A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Arm, Placebo-Controlled Maintenance Study of Mirikizumab in Patients With Moderately to Severely Active Ulcerative Colitis (LUCENT 2)
Phase: PHASE3
Conditions: Ulcerative Colitis
Sponsor: Eli Lilly and Company

 
 
 
Protocol I6T-MC-AMBG(a) 
 
 
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Arm, Placebo-Controlled 
Maintenance Study of Mirikizumab in Patients with Moderately to Severely Active Ulcerative 
Colitis. 
LUCENT 2 
  
 
NCT03524092 
 
Approval Date: 12-Sep-2019 
 
 

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 0 7 4 8 2 8
Pr ot o c ol I 6 T -M C -A M B G ( a)
A P h a s e 3, M ulti c e nt er, R a n d o mi z e d, D o u bl e -Bli n d, 
P ar all el -Ar m, Pl a c e b o -C o ntr oll e d M ai nt e n a n c e St u d y  of 
Miri ki z u m a b
i n P ati e nt s wit h M o d er at el y t o S e v er el y Acti v e 
Ul c er ati v e C oliti s
L U C E N T 2
E U D R A C T A: 2 0 1 7 -0 0 3 2 3 8 -9 6
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
miri ki z u m a b ( L Y 3 0 7 4 8 2 8 ), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt 
wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Miri ki z u m a b ( L Y 3 0 7 4 8 2 8 )
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y :  1 3 -M ar -2 0 1 8
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
A p pr o v al D at e: 1 2- S e p- 2 0 1 9 G M T

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Table of Contents
Section
Page
Protocol I6T-MC-AMBG (a) A Phase 3, Multicenter, Randomized, 
Double-Blind, Parallel-Arm, Placebo-Controlled Maintenance Study 
of Mirikizumab in Patients with Moderately to Severely Active 
Ulcerative Colitis LUCENT 2.............................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................18
3.
Introduction ......................................................................................................................30
3.1.
Study Rationale............................................................................................................30
3.2.
Background..................................................................................................................30
3.2.1.
Disease State and Treatment Goals.......................................................................30
3.2.2.
Currently Available Treatments and Unmet Need.................................................30
3.2.3.
Interleukin-23 as a Therapeutic Target in Ulcerative Colitis .................................31
3.2.4.
Preclinical and Clinical Studies of Mirikizumab...................................................32
3.2.5.
Other IL-23 Targeted Therapies in Humans..........................................................33
3.3.
Benefit/Risk Assessment..............................................................................................33
4.
Objectives and Endpoints..................................................................................................35
5.
Study Design.....................................................................................................................41
5.1.
Overall Design .............................................................................................................41
5.2.
Number of Participants.................................................................................................45
5.3.
End of Study Definition ...............................................................................................45
5.4.
Scientific Rationale for Study Design...........................................................................45
5.5.
Justification for Dose ...................................................................................................46
6.
Study Population...............................................................................................................49
6.1.
Inclusion Criteria..........................................................................................................49
6.2.
Exclusion Criteria ........................................................................................................52
6.3.
Lifestyle Restrictions....................................................................................................54
6.4.
Screen Failures.............................................................................................................54
7.
Treatments........................................................................................................................55
7.1.
Treatments Administered .............................................................................................55
7.1.1.
Packaging and Labeling .......................................................................................58
7.2.
Method of Treatment Assignment ................................................................................58
7.2.1.
Selection and Timing of Doses.............................................................................58
7.3.
Blinding .......................................................................................................................58

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7.4.
Dosage Modification....................................................................................................59
7.5.
Preparation/Handling/Storage/Accountability...............................................................59
7.6.
Treatment Compliance .................................................................................................60
7.7.
Concomitant Therapy...................................................................................................60
7.8.
Treatment after the End of the Study............................................................................61
7.8.1.
Study Extensions..................................................................................................61
7.8.2.
Treatment after Study Completion........................................................................62
7.8.3.
Special Treatment Considerations ........................................................................62
7.8.3.1.
Premedication for Infusions............................................................................62
7.8.3.2.
Management of Hypersensitivity, Infusion-Related 
Events, Infusion Site Reactions and Injection Site 
Reactions........................................................................................................62
8.
Discontinuation Criteria ....................................................................................................64
8.1.
Discontinuation from Study Treatment.........................................................................64
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................64
8.1.2.
Temporary Interruption (Withholding) of Study Treatment ..................................66
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................67
8.2.
Discontinuation from the Study....................................................................................67
8.3.
Lost to Follow-Up........................................................................................................67
9.
Study Assessments and Procedures ...................................................................................68
9.1.
Efficacy Assessments...................................................................................................69
9.1.1.
Primary Efficacy Assessments .............................................................................69
9.1.1.1.
Primary Endpoint ...........................................................................................69
9.1.1.2.
Mayo Score ....................................................................................................69
9.1.1.3.
Endoscopy......................................................................................................71
9.1.1.4.
Endoscopic Biopsies.......................................................................................72
9.1.2.
Secondary Efficacy Assessments..........................................................................72
9.1.2.1.
Major Secondary Endpoints............................................................................72
9.1.2.1.1.
Histopathology Scoring Instruments .........................................................72
9.1.2.1.2.
Patient Reported Outcome Instruments .....................................................72
9.1.2.2.
Other Secondary Endpoints ............................................................................73
9.1.2.2.1.
Physician Reported Instrument..................................................................73
9.1.2.2.2.
PRO Instruments Used to Assess Secondary 
Endpoints..................................................................................................73
9.1.3.
Exploratory Endpoints..........................................................................................73
9.1.3.1.
Inflammatory Biomarkers...............................................................................73
9.1.3.2.
Extraintestinal Manifestations.........................................................................73
9.1.3.3.
PRO Instruments Used to Assess Exploratory Endpoints ................................74

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 4
L Y 3 0 7 4 8 2 8
9. 1. 4.
A p pr o priate ness of Assess me nts ..........................................................................7 4
9. 2.
A d verse E ve nts ............................................................................................................7 4
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................7 5
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................7 6
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................7 6
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................7 7
9. 3.
Treat me nt of O ver d ose ................................................................................................. 7 7
9. 4.
S afet y ...........................................................................................................................7 7
9. 4. 1.
Vi t al Si g ns........................................................................................................... 7 7
9. 4. 2.
Electr ocar di o gra ms ..............................................................................................7 8
9. 4. 3. 
L a b orat or y Tests..................................................................................................7 8
9. 4. 3. 1.
Pre g na nc y Testi n g ..........................................................................................7 8
9. 4. 4.
I mm u n o ge nicit y Assess me nts ..............................................................................7 9
9. 4. 5.
Ot her Tests ...........................................................................................................7 9
9. 4. 5. 1.
P h ysical E xa mi nat i on .....................................................................................7 9
9. 4. 5. 2.
T u berc ul osis ...................................................................................................7 9
9. 4. 5. 3.
He pati tis B......................................................................................................8 0
9. 4. 5. 4.
He p atitis C......................................................................................................8 1
9. 4. 5. 5.
De pressi o n a n d S ui ci dalit y .............................................................................8 1
9. 4. 5. 6.
St o ol  Testi n g ..................................................................................................8 2
9. 4. 6.
S af et y M o ni t ori n g ................................................................................................8 2
9. 4. 6. 1.
He pati c Safet y M o ni t ori n g..............................................................................8 2
9. 5.
P har mac o ki net ics .........................................................................................................8 3
9. 6.
P har mac o d y na mics ......................................................................................................8 3
9. 9.
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics ...................................................8 4
1 0.
Stati stical C o nsi derati o ns ..................................................................................................8 5
1 0. 1.
S a m ple Si ze Deter mi nat i on ..........................................................................................8 5
1 0. 2.
P o p ul at i ons f or A nal yses..............................................................................................8 5
1 0 . 3. Stati stical A nal yses ......................................................................................................8 6
1 0. 3. 1.
Ge neral Statist ical C o nsi derat i ons ........................................................................8 6
1 0. 3. 1. 1.
Missi n g Data I m p utati o n:
...............................................................................8 8
1 0. 3. 1. 2.
M ul tiplici t y C o ntr ol........................................................................................8 8
1 0. 3. 2.
Treat me nt Gr o u p C o m para bilit y ...........................................................................8 8
1 0. 3. 2. 1.
P ati e nt Dis p ositio n ..........................................................................................8 8
1 0. 3. 2. 2.
P ati e nt C haracteristics ....................................................................................8 9
C CI
C CI

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10.3.2.3.
Concomitant Therapy .....................................................................................89
10.3.3.
Efficacy Analyses ................................................................................................89
10.3.3.1.
Primary Analyses ...........................................................................................89
10.3.3.2.
Secondary Analyses........................................................................................90
10.3.3.3.
Exploratory Analyses .....................................................................................90
10.3.4.
Safety Analyses....................................................................................................90
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................90
10.3.6.
Evaluation of Immunogenicity .............................................................................91
10.3.7.
Other Analyses.....................................................................................................91
10.3.7.1.
Subgroup Analyses.........................................................................................91
10.3.8.
Interim Analyses..................................................................................................92
11.
References ........................................................................................................................93
12.
Appendices .......................................................................................................................99

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List of Tables
Table
Page
Table AMBG.2.1.
Schedule of Activities – Responders from Induction Study.......................19
Table AMBG.2.2.
Schedule of Activities – Nonresponders from Induction Study..................25
Table AMBG.4.1.
Objectives and Endpoints..........................................................................35
Table AMBG.7.1.
Treatment Regimens:  Induction Clinical Responders ...............................56
Table AMBG.7.2.
Treatment Regimens:  Induction Clinical Nonresponders..........................57
Table AMBG.9.1.
Endpoint Definitions in Study AMBG ......................................................69
Table AMBG.10.1.
Analysis Populations in Study AMBG ................................................86
Table AMBG.10.2.
Analysis Cohorts in Study AMBG ......................................................86

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List of Figures
Figure
Page
Figure AMBG.5.1.
Illustration of study design for Clinical
           Protocol I6T-MC-AMBG....................................................................44

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions......................................................................100
Appendix 2.
Clinical Laboratory Tests.............................................................................105
Appendix 3.
Study Governance Considerations................................................................108
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................113
Appendix 5.
Risk Factors for Latent Tuberculosis Infection.............................................115
Appendix 6.
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity......117
Appendix 7.
Patient-Reported Outcome Instruments........................................................119
Appendix 8.
Prohibited Medications................................................................................123
Appendix 9.
Permitted Medications with Dose Stabilization............................................126
Appendix 10.
Additional Information on Systemic Drug Administration Reactions ...........128
Appendix 11.
Additional Information on the Columbia Suicide Severity Rating Scale, 
and Quick Inventory of Depressive Symptomatology (Self Report) .............130
Appendix 12.
Protocol Amendment I6T-MC-AMBG(a) Summary A Phase 3, 
Multicenter, Randomized, Double-Blind, Parallel-Arm, Placebo-
Controlled Maintenance Study of Mirikizumab in Patients with 
Moderately to Severely Active Ulcerative Colitis
LUCENT 2..................................................................................................132

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1. Synopsis
Title of Study:
A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Arm, Placebo-Controlled 
Maintenance Study of Mirikizumab in Patients with Moderately to Severely Active Ulcerative 
Colitis.
Rationale:
Mirkizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that 
binds to the p19 subunit of interleukin-23 (IL-23), a cytokine that has been implicated in mucosal 
inflammation in ulcerative colitis (UC).  Study I6T-MC-AMBG (AMBG) is a Phase 3 clinical 
study that is designed to evaluate the safety and efficacy of mirikizumab in maintaining 
remission at Week 40 in patients who completed the 12-week induction study I6T-MC-AMAN 
(AMAN).
Objective(s)/Endpoints:
Objectives
Endpoints
Primarya

To test the hypothesis that mirikizumab is superior 
to placebo in achieving clinical remission at 
Week 40 (Week 52 of continuous therapy) among 
patients induced into clinical response with 
mirikizumab in Study AMAN 

The proportion of patients in clinical remission at 
Week 40, defined as:
o
Stool frequency (SF) subscore = 0, or SF = 1 
with a ≥1-point decrease from induction 
baseline, and
o
Rectal bleeding (RB) subscore = 0, and
o
Endoscopic subscore (ES) = 0 or 1 (excluding 
friability).
Major Secondarya,b

To evaluate the efficacy of mirikizumab compared 
to placebo in maintaining clinical remission at Week 
40 (Week 52 of continuous therapy) among patients 
induced into clinical remission with mirikizumab 

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e. 
durable clinical remission). Clinical remission is 
defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES subscore = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on endoscopic remission at Week 40
among patients induced into clinical response with 
mirikizumab

The proportion of patients in endoscopic 
remission at Week 40, defined as:
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving corticosteroid-free remission 
without surgery among patients induced into 
clinical response with mirikizumab and receiving 
corticosteroids at induction baseline

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 
o
No corticosteroid use for ≥12 weeks prior to 
Week 40 

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
To evaluate the efficacy of mirikizumab compared 
to placebo on histologic remission at Week 40
among patients induced into clinical response with 
mirikizumab

Proportion of patients in histologic remission at 
Week 40, as defined in the SAP 

To evaluate the efficacy of mirikizumab compared 
to placebo on stable maintenance of symptomatic 
remission among patients who were induced into 
clinical response and symptomatic remission with 
mirikizumab 

The proportion of patients in symptomatic 
remission defined as being in symptomatic 
remission for at least 7 out of 9 visits from Week 
4 to Week 36 and being in symptomatic remission 
at Week 40 among patients in symptomatic 
remission at Week 12 of Study AMAN.

