIDS-SR16 = Quick Inventory of Depressive Symptomatology–Self Report (16 Items); RNA = ribonucleic acid; SES-CD = Simple 
Endoscopic Score for Crohn’s Disease; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; temp. = temperature; TB = tuberculosis; UV = 
unscheduled visit; V = visit.
a
Subjects who discontinue early (before V804) should have all of the V804 procedures completed at the last visit attended.
b
At V3 and V5, collect a hematology sample for CBC only, do not collect serum chemistries.  Complete blood count is also collected at all unscheduled visits.
c
Use this visit for patients who are seen by the investigator or site staff at a time point not required by the protocol (i.e., an unscheduled visit) due to disease 
exacerbation or an adverse event.  Procedures or laboratory tests may be performed at unscheduled visits at the discretion of the investigator.
d
Stool samples should not be collected on days of bowel prep or endoscopy/colonoscopy.  The stool samples may be collected up to 3 days before bowel prep 
at Visits 7 and 18.
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3. Introduction
3.1.
Study Rationale
Study I6T-MC-AMAG (AMAG) is a Phase 2 study designed to determine whether LY3074828, 
a humanized immunoglobulin G4 (IgG4)–variant monoclonal antibody that binds to the p19 
subunit of interleukin (IL)-23, is safe and efficacious in subjects with moderate to severe Crohn’s 
disease.  Despite an influx of new biologic therapies, many subjects with Crohn’s disease 
experience primary or secondary treatment failure; thus, a significant unmet need remains 
(Gordon et al. 2015).  IL-23 is a validated target for evaluation of treatment of various 
autoimmune/inflammatory diseases, including Crohn’s disease (see Section 3.2).  This Phase 2 
study will help evaluate safety and determine the clinical activity defined by improvement in 
Crohn’s disease activity measures and key patient-reported outcomes (PRO) measures.
3.2.
Background
LY3074828 is being developed for the treatment of autoimmune diseases where the IL-23 
pathway is thought to have a significant pathogenic role.  LY3074828 neutralizes IL-23 activity 
by binding the p19 subunit.
Treatment of autoimmune/inflammatory diseases with IL-23 targeted therapy is being pursued 
by several companies.  The first such biologic to demonstrate clinical benefit in autoimmune 
disease was ustekinumab, which is a Food and Drug Administration (FDA)–approved 
monoclonal antibody for the treatment of psoriasis and psoriatic arthritis (Stelara® prescribing 
information 2014) as well as Crohn’s disease (Feagan et al. 2016;Stelara® prescribing 
information 2016). Ustekinumab binds the common p40 subunit of IL-12 and IL-23; therefore, it 
targets both cytokines, rather than IL-23 specifically.  Blockade of the IL-12 pathway may 
prevent Th1 cell–induced interferon blockade of Th17 cell development, thus potentially limiting 
the clinical activity of p40 targeting antibodies.  Experimental studies suggest that blocking the 
IL-23/Th17/IL-17 immune axis alone is sufficient to treat autoimmune inflammation 
(Monteleone et al. 2009).   Agents specifically targeting the IL-23 p19 subunit have 
demonstrated clinical activity in psoriasis (including LY3074828 in Study AMAA) and Crohn’s 
disease (Sofen et al. 2014 ; Kopp et al. 2015; Krueger et al. 2015 ).  IL-23 p19-specific 
antibodies have also demonstrated clinical activity in Crohn’s disease (Sands et al. 2015; Feagan 
et al. 2016 ).  The IL-23/Th17 pathway is believed to have a significant role in this disease 
(Gheita et al. 2014; Globig et al. 2014; El-Bassat et al. 2015).
Eli Lilly and Company (hereafter Lilly) has one completed study (AMAA) and 2 ongoing studies 
(AMAD and AMAC) summarized below based upon status at the time of the AMAG protocol 
approval date.  The most updated information about these studies (see following details) can be 
found in the Investigator’s Brochure (IB).
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I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Study I6T-MC-AMAC is an ongoing, multicenter, randomized, double-blind, parallel-arm, 
placebo-controlled trial in subjects with moderate to severe ulcerative colitis (UC).  
Approximately 240 subjects will be randomized to evaluate the safety and efficacy of 
LY3074828 in subjects with UC (NCT02589665).
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY3074828 are to be found in the IB.
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I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
4.
Objectives and Endpoints
Table AMAG.1 shows the objectives and endpoints of the study.
Table AMAG.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To test the hypothesis that treatment with 
LY3074828 is superior to placebo in the proportion 
of subjects with endoscopic response at Week 12, 
defined as 50% reduction from baseline in SES-CD 
Score

Proportion of subjects achieving endoscopic 
response at Week 12
Secondary

To evaluate the safety and tolerability of treatment 
with LY3074828

To evaluate the effect of LY3074828 on the 
proportion of subjects with endoscopic response at 
Week 52, defined as 50% reduction from baseline in 
SES-CD score

To evaluate the efficacy of treatment with 
LY3074828 as superior to placebo in  endoscopic 
remission (defined as an SES-CD score of <4 
ileal-colonic or <2 for isolated ileal disease, and no 
subscore >1) at Week 12

To evaluate the effect of LY3074828 on the 
proportion of subjects with endoscopic remission 
(defined as an SES-CD score of <4 ileal-colonic or 
<2 for isolated ileal disease, and no subscore >1) at 
Week 52 

To evaluate the efficacy of treatment with 
LY3074828 as superior to placebo in PRO 
remission (defined as SF ≤2.5 and AP ≤1) at Week 
12

To evaluate the effect of LY3074828 on the 
proportion of subjects with PRO remission (defined 
as SF ≤2.5 and AP ≤1) at Week 52

To evaluate the effect of LY3074828 on health 
outcomes/quality-of-life measures (including:  
PGRS score, PGRC score, IBDQ score, SF-36 
score, and FACIT-Fatigue) at Weeks 12 and 52

To characterize the PK of LY3074828

AEs and discontinuation rates; mean change 
vital signs; laboratory values

Proportion of subjects achieving endoscopic 
response at Week 52

Proportion of subjects achieving endoscopic 
remission at Week 12

Proportion of subjects achieving endoscopic 
remission at Week 52  

Proportion of subjects achieving PRO 
remission at Week 12

Proportion of subjects achieving PRO 
remission at Week 52

The mean change from baseline for PGRS 
score, IBDQ score, FACIT-Fatigue, and 
SF-36, and the mean PGRC at Weeks 12
and 52

Clearance and volume of distribution
Tertiary/Exploratory

To evaluate the efficacy of treatment with 
LY3074828 as superior to placebo in PRO2 
response (defined as a PRO2 reduction of at least 5 
points) at Week 12

To evaluate the effect of LY3074828 on the 
proportion of subjects with PRO2 response (defined 

Proportion of subjects achieving PRO2 
response at Week 12

Proportion of subjects achieving PRO2 
response at Week 52

I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Objectives
Endpoints
as a PRO2 reduction of at least 5 points) at Week 52

To evaluate the efficacy of treatment with 
LY3074828 as superior to placebo in PRO2 
remission (defined as a PRO2 <8) at Week 12

To evaluate the effect of LY3074828 on the 
proportion of subjects with PRO2 remission 
(defined as a PRO2 <8) at Week 52

To evaluate the effect of LY3074828 on durability 
of endoscopic response at Week 52

To evaluate the effect of LY3074828 on durability 
of endoscopic remission at Week 52

To evaluate the effect of LY3074828 on durability 
of PRO2 response at Week 52

To evaluate the effect of LY3074828 on durability 
of PRO2 remission at Week 52

To evaluate the efficacy of treatment with 
LY3074828 as superior to placebo in the composite 
of endoscopic remission and PRO remission at 
Week 12

To evaluate the effect of LY3074828 on the 
proportion of subjects with composite endoscopic
remission and PRO remission at Week 52

To evaluate the effect of LY3074828 on durability 
of composite endoscopic remission and PRO 
remission at Week 52

To evaluate the relationships between LY3074828 
exposure and clinical endpoints 
reported using the BMC scale

Proportion of subjects achieving PRO2 
remission at Week 12

Proportion of subjects achieving PRO2 
remission at Week 52 

Proportion of subjects achieving endoscopic 
response at Week 52 who also had 
endoscopic response  at Week 12

Proportion of subjects achieving endoscopic 
remission at Week 52 who also had 
endoscopic remission at Week 12

Proportion of subjects achieving PRO2 
response at Week 52 who also had PRO2 
response  at Week 12

Proportion of subjects achieving PRO2 
remission at Week 52 who also had PRO2 
remission at Week 12

Proportion of subjects achieving both 
endoscopic remission and PRO remission at 
Week 12

Proportion of subjects achieving both 
endoscopic remission and PRO remission at 
Week 52

Proportion of subjects achieving both 
endoscopic remission and PRO remission at 
Week 52 who also had both endoscopic 
remission and PRO remission at Week 12

Proportion of subjects achieving a 50% 
reduction from baseline in SES-CD score at 
Weeks 12 and 52 at specific LY3074828 
exposure intervals (e.g., quartiles).  EC50
and Emax for probability of subjects 
achieving a 50% reduction from baseline in 
SES-CD score at Weeks 12 and 52.  EC50
and Emax of longitudinal relationships 
between LY3074828 exposure and CDAI 
score and PRO2, SF, and AP
subcomponents of CDAI.
all time points evaluated
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I6T-MC-AMAG(b) Clinical Protocol
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LY3074828
Objectives
Endpoints

To evaluate the effect of LY3074828 on 
QIDS-SR16 at Weeks 12 and 52

To explore the development of any anti-LY3074828 
antibodies that are formed and their effect on safety, 
PK, and PD of LY3074828

To evaluate changes in CDAI from baseline

To evaluate the elimination of neutrophils from the 
mucosa by histopathology at Week 52

Change from baseline in reported 
QIDS-SR16 score at Weeks 12 and 52

Proportion of subjects who are ADA+.  
Proportion of ADA+ subjects who 
experience certain immunogenicity-specific 
AEs.  PK/PD subgroup analyses on ADA+ 
subjects

Change from baseline in CDAI 

Absence of lamina propia and epithelial 
neutrophils at Week 52 assessed by
o
GHAS
o
RHI
Abbreviations:  ADA = anti-drug antibodies; AE = adverse event; AP = abdominal pain; BMC = bowel movement 
count; CDAI = Crohn’s Disease Activity Index;
CRP = C-reactive 
protein; EC50 = drug concentration that produces 50% of Emax; Emax = maximum effect; FACIT-Fatigue = 
Functional Assessment of Chronic Illness Therapy–Fatigue; FCP = fecal calprotectin; GHAS = Global Histologic 
Disease Activity Score; IBDQ = Inflammatory Bowel Disease Questionnaire; Pain NRS = Numeric Rating Scale; 
PD = pharmacodynamics; PK = pharmacokinetics; PGRC = Patient’s Global Rating of Change; PGRS = 
Patient’s Global Rating of Severity; PRO = patient-reported outcomes; PRO2 = Patient Reported Outcome2; 
QIDS-SR16 = Quick Inventory of Depressive Symptomatology–Self Report (16 Items); RHI = Robarts 
Histologic Index; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency; SF-36 = 
Medical Outcomes 36-Item Short Form Health Survey.
CCI
CCI

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5. Study Design
5.1.
Overall Design
Study AMAG is a multicenter, randomized, parallel-arm, placebo-controlled trial in which 
approximately 180 subjects will be randomized.  Subjects will be stratified to the following 
categories, and the exact number enrolled in either group will be dependent upon the enrollment 
rate of each subject population:

A minimum of approximately 30% of subjects will be naive to biologic Crohn’s disease
therapy (including experimental biologic Crohn’s disease therapy) (Inclusion Criterion 
4a; Section 6.1).

At least 50% of the subjects will be prior biologic Crohn’s disease therapy-experienced
(including experience with experimental biologic Crohn’s disease therapy) (Inclusion 
Criterion 4b; Section 6.1).
Study Periods:

Screening (Approximately 4 Weeks):  Subjects will be evaluated for study eligibility 
≤28 days before the baseline visit. 

Period 1 (Weeks 0 to 12):  A 12-week dosing period is designed to evaluate the efficacy 
and safety of LY3074828 administered intravenously (IV) at Weeks 0, 4, 8.  At baseline, 
subjects will be randomized with a 2:1:1:2 allocation across the 4 treatment arms (1000, 
600, 200 mg LY3074828, and placebo) and stratified on the basis of previous exposure to 
biologic therapy for treatment of Crohn’s disease.