Symptomatic remission is defined as:
o
SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline and
o
RB = 0

To evaluate the efficacy of mirikizumab compared 
to placebo on bowel movement urgency 
improvement at Week 40, among patients who: (1) 
had bowel urgency symptoms at induction baseline 
and (2) were induced into clinical response with  
mirikizumab 

The proportion of patients with bowel movement 
urgency improvement at Week 40 as defined in 
the study SAP.
Other Secondary

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission at Week 
40 among patients induced into clinical response 
with mirikizumab, in the subgroup of patients in 
whom biologic agents have failed or caused 
intolerance.

Clinical remission at Week 40 in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.  Clinical remission is defined 
as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving endoscopic remission at 
Week 40 among patients induced into clinical 
response with mirikizumab, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.

Endoscopic remission at Week 40 in the subgroup 
of patients in whom biologic agents have failed or 
caused intolerance.  Endoscopic remission is 
defined as: ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab as 
compared to placebo in maintaining clinical 
remission at Week 40 (Week 52 of continuous 
therapy) among patients induced into clinical 
remission with mirikizumab, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e. 
durable clinical remission) in whom biologic 
agents have failed or caused intolerance.  Clinical 
remission is defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

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
To evaluate the efficacy of mirikizumab compared 
to placebo in achieving corticosteroid-free remission 
without surgery among patients induced into 
clinical remission with mirikizumab and receiving 
corticosteroids at induction baseline

Corticosteroid-free remission without surgery at 
Week 40 among induction clinical remitters, 
defined as:
o
Clinical remission at Week 40, and
o
No corticosteroid use for ≥12 weeks prior to 
Week 40 

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission (using a 
more stringent ES) at Week 40  among patients 
induced into clinical response with  mirikizumab 

The proportion of patients with clinical remission 
(using a more stringent ES) at Week 40, with 
clinical remission defined as:
o
SF subscore = 0, or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0; and
o
ES = 0

To evaluate the efficacy of mirikizumab compared 
to placebo on achieving ES of 0 at Week 40 among 
patients induced into clinical response with 
mirikizumab 

The proportion of patients achieving ES = 0

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving an endoscopic response at 
Week 40 among patients induced into clinical 
response with mirikizumab

The proportion of patients in endoscopic 
response at Week 40 defined as:
o
A decrease in ES of ≥1 point from induction 
baseline.

To evaluate the treatment of mirikizumab compared 
with placebo on achieving the symptomatic 
components of clinical remission as defined by the 
modified Mayo score (MMS) at Week 40

The proportion of patients at Week 40 with SF 
subscore = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline

The proportion of patients at Week 40 with RB 
subscore = 0 

To evaluate the numerical value and change from 
baseline of the individual MMS subscores and the 
composite symptom subscore over time during 
maintenance between mirikizumab and placebo 

The numerical value and change from induction 
baseline in each of the following items:
o SF at each post baseline visit
o RB at each post baseline visit
o ES (Week 40 only)
o The sum of the SF and RB subscores at each 
post baseline visit

To evaluate the efficacy of mirikizumab compared 
to placebo in maintaining clinical response at 
Week 40 among patients induced into clinical 
response with mirikizumab

Clinical response at Week 40.  Clinical response 
is defined as:
o
A decrease in the MMS of ≥2 points and 
≥30% decrease from induction baseline, and
o
A decrease of ≥1 point in the RB subscore or 
an RB subscore = 0 or 1

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
To evaluate the efficacy of mirikizumab compared 
to placebo in reducing corticosteroid use over the 
course of maintenance treatment among patients 
induced into clinical response with mirikizumab 
and who entered the maintenance study on 
corticosteroids

The change and percent change in daily 
(average) corticosteroid dose (prednisone 
equivalent) from maintenance baseline to end of 
maintenance study (Week 40), among clinical 
responders to mirikizumab induction who 
entered the maintenance study on corticosteroids

To evaluate the effect of mirikizumab compared to 
placebo in health outcome endpoints at Week 40 

Change from induction baseline in:  
o IBDQ score at Week 40
o EQ-5D 5L index at Week 40
o WPAI:UC score at Week 40
o SF-36, V2 physical and mental component and 
domain scores at Week 40

To evaluate the efficacy of mirikizumab compared 
to placebo in inducing combined clinical remission, 
with normalization of fecal calprotectin, and 
histologic remission

The proportion of patients with all of the 
following at Week 40:
o In clinical remission, defined as:
o SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o RB subscore = 0, and
o ES = 0 or 1 (excluding friability)
o In histologic remission, as defined in the SAP
o Fecal calprotectin within limits of normal 

To evaluate the effect of mirikizumab compared to 
placebo on changes in inflammatory biomarkers 

Change from baseline at various time points in 
the following biomarkers:
o C-reactive protein 
o Fecal calprotectin

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving 24-week corticosteroid-free 
remission without surgery among patients induced 
into clinical response with mirikizumab and 
receiving corticosteroids at induction baseline 

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 
o
No corticosteroid use for ≥24 weeks prior to 
Week 40 

To evaluate the effect of mirikizumab compared to 
placebo on changes in Abdominal pain at Week 40 

Change from induction baseline at Week 40 in the 
Abdominal pain NRS score

To evaluate the efficacy of mirikizumab in reducing 
the proportion of patients undergoing surgery for 
UC, colectomy, and hospitalization for UC

The proportion of patients undergoing:
o Surgery for UC (including colectomy)
o Hospitalization for UC

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LY3074828

To evaluate the treatment of mirikizumab compared 
with placebo on achieving symptomatic remission 

The proportion of patients with symptomatic 
remission at various time points, defined as:
o
SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline, and
o
RB = 0

To evaluate key efficacy endpoints in biologic-failed 
and conventional-failed subgroups of patients 
(except those major secondary objectives noted 
above)

Key efficacy endpoints in the subgroup of 
patients in whom biologic agents have failed or
caused intolerance, and in whom conventional 
therapies have failed or caused intolerance

To evaluate key efficacy endpoints in the subgroups 
of patients on concomitant treatment for UC

Key efficacy endpoints in the subgroups of 
patients on concomitant medication for UC 
(corticosteroids and immunomodulators)

To evaluate clinical remission, clinical response and 
endoscopic remission rates with extended induction 
in patients who did not respond to mirikizumab with 
initial induction 

At Week 12 (Week 24 of continuous therapy), 
o Clinical remission, defined as:
o SF subscore = 0, or SF = 1 with a ≥1-
point decrease from induction baseline, 
and
o RB subscore = 0; and
o ES = 0 or 1 (excluding friability)
o Clinical response, defined as:
o A decrease in MMS of ≥2 points and 
≥30% decrease from induction baseline, 
and 
o A decrease of ≥1 point in the RB subscore 
from induction baseline or a RB score of 0 
or 1
o Endoscopic remission, defined as:
o ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on maintaining endoscopic remission at 
Week 40 among patients induced into endoscopic 
remission with mirikizumab

The proportion of patients in durable endoscopic 
remission at Week 40, defined asES = 0 or 1 
(excluding friability)

Evaluate the pharmacokinetics and 
pharmacokinetic/pharmacodynamic relationship of 
mirikizumab 

Clearance and volume of distribution of 
mirikizumab

Relationship between mirikizumab exposure and 
efficacy 

To evaluate the potential development of 
anti-mirikizumab antibodies and their potential 
relationship with efficacy, safety, and mirikizumab 
exposure

Relationship between TE-ADA and efficacy 

Relationship between TE-ADA and safety

Relationship between TE-ADA and mirikizumab 
pharmacokinetics

I6T-MC-AMBG(a) Clinical Protocol
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
To evaluate the efficacy of mirikizumab compared 
to placebo in UCEIS endoscopic remission at Week 
40 among patients induced into clinical response
with  mirikizumab 

The proportion of patients with a UCEIS score of 
≤1 at Week 40

To evaluate the efficacy of mirikizumab compared
to placebo in mucosal healing at Week 40 among 
patients induced into clinical response with 
mirikizumab 

The proportion of patients with mucosal healing 
at Week 40, defined as achieveing both:  
o
Histologic remission, as described in the 
SAP, and
o
Endoscopic remission,  defined as ES = 0 or 
1 (excluding friability)

To evaluate the effect of mirikizumab compared to 
placebo on change in fatigue at Week 40

Change from induction baseline at Week 40 in the 
Fatigue NRS score
Abbreviations:  EQ-5D 5L = European Quality of Life 5-Dimensions 5 Level; ES = endoscopic subscore; 
IBDQ = Inflammatory Bowel Disease Questionnaire; MMS = modified Mayo Score; NRS = numeric rating 
scale; RB = rectal bleeding; SAP = statistical analysis plan; SF = stool frequency; SF-36 = Medical Outcomes 
Study 36-Item Short Form Health Survey; UC = ulcerative colitis; WPAI:UC = Work Productivity and Activity 
Impairment Questionnaire Ulcerative Colitis; TE-ADA = treatment-emergent anti-drug antibody; 
UCEIS = Ulcerative Colitis Endoscopic Index of Severity.
a
All primary and major secondary endpoints will be evaluated for mirikizumab versus placebo.  All primary and 
major secondary endpoint analyses will utilize the multiplicity control approach based on ‘graphical multiple 
testing procedure’ to control the overall family-wise type I error rate at a 2-sided alpha level of 0.05.  The 
graphical multiple testing procedure described in Bretz et al. (2009) will be used.
b
The order of testing of the major secondary endpoints will be determined from the results of the statistical 
simulations. Therefore, the order of the secondary endpoints does not reflect the order of the statistical testing.

I6T-MC-AMBG(a) Clinical Protocol
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Summary of Study Design:
Study AMBG is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-arm study evaluating the safety and efficacy of 200 mg mirikizumab every 4 weeks 
(Q4W) subcutaneous (SC) in maintaining treatment response at Week 40 (that is, at Week 52 of 
continuous study drug treatment).
The study population includes patients with moderately to severely active UC who completed 
Study AMAN.  Study AMAN includes patients who have an inadequate response to, loss of 
response to, or are intolerant to conventional (nonbiologic) therapy for UC 
(“conventional-failed”), and those who have an inadequate response to, loss of response to, or 
are intolerant to biologic therapy for UC (“biologic-failed”).
Treatment Arms and Duration:  
Patients who achieved clinical response with blinded mirikizumab treatment during Study 
AMAN will be randomized 2:1 to blinded 200 mg mirikizumab Q4W SC or blinded placebo. 
Patients who responded to blinded placebo in their induction study will remain on blinded 
placebo in Study AMBG.  Open-label rescue therapy with 300 mg mirikizumab Q4W 
intravenous (IV) will be administered for 3 doses if these patients lose response.  
Patients who did not achieve clinical response with either blinded mirikizumab or blinded 
placebo during Study AMAN will receive open-label extended induction therapy with 300 mg 
mirikizumab Q4W IV administered for 3 doses. Patients who achieve delayed clinical response 
(defined using induction study baseline) will then receive open-label 200 mg mirikizumab Q4W 
SC.  Induction study nonresponders who do not achieve clinical response at Week 12 of Study 
AMBG will be discontinued.
Lead-in Period:  Visit [V] 1 (Week 0) should occur no more than 10 days from start of 
V5 (Week 12) of Study AMAN.  
Treatment Period:  40 weeks.  
Follow-up Period:  Up to 16 weeks.
Extension Period:  N/A. Patients who complete Study AMBG will be eligible for 
extension Study I6T-MC-AMAP.  
Continued Access Period: N/A.
Number of Patients:
Enrolled: Approximately 1044.
Statistical Analysis:
Assuming that 90% of patients complete Study AMAN (which is expected to randomize 
approximately 1160 patients), Eli Lilly and Company (Lilly) anticipates approximately 
1044 patients will enroll in Study AMBG. It is expected that approximately 470 of these patients 
will enter Study AMBG as clinical responders to mirikizumab and then will be randomized 2:1 

I6T-MC-AMBG(a) Clinical Protocol 
Page 16 
LY3074828 
to 200 mg mirikizumab SC (approximately 313 patients) and placebo (approximately 157 
patients).  Among the expected 470 mirikizumab clinical responders, approximately 180 
mirikizumab clinical remitters will be randomized to 200 mg mirikizumab SC (approximately 
120 patients) and placebo (approximately 60 patients).  This assumes that: 
 The induction study (AMAN, which has a mixed population with approximately 50% 
biologic-failed patients) is expected to have an overall clinical remission rate of 23% and 
response rate of 60% with mirikizumab. 
 75% of induction patients receive treatment with mirikizumab, based on a 3:1 
randomization ratio for the induction study. 
 10% dropout rate from induction to maintenance. 
The primary endpoint, clinical remission at Week 40, will be assessed on patients who achieved 
clinical response to mirikizumab induction treatment.  Assuming mirikizumab and placebo 
clinical remission rates of 47% and 27%, respectively, this study based on the 470 mirikizumab 
induction responders is expected to have >95% power to demonstrate that mirikizumab is 
superior to placebo by using a chi-square test with a 2-sided significance level of 0.05.  In 
addition, the sample size is expected to provide adequate power (>80%) to demonstrate that 
mirikizumab is superior to placebo for endoscopic remission, histologic remission, and 
corticosteroid-free remission at Week 40, among responders to mirikizumab induction treatment 
by using a chi-square test with a 2-sided significance level of 0.05.  
Summary statistics for continuous variables may include mean, standard deviation, median, and 
minimum and maximum values.  Categorical variables will be presented as counts and 
percentages.  Unless otherwise specified, variables will be analyzed in the original scale on 
which they are measured.  All hypothesis tests of treatment effects will be 2-sided, unless 
otherwise stated. 
For assessments of the primary endpoint and other categorical efficacy endpoints among induced 
responders, the Cochran-Mantel-Haenszel (CMH) chi-square test will be used to compare 
mirikizumab and placebo with stratification factors:  (a) previous biologic therapy failure (yes or 
no), (b) baseline corticosteroid use (yes or no), (c) region (North America/Europe/Other), (d) 
induction remission status (yes/no).  The CMH chi-square p-value and the relative risk along 
with its 95% 2-sided confidence interval will be provided. 
Treatment comparisons of continuous efficacy and health outcome variables with a single 
post-baseline time point will be made using analysis of covariance with:  (a) treatment group, 
(b) previous biologic therapy failure (yes or no), (c) corticosteroid use (yes or no), (d) region 
(North America/Europe/Other), (e) baseline value in the model, and (f) induction remission 
status. 
A prespecified multiple testing scheme based on graphical approach (Bretz et al. 2009, 2011) 
will be used to test the primary and major secondary hypotheses at overall family wise type 1 
error rate (FWER) of 0.05.  The graphical approach is a closed testing procedure, hence, it 
strongly controls the FWER across all endpoints (Alosh et al. 2014).  Details of the specific 
graphical testing scheme (including testing order, interrelationships, type I error allocation for 

I6T-MC-AMBG(a) Clinical Protocol
Page 17
LY3074828
the major secondary endpoints, and the associated propagation) will be prespecified in the 
statistical analysis plans (SAPs) prior to first unblinding of efficacy.
The Fisher exact test will be used to perform the between-treatment group comparisons for 
adverse events (AEs), discontinuations, and other categorical safety data.  The change from 
baseline in continuous vital signs, physical characteristics, and other continuous safety variables, 
including laboratory variables, will be summarized by visit and treatment.  Shift tables for 
categorical safety analyses (for example, “high” or “low” laboratory results) will also be 
produced.
No multiplicity control approach will be used for testing of other secondary endpoints.

I6T-MC-AMBG(a) Clinical Protocol
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2. Schedule of Activities

I6T-MC-AMBG(a) Clinical Protocol
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Table AMBG.2.1.
Schedule of Activities – Responders from Induction Study
Procedure
Randomized Maintenance Period
Post-
treatment 
Follow-up
Notes
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10 V11 N/A V997 801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV
ETV UV
LV or 
ETV
+4
LV  or 
ETV
+12/16b
Day and/or Visit 
Interval Tolerance
1a
29 
+/-7
57 
+/-7
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7 N/A N/A +/-10 +/-10
Informed consent
X
Patients may consent between the start of V5 of 
Study AMAN and before any procedures at 
V1/Week 0 are performed.
Inclusion and exclusion 
criteria
X
Can begin at Week 12 of induction and continue 
until dosing is initiated in Study AMBG.
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tobacco/nicotine use
Xc
X
X
X
X
IP Administration
IWRS/Randomization
X
IP SC administration
X
X
X
X
X
X
X
X
X
X
Rescue mirikizumab IV 
dosing
Xd
Xd:  Three Q4W IV rescue doses administered 
instead of SC dosing, if secondary loss of 
response (LOR) is confirmed.  The IV dosing 
must start no later than V8/Week 28.  The IV 
dosing visit window may shift if first rescue dose 
is given outside of SC dosing visit window.  
Rescue IV doses to be given Q4W with visit 
window tolerance of +/- 3 days.
Physical Examination 
Vital signs (T, BP, and 
PR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
Xc
X
X
X

I6T-MC-AMBG(a) Clinical Protocol
Page 20
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Procedure
Randomized Maintenance Period
Post-
treatment 
Follow-up
Notes
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10 V11 N/A V997 801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV
ETV UV
LV or 
ETV
+4
LV  or 
ETV
+12/16b
Day and/or Visit 
Interval Tolerance
1a
29 
+/-7
57 
+/-7
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7 N/A N/A +/-10 +/-10
Physical examination 
Xc
Xd
X
X
Xd
Xd:  A targeted physical exam to be performed as 
appropriate for patients with secondary LOR.  
Evaluate for EIMs
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 9.1.3.2.  
12-lead ECG
Xc
X
X
Laboratory Investigations
Urine pregnancy test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Only in women of childbearing potential.  Done 
locally and prior to dosing.  
HBV DNAd
Xc,d
Xd
Xd
Xd
Xd
Xd:  For patients who were HBsAg-, anti-HBc+, 
and HBV DNA not detected in Study AMAN.  
See Section 9.4.5.2.
Hematology
Xc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
Xc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid profilee
Xc
X
X
hsCRPe
Xc
X
X
FSH (optional in 
women to confirm 
nonchild-bearing 
potential)e
X
Optional, to confirm post-menopausal status in 
women ≥50 years with amenorrhea for >1 year.  
Serum and plasma for 
cytokines
Xc
X
X
X

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 3 0 7 4 8 2 8
Pr oce d ure
R a n d o mize d M ai nte n a nce Peri o d
P ost -
tre at me nt 
F oll o w -u p
N otes
Visit
V 1
V 2
V 3  
V 4  
V 5
V 6
V 7  
V 8  
V 9
V 1 0
V 1 1
N/ A
V 9 9 7
8 0 1 
8 0 2
Wee k 
0 
4 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6
4 0
L V
E T V
U V
L V or 
E T V
+4
L V  o r 
E T V
+12/16 b
D a y a n d/ or Visit 
I nter v al T oler a nce
1 a
2 9 
+/ - 7
5 7 
+/ - 7
8 5 
+/ - 7
1 1 3 
+/ - 7
1 4 1 
+/ - 7
1 6 9 
+/ - 7
1 9 7 
+/ - 7
2 2 5 
+/ - 7
2 5 3 
+/ - 7
2 8 1 
+/ - 7 N/ A
N/ A
+/ - 1 0 +/ - 1 0
P K assess me nt
X c
X  
X  
X d
X d
X  
X d
X d
X d
X  
X  
X d
X
Ser u m f or P K assess me nt 
 
  See Secti o n 9. 5 .  I n a d diti o n, 
patie nts wit h p ote ntial h y perse nsiti vit y or 
i nf usi o n-relate d e ve nt s h o ul d ha ve sa m ple ta ke n 
as s o o n as p ossi ble after e ve nt occ urs, at 4 a n d 
1 2 t o 1 6 wee ks after t he e ve nt. 
X d:  Patie nts wit h c o nfir me d sec o n dar y L O R 
s h o ul d ha ve sa m ples ta ke n pri or t o I V 
miri kiz u ma b resc ue d osi n g, a n d 4 a n d 1 2 wee ks 
after resc ue i nitiati o n.  
A D A assess me nt
X c
X  
X  
X d
X d
X  
X d
X d
X d
X  
X  
X d
X
See Secti o n 9. 4. 4 .  I n a d diti o n, patie nts wit h 
p ossi ble h y perse nsiti vit y or i nf usi o n -relate d 
e ve nt s h o ul d ha ve sa m ple ta ke n as s o o n as 
p ossi ble after e ve nt occ ur s, at 4 a n d 1 2 t o 1 6 
wee ks after t he e ve nt. 
X d:  Patie nts wit h c o nfir me d sec o n dar y L O R 
s h o ul d ha ve sa m ples ta ke n pri or t o I V 
miri kiz u ma b resc ue d osi n g, a n d 4 a n d 1 2 wee ks 
after resc ue i nitiati o n.  
Ser u m, plas ma a n d wh ole 
bl o o d f or e x pl orat or y 
bi o mar kers 
X c
X
X
X  
X
A d diti o n al P atie nt -Re p orte d Tests
C- S S R S, Self -Har m 
S u p ple me nt F or m, a n d 
Self -Har m “ F oll o w -U p” 
F or m
X
QI D S -S R 1 6
X c
X
X
X  
X
C CI

I6T-MC-AMBG(a) Clinical Protocol
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Procedure
Randomized Maintenance Period
Post-
treatment 
Follow-up
Notes
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10 V11 N/A V997 801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV
ETV UV
LV or 
ETV
+4
LV  or 
ETV
+12/16b
Day and/or Visit 
Interval Tolerance
1a
29 
+/-7
57 
+/-7
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7 N/A N/A +/-10 +/-10
Stool Samples
C. difficile testing
Xd
X
Xd
Xd:  Collection only at time of the first LOR 
assessment. 
Additional local stool testing (e.g., ova and 
parasites) is allowed at the investigator’s 
discretion.
Fecal calprotectin and 
exploratory fecal 
biomarkers
Xc
Xd
X
X
Xd
Xd: Collection at time of the first LOR 
assessment.  
Endoscopic Procedure
Endoscopy with biopsies
Xd
X
X
Xd
Xd:  At least 1 endoscopy is performed at Week 
40/ETV or if LOR is confirmed.  LOR 
confirmation based on endoscopy can only occur 
at a scheduled or unscheduled visit between V4 
and V8. Please refer to Section 9.1.1.3 for 
procedure clarification.
UC Activity Assessments
Patient diary device 
dispensed 
X
Patient diary compliance 
review
X
X
X
X
X
X
X
X
X
X
X
X
PGA
Xc
Xd
X
X
Xd
Xd:  Performed at the second of 2 LOR 
assessments which may occur at a scheduled or 
unscheduled visit, at least 7 days from first LOR 
assessment.  See Section 5.1.