Period 2 (Weeks 12 to 52):  Patients will receive both IV and SC dosing to maintain 
blinding from Weeks 12 through 48. All patients who received LY3074828 treatment in 
Period 1 and who achieved an improvement in their Simple Endoscopic Score for 
Crohn’s Disease (SES-CD) score from baseline at Week 12 (determined by the central 
reader) will be randomized evenly to either (i) continue Period 1 treatment assignment 
(IV LY3074828 1000 mg, 600 mg, or 200 mg every 4 weeks [Q4W]) with placebo 
administered subcutaneously OR (ii) IV placebo Q4W with SC LY3074828 300 mg 
Q4W.  

All patients who received LY3074828 treatment in Period 1 and who did not achieve an 
improvement from baseline SES-CD score at Week 12 will receive IV LY3074828 
1000 mg and SC placebo Q4W.
All patients who received placebo in Period 1 will receive IV LY3074828 1000 mg and 
SC placebo Q4W.
Randomization will be stratified based on endoscopic response (i.e. achieving a 50% 
reduction in SES-CD score from baseline).

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
Period 3 (Weeks 52 to 104):  All subjects having clinical benefit per investigator and 
continuing on study treatment may proceed to Period 3 and receive 300 mg SC 
LY3074828 Q4W open-label starting at Week 52 through Week 104. Patients not 
receiving clinical benefit at Week 52 will discontinue treatment and will enter the 
Follow-Up period.

Follow-Up (Weeks 104 to 120):  At Week 104, subjects will stop treatment and be 
followed for safety for an additional 16 weeks.  

Figure AMAG.1 illustrates the study design.
Abbreviations:  IV = intravenous; Q4W = every 4 weeks; SC = subcutaneous; 
SES-CD = Simple Endoscopic Score for Crohn’s Disease.
*Subjects who have not had any improvement in SES-CD score from baseline at 
Week 12, as determined by the central reader, will receive IV LY3074828 1000 mg + 
SC placebo.
Figure AMAG.1.
Illustration of study design for Clinical Protocol I6T-MC-AMAG.
5.2.
Number of Participants
Approximately 180 participants will be randomized with a 2:1:1:2 allocation across the 
4 treatment arms (1000, 600, 200 mg LY3074828, and placebo). 
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.

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5.4.
Scientific Rationale for Study Design
IL-23 is a validated target for evaluation of treatment of various autoimmune/inflammatory 
diseases, including Crohn’s disease (see Section 3.2).  Period 1 is designed to establish the 
efficacy (endoscopic changes and key PRO) and safety of LY3074828 versus placebo in subjects 
with moderate to severe Crohn’s disease.  Subjects may continue background pharmacotherapies 
for Crohn’s disease as permitted per protocol; therefore, the selection of placebo as a comparator 
in this subject population is justified to effectively evaluate the safety and efficacy of 
LY3074828.  Period 2 (Weeks 12 to 52) will allow for continued evaluation of efficacy and 
safety with baseline treatment regimens and exploration of SC dosing—except for all subjects in 
the placebo group and subjects in the LY3074828 treatment groups who have not had any 
improvement in SES-CD score from baseline at Week 12.  Period 3 is intended to provide 
extension therapy for subjects considered to be demonstrating clinical benefit and will provide 
longer term evaluation of safety and durability of clinical benefit.
5.5.
Justification for Dose
The dose levels and regimens planned for this study were selected based on analyses of PK, 
safety, and efficacy data from the single-dose studies AMAA and AMAD, literature information 
about doses and exposures for other IL-23 antibodies, and nonclinical safety data.
On the basis of simulations conducted using the PK data collected in Study AMAA, a Q4W 
dosing frequency is not expected to result in any accumulation and the planned doses of 200, 600, 
and 1000 mg Q4W during the induction period (Period 1) are projected to produce mean trough 
concentrations of 2.7 to 13 g/ml.  The projected exposures for the planned doses are similar to 
those that have been evaluated and found to be effective induction regimens in Crohn’s disease
for the IL-12/IL-23 antibody ustekinumab (Sandborn et al. 2012; Adedokun et al. 2016; and the 
IL-23 antibody BI-655066 (Feagan et al. 2016).
In Period 2, patients will be randomized to continue their induction regimen or be reduced to a 
300 mg SC LY3074828 Q4W regimen.  In Period 3, all subjects will be administered 300 mg 
subcutaneously Q4W.  Based on the SC bioavailability of LY3074828, a 300 mg SC dose will 
produce an exposure area under the plasma concentration versus time curve (AUC)
approximately 40% lower and a trough concentration (3.2 g/ml) that is slightly higher than the 
lowest induction dose (IV 200 mg).  Therefore, data from Period 2 will allow evaluation of 
response with continued treatment at the induction dose levels versus reduction to a lower 
exposure level.  Experience with anti-tumor necrosis factor (anti-TNF) antibodies in 
inflammatory bowel disease (IBD) suggests that the exposure required to maintain response in 
subjects with IBD may be lower than the exposure required to induce response (Rutgeerts et al. 
2004).
The margin of safety for the high dose of IV 1000 mg relative to the no-observed-adverse-effect 
level (NOAEL) observed in the 6-month nonclinical toxicology study in cynomolgus monkeys is 
8 based on dose and 1.9 based on AUC (Table AMAG.2).  No adverse effects were observed in 
the 6-month nonclinical toxicology study in cynomolgus monkeys at the highest tested dose 
(100 mg/kg subcutaneously Q4W).

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Table AMAG.2.
Margin of Safety for LY3074828 Based on Administered Dose and 
Predicted Exposure
Dose
(mg/kg)
Dose
Multiplea
AUC0-672h,ss
(g*h/mL)
Margin of 
Safetyb
Human highest dose (1000 mg IV)c
12.5 (IV)
8
45600
1.9
Monkey NOAELd
100 (SC)
85800e
Abbreviations:  AUC = area under the plasma concentration versus time curve; AUCh,ss = AUC over 672 hours 
at steady state; IV = intravenous; NOAEL = no-observed-adverse-effect level; SC = subcutaneous.
a
Dose multiple is the dose in animals divided by the dose in humans.
b
Margin of safety is the calculated AUC in animals divided by predicted AUC in humans after adjusting for 
differences in dosing frequency.
c
Highest proposed dose in this study; a body weight of 80 kg is assumed.  Human AUCh,ss at IV 1000 mg is 
predicted on the basis of the average IV clearance observed in Study AMAA for doses between 5 and 600 mg.
d
NOAEL was determined in a 6-month repeat-dose toxicity study (Study 20043324).
e
Monkey AUC value was based on average of male and female Day 176 means of AUC0-168h and has been 
multiplied by 4 to align with the 4-week AUC interval projected for humans and planned for this study.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects will be eligible for the study only if they meet all of the following criteria within the 
screening period, which is ≤28 days prior to the start of study treatment, unless specifically 
defined:
Type of Subject and Disease Characteristics
[1]
have had a diagnosis of Crohn’s disease for ≥3 months before baseline 
[2]
have active Crohn’s disease as defined absolute SF ≥4 (loose and watery 
stools defined as Bristol Stool Scale Category 6 or 7) AND/OR AP ≥2 at 
baseline (refer Section 9.1.2 for details)
[3]
have a SES-CD score ≥7 (centrally read) for subjects with ileal-colonic or ≥4 
for subjects with isolated ileal disease within 14 days before the first dose of 
study treatment
Prior IBD Treatment
[4]
must have received prior treatment for Crohn’s disease (according to either 
“a)” or “b)” below or combination of both):
a) history of inadequate response to, or failure to tolerate treatment with
aminosalicylates, 6-mercaptopurine (6-MP) or azathioprine (AZA), oral or 
IV corticosteroids or history of corticosteroid dependence (an inability to 
successfully taper corticosteroids without return of Crohn’s disease)
OR
b) have received treatment with ≥1 biologic agents (such as TNF antagonists, 
vedolizumab, experimental biologic Crohn’s disease therapeutics) with or 
without documented history of failure to respond to or tolerate such 
treatment:
o
The treatment must have been discontinued according to the following 
timeline:

anti-TNF therapy at least 8 weeks before baseline

vedolizumab treatment at least 12 weeks before baseline

experimental biologic Crohn’s disease therapy at least 8 weeks before 
baseline.
[5]
may be receiving a therapeutic dosage of the following drugs:

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
Oral 5-aminosalicylic (ASA) compounds:  if the prescribed dose has been stable 
for at least 3 weeks before screening colonoscopy or stopped treatment at least 
3 weeks prior to screening colonoscopy.

Oral corticosteroids must be at a prednisone-equivalent dose of ≤20 mg/day, or 
≤9 mg/day of budesonide, and have been at a stable dose for at least 3 weeks prior 
to the screening colonoscopy.  If stopping oral corticosteroid treatment prior to 
baseline, they must be stopped at least 3 weeks prior to screening colonoscopy.

AZA, 6-MP, or methotrexate (MTX):  if the prescribed dose has been stable for at 
least 4 weeks before screening endoscopy.  Subjects who have discontinued 
therapy with AZA, 6-MP, or MTX must have stopped the medication at least 
4 weeks prior to screening endoscopy to be considered eligible for enrollment.

Crohn’s disease-specific antibiotics:  if the prescribed dose has been stable 
4 weeks prior to baseline or stopped treatment at least 3 weeks prior to screening 
endoscopy.
Subject Characteristics
[6]
Male subjects agree to use a reliable method of birth control during the study 
and for 3 months, or which is greater than 5 half-lives, after the last dose of 
investigational product.
[7]
Women of child-bearing potential must agree to either remain abstinent or use
effective methods of contraception for the entirety of the study.  Abstinence or 
contraception must continue 3 months following completion of study drug 
administration which is greater than 5 half-lives:

Women of child-bearing potential 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.

Two effective methods of contraception will be used.  The subject may choose to 
use a double barrier method of contraception.  Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method.  Thus, 
each barrier method must include use of a spermicide (that is, condom with 
spermicide, diaphragm with spermicide, female condom with spermicide). It 
should be noted that the use of male and female condoms as a double barrier 
method is not considered acceptable due to the high failure rate when these 
methods are combined.
[8]
Women not of child-bearing potential may participate and include those who 
are:

infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as Müllerian agenesis; or

post-menopausal – defined as either 
o
a woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either 

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
cessation of menses for at least 1 year, or 

at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone (FSH) >40 mIU/mL; or
o
a woman ≥55 years of age not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea; or
o
a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
[9]
venous access sufficient to allow blood sampling and IV administration as per 
the protocol 
[10] are willing and able to complete the scheduled study assessments, including 
endoscopy
[11] have an adequate organ function, including:

hematologic:  absolute neutrophil count ≥1.5 x 109/L (≥1.5 x 103/µL or 
≥1.5 GI/L), platelet count ≥100 x 109/L (≥100 x 103/µL or ≥100 GI/L), 
hemoglobin level ≥10.0 g/dL (≥100 g/L), absolute lymphocyte count >500 
cells/µL (>0.50 x 103/µL or >0.50 GI/L, and total white blood cell count ≥3.0 x 
109/L (≥3.0 x 103/µL or ≥3.0 GI/L)

chemistry:  serum creatinine, total bilirubin level (TBL; subjects with Gilbert’s 
syndrome must have serum direct bilirubin <1.5 mg/dL), alkaline phosphatase
(ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 
levels less than or equal to 2 times the upper limit of normal (≤2X ULN).
[12] have given written informed consent approved by the ethical review board 
(ERB) governing the site
[13] are male or female subjects ≥18 and ≤75 years of age at the time of initial 
screening.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria within 
the screening period, which is ≤28 days prior to the start of study treatment, unless specifically 
defined:
Study Disease Conditions or Treatments
[14] have complications of Crohn’s disease such as strictures, stenoses, or any 
other manifestation for which surgery might be indicated or could confound 
the evaluation of efficacy
[15] diagnosis of conditions affecting the digestive tract, such as UC, indeterminate 
colitis, fistulizing disease, abdominal or perianal abscess, adenomatous 
colonic polyps not excised, colonic mucosal dysplasia, and short bowel 
syndrome

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[16] have had any kind of bowel resection, diversion, or placement of a stoma 
within 6 months or any other intra-abdominal surgery within 3 months prior to 
screening
[17] have received any of the following for treatment of Crohn’s disease:  

6-thioguanine (6-TG), cyclosporine, tacrolimus, sirolimus, pentoxifylline, or 
mycophenolate mofetil within 8 weeks prior to baseline  

corticosteroid enemas, IV corticosteroids, corticosteroid suppositories, or topical 
treatment within 3 weeks prior to screening colonoscopy 

rectal 5-ASA within 3 weeks prior to screening colonoscopy

have used apheresis (for example, Adacolumn apheresis) ≤2 weeks prior to 
screening.
[18] have previous exposure to any biologic therapy targeting IL-23 p19 either 
licensed or investigational, or prior exposure to ustekinumab
[19] have received natalizumab or agents that deplete B or T cells (for example, 
rituximab, alemtuzumab, or visilizumab) within 12 months of screening, or, if 
after receiving these agents, evidence is available at screening of persistent 
depletion of the targeted lymphocyte population
[20] have been treated with any investigational drug for Crohn’s disease within 
8 weeks prior to baseline or 5 half-lives of the drug (whichever is longer), OR 
with interferon therapy within 8 weeks before baseline
General Eligibility Criteria
[21] have evidence of active or latent tuberculosis (TB) (refer Section 9.5.4.1 for 
details on full TB exclusion criteria) 
[22] have had any malignancy within 5 years of screening, except for basal cell or 
squamous epithelial carcinoma of the skin that has been resected with no 
evidence of metastatic disease for at least 3 years OR cervical carcinoma in 
situ with no evidence of recurrence within 5 years of screening
[23] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[24] increases the risks associated with participating in the study if the presence or 
history within 12 months prior to screening of significant uncontrolled 
cerebrocardiovascular (for example, myocardial infarction, unstable angina, 
unstable arterial hypertension, moderate-to-severe heart failure [New York 
Heart Association class III/IV], or cerebrovascular accident); presence of 
respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or 
abnormal laboratory values at screening that, in the opinion of the 
investigator, pose an unacceptable risk to the subject if participating in the 
study or of interfering with the interpretation of data

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[25] presence of significant uncontrolled neuropsychiatric disorder, have history of 
a suicide attempt or have a score of 3 on Item 12 (Thoughts of Death or 
Suicide) of the Quick Inventory of Depressive Symptomatology–Self Report 
(16 Items) (QIDS-SR16) at screening (Visit 1) or baseline (Week 0; Visit 2) 
[26] are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[27] are Lilly employees or employees of third-party organizations (TPOs) 
involved with the study
[28] are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device, OR are concurrently enrolled in any 
other type of medical research not scientifically or medically compatible with 
this study, per investigator judgment
[29] have previously completed or withdrawn from this study or any other study 
investigating LY3074828.  This criterion does not apply to subjects 
undergoing rescreening procedures.
[30] have received live, attenuated vaccine(s) within 2 months of screening or 
intend to receive such during the study; vaccines should be avoided for 
2 months after the last dose of study drug.  Uses of nonlive (inactivated) 
vaccinations are allowed for all subjects.
[31] have human immunodeficiency virus/acquired immune deficiency syndrome
(HIV/AIDS) or test positive for antibodies at screening
[32] have hepatitis B or test positive for hepatitis B virus (HBV) at screening, 
defined as:  (1) positive for hepatitis B surface antigen or (2) positive for anti–
hepatitis B core antibody (HBcAb+) and positive confirmatory polymerase 
chain reaction (PCR) for HBV, regardless of anti-hepatitis B surface antibody 
status
[33] have hepatitis C or test positive hepatitis C virus at screening, defined as:  
positive result for hepatitis C antibody and positive confirmatory PCR test for 
hepatitis C virus
[34] had Clostridium difficile (C diff) infection within 60 days of screening or test 
positive at screening, or other intestinal pathogen with 30 days before 
screening endoscopy.  Subject must not have signs of an ongoing infection 
related to an intestinal pathogen. 
[35] have any clinically significant extra-intestinal infection or opportunistic, 
chronic, or recurring infection within 6 months before screening.  Examples 
include but are not limited to infections requiring IV antibiotics, 
hospitalization, or prolonged treatment.
[36] have received a systemic (including oral) anti-infective agent for an infection 
within 28 days of baseline

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[37] are pregnant, lactating, or planning pregnancy (both men and women) while 
enrolled in the study, or within 3 months after receiving the last dose of study 
agent
[38] have significant allergies to humanized monoclonal antibodies or any 
components of the LY3074828 product formulation
[39] history of alcohol or other drug abuse within the last year
[40] are unsuitable for inclusion in the study in the opinion of the investigator or
sponsor for any reason that may compromise the subject’s safety or confound 
data interpretation.
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study or
for 16 weeks following their last dose.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Subjects may be rescreened due to the following criteria [1], [2], [3], [4], [5], [6], 
[7], [8], [9], [10], [11], [12], [13], [14], [16], [17], [19], [20], [21], [22], [23], [24], [26], [27], 
[28], [29], [30], [34], [35], [36], [37],or [39].  Individuals may be rescreened up to 2 times.  Each 
time rescreening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number.

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7. Treatments
7.1.
Treatments Administered
Table AMAG.3 shows the treatment regimens.
Table AMAG.3.
Treatment Regimens
Treatment Group
Description
Period 1 (Double Blind)
LY Dose Arm 1
1000 mg IV LY Q4W 
LY Dose Arm 2
600 mg IV LY Q4W
LY Dose Arm 3
200 mg IV LY Q4W
Placebo
Placebo given IV Q4W
Period 2 (Double Blind and Double Dummy)
LY Dose Arm 1
1000 mg IV LY Q4W* or 300 mg SC LY 
Q4W*
LY Dose Arm 2
600 mg IV LY Q4W* or 300 mg SC LY Q4W*
LY Dose Arm 3 
200 mg IV LY Q4W* or 300 mg SC LY Q4W*
LY Subjects with no Week 12 SES-CD improvement 
1000 mg IV Q4W + SC Placebo Q4W
Placebo
1000 mg IV Q4W+ SC Placebo Q4W
Period 3 (Open Label)
LY Dose Arm 1 
300 mg SC LY Q4W
LY Dose Arm 2
300 mg SC LY Q4W
LY Dose Arm 3
300 mg SC LY Q4W
Placebo
300 mg SC LY Q4W
Abbreviations:  IV = intravenous; LY = LY3074828; Q4W = every 4 weeks; SC = subcutaneous. 
* Also administer the placebo by the appropriate route; for example, if active LY is administered intravenously, 
then administer placebo via SC route, and vice versa.  Administer IV preparation first, followed by SC 
preparation.
Intravenous infusion of mirikizumab or placebo will occur over at least 2 hours.  All patients 
receiving IV infusion should be monitored for 1 hour or longer (per investigator discretion or 
local standard of care) after IV dosing is complete. Sites must have resuscitation equipment, 
emergency medications, and appropriately trained staff available during the infusion and 
monitoring period.  Detailed instructions for investigational product administration will be 
provided separately by the sponsor.  
Subcutaneous administration of mirikizumab or placebo will be given in 3 injections. Detailed 
instructions regarding supplies and preparation and handling of LY3074828 will be provided by 
the sponsor.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

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
at the end of the study, returning all unused medication to Lilly, or its designee, unless 
the sponsor and sites have agreed all unused medication is to be destroyed by the site, as
allowed by local law.
7.1.1. Packaging and Labeling
LY3074828 will be supplied to the investigator by Lilly.  Clinical trial materials are 
manufactured in accordance with good manufacturing practices.  All investigational products 
will be stored, inventoried, reconciled, and destroyed according to applicable regulations.
LY3074828 is supplied for clinical trial use as lyophilized powder in a glass vial and should be 
stored in refrigerated conditions (2ºC to 8ºC).  The vial is manufactured to deliver 75 mg of 
LY3074828 and will be reconstituted with sterile water for injection and further diluted with 
normal saline (0.9% sodium chloride) before administration.  Placebo will be sterile normal 
saline (0.9% sodium chloride for injection).
When reconstituted and in a syringe, LY3074828 cannot be distinguished visually from placebo.
Detailed instructions regarding supplies and preparation and handling of LY3074828 will be 
provided by the sponsor.
Clinical trial materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Subjects who meet all criteria for enrollment will be randomized to treatment at Visit 2.  
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  To achieve between-group comparability, 
subjects will be stratified to these arms based upon their prior therapy (below); this stratification 
will be controlled by IWRS. 

A minimum of approximately 30% of subjects will be naive to biologic Crohn’s disease
therapy (including experimental biologic Crohn’s disease therapy).

At least 50% of the subjects will be prior biologic Crohn’s disease therapy-experienced 
(including experience with experimental biologic Crohn’s disease therapy).

For Period 2, subjects assigned to LY3074828 at baseline will be randomized to either 
baseline treatment assignment or 300 mg SC LY3074828 Q4W —except for all subjects 
in the placebo group, and subjects in the LY3074828 treatment groups who have not had 
any improvement in SES-CD score from baseline at Week 12 (determined by the central 
reader), who will receive 1000 mg IV LY3074828 Q4W.  All subjects will receive IV 
and SC administration of either LY3074828 or placebo during Period 2 in a 
double-dummy design. The randomization will be stratified based on endoscopic 
response (as defined for the primary endpoint).

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7.2.1. Selection and Timing of Doses
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF). All study procedures (including blood tests) are to be performed predose unless 
otherwise specified in the Schedule of Activities.
7.3.
Blinding
This is a double-blind study; to preserve the blinding of the study, a minimum number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
complete.  Only a study site pharmacist or other trained person will be unblinded at the site for 
investigational product preparation.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
should be used ONLY if the subject’s well-being requires knowledge of the subject’s treatment 
assignment.  All notifications resulting in an unblinding event are recorded and reported by the 
IWRS.
If an investigator, site personnel performing assessments, or subject is unblinded, the subject 
must be discontinued from the study.  In cases where there are ethical reasons to have the subject 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the subject to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding
of a subject’s treatment assignment is warranted.  Subject safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a subject’s treatment assignment unless this could delay emergency treatment of the subject.  If a 
subject’s treatment assignment is unblinded, Lilly must be notified immediately.
7.4.
Dosage Modification
Dose adjustments are not permitted in this study, except as noted in Section 7.8.2.
7.5.
Preparation/Handling/Storage/Accountability
Detailed instructions regarding supplies and preparation and handling of LY3074828 will be 
provided by the sponsor.
7.6.
Treatment Compliance
Every attempt will be made to select subjects 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 subject before randomization.  
All doses of study medication will be administered at the study site.  Deviation(s) from the 
prescribed dosage regimen should be recorded in the CRF.

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If a subject is noncompliant with study procedures and/or investigational product administration, 
the investigator should assess the subject to determine the reason for noncompliance and educate 
and/or manage the subject 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 subject should be discontinued from the study.  A subject will be considered noncompliant if 
he or she fails to attend for administration of study medication within the required treatment 
window as defined in the Schedule of Activities (Section 2).
7.7.
Concomitant Medications
All concomitant medication taken during the study must be recorded on the concomitant 
medication CRF.  All subjects should maintain their usual medication regimens for concomitant 
conditions or diseases throughout the study unless those medications are specifically excluded in 
the protocol.  Subjects taking concomitant medications should be on stable dosages at the time of 
baseline and should remain at stable dosages throughout the study unless changes need to be 
made because of AEs.  Additional systemic drugs are to be avoided during the study, unless 
required to treat AEs.  Other medications may be allowed if they are approved by the sponsor or 
its designee.
Use of nonlive (inactivated) vaccinations are allowed for all subjects.  Use of live, attenuated 
vaccines is prohibited.  Occasional use of acetaminophen in over-the-counter dose ranges for 
headache, menstrual pain, or other transient conditions is acceptable but should be held on study 
visit days until after assessments have been completed, as much as possible; use of prophylactic 
daily aspirin (up to 162.5 mg) is permitted.  
Concomitant therapies for treatment of Crohn’s disease during the study are permitted only as 
outlined in Table AMAG.4. The corticosteroid tapering regimen is outlined in Table AMAG.4.
Table AMAG.4.
Permitted Concomitant Therapies for Crohn’s Disease
Drug Class
Conditions for Use
Oral 5-aminosalicylic (ASA) or 
sulfasalazine 
Subjects were receiving the medications at baseline and the prescribed 
dose was stable for at least 3 weeks before screening colonoscopy.  
Dosages should remain stable throughout the study unless the 
medication is discontinued because of toxicity.  If stopped, the 
medication should not be restarted during the study.
Azathioprine (AZA) or 
6-mercaptopurine (6-MP)
Subjects were receiving the medications at baseline and the prescribed 
dose was stable for at least 4 weeks before screening colonoscopy.  
Dosages should remain stable throughout the study unless the 
medication is discontinued because of toxicity.  If stopped, the 
medication should not be restarted during the study.
Methotrexate (MTX)
Subjects were receiving the medications at baseline and the prescribed 
dose was stable for at least 4 weeks before screening colonoscopy.  
Dosages should remain stable throughout the study unless the 
medication is discontinued because of toxicity.  If stopped, the 
medication should not be restarted during the study.