I6T-MC-AMBG(a) Clinical Protocol
Page 23
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Procedure
Randomized Maintenance Period
Post-
treatment 
Follow-up
Notes
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10 V11 N/A V997 801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV
ETV UV
LV or 
ETV
+4
LV  or 
ETV
+12/16b
Day and/or Visit 
Interval Tolerance
1a
29 
+/-7
57 
+/-7
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7 N/A N/A +/-10 +/-10
Review modified Mayo 
Score
Xc
Xd
X
X
Xd
Xd:  Performed at the second of 2 LOR 
assessments which may occur at a scheduled or 
unscheduled visit, at least 7 days from first LOR 
assessment.  See Section 5.1.
Patient diary device 
collected
X
X
Health Outcome Assessment
IBDQ 
Xc
Xd
X
X
Xd
Xd:  To be performed for patients who have LOR 
confirmed by endoscopy before rescue dosing. 
EQ-5D 5L
Xc
Xd
X
X
Xd
PGRC
Xd
X
X
Xd
Xd:  To be performed for patients who have LOR 
confirmed by endoscopy before rescue dosing. 
SF-36
Xc
X
X
WPAI:UC
Xc
X
X

I6T-MC-AMBG(a) Clinical Protocol
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Footnotes for Table AMBG.2.1
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; anti-HBc+ = positive for anti-hepatitis B core antibody; BP = blood pressure; C-SSRS = 
Columbia-Suicide Severity Rating Scale; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EIM = extraintestinal manifestation; EQ-5D-5L = European 
Quality of Life 5-Dimension 5 Level; ETV = early termination visit; FSH = follicle-stimulating hormone; HBsAg- = negative for hepatitis B surface antigen; 
HBV = hepatitis B virus ; hsCRP = high-sensitivity C-reactive protein; IBDQ = Inflammatory Bowel Disease Questionnaire; IP = investigational product; IV = 
intravenous; IWRS = interactive web-response system; LOR = loss of response; LV = last visit; N/A = not applicable; PGA = Physician’s Global Assessment; 
PGRC = Patient’s Global Rating of Change; PK = pharmacokinetic; PR = pulse rate; Q4W = every 4 weeks; QIDS-SR16 = Quick Inventory of Depressive 
Symptomatology—Self-Report (16 Items); SC = subcutaneous; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; T = temperature; 
UV = unscheduled visit; V = visit; WPAI:UC = Work Productivity and Activity Impairment Questionnaire Ulcerative Colitis.
Notes: All activities should be completed prior to any study drug administration unless otherwise stated.  Last visit or ETV is last visit prior to entering long term 
extension Study AMAP or post-treatment follow-up.  Post-treatment follow-up visits should only occur if the patient is not proceeding to long term extension 
Study AMAP or if they discontinue treatment in Study AMBG early.
a
V1 (Week 0) should occur no more than 14 days from the start of the Visit 5/Week 12 visit of Study AMAN.
b
Patients who discontinue study drug with last dose administered IV will return for an LV +16 week post-treatment follow-up visit without a 12 week follow-
up.  Patients who discontinue study drug with last dose administered SC will return for an LV + 12 week post-treatment follow-up visit without a 16 week 
follow-up.
c
Results from Week 12 of Study AMAN will be used for Week 0 of this study.
d
Activity to be performed on a subpopulation of patients. See Notes column in table.
e
These tests will be run from the “chemistry” sample.

I6T-MC-AMBG(a) Clinical Protocol
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Table AMBG.2.2.
Schedule of Activities – Nonresponders from Induction Study
Procedure
Extended 
Induction
Open-Label Maintenance Period
Post-
treatment 
Follow-up 
Notes
Visit 
V1
V2
V3
V4a
V5
V6
V7
V8
V9 V10 V11
V997
801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV 
ETV
UV
LV 
+ 4
LV 
+12/16c
Day and/or Visit Interval 
Tolerance
1b
29 
+/-3
57 
+/-3
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7
N/A +/-10 +/-10
Informed consent
X
Patients may consent between the start of V5 of 
Study AMAN and before any procedures at 
V1/Week 0 are performed. 
Inclusion and exclusion 
criteria
X
Can begin at Week 12 of induction and continue 
until dosing is initiated in Study AMBG.
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tobacco/nicotine use
Xd
X
X
X
X
IP Administration
IWRS/Randomization
X
Open-label mirikizumab 
extended IV dosing
X
X
X
Open-label mirikizumab SC 
dosing
X
X
X
X
X
X
X
Physical Examination 
Vital signs (T, BP, and PR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
Xd
X
X
X
X
Physical examination 
Xd
X
X
Evaluate for EIMs
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 9.1.3.2.  
12-lead ECG 
Xd
X
X
Laboratory Investigations
Urine pregnancy test 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Only in women of childbearing potential.  Done 
locally and prior to dosing.  

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 2 6
L Y 3 0 7 4 8 2 8
Pr oce d ure
E xte n de d 
I n d ucti o n
O pe n -L a bel M ai nte n a nce Peri o d
P ost -
tre at me nt 
F oll o w -u p 
N otes
Visit 
V 1
V 2  
V 3
V 4 a
V 5
V 6  
V 7
V 8
V 9
V 1 0
V 1 1
V 9 9 7
8 0 1 
8 0 2
Wee k 
0 
4 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6
4 0
L V 
E T V
U V
L V 
+ 4
L V 
+12/16 c
Da y  a n d/ or Visit I nter val 
T olera nce
1 b
2 9 
+/ - 3
5 7 
+/ - 3
8 5 
+/ - 7
1 1 3 
+/ - 7
1 4 1 
+/ - 7
1 6 9 
+/ - 7
1 9 7 
+/ - 7
2 2 5 
+/ - 7
2 5 3 
+/ - 7
2 8 1 
+/ - 7
N/ A
+/ - 1 0 +/ - 1 0
H B V D N A e
X d,e
X e
X e
X e
X e
X e  F or patie nts w h o were H Bs A g -, a nti-H Bc +, 
a n d H B V D N A n ot detecte d at V 0 i n St u d y 
A M A N.  Se e Secti o n 9. 4. 5. 2 .
He mat ol o g y 
X d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y 
X d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Fasti n g li pi d pr ofile f
X d
X  
X
hs C R P f
X d
X
X  
X
F S H ( o pti o nal i n w o me n 
t o c o nfir m n o nc hil d-
beari n g p ote ntial) f
X
O pti o nal, t o c o nfir m p ost -me n o pa usal stat us i n 
w o me n ≥5 0 years wit h a me n orr hea f or > 1 year.  
Ser u m a n d plas ma f or 
c yt oki nes
X d
X
X
X  
X
P K assess me nt
X d
X  
X
X
X  
X  
X  
X
Ser u m f or P K assess me nt 
 
  See Secti o n 9. 5 .
I n a d diti o n, patie nts wit h p ote ntial 
h y perse nsiti vit y or i nf usi o n -relate d e ve nt s h o ul d 
ha ve sa m ple ta ke n as s o o n as p ossi ble after e ve nt 
occ urs, at 4 a n d 1 2 t o 1 6 wee ks after t he e ve nt.
A D A assess me nt
X d
X  
X
X
X  
X  
X  
X
See Secti o n 9. 4. 4 .
I n a d diti o n, patie nts wit h p ossi ble h y perse nsiti vit y 
or  i nf usi o n-r elate d e ve nt s h o ul d ha ve sa m ple 
ta ke n as s o o n as p ossi ble after e ve nt occ urs, at 4 
a n d 1 2 t o 1 6 wee ks after t he e ve nt.
Ser u m, plas ma a n d w h ole 
bl o o d f or e x pl orat or y 
bi o mar kers
X d
X
X
X  
X
C CI

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Procedure
Extended 
Induction
Open-Label Maintenance Period
Post-
treatment 
Follow-up 
Notes
Visit 
V1
V2
V3
V4a
V5
V6
V7
V8
V9 V10 V11
V997
801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV 
ETV
UV
LV 
+ 4
LV 
+12/16c
Day and/or Visit Interval 
Tolerance
1b
29 
+/-3
57 
+/-3
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7
N/A +/-10 +/-10
Additional Patient-Reported Tests
C-SSRS, Self-Harm 
Supplement Form, and 
Self-Harm “Follow-Up” 
Form
X
QIDS-SR16
Xd
X
X
X
X
Stool Samples
C. difficile testing
X
Xe
X
Xe:  Should be performed if clinical response is 
not achieved with extended induction. 
In addition, may be performed if loss of clinical
benefit, per investigator discretion, on OL SC 
maintenance dosing.
Additional local stool testing (e.g., ova and 
parasites) is allowed at the investigator’s 
discretion. V1 C. difficile testing does not need to 
be completed before the patient can start study 
drug therapy. 
Fecal calprotectin and 
exploratory fecal 
biomarkers
Xd
X
X
X
Endoscopic Procedure
Endoscopy with biopsies
X
X
X
Please refer to Section 9.1.1.3 for procedure 
clarification.
UC Activity Assessments
Patient diary device 
dispensed 
X

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Procedure
Extended 
Induction
Open-Label Maintenance Period
Post-
treatment 
Follow-up 
Notes
Visit 
V1
V2
V3
V4a
V5
V6
V7
V8
V9 V10 V11
V997
801
802
Week 
0
4
8
12
16
20
24
28
32
36
40
LV 
ETV
UV
LV 
+ 4
LV 
+12/16c
Day and/or Visit Interval 
Tolerance
1b
29 
+/-3
57 
+/-3
85 
+/-7
113 
+/-7
141 
+/-7
169 
+/-7
197 
+/-7
225 
+/-7
253 
+/-7
281 
+/-7
N/A +/-10 +/-10
Patient diary compliance 
review
X
X
X
X
X
X
X
X
X
X
X
X
PGA
Xd
X
X
X
Review Modified Mayo 
Score
Xd
X
X
X
In addition, may be performed if loss of clinical 
benefit, per investigator discretion, on OL SC 
maintenance dosing
Patient diary device 
collected
X
X
Health Outcome Assessments
IBDQ
Xd
X
X
X
EQ-5D 5L
Xd
X
X
X
PGRC
X
X
X
SF-36
Xd
X
X
WPAI:UC
Xd
X
X

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Footnotes for Table AMBG.2.2
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; anti-HBc+ = positive for anti-hepatitis B core antibody; BP = blood pressure; C-SSRS = 
Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EIM = extraintestinal manifestation; EQ-5D 5L = European Quality of Life 5-Dimension
5 Level; ETV = early termination visit; FSH = follicle-stimulating hormone; HBsAg- = negative for hepatitis B surface antigen; HBV = hepatitis B virus; 
hsCRP = high-sensitivity C-reactive protein; IBDQ = Inflammatory Bowel Disease Questionnaire; IP = investigational product; IV = intravenous; IWRS = 
interactive web-response system; LV = last visit; N/A = not applicable; PGA = Physician’s Global Assessment; PGRC = Patient’s Global Rating of Change; 
PK = pharmacokinetic; PR = pulse rate; QIDS-SR16 = Quick Inventory of Depressive Symptomatology—Self-Report (16 Items); SC = subcutaneous; 
SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; T = temperature; UV = unscheduled visit; V = visit; WPAI:UC = Work Productivity 
and Activity Impairment Questionnaire Ulcerative Colitis.
Notes:  All activities should be completed prior to any study drug administration unless otherwise stated.  Last visit or ETV is last visit prior to entering long term
extension Study AMAP or post-treatment follow-up.  Post-treatment follow-up visits should only occur if the patient is not proceeding to long term extension 
Study AMAP or if they discontinue treatment in Study AMBG early (i.e. patients who do not achieve delayed clinical response).
a
For patients who cannot continue beyond V4 because they did not achieve delayed clinical response, ETV activites that are performed as part of V4 do not 
need to be repeated. Only those ETV activities that are not part of V4 should be completed during the ETV.
b
V1 (Week 0) should occur no more than 14 days from the start of the Visit 5/Week 12 visit of Study AMAN.
c
Patients who discontinue study drug with last dose administered IV will return for an LV +16 week post-treatment follow-up visit without a 12 week follow-
up.  Patients who discontinue study drug with last dose administered SC will return for an LV + 12 week post-treatment follow-up visit without a 16 week 
follow-up.
d
Results from V5 (Week 12) of Study AMAN will be used for Week 0 of this study.
e
Activity to be performed on a subpopulation of patients. See Notes column in table.
f
These tests will be run from the “chemistry” sample

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3. Introduction
3.1.
Study Rationale
Mirikizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody 
that binds to the p19 subunit of interleukin-23 (IL-23), a cytokine that has been implicated in 
mucosal inflammation.  Study I6T-MC-AMBG (AMBG) is a Phase 3 clinical study that is 
designed to evaluate the safety and efficacy of mirikizumab in maintaining remission of 
ulcerative colitis (UC) at Week 40 in patients who completed the 12-week induction study
I6T-MC-AMAN (AMAN).  Study AMAN includes patients with moderate to severely active UC
who have an inadequate response to, loss of response to, or are intolerant to conventional 
(nonbiologic) therapy for UC (“conventional-failed”), and those who have an inadequate 
response to, loss of response to, or are intolerant to biologic therapy for UC (“biologic-failed”).  
3.2.
Background
3.2.1. Disease State and Treatment Goals 
Ulcerative colitis is a chronic disease of unknown etiology that is characterized by inflammation 
of the rectum and colon.  Symptoms include diarrhea, rectal bleeding (RB), urgency, and 
tenesmus (a feeling of incomplete evacuation of the rectum after defecation).  Ulcerative colitis
has a relapsing-remitting course, meaning that many patients have intermittent disease flares that 
are interspersed with periods of remission.  Treatment goals in UC include induction of 
remission (typically within a 6 to 12 week time frame) and maintenance of remission in the 
longer term (assessed over 52 weeks of continuous treatment in clinical trials).  In both clinical 
practice and clinical trials, clinical response and clinical remission are assessed by a combination 
of endoscopy (improvement in the endoscopic appearance of the mucosa and healing of ulcers) 
and patient-reported outcomes (PROs), including a reduction in stool frequency (SF) and a 
resolution of RB (Levesque et al. 2015).  Control of intestinal inflammation in UC is also 
associated with a reduction in the risk of hospitalization, colectomy and, in the longer term, 
UC-associated dysplasia and colorectal cancer.
3.2.2. Currently Available Treatments and Unmet Need 
Medications used for the treatment of UC include 5-aminosalicylic acid (5-ASA)–containing 
medications (sulfasalazine, mesalazine, balsalazide, olsalazine), corticosteroids, 
immunomodulators such as azathioprine (AZA) and 6-mercaptopurine (6-MP), and biologic 
medications.  A significant proportion of patients with moderately to severely active UC may 
have an inadequate response to medicines such as 5-ASAs or corticosteroids, be unable to 
maintain a clinical response to 5-ASAs or AZA, or be unable to discontinue corticosteroids 
without a relapse in disease activity (reviewed in Dignass et al. 2012).  Many of these patients 
require additional treatment with the next line of therapy, which could include medical treatment 
with a biologic medication or surgical treatment with a colectomy.  Biologics, including 
antitumor necrosis factor (TNF) antibodies (infliximab, adalimumab, golimumab) and 
vedolizumab, an anti-α4β7 integrin antibody, are indicated for the treatment of UC in patients 
who fail to respond to, have an inadequate response to, or are intolerant to other medications 

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

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3.2.4. Preclinical and Clinical Studies of Mirikizumab
Mirikizumab binds to the IL-23p19 subunit of human IL-23 and prevents binding of IL-23 to the 
IL-23R, neutralizing the activity of human IL-23 in vitro.  Mirikizumab also neutralizes human 
IL-23 in vivo, ameliorating the development of psoriasis-like skin inflammation in mice 
following subcutaneous (SC) injection of human IL-23.  Mirikizumab does not prevent IL-12 
signaling in vitro.
LSN2479016 is the mouse anti-mouse surrogate antibody for mirikizumab.  This was developed 
to enable preclinical testing in mice, as mirikizumab does not cross-react with mouse IL-23.  
LSN2479016 inhibits the development of skin inflammation in the imiquimod-induced 
psoriasis-like mouse model, inhibits the development of colonic inflammation in the CD45RBhi
adoptive transfer mouse model of colitis, and reduces the development of curdlan-induced 
spondyloarthritis and Crohn’s disease-like intestinal inflammation in SKG mice.  Additional 
preclinical data are summarized in the Investigator’s Brochure (IB).
A number of clinical studies of mirikizumab have been completed or are currently ongoing in 
patients with psoriasis, UC, and Crohn’s disease.
Study I6T-MC-AMAA (AMAA) is a Phase 1, single-dose administration (up to 600 mg), 
dose-escalation study that included 40 subjects with psoriasis and 5 healthy controls.  Efficacy
data from this study show improvement of psoriasis at Week 12, as assessed by the Psoriasis 
Area and Severity Index (PASI), after a single dose of mirikizumab in the higher-dose cohorts.
Study 16T-MC-AMAF (AMAF) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with psoriasis, for which preliminary primary analysis results are 
available.  In Study AMAF, patients with moderate-to-severe plaque psoriasis received placebo 
(n = 52) or mirikizumab 30 mg (n = 51), 100 mg (n = 51) or 300 mg (n = 51) SC at Weeks 0 
and 8.  The primary objective was to evaluate the superiority of mirikizumab over placebo in 
achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) response at 
Week 16.  The primary efficacy end point at Week 16 was met for each dose group with PASI 90 
responses of 0%, 29.4% (p<.01), 58.8% (p<.001) and 66.7% (p<.001), respectively, for patients 
treated with placebo and mirikizumab 30 mg, 100 mg and 300 mg (Reich et al. 2017a). 
Study 16T-MC-AMAC (AMAC) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with moderate-to-severe UC, for which preliminary primary analysis 
results are available.  Patients with moderately to severely active UC received placebo (n=63) or 
mirikizumab 50 mg (n = 63), 200 mg (n = 62) or 600 mg (n = 61) intravenous (IV) at Weeks 0, 4 
and 8.  Exposure-based dose adjustments were applied in 2 treatment groups.  Based on plasma 
concentrations of mirikizumab, dose levels in subjects in the 50 mg and 200 mg groups could be 
increased at the Week 4 and Week 8 visits if the projected trough concentrations for those visits 
fell below prespecified thresholds: 73% of patients in the 50 mg mirikizumab group and 44% of 
patients in 200 mg mirikizumab group experienced exposure-based dose adjustments before 
Week 12, resulting in group mean doses of 100 mg and 250 mg, respectively in these groups.  
The 600-mg dose group remained on a fixed dose throughout the induction period. The primary 
efficacy endpoint was clinical remission at Week 12.  Clinical remission rates at Week 12 were 

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4.8%, 15.9% (p=.07), 22.6% (p<.01), and 11.5% (p=.14) for patients treated with placebo and 
mirikizumab 50 mg, 200 mg, and 600 mg, respectively.  Clinical response rates at Week 12 were 
20.6%, 41.3%, 59.7%, and 49.2% for patients treated with placebo and mirikizumab 50 mg, 200 
mg, and 600 mg, respectively.  Endoscopic healing rates (ES=0 or 1, excluding friability; termed
“endoscopic remission” in this protocol) were numerically higher in the 50-mg mirikizumab 
group (23.8%) and 200-mg mirikizumab group (30.6%) compared to placebo (6.3%).  
Symptomatic remission rates were numerically higher in the 200-mg mirikizumab group 
(58.1%,) and 600-mg mirikizumab group (45.9%) compared to placebo (20.6%).
Study 16T-MC-AMAG (AMAG) is a Phase 2, placebo-controlled, double-blind clinical trial of 
mirikizumab in patients with active Crohn’s disease.  At the time of writing, this study is
ongoing.
Additional clinical trial data are summarized in the IB.
3.2.5. Other IL-23 Targeted Therapies in Humans
IL-23-targeted therapy is the mechanism of action for several compounds under development for 
the treatment of inflammatory diseases, including the human IL-12 and IL-23 antagonist,
ustekinumab, which is a monoclonal antibody against IL-12p40, and the human IL-23 
antagonists, guselkumab, risankizumab, tildrakizumab, and brazikumab, which are monoclonal 
antibodies against IL-23p19.
Ustekinumab binds IL-12p40, the subunit common to both IL-12 and IL-23, targeting both 
cytokines, rather than IL-23 specifically.  Ustekinumab was the first biologic therapy with an 
anti-IL-23 action to show clinical benefit in psoriasis (Leonardi et al. 2008; Papp et al. 2008), 
psoriatic arthritis (Gottlieb et al. 2009), and Crohn’s disease (Sandborn et al. 2012b; Feagan et al.
2016).  Blockade of the IL-12 pathway may prevent type 1 T helper cell (Th1)-induced inhibition 
of Th17 cell development, thus potentially limiting the clinical activity of IL-12p40-targeting 
antibodies.  Experimental studies suggest that blocking the IL-23/Th17/IL-17 immune axis, 
without blocking the IL-12/Th1/IFN-γ axis, is sufficient to treat autoimmune inflammation 
(Monteleone et al. 2009).
To date, guselkumab, an IL-23p19 antibody, has been approved for the treatment of psoriasis,
and other agents specifically targeting the IL-23p19 subunit, including mirikizumab, have 
demonstrated clinical activity in psoriasis (Sofen et al. 2014; Kopp et al. 2015; Krueger et al. 
2015; Papp et al. 2015; Blauvelt et al. 2017; Papp et al. 2017; Reich et al. 2017b).  IL-23p19 
inhibition is also under investigation for the treatment of inflammatory bowel disease and several 
anti-IL-23p19 antibodies have shown efficacy in the treatment of Crohn’s disease (Deepak and 
Sandborn 2017; Feagan et al. 2017; Sands et al. 2017).
3.3.
Benefit/Risk Assessment
Ulcerative colitis remains an important public health challenge.  The data for currently available 
treatments demonstrate the unmet need for new medications for UC (Section 3.2.2), and 
published literature supports the concept of IL-23 as a therapeutic target for UC therapies 
(Section 3.2.3).  Based on data from the Phase 2 study of mirikizumab in patients with UC 

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(Study AMAC, Section 3.2.4), potential benefits to patients who may receive mirikizumab while 
participating in Study AMBG may be reasonably anticipated.
At the time of this benefit/risk assessment, evaluation of unblinded safety data from the 
completed or ongoing clinical studies, including the unblinded period of the Study AMAC, 
which tests mirikizumab doses up to 600 mg IV Q4W, have not revealed any dose-related safety 
or tolerability concerns. In addition, evaluation of blinded safety data in ongoing studies in 
psoriasis, UC, and Crohn’s disease with doses up to 200/300 mg SC Q4W administered up to 92 
weeks, and up to 1000 mg IV Q4W for up to 52 weeks have not revealed safety or tolerability 
concerns. Across ongoing studies, immediate hypersensitivity reactions, including serious 
nonfatal anaphylaxis, have been reported at the onset or during IV infusion of mirikizumab. As 
noted in the IB, such reactions are considered by the sponsor to be related to mirikizumab and 
hence have been identified as adverse drug reactions (ADRs).  Consult the most current IB for 
information regarding ADRs and potential risks with mirikizumab.  
Adverse events of special interest (AESIs)—which are not necessarily ADRs but are of special 
interest based on standard drug registration topics, safety findings from previous studies in 
development program, potential risks associated with biologic immunomodulators as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations—are noted in Section 9.2.2 of this protocol.  For all AESIs, including 
hypersensitivity events, the protocol and IB provide monitoring or management guidance to the 
investigator.  In addition, an independent, external data monitoring committee (DMC) will 
review clinical trial data at prespecified, regular intervals during the study (Section 10.3.8).  This 
independent assessment of clinical trial data will contribute to the overall ongoing evaluation and 
management of potential risks associated with mirikizumab administration.
The dose levels and regimens to be used in Study AMBG were chosen based on nonclinical 
safety data and on analyses of safety, efficacy, and pharmacokinetic (PK) data from the primary 
analysis of Study AMAC (Section 5.5).
In summary, the efficacy and safety data from the Phase 2 UC study support the continued 
clinical development of mirikizumab as a treatment for patients with UC.
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated adverse events (AEs) of mirikizumab are to be found in the IB.