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7.8.
Treatment after the End of the Study
7.8.1. Continued Access
LY3074828 will not be made available to subjects after conclusion of the study.
7.8.2.Special Treatment Considerations
7.8.2.1.
Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigators.  
Any premedication given will be documented as a concomitant therapy.
7.8.2.2.
Management of Hypersensitivity Events, Fever Associated Reactions,
and Infusion/Injection Site Reactions
During and after study drug administration, patients should be closely monitored for signs or 
symptoms of AEs, including hypersensitivity events, other fever associated reactions and 
infusion or injection site reactions.
Systemic Hypersensitivity Events
If a patient experiences a systemic hypersensitivity event involving the skin or mucous 
membranes, respiratory, cardiovascular, gastrointestinal, or urinary systems, during or up to 
6 hours after an infusion of study drug, the following guidance should be followed (see 
Appendix 6 for additional information): 

Study drug infusion should be stopped immediately and appropriate supportive care 
provided according to local standard practice (for example, administration of epinephrine, 
anti-histamine, systemic steroids, and/or bronchodilators).
Oral corticosteroid therapy (prednisone 
at a stable dosage ≤20 mg/d or 
equivalent oral steroid)
Oral steroids are allowed during the study up to 20 mg/d of prednisone 
or equivalent, providing that they must be stable for 3 weeks prior to the 
screening colonoscopy.  Decrease of the steroid dosage due to tapering 
regimen is allowed during the study per investigator judgment, except 
during Period 1.  If the steroid tapering is commenced, the daily dose of 
prednisone or equivalent is recommended to be decreased by 2.5 mg 
every week until dose 0.
Equivalent of oral budesonide up to 9 mg/d must be stable for 3 weeks 
prior to the screening colonoscopy.  Decrease of the steroid dosage due 
to tapering regimen is allowed during the study per investigator 
judgment, except during Period 1.  If the steroid tapering is commenced, 
is recommended to be decreased by 3 mg every week until dose 0.
Dosages should remain stable throughout the study unless the 
medication is discontinued because of toxicity.  If stopped, the 
medication should not be restarted during the study.

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
After the patient’s stabilization, additional immunogenicity, PK, and hypersensitivity
markers samples should be collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

The patient should continue to be monitored until resolution or stabilization of the 
symptoms, as clinically appropriate. 

Permanently discontinue the study drug after a systemic drug administration reaction.  

If the patient discontinues study drug but remains in the study, management should 
follow as outlined in Section 8.1.1, and immunogenicity, PK, and hypersensitivity
markers should be collected at 4 and 12 weeks after the event.

If the patient discontinues participation in the study, the patient should proceed to early 
termination procedures.  The patient will need to return after early termination procedures 
for 4 and 12 week immunogenicity, PK, and hypersensitivity markers collections.  

The medical monitor should be notified as soon as feasible.
Fever-Associated Reactions
If a patient experiences a fever-associated reaction consisting of headache, rigors and/or 
temperature >38°C (in the absence of signs or symptoms of a systemic hypersensitivity event) 
during or up to 6 hours after an infusion of study drug, the following guidance should be 
followed:

Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, nonsteroidal anti-inflammatory drugs [NSAIDS], anti-
pyretics or antihistamines).

Additional immunogenicity, PK, and hypersensitivity markers samples should be
collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

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 
readminstration.

Patient should remain in observation, as is clinically appropriate for the patient’s 
symptoms.

Premedication prior to subsequent study drug administration may be considered, if
judged by the investigator to be appropriate for the individual patient.  

If the patient discontinues study drug but remain in the study, management should follow 
as outlined in Section 8.1.1, and immunogenicity, PK, and hypersensitivity markers 
should be collected at 4 and 12 weeks after the event.

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
If the patient discontinues from the study early for any reason, they should return to 
complete 4 and 12 week follow-up immunogenicity, PK, and hypersensitivity markers
collections.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity event.
Infusion Site Reactions
If a patient experiences an infusion site reaction, including urticaria, pruritus, or angioedema 
localized to the IV infusion site (in the absence of systemic hypersensitivity signs or symptoms), 
during or up to 6 hours after an infusion of study drug, the following guidance should be 
followed:

Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, NSAIDS, anti-pyretics or antihistamines).  

Additional immunogenicity, PK, and hypersensitivity markers samples should be
collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

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 
readminstration.

Patient should remain in observation, as is clinically appropriate for the patient’s 
symptoms.

Premedication prior to subsequent study drug administration may be considered, if
judged by the investigator to be appropriate for the individual patient.

If the patient discontinues from the study early for any reason, they should return to 
complete 4 and 12 week follow-up immunogenicity, PK, and hypersensitivity markers
collections.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity event.
Injection Site Reactions
If a patient experiences an injection site reaction, including pain, erythema, urticaria, pruritus, or 
angioedema localized to the SC injection site (in the absence of systemic hypersensitivity signs 
or symptoms), the following guidance should be followed:

Patient should be instructed to contact the study site to report any symptoms experienced 
following a SC injection. 

Premedication prior to subsequent study drug administration may be considered as 
appropriate for the individual patient.

If the patient develops systemic hypersensitivity symptoms, they should be managed as 
described above for a systemic hypersensitivity event.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets one of the following conditions after consultation with the 
Lilly designated medical monitor:

ALT or AST >8xULN

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and TBL >2xULN or prothrombin time >1.5xULN

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP >3xULN

ALP >2.5xULN and TBL >2xULN

ALP >2.5xULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
Subjects may discontinue treatment for any of the reasons noted above, or for other reasons such 
as the development of a serious adverse event. To better communicate patient flow throughout 
the study, different study period situations are provided below:

Subjects who discontinue the investigational product in Period 1 or Period 2 may
continue in the study according to the visit schedule (Section 2).

At Week 52/Visit 18, subjects who have previously discontinued the investigational 
product will continue to Visit 801 of the Follow-up Period.

Subjects who discontinue the investigational product in Period 3 may continue in Period 
3 and then proceed to Week 104/Visit 801 of the Follow-up Period.
Investigational product is to be discontinued for patients who experience clinically significant 
systemic hypersensitivity events (such as anaphylaxis) following administration of 
investigational product.
8.1.2. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identify a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled subject to continue in the study with or without treatment with 
investigational product.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

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
enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

subject decision
o
the subject requests to be withdrawn from the study

AE 
o
If the investigator decides that the subject should be withdrawn because of an 
AE/SAE or a clinically significant laboratory value, the investigational product is 
to be discontinued and appropriate measures are to be taken.  Lilly or its designee 
is to be alerted immediately.  Refer to Safety Evaluations, Sections 9.5.5 and 
10.3.4.

subject becomes pregnant.
Subjects who discontinue the study early will have end-of-study procedures as outlined in 
Visit 804 in the Schedule of Activities (Section 2).  Any medical data and biological samples 
collected through the early termination visit will still be evaluated in an anonymized manner.
8.3.
Lost to Follow-Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Lilly personnel will not be involved in any attempts to collect vital status information.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy outcome measure is endoscopic response of LY3074828 versus placebo at 
Week 12.  Endoscopic response is defined as having 50% reduction from baseline in SES-CD 
Score (Vuitton et al. 2015).  
The SES-CD (Daperno et al. 2004) tool will be utilized by central readers to evaluate endoscopy 
video that is collected during subject endoscopic (colonoscopy) examination
9.1.2. Secondary Efficacy Assessments
Secondary efficacy assessments will include an assessment of the SES-CD score using centrally 
read endoscopy at Weeks 12 and 52, and an assessment of SF and AP at Weeks 12 and 52, using 
patient-reported data recorded in the patient diary, as detailed below.  Changes in health outcome 
measures/quality-of-life measures from baseline to Weeks 12 and 52, and the PK properties of 
LY3074828 will also be assessed.  Effects on safety parameters will also be assessed (see 
Section 9.5).

Endoscopic remission is defined as an SES-CD score of <4 for ileal-colonic disease or <2 
for isolated ileal disease, and no subscore >1.

PRO scores will be determined as an average of 7 days of data recorded by the subject
within a 12-day period prior to a specified visit. Fewer than 4 days of data within a 
12-day period prior to a specified visit will constitute a missing data score.  Data will be 
excluded from score calculation when collected on day(s) of colonoscopy prep, day of 
colonoscopy procedure, and 2 days after colonoscopy procedure.  PRO remission is 
defined as having an average daily AP score ≤1 and an average daily SF ≤2.5 (absolute 
number of liquid or very soft stools defined using the Bristol Stool Scale Category 6 or 7 
[Lewis and Heaton 1997], that is, liquid or watery stools).
9.1.3. Subject Diary
Subjects will be provided with a diary tool during screening in order to record information 
pertaining to subjects’ signs and symptoms on a daily basis:

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1. Patient Global Rating of Severity (PGRS)
2. Crohn’s Disease Activity Index (CDAI)
a.
b. absolute number of liquid or soft stools (Bristol Stool Scale Category 6 or 7
[Lewis and Heaton 1997] that is, liquid or watery stools). 
c.
general well-being (5-point scale)
3.
4. Bowel movement count (BMC; that is, absolute number of stools irrespective of quantity 
and consistency).
Diary data will be assessed at the clinic, at each visit defined in the Schedule of Activities.  
Information regarding 
; number of 
liquid or very soft stools; and general well-being score (5-point scale:  0=generally well, 
1=slightly under par, 2=poor, 3=very poor, 4=terrible) will be collected daily to calculate the 
subjects’ PRO2 and CDAI scores (see Section 9.1.5).
Data will include information collected over 7 days during a 12-day period prior to each study 
visit (<4 days of data within a 12-day period prior to a specified visit will constitute a missing 
data score). During visits when colonoscopy is required, subject diary data from colonoscopy 
preparation day(s), day of the colonoscopy procedure, and two days after the colonoscopy 
procedure will be excluded from score calculations.  
In order to encourage consistent diary recording, subject should enter daily diary data 
continuously throughout the study.  
The study data completion guidelines and study data management plan will provide detailed 
information on use of PRO measures and the subject diary.
9.1.4. Endoscopy 
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. 
During the study, the SES-CD will be evaluated by both the investigator/endoscopist and by a 
central reader blinded to study treatment. However, only the SES-CD score from the central 
reader will be used 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 subject, 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 a qualified gastroenterologist according 
to the image review charter.  
Biopsies will be collected during the endoscopy procedure.  The details of  biopsy sample 
collection will be provided in the laboratory manual.  Biopsies will be used for 
 
and histopathological assessment (Appendix 5).  To ensure quality data and 
standardization, bowel tissue histopathologic scoring will be performed by the central reading 
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laboratory.  A detailed image review charter from the central reading laboratory will outline the 
histopathologic procedures to be used for secure specimen transfer, processing, slide preparation, 
and digitization of slides for histopathologic scoring.  The  images will be read centrally in a 
blinded manner by a qualified pathologist according to the image review charter.
9.1.5. Other Assessments
Crohn’s Disease Activity Index (CDAI):  CDAI is an 8-item disease activity measure 
comprised of 3 patient-reported and 5 physician-reported/laboratory items.  Subject responses are 
summed over a 7-day period and subsequently weighted, yielding a total score range of 0 to 
600 points with a score of <150 points defined as remission.  A score of 220 to 450 points 
indicates moderate to severe disease activity, and a score of >450 points indicates severe disease 
activity.
Patient Reported Outcome 2 (PRO2) is a 2-item index comprised of the SF and AP items from 
the CDAI.  The total PRO2 comprises the average daily scores over 7 days and is weighted using 
the CDAI multiplication factors for SF and AP items.
For both of these items (CDAI and PRO2), 7 days of subject-reported data within a 12-day 
period prior to a visit will be utilized to calculate scores.  Data will be excluded from score 
calculation when collected on day(s) of colonoscopy prep, day of colonoscopy procedure, and 
2 days after colonoscopy procedure.
9.1.6. Appropriateness of Assessments
The clinical safety parameters in this study are routine elements of clinical health assessment and 
Phase 2 drug development.  The disease activity and health outcomes measurements are used 
both in clinical practice and Crohn’s disease clinical trials.
9.2.
Health Outcomes/Quality of Life
Patient’s Global Rating of Severity (PGRS) (daily):  The PGRS is a 1-item patient-rated 
questionnaire designed to assess the subjects’ rating of their disease symptom severity over the 
past 24 hours.  Responses are graded on a 6-point scale in which a score of 1 indicates the 
subject has no symptoms (that is, “none”) and a score of 6 indicates that the subject’s
symptom(s) are “very severe.”
Patient’s Global Rating of Change (PGRC):  The PGRC scale is a patient-rated instrument 
designed to assess the subjects’ rating of change in their symptom(s).  Responses are graded on a 
7-point Likert scale in which a score of 1 indicates that the subject’s symptom(s) is “very much 
better,” a score of 4 indicates that the subject’s symptom has experienced “no change,” and a 
score of 7 indicates that the subject’s symptom(s) is “very much worse.”
Inflammatory Bowel Disease Questionnaire (IBDQ):  The IBDQ is a 32-item 
patient-completed questionnaire that measures 4 aspects of subjects’ lives:  symptoms directly 
related to the primary bowel disturbance, systemic symptoms, emotional function, and social 
function.  Responses are graded on a 7-point Likert scale in which 7 denotes “not a problem at 

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all” and 1 denotes “a very severe problem.” Scores range from 32 to 224; a higher score indicates 
a better quality of life.
Medical Outcomes 36-Item Short Form Health Survey (SF-36):  The SF-36 is a 36-item 
patient-completed measure designed to be a short, multipurpose assessment of health in the areas 
of physical functioning, role–physical, role–emotional, bodily pain, vitality, social functioning, 
mental health, and general health.  The 2 overarching domains of mental well-being and physical 
well-being are captured by the mental and physical component summary scores.  Responses are 
graded on Likert scales of varying lengths/points.  The summary scores range from 0 to 100; 
higher scores indicate better levels of function and/or better health.
Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue):  
FACIT-Fatigue is a 13-item instrument developed to measure fatigue in chronic illness patients.  
It has been validated for use in IBD patients.  Total score ranges from 0 to 52 based on a rating 
of 4-point Likert scale.
Bowel Movement Count (BMC):  Due to the significant impact of SF on subjects’ lives, Lilly 
plans to measure and validate “stool frequency in the past 24 hours” using an electronic daily 
diary approach.  Seven days of subject diary data during a 12-day period prior to the visit must 
be completed and assessed, excluding colonoscopy preparation day(s), day of the colonoscopy 
procedure, and 2 days after colonoscopy procedure.  In order to encourage consistent diary 
recording, subjects should enter daily diary data continuously throughout the study.
Quick Inventory of Depressive Symptomatology–Self Report (16 Items) (QIDS-SR16):  The 
QIDS-SR16 is a self-administered, 16-item instrument intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association’s 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (APA 1994).  A 
subject is asked to consider each statement as it relates to the way they have felt for the past 7 
days.  There is a 4-point scale for each item ranging from 0 to 3.  The 16 items corresponding to 
9 depression domains are summed to give a single score ranging from 0 to 27, with higher scores 
denoting greater symptom severity.  The domains assessed by the instrument include:  (1) sad 
mood, (2) concentration, (3) self-criticism, (4) suicidal ideation, (5) interest, (6) energy/fatigue, 
(7) sleep disturbance (initial, middle, and late insomnia or hypersomnia), (8) decrease/increase in 
appetite/weight, and (9) psychomotor agitation/retardation.  Additional information and the 
QIDS-SR16 questions may be found at the University of Pittsburgh IDS/QIDS internet page 
[www.http://www.ids-qids.org/].
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9.3.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via electronic case report form (eCRF) 
the occurrence and nature of each subject’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) and any new conditions as AEs. 
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure, investigational product, via eCRF. 
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The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a subject’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. 
9.3.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
begins after the subject has signed the ICF and has received investigational product.  However, if 
an SAE occurs after signing the ICF, but prior to receiving investigational product, it needs to be 
reported ONLY 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.
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.

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Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.3.1.1.
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 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.3.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Subject will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.4.
Treatment of Overdose
In case of suspected overdose, hematology, chemistry, vital signs, and oxygen saturation should 
be monitored and supportive care provided as necessary.  There is no known antidote for 
LY3074828.  
9.5.
Safety
9.5.1. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  
Electrocardiograms should be recorded according to the study-specific recommendations 
included in the Schedule of Activities. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational treatment should be reported to Lilly or its 
designee as an AE via eCRF.
9.5.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).

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Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the subject receives the first dose of study treatment should be reported to Lilly 
or its designee as an AE via eCRF.
9.5.3. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the subject receives the first dose of investigational product should be reported to Lilly or 
its designee as an AE via eCRF.
9.5.4. Other Tests
9.5.4.1.
Chest Radiography and Tuberculosis Testing
Posterior-anterior view chest radiography (CXR) will be obtained at screening (Visit 1) (unless 
local standards dictate posterior–anterior and lateral views), unless the radiographs or medical 
report from chest radiography performed within 3 months before initial screening (per local 
standard of care for TB evaluation) are available to the investigator for review.  
In addition, subjects will be tested as indicated in the Schedule of Activities for evidence of 
active or latent TB.  A positive TB test result is indicated by a purified protein derivative (PPD) 
skin test response ≥5 mm induration documented 48 to 72 hours after test application (regardless 
of Bacillus Calmette-Guerin vaccination history).  In countries where the QuantiFERON-TB 
Gold test (or equivalent, for example, T-SPOT) is available and is preferred (in the judgment of 
the investigator) as an alternative to the PPD skin test for the evaluation of TB infection in a 
subject, that test may be used instead of the PPD test.  Retesting following a positive test is 
allowed in patients, who in the opinion of the investigator, are unlikely to be infected with 
Mycobacterium tuberculosis.  In this circumstance, 2 positive tests is considered evidence of 
active or latent TB infection.  Patients in whom retesting has been performed must be discussed 
with the medical monitor prior to inclusion in the study.
If the QuantiFERON-TB Gold test is indeterminate, 1 retest is allowed.  If the retest is 
indeterminate, then the subject is excluded from the study.
Subjects with documentation of negative TB test results within 3 months before initial screening 
may not need to repeat TB testing at screening (Visit 1) based on judgment of the investigator.  
Documentation of this previous test result must include a record of the size (in millimeters) of 
the induration response.  A PPD test recorded as “negative” without documenting the size of 
induration (in millimeters) will not be acceptable and will require a retest.
However, subjects with a PPD skin test response ≥5 mm induration or a positive 
QuantiFERON-TB Gold test result at screening and no other evidence of active TB may be 
rescreened once and enrolled according to the following requirements:

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
after receiving at least 4 weeks of appropriate ongoing prophylactic therapy for latent TB 
as per local standard of care

no evidence of treatment hepatotoxicity (ALT and AST levels must remain ≤2xULN) 
upon retesting of serum ALT and AST levels before randomization)
Such subjects must continue and complete appropriate latent TB therapy during the course of the 
study to remain eligible and must continue to meet all other inclusion and exclusion criteria for 
participation.  
Subjects who have a documented history of completing an appropriate TB prophylaxis regimen 
with no history of re-exposure since their treatments were completed and no evidence of active 
TB are eligible to participate in the study; these subjects should not undergo PPD testing.  
Subjects who have had household contact with a person with active TB must be excluded unless 
appropriate and documented prophylaxis for TB has been given, as described above.
Subjects with any history of active TB are excluded from the study, regardless of previous or 
current TB treatments.
9.5.5. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
If a study patient/subject experiences elevated ALT ≥3xULN, ALP ≥2xULN, or elevated TBL 
≥2xULN, clinical and laboratory monitoring should be initiated by the investigator.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities.  To ensure patient/subject safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Appendix 4).
Any enrolled subject who is HBcAb+ will undergo periodic monitoring of HBV 
deoxyribonucleic acid (DNA) per the Schedule of Activities.
In addition to the above, any enrolled subject who is HBcAb+ or tests positive for hepatitis B 
surface antibody and who experiences an elevated ALT or AST level >3xULN must undergo 
HBV DNA testing.  If the HBV PCR test is negative, the investigator should consult with the 
Lilly-designated medical monitor regarding further management of the subject.  
If the result of any HBV PCR test is positive at any time, the subject must be discontinued from 
the study and should receive appropriate follow -up medical care, including consideration for 
antiviral therapy.  A specialist physician in the care of patients with hepatitis (for example, 
infectious disease or hepatologist subspecialists) should be consulted and potentially start 
antiviral therapy.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring board (an advisory group for this study 

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formed to protect the integrity of data; refer Section 10.3.7, Interim Analyses) can conduct 
additional analyses of the safety data.
9.6.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine the serum concentrations of LY3074828.
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
24-hour clock time of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last subject visit for the study.
9.7.
Pharmacodynamics
Not applicable.
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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 180 participants will be randomized with a 2:1:1:2 allocation across 4 treatment 
arms (1000, 600, 200 mg LY3074828, and placebo).
The primary endpoint is Week 12 endoscopic response rate (as defined as a 50% reduction in 
SES-CD).  Based on 60 patients per comparison treatment arm and the assumed LY3074828 and 
placebo endoscopic response rates of 35% and 15%, respectively, the test of the superiority 
versus placebo will have 81% power when performed via a chi-squared test at a 2-sided 0.1 
significance level.
Subjects will be stratified by prior biologic Crohn’s disease therapy use (yes/no).  The exact 
number enrolled in either group will be dependent upon the enrollment rate of the patient 
populations described below:

A minimum of approximately 30% of subjects will be naive to biologic Crohn’s disease
therapy (including experimental biologic Crohn’s disease therapy).

At least 50% of the subjects will be prior biologic Crohn’s disease therapy-experienced 
(including experience with experimental biologic Crohn’s disease therapy).
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Intent-to-Treat (ITT) 
The ITT population is defined as all randomized patients, even if the subject 
does not take the assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol.  Subjects will be analyzed according to 
the treatment to which they were randomized.
Safety
All randomized participants who take at least 1 dose of double-blind study 
treatment.  Participants will be included in the treatment group to which they 
were randomized.  
Additional subpopulations may be identified.  Full details would be provided in the study 
statistical analysis plan (SAP).
10.3. Statistical Analyses
10.3.1. 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 
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Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
Continuous data will be summarized in terms of the mean, standard deviation, minimum, 
maximum, median, and number of observations.  Categorical data will be summarized as 
frequency counts and percentages.  Unless otherwise specified, statistical tests of treatment 
effects will be conducted using 2-sided tests at an alpha level of 0.1.  This will include the tests 
for continuous variables and categorical variables. 
Treatment comparisons of categorical efficacy variables will be conducted using a logistic 
regression analysis with treatment, geographic region and prior biologic Crohn’s disease therapy 
use (yes/no) in the model.  The proportions and 90% confidence intervals (CI) will be reported.
Treatment comparisons of continuous efficacy and health outcome variables will be made using 
mixed effects for repeated measures (MMRM) analysis.  When the MMRM model is used, the 
model includes treatment, geographic region, prior biologic Crohn’s disease therapy use, 
baseline value, visit, and the interactions of treatment-by-visit and baseline-by-visit as fixed 
factors.  The covariance structure to model the within-patient errors will be unstructured.  If the 
unstructured covariance matrix results in a lack of convergence, the heterogeneous Toeplitz 
covariance structure, followed by the heterogeneous autoregressive covariance structure will be 
used.  The Kenward-Roger method will be used to estimate the denominator degrees of freedom.  
Type III sums of squares for the least-squares (LS) means will be used for the statistical 
comparison; the 90% CI will also be reported. 
When necessary, additional analyses of categorical efficacy variables may be conducted to 
address sparse data or small sample sizes.  Additional sensitivity analyses of continuous efficacy 
and health outcomes variables will be conducted using an analysis of covariance (ANCOVA).
Full details of these analyses including missing imputation methods and covariates will be 
provided in the SAP.  
10.3.1.1. Analysis of Populations
Unless otherwise specified, efficacy and health outcomes analyses will be conducted on the 
intent-to-treat population (ITT), as defined in Section 10.2.
Unless otherwise specified, safety analyses will be conducted on the safety population, as 
defined in Section 10.2.
Additional subpopulations may be identified.  Full details would be provided in the SAP.
10.3.1.2. Missing Data Imputation 
Analysis of categorical efficacy and health outcome variables will be assessed using a 
non-responder imputation (NRI) method.  Subjects will be considered a non-responder for the 
analysis if they do not meet the response criteria or have missing response data at the analysis 