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4. Objectives and Endpoints
Table AMBG.4.1 shows the objectives and endpoints of the study.
Table AMBG.4.1.
Objectives and Endpoints
Objective(s)/Endpoints:
Objectives
Endpoints
Primarya

To test the hypothesis that mirikizumab is superior 
to placebo in achieving clinical remission at 
Week 40 (Week 52 of continuous therapy) among 
patients induced into clinical response with 
mirikizumab in Study AMAN 

The proportion of patients in clinical remission at 
Week 40, defined as:
o
Stool frequency (SF) subscore = 0, or SF = 1 
with a ≥1-point decrease from induction 
baseline, and
o
Rectal bleeding (RB) subscore = 0, and
o
Endoscopic subscore (ES) = 0 or 1 (excluding 
friability).
Major Secondarya,b

To evaluate the efficacy of mirikizumab compared 
to placebo in maintaining clinical remission at Week 
40 (Week 52 of continuous therapy) among patients 
induced into clinical remission with mirikizumab 

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e. 
durable clinical remission). Clinical remission is 
defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES subscore = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on endoscopic remission at Week 40
among patients induced into clinical response with 
mirikizumab

The proportion of patients in endoscopic 
remission at Week 40, defined as:
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving corticosteroid-free remission 
without surgery among patients induced into 
clinical response with mirikizumab and receiving 
corticosteroids at induction baseline

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 
o
No corticosteroid use for ≥12 weeks prior to 
Week 40 

To evaluate the efficacy of mirikizumab compared 
to placebo on histologic remission at Week 40
among patients induced into clinical response with 
mirikizumab

Proportion of patients in histologic remission at 
Week 40, as defined in the SAP 

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
To evaluate the efficacy of mirikizumab compared 
to placebo on stable maintenance of symptomatic 
remission among patients who were induced into 
clinical response and symptomatic remission with 
mirikizumab 

The proportion of patients in symptomatic 
remission defined as being in symptomatic 
remission for at least 7 out of 9 visits from 
Week 4 to Week 36 and being in symptomatic 
remission at Week 40 among patients in 
symptomatic remission at Week 12 of Study 
AMAN.

Symptomatic remission is defined as:
o
SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline and
o
RB = 0

To evaluate the efficacy of mirikizumab compared 
to placebo on bowel movement urgency 
improvement at Week 40, among patients who: (1) 
had bowel urgency symptoms at induction baseline 
and (2) were induced into clinical response with  
mirikizumab 

The proportion of patients with bowel movement 
urgency improvement at Week 40 as defined in 
the study SAP.
Other Secondary

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission at Week 
40 among patients induced into clinical response 
with mirikizumab, in the subgroup of patients in 
whom biologic agents have failed or caused 
intolerance.

Clinical remission at Week 40 in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.  Clinical remission is defined 
as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving endoscopic remission at 
Week 40 among patients induced into clinical 
response with mirikizumab, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.

Endoscopic remission at Week 40 in the subgroup 
of patients in whom biologic agents have failed or 
caused intolerance.  Endoscopic remission is 
defined as: ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab as 
compared to placebo in maintaining clinical 
remission at Week 40 (Week 52 of continuous 
therapy) among patients induced into clinical 
remission with mirikizumab, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e. 
durable clinical remission) in whom biologic 
agents have failed or caused intolerance.  Clinical 
remission is defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving corticosteroid-free remission 
without surgery among patients induced into 
clinical remission with mirikizumab and receiving 
corticosteroids at induction baseline

Corticosteroid-free remission without surgery at 
Week 40 among induction clinical remitters, 
defined as:
o
Clinical remission at Week 40, and
o
No corticosteroid use for ≥12 weeks prior to 
Week 40 

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
To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission (using a 
more stringent ES) at Week 40  among patients 
induced into clinical response with  mirikizumab 

The proportion of patients with clinical remission 
(using a more stringent ES) at Week 40, with 
clinical remission defined as:
o
SF subscore = 0, or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0; and
o
ES = 0

To evaluate the efficacy of mirikizumab compared 
to placebo on achieving ES of 0 at Week 40 among 
patients induced into clinical response with 
mirikizumab 

The proportion of patients achieving ES = 0

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving an endoscopic response at 
Week 40 among patients induced into clinical 
response with mirikizumab

The proportion of patients in endoscopic 
response at Week 40 defined as:
o
A decrease in ES of ≥1 point from induction 
baseline.

To evaluate the treatment of mirikizumab compared 
with placebo on achieving the symptomatic 
components of clinical remission as defined by the 
modified Mayo score (MMS) at Week 40

The proportion of patients at Week 40 with SF 
subscore = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline

The proportion of patients at Week 40 with RB 
subscore = 0 

To evaluate the numerical value and change from 
baseline of the individual MMS subscores and the 
composite symptom subscore over time during 
maintenance between mirikizumab and placebo 

The numerical value and change from induction 
baseline in each of the following items:
o SF at each post baseline visit
o RB at each post baseline visit
o ES (Week 40 only)
o The sum of the SF and RB subscores at each 
post baseline visit

To evaluate the efficacy of mirikizumab compared 
to placebo in maintaining clinical response at
Week 40 among patients induced into clinical 
response with mirikizumab

Clinical response at Week 40.  Clinical response 
is defined as:
o
A decrease in the MMS of ≥2 points and 
≥30% decrease from induction baseline, and
o
A decrease of ≥1 point in the RB subscore or 
an RB subscore = 0 or 1

To evaluate the efficacy of mirikizumab compared 
to placebo in reducing corticosteroid use over the 
course of maintenance treatment among patients 
induced into clinical response with mirikizumab 
and who entered the maintenance study on 
corticosteroids

The change and percent change in daily 
(average) corticosteroid dose (prednisone 
equivalent) from maintenance baseline to end of 
maintenance study (Week 40), among clinical 
responders to mirikizumab induction who 
entered the maintenance study on corticosteroids

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
To evaluate the effect of mirikizumab compared to 
placebo in health outcome endpoints at Week 40 

Change from induction baseline in:  
o IBDQ score at Week 40
o EQ-5D 5L index at Week 40
o WPAI:UC score at Week 40
o SF-36, V2 physical and mental component and 
domain scores at Week 40

To evaluate the efficacy of mirikizumab compared 
to placebo in inducing combined clinical remission, 
with normalization of fecal calprotectin, and 
histologic remission

The proportion of patients with all of the 
following at Week 40:
o In clinical remission, defined as:
o SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o RB subscore = 0, and
o ES = 0 or 1 (excluding friability)
o In histologic remission, as defined in the SAP
o Fecal calprotectin within limits of normal 

To evaluate the effect of mirikizumab compared to 
placebo on changes in inflammatory biomarkers 

Change from baseline at various time points in 
the following biomarkers:
o C-reactive protein 
o Fecal calprotectin

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving 24-week corticosteroid-free 
remission without surgery among patients induced 
into clinical response with mirikizumab and 
receiving corticosteroids at induction baseline 

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 
o
No corticosteroid use for ≥24 weeks prior to 
Week 40 

To evaluate the effect of mirikizumab compared to 
placebo on changes in Abdominal pain at Week 40 

Change from induction baseline at Week 40 in the 
Abdominal pain NRS score

To evaluate the efficacy of mirikizumab in reducing 
the proportion of patients undergoing surgery for 
UC, colectomy, and hospitalization for UC

The proportion of patients undergoing:
o Surgery for UC (including colectomy)
o Hospitalization for UC

To evaluate the treatment of mirikizumab compared 
with placebo on achieving symptomatic remission 

The proportion of patients with symptomatic 
remission at various time points, defined as:
o
SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline, and
o
RB = 0

To evaluate key efficacy endpoints in biologic-failed 
and conventional-failed subgroups of patients 
(except those major secondary objectives noted 
above)

Key efficacy endpoints in the subgroup of 
patients in whom biologic agents have failed or
caused intolerance, and in whom conventional 
therapies have failed or caused intolerance

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
To evaluate key efficacy endpoints in the subgroups 
of patients on concomitant treatment for UC

Key efficacy endpoints in the subgroups of 
patients on concomitant medication for UC 
(corticosteroids and immunomodulators)

To evaluate clinical remission, clinical response and 
endoscopic remission rates with extended induction 
in patients who did not respond to mirikizumab with 
initial induction 

At Week 12 (Week 24 of continuous therapy), 
o Clinical remission, defined as:
o SF subscore = 0, or SF = 1 with a ≥1-
point decrease from induction baseline, 
and
o RB subscore = 0; and
o ES = 0 or 1 (excluding friability)
o Clinical response, defined as:
o A decrease in MMS of ≥2 points and 
≥30% decrease from induction baseline, 
and 
o A decrease of ≥1 point in the RB subscore 
from induction baseline or a RB score of 0 
or 1
o Endoscopic remission, defined as:
o ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on maintaining endoscopic remission at 
Week 40 among patients induced into endoscopic 
remission with mirikizumab

The proportion of patients in durable endoscopic 
remission at Week 40, defined asES = 0 or 1 
(excluding friability)

Evaluate the pharmacokinetics and 
pharmacokinetic/pharmacodynamic relationship of 
mirikizumab 

Clearance and volume of distribution of 
mirikizumab

Relationship between mirikizumab exposure and 
efficacy 

To evaluate the potential development of 
anti-mirikizumab antibodies and their potential 
relationship with efficacy, safety, and mirikizumab 
exposure

Relationship between TE-ADA and efficacy 

Relationship between TE-ADA and safety

Relationship between TE-ADA and mirikizumab 
pharmacokinetics

To evaluate the efficacy of mirikizumab compared 
to placebo in UCEIS endoscopic remission at Week 
40 among patients induced into clinical response
with  mirikizumab 

The proportion of patients with a UCEIS score of 
≤1 at Week 40

To evaluate the efficacy of mirikizumab compared
to placebo in mucosal healing at Week 40 among 
patients induced into clinical response with 
mirikizumab 

The proportion of patients with mucosal healing 
at Week 40, defined as achieveing both:  
o
Histologic remission, as described in the 
SAP, and
o
Endoscopic remission,  defined as ES = 0 or 
1 (excluding friability)

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
To evaluate the effect of mirikizumab compared to 
placebo on change in fatigue at Week 40

Change from induction baseline at Week 40 in the 
Fatigue NRS score
Abbreviations:  EQ-5D 5L = European Quality of Life 5-Dimensions 5 Level; ES = endoscopic subscore; 
IBDQ = Inflammatory Bowel Disease Questionnaire; MMS = modified Mayo Score; NRS = numeric rating 
scale; RB = rectal bleeding; SAP = statistical analysis plan; SF = stool frequency; SF-36 = Medical Outcomes 
Study 36-Item Short Form Health Survey; UC = ulcerative colitis; WPAI:UC = Work Productivity and Activity 
Impairment Questionnaire Ulcerative Colitis; TE-ADA = treatment-emergent anti-drug antibody; 
UCEIS = Ulcerative Colitis Endoscopic Index of Severity.
a
All primary and major secondary endpoints will be evaluated for mirikizumab versus placebo.  All primary and 
major secondary endpoint analyses will utilize the multiplicity control approach based on ‘graphical multiple 
testing procedure’ to control the overall family-wise type I error rate at a 2-sided alpha level of 0.05.  The 
graphical multiple testing procedure described in Bretz et al. (2009) will be used.
b
The order of testing of the major secondary endpoints will be determined from the results of the statistical 
simulations. Therefore, the order of the secondary endpoints does not reflect the order of the statistical testing.