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time point.  Randomized subjects without at least 1 postbaseline observation will also be defined 
as non-responders for the NRI analysis.
Full details of the NRI methodology will be provided in the SAP.  Additional missing data 
imputation methodologies may be considered and will be fully detailed in the SAP. 
10.3.1.3. Adjustment for Multiple Comparisons
Unless otherwise specified, no multiplicity adjustment will be applied for planned analyses. 
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number of randomized patients will be summarized by treatment period.  Frequency counts 
and percentages of all patients who are randomized and completing the study or discontinue the 
study drug/study early will be presented for each treatment period.  Reasons for discontinuing 
the study drug/study will be summarized by treatment period.
A detailed description of patient disposition will be provided at the end of the study. 
10.3.2.2. Patient Characteristics
Year of birth, sex, weight, height, smoking habits, prior biologic Crohn’s disease therapy, and 
other demographic characteristics will be recorded and summarized for all patients.  Age and 
body mass index will be calculated.  Demographic and baseline characteristics will be 
summarized for each treatment group.  Certain characteristics, such as weight, that are collected 
after baseline, will be reported as a listing.
10.3.2.3. Concomitant Therapy 
Concomitant therapy will be collected at each visit, and the reported term will be classified by 
the World Health Organization (WHO) drug dictionary.  Previous concomitant therapy (reported 
before randomization) and current concomitant therapy (reported after randomization) will be 
presented separately in frequency tables by drug name for all randomized subjects.
Concomitant therapy may be summarized for the prior biologic Crohn’s disease therapy patient 
populations separately.  
The number and percentage of patients taking concomitant Crohn’s disease therapies (overall 
and by therapy type) and corticosteroid products (overall and by steroid type) will be 
summarized by treatment group and study period if appropriate.
Full details of the analysis of concomitant medication will be described in the SAP. 
10.3.2.4. Treatment Compliance 
Subjects who are noncompliant according to the definition in Section 7.6 will be listed by 
treatment.  A contingency table of numbers of noncompliant subjects by treatment will be 
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10.3.3. Efficacy Analyses
10.3.3.1. Primary Efficacy Analyses
Rates of endoscopic response at Week 12, as defined in Section 10.1, will be analyzed.  Subjects 
who do not achieve endoscopic response by Week 12 or who do not reach the Week 12 
assessment will be considered to be non-responders at Week 12.  Details of the NRI are provided 
in Section 10.3.1.2.
The primary endpoint analysis will utilize the statistical methodology described in Section 10.3.
Additional analyses of the primary endpoint may be considered and will be fully detailed in the 
SAP. 
10.3.3.2. Secondary Efficacy Analyses
The secondary efficacy endpoints of the trial are:

To evaluate the efficacy of treatment with LY3074828 on endoscopic response at 
Week 52 (defined as 50% reduction from baseline in SES-CD Score). 

To evaluate the efficacy of treatment with LY3074828 on endoscopic remission at 
Weeks 12 and 52 (defined as a SES-CD score of <4 ileal-colonic disease or <2 for 
isolated ileal disease, and no subscore >1).

To evaluate the efficacy of treatment with LY3074828 on PRO remission at Weeks 12 
and 52 (defined as SF ≤2.5 and AP ≤1).
For endoscopic remission and PRO remission, subjects who do not achieve remission or who do 
not reach the assessment time point (Week 12 or 52) will be considered to be non-remitters for 
that particular endpoint at that time point and later time points if applicable. 
Details of the NRI are provided in Section 10.3.1.2.
Details of the analysis methods that will be utilized are provided in Section 10.3.1.
Additional analyses of the secondary efficacy endpoints may be considered and will be fully 
detailed in the SAP. 
10.3.3.3. Health Outcomes/Quality-of-Life Analyses
There are 10 additional self-administered questionnaires used to evaluate the effect of 
LY3074828 on health outcomes/quality-of-life measures in this trial:  PGRS, PGRC, IBDQ, 
SF-36, FACIT-Fatigue, 
 BMC, QIDS-SR16, 
 and 
.
Where appropriate, the total scores and sub-totals for individual dimensions collected will be 
summarized with means and 90% CI by time point and by treatment group.  The summary table 
will also include the change from baseline scores wherever applicable.
The intent-to-treat (ITT) population will be used for all health outcome analyses.
10.3.3.4. Exploratory Efficacy Analyses
There are a number of exploratory efficacy endpoints defined: 
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
To evaluate durability of endoscopic response and remission at Week 52

To evaluate PRO2 response (defined as a decrease in PRO2 of at least 5 points) at 
Weeks 12 and 52 

To evaluate PRO2 remission at Weeks 12 and 52 (defined as PRO2 <8)

To evaluate durability of PRO2 response and remission at Week 52

To evaluate composite endoscopic remission and PRO remission at Weeks 12 and 52

To evaluate durability of composite endoscopic remission and PRO remission at Week 52




To evaluate the effect of LY3074828 on BMC

To explore the development of any anti-LY3074828 antibodies that are formed and their 
effect on safety, PK, and pharmacodynamics (PD) of LY3074828

To evaluate changes in CDAI from baseline

To evaluate the effect of LY3074828 on QIDS-SR16 at Weeks 12 and 52.

To assess the psychometric properties (including reliability, validity, and responsiveness) 
of the
, BMC, 
.
Details of the analysis of exploratory endpoints will be fully detailed in the SAP.
10.3.4. Safety Analyses
The evaluation of safety and tolerability of treatment with LY3074828 is a secondary endpoint of 
this trial. 
Safety will be assessed by evaluating all reported AEs and changes in laboratory analytes, ECGs, 
and vital signs (including body weight). 
Duration of exposure to therapy during the treatment periods will be calculated for each subject 
and summarized by treatment group.  AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC), preferred term
(PT), severity, and relationship to investigational product. 
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.  
Treatment-related TEAEs are defined as events that are indicated by the investigator on the CRF 
to be related to treatment.  If a subject 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, and the 
most severe of the most related of those events will be included in the summary tables of 
treatment-related events.  TEAEs of interest may be presented. 
An overall summary of AEs will be provided for the study.  This includes the number and 
percentage of subjects who experienced TEAE, TEAE by maximum severity, death, SAE, TEAE 
related to study drug, discontinuations from the treatment due to an AE.  Treatment-emergent 
adverse events (all, by maximum severity, and TEAEs possibly related to study drug by the 
investigator), SAEs including deaths, AEs that lead to treatment discontinuation will be 
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summarized and analyzed by MedDRA SOC and PT or by PT alone.  Study periods may also be 
summarized separately for key safety displays.
Additional safety parameters include laboratory test results, ECGs (when reported, see 
Section 9.5.1), and vital sign measurements.  The parameters will be listed and summarized with 
standard descriptive statistics.  Change from baseline will also be summarized by randomized 
treatment where appropriate.
Assessment of immunogenicity with respect to safety will include comparison of subjects who 
experience TEAEs of systemic allergy/hypersensitivity and of injection-site reactions and who 
also develop treatment-emergent anti-LY3074828 antibody positivity with subjects who 
experience the same types of TEAEs but who remain treatment-emergent anti-LY3074828 
antibody negative.  Anti-LY3074828 antibody titers will also be evaluated in anti-LY3074828 
antibody positive subjects who experience these events.
Other safety parameters, including body weight, will be descriptively summarized by treatment 
groups.  Further analyses may be performed comparing the treatment groups.
All safety analyses will be fully detailed in the SAP. 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Analyses of data will be performed using a nonlinear mixed-effect modeling (NONMEM) 
approach as implemented in NONMEM software on a computer that meets or exceeds the 
minimum system requirements for this program.  It is possible that other validated equivalent 
software programs may be used if appropriate.  The version of any software used for the analysis 
will be documented.
Population PK analyses will be performed to characterize the PK of LY3074828.  These analyses 
will include model-based and graphical evaluations of the data.  Estimates of PK model 
parameters and covariate effects and corresponding 90% CI will be reported.
Analyses of exposure-response relationships will be conducted using both exploratory graphical 
approaches and model based approaches.  Exploratory graphical analysis approaches for 
SES-CD may consist of graphs showing the percentage of subjects who achieve a 50% reduction 
at different percentiles (for example, quartiles) of exposure of LY3074828 at Weeks 12 and 52. 
Measures of exposure may include population PK estimated average concentrations (Css,avg) or 
observed trough concentrations.  Model based analyses of SES-CD will utilize population 
exposure-response models, where maximum effect (Emax) or other model structures may be used 
to relate exposure to either the change in SES-CD score and/or the probability of achieving a 
50% reduction in SES-CD score.  These models may be used to evaluate subject factors that may 
impact the relationship between exposure and response.  Longitudinal exposure-response models 
for CDAI scores or subcomponents of the CDAI score (PRO2, SF, AP) may be developed, which 
relate the time course and magnitude of LY3074828 exposure to the time course and magnitude 
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Additional analyses may be conducted if they are deemed appropriate.  Further details on PK and 
PK/PD analyses will be provided in the PK/PD analysis plan.
10.3.6. Other Analyses
10.3.7. Interim Analyses
Planned interim analyses that may occur before the primary efficacy data lock include: 

when efficacy data from approximately 50% of subjects through Week 12 are available

when efficacy data from approximately 50% of subjects through Week 52 are available.
The purpose of all interim analyses will be to support further development planning.  The study 
will not be stopped for futility or efficacy and, as such, will not require an alpha penalty. 
Changes to the timing and number of interim analyses may occur.  Any changes to the planned 
analyses which occur prior to the primary endpoint analysis (100% of subjects through Week 12) 
will be fully captured in the SAP.  Additional analyses and snapshots of study data occurring 
after the primary endpoint data lock may be performed after an adequate number of subjects 
have completed 52 weeks of treatment.  To minimize any bias being introduced into the analysis 
of the study, the SAP and PK/PD analysis plan will be approved before the efficacy interim 
analysis is initiated.  
A limited number of pre-identified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan, prior to the interim or final database lock, in order to initiate the 
final population PK/PD model development processes for interim or final analyses.  Information 
that may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded.
Unblinding details are specified in the unblinding plan section of the SAP.
Interim assessments will be conducted by a sponsor Assessment Committee comprised of a 
limited number of preidentified team members who do not have direct site contact or data 
entry/validation responsibilities.
Ongoing monitoring of safety data (including AEs, SAEs, and selected laboratory 
measurements) will be continued throughout the study using blinded data.  Details of the trial 
level safety review (TLSR) are specified in the TLSR plan or a separate document.
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11.
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Stelara [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; 2014. Available at: 
www.stelarainfo.com/pdf/PrescribingInformation.pdf. Accessed 13 July 2016.
Vuitton L, Marteau P, Sandborn WJ, Levesque BG, Feagan B, Vermeire S, et al. IOIBD 
technical review on endoscopic indices for Crohn’s disease clinical trials. Gut. 2015. doi: 
10.1136/gutjnl-2015-309903. [Epub ahead of print].

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
6-MP
6-mercaptopurine
ADA
anti-drug antibodies
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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
abdominal pain
ASA
aminosalicylic
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AZA
azathioprine 
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the subject are not.
A double-blind study is one in which neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BMC
bowel movement count 
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
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.
CRF/eCRF
case report form/electronic case report form
CCI

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CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CSR
clinical study report
ECG
electrocardiogram
eCOA
electronic clinical outcome assessments
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy–Fatigue
FCP
fecal calprotectin
GCP
good clinical practice
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Council for Harmonisation
IgG
immunoglobulin G
IL
interleukin
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to gain 
further information about the authorized form.
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a subject (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the consequence 
that subjects allocated to a treatment group should be followed up, assessed, and analyzed 
as members of that group irrespective of their compliance to the planned course of 
treatment.