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5. Study Design
5.1.
Overall Design
Study AMBG is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-arm study evaluating the safety and efficacy of 200 mg mirikizumab Q4W SC in 
maintaining treatment response at Week 40 (that is, 52 weeks of continuous therapy).  The study 
also will evaluate the safety and efficacy of: (a) extended induction with 300 mg mirikizumab 
IV for patients who did not have a clinical response at Week 12 of Study AMAN, and (b) rescue 
induction for patients who achieved clinical response in Study AMAN and subsequently lose 
clinical response during Study AMBG.  
Patient Population
Patients with moderately to severely active UC who completed Study AMAN and who meet 
eligibility requirements will enroll in this study.  The study will enroll patients who achieve 
clinical response or clinical remission with blinded mirikizumab or placebo dosing in Study 
AMAN, as well as patients who do not achieve clinical response with blinded mirikizumab or 
placebo during Study AMAN.
Treatment Assignments
Maintenance study treatment assignment will be dependent on whether patients responded to 
study drug dosing in AMAN and whether they experience a loss of response (LOR) during this 
study as follows:

Mirikizumab Responders from Study AMAN
Patients who achieve clinical response with blinded mirikizumab in induction Study 
AMAN will be randomized to receive blinded 200 mg mirikizumab Q4W SC or blinded 
placebo SC Q4W (randomized withdrawal) in a 2:1 ratio.  Randomization will be 
stratified to achieve between-group comparability, based on biologic-failed status (yes or 
no), induction remission status (yes or no), baseline corticosteroid use (yes or no), and 
region (North America/Europe/Other).
Patients will continue on the randomized treatment assignment for the remainder of Study 
AMBG unless they develop secondary LOR.  
Loss of Response (LOR) is defined as:

≥2-point increase from Study AMBG baseline in the combined SF + RB scores 
AND combined SF + RB score of ≥4, on 2 consecutive visits (≥7 days apart), and 
with confirmation of negative C. difficile testing (first assessment can start as 
early as Week 8/Visit 3), 
AND

Confirmed by centrally read endoscopic subscore (ES) of 2 or 3 not sooner than 
Week 12/Visit 4. 

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SC dosing should be continued according to dosing schedule until endoscopy determines 
whether LOR is confirmed.  If LOR is confirmed based on endoscopy at or after Week 12
(and C. difficile stool toxin testing is negative), patients will be rescued with open-label 
300 mg mirikizumab Q4W IV for 3 doses. The first IV rescue dose may be administered
as soon as LOR is confirmed by centrally read endoscopy, if ≥7 days from the most 
recent SC dose.  Subsequent doses will be given every 4 weeks for total of 3 doses.
If endoscopy does not confirm secondary LOR, patients are encouraged to continue SC
study drug dosing, maintaining the scheduled dosing interval.  If study drug dosing is 
continued, an additional endoscopy would be performed at Week 40, early termination 
visit (ETV) or unscheduled visit (UV).
Patients who, in the opinion of the investigator, receive clinical benefit after completion 
of the LOR rescue therapy (12 weeks after first IV rescue dose) may be considered for 
enrollment into the long term extension study I6T-MC-AMAP (AMAP) to receive further 
SC dosing. Once the LOR IV rescue therapy is initiated, no further SC dosing will be 
available in AMBG. 
If study drug is discontinued, procedures for early termination from study drug will be 
performed and the patient should undergo post-treatment follow-up as described in the 
schedule of activities (Section 2).

Placebo Responders from Study AMAN
Patients who achieve clinical response with blinded placebo in the induction study will 
continue to receive blinded placebo for the remainder of the maintenance study.  Placebo 
SC injections will be administered Q4W to maintain study blind. If LOR is confirmed 
based on endoscopy at or after Week 12 (and C. difficile stool toxin testing is negative), 
patients will be rescued with open-label mirikizumab 300 mg Q4W IV for 3 doses. The 
same LOR assessments and procedures should be performed as described for the 
mirikizumab responders from Study AMAN. 

Mirikizumab and Placebo Nonresponders from Study AMAN
Patients who do not achieve clinical response to blinded mirikizumab or blinded placebo 
in Study AMAN will receive open-label extended induction therapy with 300 mg
mirikizumab IV at Weeks 0, 4, and 8, and undergo endoscopy at Week 12.
Patients who achieve delayed clinical response (compared to induction study baseline)
with extended mirikizumab induction therapy at Week 12 may subsequently receive 
open-label 200 mg mirikizumab Q4W SC starting at Week 12.  Patients will continue on 
this dose regimen and undergo endoscopy at Week 40.  Patients who, in the opinion of 
the investigator, receive clinical benefit may be considered for enrollment into the long 
term extension study AMAP to receive further SC dosing.  Patients who discontinue 
study drug before Week 40 will undergo endoscopy and procedures for early termination 
of the study drug, including post-treatment follow-up as described in the schedule of 
activities (Section 2).

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Patients who do not achieve clinical response to mirikizumab IV extended induction
therapy at Week 12, compared to induction baseline, will discontinue study drug and 
undergo procedures for early termination of the study drug, including post-treatment 
follow-up as described in the schedule of activities (Section 2).
Post-Treatment Follow-up Period
Patients will undergo a maximum 16-week post-treatment follow-up period:

Patients who discontinue study drug with last dose administered IV will return for post-
treatment follow-up visits (Visit 801 and 802) at 4 and 16 weeks after the 
end-of-treatment visit. 

Patients who discontinue study drug with last dose administered SC will return for post-
treatment follow-up visits (Visit 801 and 802) at 4 and 12 weeks after the 
end-of-treatment visit.

Patients who subsequently enter the long term extension study AMAP do not need to 
complete the post-treatment follow-up period. 
Figure AMBG.5.1 illustrates the study design.  Study governance considerations are described in 
detail in Appendix 3.

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Figure AMBG.5.1.
Illustration of study design for Clinical Protocol I6T-MC-AMBG.
Miri 200 mg Q4W SC
Placebo Q4W SC
Placebo Q4W SC
Placebo IV
Weeks          W0 
W12                                                      
W40                 
W12 of
Induction Studies
W52 continuous treatment 
End of Treatment Visit
R
Blinded Randomized Withdrawal Maintenance Period
Blinded Induction 
Study
For eligible patients 
who complete Week 
40 or LOR IV Rescue: 
Long Term 
Extension Study 
(AMAP) 
For patients who 
discontinue study 
drug (SC or IV):
Post-Treatment 
Follow-Up Period
2:1 Miri: PBO
Placebo IV 
D/C Miri
OL Miri 200 mg Q4W SC
Responders 
Responders
Miri IV 300 mg 
Nonresponders
LORa
AMAP
D/C Miri  
LORa
LORa
OL Miri 300 mg 
Q4W IV (x 3 doses)
Nonresponders
Blinded Induction 
Study
OL               
Extended Induction
Study AMAN
Study AMBG
OL Maintenance Period
Clin. 
Benefit
Clin. 
Benefit
Clin. 
Benefit
Yes
Yes
Yes
No
No
Yes
Yes
AMAP
AMAP
No
No
D/C Miri 
D/C Miri 
(x3 doses)
OL Miri 300 mg Q4W IV 
OL Miri 300 mg 
Q4W IV (x 3 doses)
OL Miri 300 mg 
Q4W IV (x 3 doses)
Miri IV 300 mg 

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Footnotes for Figure AMBG.5.1
Abbreviations: D/C = discontinue; IV = intravenous; LOR = loss of response; 
Miri = mirikizumab; OL = open-label; PBO = placebo; Q4W = every 4 weeks; 
R = randomization; RB = rectal bleeding; SC = subcutaneous; SF = stool frequency; 
W = week.
Note:  LOR is defined as ≥2-point increase from maintenance baseline in the combined 
SF + RB scores, AND combined SF + RB score of ≥4 on 2 consecutive visits, AND 
confirmed by an endoscopic subscore of 2 or 3.
a = Loss of response at or after Week 12 and up to and including Week 28.
5.2.
Number of Participants
The number of participants in Study AMBG will depend on the number of patients completing 
the induction study and who fulfill the enrollment criteria. It is estimated that approximately 
1044 patients will enter Study AMBG from the induction study AMAN as either induction 
responders or nonresponders.
5.3.
End of Study Definition
End of study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
The Phase 3 clinical trial program of mirikizumab in patients with moderate-to-severe UC 
consists of the following studies:

Study AMAN:  An induction study with a 12-week treatment duration.

Study AMBG:  A maintenance study with a 40-week treatment duration.

Study AMAP:  An open-label long-term extension study.
Study AMBG is designed to evaluate the maintenance of efficacy with blinded 200 mg 
mirikizumab Q4W in patients induced into clinical response with mirikizumab during the 
12-week induction study, Study AMAN.  Study AMAN includes patients with moderate to 
severely active UC.  
Randomized withdrawal of mirikizumab clinical responders from Study AMAN to either 
placebo or continuation of mirikizumab administered SC, will enable evaluation of the benefits 
of maintenance dosing of mirikizumab following induction dosing.  
Because randomized withdrawal of mirikizumab clinical responders to placebo may precipitate 
secondary LOR, 300 mg mirikizumab IV rescue will be provided to LOR patients who lose 
response after patients have completed at least 12 weeks of the maintenance study.  Loss of 
response will be defined based on symptomatic criteria (that is, SF and RB) confirmed by 
endoscopic criteria (see Section 5.1). 
The 40-week duration of this study provides a total of 52 weeks of continuous therapy (induction 
and maintenance) for mirikizumab patients who complete the 12-week induction study.  The 
40-week duration of randomized withdrawal in the maintenance study is expected to provide 

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adequate time for separation of efficacy effects between mirikizumab and placebo arms based on 
the approximate 10-day half-life of mirikizumab. 
The primary endpoint tests whether mirikizumab maintains clinical remission among patients 
who achieved clinical remission to induction treatment with mirikizumab. Clinical remission is a 
clinically relevant composite endpoint, as it combines symptomatic improvement as well as 
endoscopic remission (anti-inflammatory effect) in the individual patient.
Patients are allowed to remain on a stable background dose regimen of conventional UC 
therapies during the study, except for oral corticosteroids.  Corticosteroid tapering using a 
standardized algorithm will be mandated per protocol for patients who achieve clinical response 
to study drug in Study AMAN, or with extended induction for nonresponders from Study 
AMAN (see Section 7.7).
Patients randomized to placebo in Study AMAN and who achieved clinical response will be 
assigned to blinded placebo maintenance dosing in Study AMBG. These patients provide “true” 
placebo data for evaluation of safety and efficacy outcomes. Patients will continue on blinded 
placebo unless they meet the criteria for LOR, at which point they will receive rescue treatment 
with mirikizumab 300 mg Q4W IV for 3 doses. 
An extended induction is available to patients who do not achieve clinical response at the end of 
the induction study. The extended induction dosing will only include IV mirikizumab and is 
intended to increase the likelihood of the patient achieving clinical response. Patients who did 
not respond to blinded placebo therapy in the previous induction study will receive IV 
mirikizumab for the first time in Study AMBG.
A daily diary will be used to record PROs, including SF and RB.  Use of a daily diary to collect 
data over a short recall period offers potential advantages over collecting data intermittently at 
clinic visits.  Daily diary entries will be used to assess the effect of mirikizumab on achieving the 
primary and secondary endpoints.  
5.5.
Justification for Dose
The maintenance dose regimen selected for this study was based primarily on analyses of interim 
PK, safety, and efficacy data from the Phase 2 Study AMAC, safety data from other clinical 
studies evaluating mirikizumab, and nonclinical safety data.
Safety Considerations
The safety data collected in completed and ongoing clinical studies and in nonclinical toxicology 
studies support the proposed dose regimen.  In particular, there were no dose-related safety or 
tolerability issues observed in Study AMAC in patients with UC, for a period of up to 92 weeks
with doses up to 200 mg SC Q4W.
Single IV doses of up to 600 mg were evaluated in Study AMAA (healthy subjects and psoriasis 
patients) and up to 1200 mg in Study I6T-JE-AMAD (AMAD) (healthy subjects); no dose-
related safety or tolerability issues were observed in either study.  Study AMAG is evaluating 
dose regimens of up to 1000 mg IV Q4W for up to 52 weeks in patients with Crohn’s disease, 