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IV
intravenous
IVRS/IWRS
interactive voice-response system/interactive web-response system
MedDRA
Medical Dictionary for Regulatory Activities
MTX
methotrexate
NOAEL
no-observed-adverse-effect level
NSAIDS
nonsteroidal anti-inflammatory drugs 
NRI
non-responder imputation
PCR
polymerase chain reaction
PD
pharmacodynamics
PGRC
Patient’s Global Rating of Change (Crohn’s disease)
PGRS
Patient’s Global Rating of Severity (Crohn’s disease)
PK
pharmacokinetics
PPD
purified protein derivative
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
PRO2
Patient Reported Outcome2:  a 2-item index comprised of the SF and AP items from the 
CDAI
PT
preferred term
Q4W
every 4 weeks
QIDS-SR16
Quick Inventory of Depressive Symptomatology–Self Report (16 Items)
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
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
CCI

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SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
TBL
total bilirubin level
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, which and does not necessarily have to have a causal relationship with 
this treatment.
TNF
tumor necrosis factor
UC
ulcerative colitis
ULN
upper limit of normal

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests 
Hematologya:
Clinical Chemistrya:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count
Chloride
Mean cell volume 
Bicarbonate
Mean cell hemoglobin concentration 
Potassium
Leukocytes
Total bilirubin
Neutrophils, segmented
Direct bilirubin
Lymphocytes
Alkaline phosphatase (ALP)
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Gamma-glutamyl transferase (GGT)
Platelets
Blood urea nitrogen
Cell morphology
Creatinine
Urinalysisa:
Uric acid
Specific gravity
Calcium
pH
Glucose (random) 
Protein
Albumin
Glucose
Total protein
Ketones
Total cholesterol
Blood
Creatine phosphokinase (CPK)
Urine leukocyte esterase
Nitrite
Other Tests:
QuantiFERON-TB Goldb or PPD
Biopsy material
high sensitivity C-reactive protein (hsCRP)
LY3074828 concentration (PK)
Pregnancyc
Follicle-stimulating hormone (FSH)
Human immunodeficiency virus antibodyd
Fecal calprotectin (FCP)
Hepatitis B surface antigend
Exploratory storage samples (whole blood, serum, 
Hepatitis B surface antibodyd
    plasma, colonic tissue, stool, RNA and DNA)
Hepatitis B core antibodyd
Anti-LY3074828 antibodies (immunogenicity)
Hepatitis B DNA PCR (if indicated)e
Clostridium difficile (C diff) d
Hepatitis C antibodyd
Hepatitis C RNA PCR (if indicated)
Hypersensitivity Markersf
Abbreviations:  PCR = polymerase chain reaction; PK = pharmacokinetics; PPD = purified protein derivative.
a
Unscheduled blood chemistry, hematology, & urinalysis panels may be performed at discretion of investigator as 
needed.  
b
Can be performed centrally or locally.
c
Serum pregnancy test.
d
Test required only at screening (Visit 1) to determine eligibility of subject for the study.  
CCI

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e
Hepatitis B PCR testing will be performed in subjects (i) who test positive for HBsAb, HBsAg, or Hepatitis B 
core antibody at baseline, and (ii) at protocol-specified intervals in patients with the following HBV serology 
status at baseline: HBsAg-,  HBcAb+, with no detectable HBV DNA at baseline.
f
See Section 7.8.2.2

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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the subject understands the potential risks and benefits of participating in 
the study

that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and 
prior to the administration of investigational product.

answering any questions the subject may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
subject’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Conference on Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF and Assent Form must be provided 
to Lilly before the study may begin at the investigative site(s).  Lilly or its representatives must 
approve the ICF, including any changes made by the ERBs, before it is used at the investigative 
site(s). All ICFs must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent form

relevant curricula vitae

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Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 3.1.4.
Investigator Information
Physicians with a specialty in gastroenterology will participate as investigators in this clinical 
trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator, selected by the sponsor, 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.  If this investigator is unable to fulfill this 
function, another investigator will be chosen by Lilly to serve as the CSR coordinating 
investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

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
be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic Clinical Outcome Assessments (eCOA) (for example, a rating scale) or other data 
reported directly by the subject (for example, event diary), or clinician (for example, tablet) are 
entered into an eCOA instrument (for example, personal digital assistant [PDA], tablet, or by 
means of IWRS) at the time that the information is obtained.  In these instances where there is no 
prior written or electronic source data at the site, the eCOA instrument record will serve as the 
source.
If eCOA records are stored at a third party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Any data for which the eCOA instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data collected by a third-party will be encoded by the third-party and stored 
electronically in the third-party’s database system.  Validated data will subsequently be 
transferred to the sponsor’s data warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse. 
Any data for which paper documentation provided by the subject will serve as the source 
document will be identified and documented by each site in that site’s study file.  
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
MCV
Prothrombin Time, INR
MCHC
WBC
Hepatic Serologiesa,b
Neutrophils, segmented
Hepatitis A antibody, total
Lymphocytes
Hepatitis A antibody, IgM
Monocytes
Hepatitis B surface antigen
Eosinophils
Hepatitis B surface antibody
Basophils
Hepatitis B Core antibody
Platelets
Hepatitis C antibody
RBC morphology
Hepatitis E antibody, IgG
Hepatitis E antibody, IgM
Hepatic Chemistrya
Total bilirubin
Anti-nuclear antibodya
Direct bilirubin
ALP
ALP isoenzymesa
ALT
AST
Anti-smooth muscle antibody (or anti-actin antibody)a
GGT
CPK
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspirate aminotransferase; 
CPK = creatinine phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = 
international normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Histologic Grading Indices
RHI Scorea
Histologic Finding
Range/Weight
Scores Allowed for Histologic Remission in 
CD
Chronic inflammatory infiltrate
(0-3)x1
0-3
Lamina propria neutrophils
(0-3)x2
0
Neutrophils in epithelium
(0-3)x3
0
Erosion or ulceration
(0-3)x5
0
Max RHI = 3 as long as LP neutrophils, 
neutrophils in epithelium, and erosion or 
ulceration are 0.
Abbreviations:  CD = Crohn’s disease; RHI = Robarts Histologic Index.
a
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, Shackelton LM, Walker CW, Nelson S, 
Vandervoort MK, Frisbie V, Samaan MA, Jairath V, Driman DK,  Geboes K, Valasek MA, Pai RK, Lauwers 
GY, Riddell R, Stitt LW, Levesque BG. Development and validation of a histological index for UC. Gut. 
2017;66(1):50-58.
GHAS Scorea
Histologic Finding
Range
Scores allowed for histologic remission
Epithelial damage
0-2
0
Architectural damage
0-2
0-2
Infiltration of mononuclear cells in the 
lamina propria
0-2
0-2
Infiltration of polymorphonuclear cells in 
lamina propria
0-2
0
Polymorphonuclear cells in epithelium
0-3
0
Presence of erosions and/or ulcers
0-1
0
Presence of granuloma
0-1
0-1
No. of biopsy specimens affected
0-3
0-3
MAX GHAS = 8 as long as epithelial damage, 
infiltration of polymorphonuclear cells in lamina 
propria, polymorphonuclear cells in epithelium, and 
erosions/ulcers are all 0.
Abbreviation:  GHAS = Global Histologic Disease Activity Score.
a
D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s 
disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology. 1998;114(2):262-267.
Note:  Minor changes to the indices above may be made without protocol amendment by including detailed 
description of the changes in the clinical study report.

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Appendix 6.
Additional Information on Systemic Drug 
Administration Reactions
Per investigator’s judgement, in the absence of other plausible and more likely etiology, a
systemic drug administration reaction is defined as the presence of any of the following 
symptoms (list is not exhaustive): 

Generalized urticaria or pruritus 

Angioedema at a location other than the injection site

Throat tightness

Difficulty swallowing/talking

Stridor

Chest tightness/dyspnea

Wheeze/bronchospasm

Hypoxemia

Sense of impending doom

Hypotension (systolic blood pressure change >20 mmHg from baseline)

Syncope

Cardiovascular collapse

Vomiting 

Abdominal pain

Diarrhea

Bladder/bowel incontinence

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Appendix 7.
Protocol Amendment I6T MC AMAG(b) 
Summary: A Phase 2, Multicenter, Randomized, 
Parallel-Arm, Placebo-Controlled Study of LY3074828 in 
Subjects with Active Crohn’s Disease (SERENITY)
Overview
Protocol I6T-MC-AMAG (A Phase 2, Multicenter, Randomized, Parallel-Arm, 
Placebo-Controlled Study of LY3074828 in Subjects with Active Crohn’s Disease
[SERENITY]) has been amended.  The new protocol is indicated by amendment (b) and will be 
used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Increased duration of all IV study drug administration to 2 hours. The 2-hour duration 
provides a rate (at the highest dose in Study AMAG) that approximates the rate being 
used across other mirikizumab studies.

Addition of a 1-hour post infusion observation period to allow adequate evaluation of 
potential hypersensitivity or infusion related reactions.

Added text on how to manage hypersensitivity events, including guidance on the 
collection of additional immunogenicity, PK, and hypersensitivity markers samples
following a possible infusion related hypersensitivity event.  Samples will be used to 
evaluate for possible etiologies of hypersensitivity reactions.

Clarification added that patients who experience serious adverse reactions (anaphylaxis, 
systemic hypersensitivity event) related to an infusion are to have their investigational 
product discontinued.

Clarification comments added to Schedule of Activities that additional immunogenicity, 
PK, and hypersensitivity markers samples may be collected in order to understand 
etiology of infusion related events

Correction in Schedule of Activities that V8 is to include Days 86-92, instead of Days 
85-92

Clarification comment added to Schedule of Activities that colonoscopy/SES-CD is 
performed only at the early termination visit if the visit occurs 16 weeks after the last 
colonoscopy.  Additionally, for patients who discontinue treatment but continue in the 
study the colonoscopy is to be performed within 4 weeks of last dose of study drug. The 
colonoscopy/SES-CD is not to be performed at Period 1, Period 3 or Visit 804.  

Replaced eligibility criteria of patients to proceed to Period 3 with clinical benefit as 
determined by the investigator.  Allowing patients with a clinical benefit as determined 
by the investigator to proceed to Period 3 allows assessment of long-term efficacy of 
mirikizumab in a broad population felt to be receiving benefit.

Clarification added that the intent of the treatment regimens is to keep the dosing within 
the visit windows and as close to every 4 weeks as possible.

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
Appendix 6 added that provides additional information on systemic drug administration 
reactions.

Appendix 2 removed Treg/TH17 from list of tests because it is not being performed in 
the study and added hypersensitivity markers.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Synopsis

Period 3 (Weeks 52 to 104):  All subjects having clinical benefit per investigator and 
continuing on study treatment may proceed to Period 3 and receive 300 mg SC LY3074828 
Q4W open-label starting at Week 52 through Week 104.  Clinical benefit is defined as 
having an endoscopic response (50% reduction from baseline in SES-CD score), or a 25% 
reduction from baseline in SES-CD score, combined with a 40% reduction from baseline in 
stool frequency (SF) or abdominal pain (AP) score.  Patients not receiving clinical benefit at 
Week 52 will discontinue treatment and will enter the Follow-Up period.

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2. Schedule of Activities
Screening and Period 1 [V1–V7] Schedule of Activities
Visit Number:
V1
Screening
V2
Baseline/ 
Randomization
V3
V4
V5
V6
V7
Comments
Week Relative to 
Study Drug Start
-4
0
2
4
6
8
11-12
All activities should be completed prior to any 
study drug administration unless otherwise stated 
below.
Visit Tolerance 
Interval (days)
≤28 
from 
V2
1± 3
15± 3 
29 ± 3 
43 ± 3
57 ± 3 
78-85  
Visit 1 procedures may be conducted over more 
than 1 day as long as all tasks are completed within 
the allowable visit tolerance (at least 3 days should 
be allowed for receipt of laboratory test results).  
LY3074828 PK 
Samples
Pre-dose and 
end of 
infusion
X
Pre-dose 
& end of 
infusion
X
Pre-dose 
& end of 
infusion
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be collected. 
See Section 7.8.2.2.
Immunogenicity 
Samples
X
X
X
X
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be collected. 
See Section 7.8.2.2.
Period 2 [V8–V18] Schedule of Activities
Visit Number:
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Comments
Week Relative to 
Study Drug Start
12-13
16
20
24
28
32
36
40
44
48
52
All activities should be completed prior to any 
study dose administration unless otherwise stated 
below.
Day with Visit 
Tolerance Interval
8586-
92
113
5
141
5
169 
5
197  
5
225  
5
253 
5
281 
5
309 
5
337 
5
365 
5
LY3074828 PK 
Samples
X
X
X
X
X
X
X
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be 
collected. See Section 7.8.2.2.
Immunogenicity 
Samples
X
X
X
X
X
Additional immunogenicity, PK, and 
hypersensitivity markers samples may be 
collected. See Section 7.8.2.2.

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Period 3 [V19–V31] Schedule of Activities
Visit Number:
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30
V31
Comments
Week Relative to 
Study Drug Start
56
60
64
68
72
76
80
84
88
92
96
100
104
All activities should be completed 
prior to any study drug 
administration unless otherwise 
stated below.
Day with Visit 
Tolerance Interval
393
5
421 
5
449
5
477 
5
505
5
533
5
561 
5
589
5
617
5
645
5
673
5
701
5
729
5
LY3074828 PK 
Samples
X
X
X
X
X
X
Additional immunogenicity, PK, 
and hypersensitivity markers 
samples may be collected.  See 
Section 7.8.2.2.
Immunogenicity 
Samples
X
X
X
X
X
X
Additional immunogenicity, PK, 
and hypersensitivity markers 
samples may be collected. See 
Section 7.8.2.2.
Unscheduled Visit / Follow-Up Period
Visit Number:
UVc
V801
V802
V803
V804/ETa
Comments
Week Relative to Study Drug Start
N/A
108
112
116
120
Visit Tolerance Interval (days)
N/A
757 5
785 5
813 5
841 5
Colonoscopy/ SES-CD
Xa
Performed only at early termination visit if the visit occurs 16 
weeks after last colonoscopy.  For patients who discontinue 
treatment but continue in the study perform colonoscopy 
within 4 weeks of last dose of study drug.  Colonoscopy/SES-
CD is not to be performed at Period 1, Period 3 or not at Visit 
804.  
LY3074828 PK Samples
X
X
X
X
Additional immunogenicity, PK, and hypersensitivity markers 
samples may be collected. See Section 7.8.2.2.
Immunogenicity Samples
X
X
X
X
Additional immunogenicity, PK, and hypersensitivity markers 
samples may be collected. See Section 7.8.2.2.

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5.1 Overall design

Period 3 (Weeks 52 to 104):  All subjects withhaving clinical benefit per investigator and 
continuing on study treatment may proceed to Period 3 and receive SC 300 mg SC
LY3074828 Q4W open-label starting at Week 52 through Week 104.  Clinical benefit is 
defined as having an endoscopic response (50% reduction from baseline in SES-CD score), 
or a 25% reduction from baseline in SES-CD score, combined with a 40% reduction from 
baseline in stool frequency (SF) or abdominal pain (AP) score.  Patients not receiving clinical 
benefit at Week 52 will discontinue treatment and will enter the Follow-Up period.
5.4 Scientific Rationale for Study Design
Period 3 is intended to provide extension therapy for subjects considered to be 
demonstratingreceiving clinical benefit and will provide longer term evaluation of safety and 
durability of clinical benefit.
7.1 Treatments Administered
Intravenous infusion of mirikizumab or placebo will occur over at least 2 hours.  All patients 
receiving IV infusion should be monitored for 1 hour or longer (per investigator discretion or 
local standard of care) after IV dosing is complete.  Sites must have resuscitation equipment, 
emergency medications, and appropriately trained staff available during the infusion and 
monitoring period.  Detailed instructions for investigational product administration will be 
provided separately by the sponsor. 
Subcutaneous administration of mirikizumab or placebo will be given in 3 injections.  Detailed 
instructions regarding supplies and preparation and handling of LY3074828 will be provided by 
the sponsor.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study, returning all unused medication to Lilly, or its designee, unless 
the sponsor and sites have agreed all unused medication is to be destroyed by the site, as 
allowed by local law.
7.8.2.2 Management of Hypersensitivity Events, Fever Associated Reactions, and
Infusion/Injection Site Reactions
During and after study drug administration, patients should be closely monitored for signs or 
symptoms of AEs, including hypersensitivity events, other fever associated reactions and 
infusion or injection site reactions.
Systemic Hypersensitivity Events
If a patient experiences a systemic hypersensitivity event involving the skin or mucous 
membranes, respiratory, cardiovascular, gastrointestinal, or urinary systems, during or up to 

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6 hours after an infusion of study drug, the following guidance should be followed (see 
Appendix 6 for additional information): 

Study drug infusion should be stopped immediately and appropriate supportive care 
provided according to local standard practice (for example, administration of epinephrine, 
anti-histamine, systemic steroids, and/or bronchodilators).

After the patient’s stabilization, additional immunogenicity, PK, and hypersensitivity 
markers samples should be collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

The patient should continue to be monitored until resolution or stabilization of the 
symptoms, as clinically appropriate. 

Permanently discontinue the study drug after a systemic drug administration reaction.  

If the patient discontinues study drug but remains in the study, management should 
follow as outlined in Section 8.1.1, and immunogenicity, PK, and hypersensitivity 
markers should be collected at 4 and 12 weeks after the event.

If the patient discontinues participation in the study, the patient should proceed to early 
termination procedures.  The patient will need to return after early termination procedures 
for 4 and 12 week immunogenicity, PK, and hypersensitivity markers collections.  

The medical monitor should be notified as soon as feasible.
Fever-Associated Reactions
If a patient experiences a fever-associated reaction consisting of headache, rigors and/or 
temperature >38°C (in the absence of signs or symptoms of a systemic hypersensitivity event) 
during or up to 6 hours after an infusion of study drug, the following guidance should be 
followed:

Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, nonsteroidal anti-inflammatory drugs [NSAIDS], anti-
pyretics or antihistamines).

Additional immunogenicity, PK, and hypersensitivity markers samples should be 
collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

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 
readminstration.

Patient should remain in observation, as is clinically appropriate for the patient’s 
symptoms.

Premedication prior to subsequent study drug administration may be considered, if 
judged by the investigator to be appropriate for the individual patient.  

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
If the patient discontinues study drug but remain in the study, management should follow 
as outlined in Section 8.1.1, and immunogenicity, PK, and hypersensitivity markers 
should be collected at 4 and 12 weeks after the event.

If the patient discontinues from the study early for any reason, they should return to 
complete 4 and 12 week follow-up immunogenicity, PK, and hypersensitivity markers 
collections.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity event.
Infusion Site Reactions
If a patient experiences an infusion site reaction, including urticaria, pruritus, or angioedema 
localized to the IV infusion site (in the absence of systemic hypersensitivity signs or symptoms), 
during or up to 6 hours after an infusion of study drug, the following guidance should be 
followed:

Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, NSAIDS, anti-pyretics or antihistamines).  

Additional immunogenicity, PK, and hypersensitivity markers samples should be 
collected as follows:
o
As soon as possible after the event occurs
o
4 weeks after the event
o
12 weeks after the event 

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 
readminstration.

Patient should remain in observation, as is clinically appropriate for the patient’s 
symptoms.

Premedication prior to subsequent study drug administration may be considered, if 
judged by the investigator to be appropriate for the individual patient.

If the patient discontinues from the study early for any reason, they should return to 
complete 4 and 12 week follow-up immunogenicity, PK, and hypersensitivity markers 
collections.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity event.
Injection Site Reactions
If a patient experiences an injection site reaction, including pain, erythema, urticaria, pruritus, or 
angioedema localized to the SC injection site (in the absence of systemic hypersensitivity signs 
or symptoms), the following guidance should be followed:

Patient should be instructed to contact the study site to report any symptoms experienced 
following a SC injection. 

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
Premedication prior to subsequent study drug administration may be considered as 
appropriate for the individual patient.

If the patient develops systemic hypersensitivity symptoms, they should be managed as 
described above for a systemic hypersensitivity event.
Because of the risk of an infusion reaction with any biological agent, all subjects should be 
monitored according to local standard of care.  Symptoms and signs that may occur as part of an 
infusion reaction include but are not limited to fever, chill, nausea, headache, bronchospasm, 
hypotension, angioedema, throat irritation, rash, pruritus, myalgia, and/or dizziness.  In the event 
that a significant infusion reaction occurs, the following guidance should be followed:  

the investigational product infusion should be slowed or stopped, depending on the 
symptoms or signs present:
o
supportive care should be employed in accordance with the symptoms or signs
o
if slowed or stopped, the infusion may be continued in accordance with signs and 
symptoms at the investigator’s discretion.
All biological agents carry the risk of an injection site and/or hypersensitivity general reaction.  
Therefore, all subjects should be closely monitored for signs or symptoms that could result from 
such reactions.  Sites should have appropriately trained medical staff and appropriate medical 
equipment available when subjects are receiving study drug.  If a subject experiences an acute 
hypersensitivity reaction after an injection of study drug, he or she should receive appropriate 
supportive care and consideration for any premedication; future injections will be agreed upon 
between the investigator and sponsor.
8.1.1 Permanent Discontinuation from Study Treatment
Subjects may discontinue treatment for any of the reasons noted above, or for other reasons such 
as the development of a serious adverse event. To better communicate patient flow throughout 
the study, different study period situations are provided below:

Subjects who discontinue the investigational product in Period 1 or Period 2 may
continue in the study according to the visit schedule (Section 2).

At Week 52/Visit 18, subjects who have previously discontinued the investigational 
product will continue to Visit 801 of the Follow-up Period.

Subjects who discontinue the investigational product in Period 3 may continue in Period 
3 and then proceed to Week 104/Visit 801 of the Follow-up Period.
Investigational product is to be discontinued for patients who experience clinically significant 
systemic hypersensitivity events (such as anaphylaxis) following administration of 
investigational product. 
Appendix 1 Abbreviations and Definitions
NSAIDS
nonsteroidal anti-inflammatory drugs 

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Appendix 2 Clinical Laboratory Tests
Other Tests:
Treg/Th17 
Biopsy material
QuantiFERON-TB Goldb or PPD
LY3074828 concentration (PK)
high sensitivity C-reactive protein (hsCRP)
Pregnancyc
Fecal calprotectin (FCP)
Human immunodeficiency virus antibodyd
Exploratory storage samples (whole blood, serum, 
Hepatitis B surface antigend
    plasma, colonic tissue, stool, RNA and DNA)
Hepatitis B surface antibodyd
Anti-LY3074828 antibodies (immunogenicity)
Hepatitis B core antibodyd
Clostridium difficile (C diff) d
Hepatitis B DNA PCR (if indicated)e
Hepatitis C antibodyd
Hepatitis C RNA PCR (if indicated)
Hypersensitivity Markersf
Abbreviations:  PCR = polymerase chain reaction; PK = pharmacokinetics; PPD = purified protein derivative;
Treg/Th17 = T-regulatory/T-helper 17 cells.
f
See Section 7.8.2.2.
Appendix 6 Additional Information on Systemic Drug Administration Reactions
Per investigator’s judgement, in the absence of other plausible and more likely etiology, a 
systemic drug administration reaction is defined as the presence of any of the following 
symptoms (list is not exhaustive): 

Generalized urticaria or pruritus 

Angioedema at a location other than the injection site

Throat tightness

Difficulty swallowing/talking

Stridor

Chest tightness/dyspnea

Wheeze/bronchospasm

Hypoxemia

Sense of impending doom

Hypotension (systolic blood pressure change >20 mmHg from baseline)

Syncope

Cardiovascular collapse

Vomiting 

Abdominal pain

Diarrhea

Bladder/bowel incontinence 
Appendix 67 Protocol Amendment I6T-MC-AMAG(ab) Summary
CCI
CCI

Leo Document ID = f44145a7-668f-4e3a-b25d-e07d0da9bd03
Approver: 
Approval Date & Time: 11-Jul-2018 19:02:28 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Jul-2018 19:02:28 GMT
Signature meaning: Approved
PPD
PPD