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and up to 92 weeks with 300 mg SC Q4W.  Evaluation of the unblinded safety data available to 
date in the ongoing Phase 2 study in patients with psoriasis (Study AMAF) and of the blinded 
safety data available to date in the ongoing Phase 2 study in patients with Crohn’s disease (Study 
AMAG) has not revealed a safety concern that differs from the safety findings noted for Study 
AMAC.
The nonclinical safety profile of mirikizumab supports the proposed clinical study on the basis of 
the no-observed-adverse-effect levels (NOAELs) established in studies in monkeys.  The margin 
of safety (MOS) for the 300 mg Q4W (IV) LOR dose regimen proposed relative to the NOAEL 
level in the 6-month nonclinical toxicology study in cynomolgus monkeys is 6.5, based on area 
under the plasma concentration versus time curve. The MOS for the maintenance dose of 200 
mg Q4W (SC) is 23.
Considerations of Efficacy and Exposure-Response Relationship
200 mg SC Q4W Maintenance Dose Regimen
The available data from the maintenance period of Study AMAC indicate that the rates for 
efficacy endpoints at Week 52 were similar between the 200 mg SC Q4W and 200 mg SC Q12W 
mirikizumab maintenance groups, although there was a trend for higher rates across clinical and 
symptomatic remission and response endpoints in the Q4W group.  Examination of the rectal 
bleeding timecourse shows a pattern of loss of response before each dose administration in the 
200 mg SC Q12W arm.  This suggestion of increased bleeding between doses accompanies a 
finding that Q12W dosing results in mirikizumab trough concentrations below quantifiable 
detection limits at time periods between dosing.  External experts have interpreted these patterns 
to suggest that Q12W dosing is inadequate on the basis of inadequately-treated underlying 
inflammation, as well as on the basis of bleeding symptoms between doses.  The Q12W regimen 
produced a more intermittent mirikizumab concentration profile, while the Q4W concentration 
profile was more consistent, which may correlate with more consistent maintenance of lower 
(better) rectal bleeding subscores.  The Q4W regimen also produced trough concentrations that 
were similar to the Week-12 trough concentration produced in the 200 mg induction cohort that 
achieved the best efficacy.  Subjects that achieved clinical response or clinical remission at 
Week 52 also tended to have higher maintenance exposures.  
Therefore, a maintenance dose regimen of 200 mg SC Q4W was selected for Study AMBG.
300 mg IV Q4W Loss of Response Dose Regimen
The dose regimen selected for patients that lose response during maintenance is the same dose 
and regimen as used during the 12-week induction study, AMAN. The induction dose and 
regimen was based on the observed data in the Phase 2 study, AMAC, that showed significant 
efficacy relative to placebo at Week 12 in the 50-mg and 200-mg IV Q4W cohorts.  Due to the 
application of exposure-based dose adjustments in Study AMAC, the overall average induction 
dose received by subjects in the 50- and 200-mg cohorts were 100 and 250 mg, respectively.  
Although exposure increased in proportion to dose, patients in the 600-mg mirikizumab cohort 
did not respond better to treatment at Week 12 than patients in the 200-mg mirikizumab cohort.  

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Examination of the relationship between observed individual subject mirikizumab exposures and 
Week 12 clinical response and remission, and model based analyses of these relationships,
suggests that the probability of a subject achieving these clinical endpoints was not strongly 
dependent on exposure within the range of exposures that were evaluated in Study AMAC.  
However, model based analyses of the relationship between mirikizumab exposure and reduction 
in the modified Mayo Score (MMS) at Week 12 indicated that doses below 300 mg may lead to 
decreased efficacy, while doses above 300mg are not likely to provide meaningful improvements 
in efficacy.  Furthermore, a dose of 300 mg is expected to produce a median average 
concentration that covers approximately 90% of individual subject exposures observed in the 
200-mg cohort in Study AMAC.  
Therefore, the observed results in Study AMAC and the analyses of exposure-response 
relationships support the selection of 300 mg IV Q4W for subjects that lose response during 
maintenance in Study AMBG.

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6. Study Population
Study AMBG is a continuation of the induction Study AMAN. The AMBG patient population 
will consist of patients who complete Study AMAN through Week 12 and who meet all Study 
AMBG enrollment criteria, irrespective of their treatment assignment in Study AMAN and their 
clinical response to the investigational product in that study.
Patients will enter Study AMBG directly from Study AMAN once they sign a study-specific 
Institutional Review Board/Ethics Committee-approved informed consent. A patient is 
considered enrolled into the study once the patient is randomized and assigned to treatment.  
Besides a maximum 14-day window between the start of the Visit 5 (Week 12) visit of the 
induction study AMAN and the start of Visit 1 (Week 0) of Study AMBG, no screening period is 
allowed for Study AMBG. Data collected during the last visit of the induction study AMAN, 
including laboratory evaluations, endoscopy, and PRO data, will be used to review enrollment
criteria for Study AMBG. A visit window (14 days) is provided to allow laboratory results and 
central reading of the endoscopy to be available for the investigator to appropriately evaluate a 
patient and to ensure compliance with enrollment criteria. Patients who do not meet one or more 
hepatic or hematologic laboratory enrollment criteria may have these blood measures repeated 
one time at the investigator’s discretion prior to study entry, as long as all testing is completed 
within 14 calendar days from the start of the Visit 5 (Week 12) visit of Study AMAN. Patients 
who terminate from the induction study early for any reason or permanently discontinue study 
drug during the induction study are not eligible to enter Study AMBG.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
maintenance study baseline, unless specifically defined:
Informed Consent
[1.]
Have given written informed consent approved by the ethical review board 
(ERB) governing the site prior to any study-specific procedures being 
completed.
Patient Characteristics
[2.]
Have completed Study AMAN through the Week 12 visit (Visit 5) and have a 
Visit 5 MMS and have received at least 1 study drug administration without 
early termination of study drug.
[3.]
Are willing and able to complete the scheduled study assessments, including 
endoscopy and daily diary entry. 

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[4.]
Contraception 
[4a.]
Male patients:
No male contraception required except in compliance with specific 
local government study requirements
[4b.]
Female patients:
Women of childbearing potential:
A. Must test negative for pregnancy prior to initiation of treatment as 
indicated by a negative urine pregnancy test at Visit 1/Week 0 of this 
study.
AND
B. Must agree to either remain abstinent, if complete abstinence is their 
preferred and usual lifestyle, or remain in same-sex relationships, if part 
of their preferred and usual lifestyle, without sexual relationships with 
males.  Periodic abstinence (for example, calendar, ovulation, 
symptothermal, or post-ovulation methods), declaration of abstinence 
just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
OR
Must use 2 effective methods of contraception for the entirety of the 
study.  Abstinence or contraception must continue following completion 
of study drug administration for 20 weeks
i.
2 effective methods of contraception (such as male or female 
condoms with spermicide, diaphragms with spermicide or cervical 
sponges) will be used.  The patient may choose to use a double 
barrier method of contraception.  Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable 
method.  Thus, each barrier method must include use of a 
spermicide.  It should be noted that the use of male and female 
condoms as a double barrier method is not considered acceptable due 
to the high failure rate when these methods are combined.
ii.
Of note, 1 of the 2 methods of contraception may be a highly 
effective (less than 1% failure rate) method of contraception (such as 
combination oral contraceptives, implanted contraceptives or 
intrauterine devices).

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Women not of childbearing potential may participate and include those who are:
A. Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly, such as mullerian 
agenesis; or
B. Postmenopausal – defined as either 
i.
A woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either 

Cessation of menses for at least 1 year or 

At least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone (FSH) >40 mIU/mL; or
ii.
A woman 55 years or older not on hormone therapy, who has had at 
least 6 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy.
[5.]
Have documentation of the following:
[5a.]
A surveillance colonoscopy (performed according to local standard) 
within 12 months before baseline for:

Patients with pancolitis of >8 years’ duration, or

Patients with left-sided colitis of >12 years’ duration, or

Patients with primary sclerosing cholangitis.
OR
[5b.]
In patients for whom Inclusion Criterion [5a] does not apply, 
up-to-date screening for colorectal cancer (performed according to 
local standard).  
A full colonoscopy can be performed as part of the Week 12 procedures in Study 
AMAN to satisfy this inclusion criterion for Study AMBG.  

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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
maintenance study baseline, unless specifically defined:
Gastrointestinal Exclusion Criteria
[6.]
Have been diagnosed during the previous induction study AMAN with 
Crohn’s disease or Inflammatory Bowel Disease-Unclassified (IBD-U, 
formerly known as indeterminate colitis).
[7.]
Have had bowel resection or other surgery for the treatment of UC during the 
previous induction study AMAN, or are likely to require surgery for the 
treatment of UC during Study AMBG. 
[8.]
Have evidence of colonic dysplasia (including dysplasia in flat mucosa or 
dysplasia-associated lesion or mass [DALM]) at maintenance baseline (Study 
AMAN Visit 5 [Week 12] endoscopy) or have been diagnosed with cancer of 
the gastrointestinal tract during Study AMAN. 
[9.]
Have current adenomatous polyps that have not been removed.  Once 
removed, the patient may be eligible for study after confirming no dysplasia 
or malignancy on local histology report.  
Infectious Disease Exclusion
[10.] Have been diagnosed with clinically important infection including, but not 
limited to, hepatitis B, hepatitis C, HIV/AIDS, and active tuberculosis (TB)
during the induction study AMAN.
[11.] Have detectable hepatitis B virus (HBV) DNA detected at any time in Study 
AMAN 
[12.] Have been diagnosed with latent TB during the induction study AMAN and 
are not willing to comply with completing TB treatment as appropriate.
[13.] Intend to receive a Bacillus Calmette-Guerin (BCG) vaccination or live 
attenuated vaccine(s) during the study.
General Exclusion Criteria
[14.] Initiation of a new prohibited medication (see Appendix 8) during the 
induction study AMAN.
[15.] Presence of a hepatic or hematologic laboratory abnormality prior to 
Visit 1/Week 0 that would require permanent discontinuation from study 
drug (see Section 8.1.1).

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[16.] Presence of significant uncontrolled neuropsychiatric disorder or judged at 
risk of suicide in the opinion of the investigator; 
OR
Marked “yes” to Columbia-Suicide Severity Rating Scale (C-SSRS) question 
4 or 5 on ideation prior to dosing;
OR
Marked “yes” to C-SSRS suicide behaviors questions prior to dosing at 
Week 0; 
AND
The ideation or behavior occurred within the past month. 
[17.] Have an unstable or uncontrolled illness, including, but not limited to,
cerebro-cardiovascular, respiratory, gastrointestinal (excluding UC), hepatic, 
renal, endocrine, hematologic or neurological disorders or malignancy that 
would potentially affect patient safety within the study or confound efficacy 
assessment.
[18.] Have a known systemic hypersensitivity to any component of this 
investigational product, or has experienced an acute systemic hypersensitivity 
event with previous study drug administration, that precludes mirikizumab 
therapy.
[19.] Are pregnant, lactating, or planning pregnancy (women only) while enrolled 
in the study, or within 12 weeks after receiving the last dose of study drug (or 
within 20 weeks if patient received less than 2 SC doses and decides to 
terminate study participation early for any reason during Study AMBG).
[20.] Became a Lilly employee, employee of third party organizations involved 
with the study, or investigator site personnel directly affiliated with this study 
and/or their immediate families, during the previous induction study AMAN.  
[21.] Have enrolled in another clinical trial involving an investigational product or 
nonapproved use of a drug or device during Study AMAN, OR are currently 
enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[22.] Have previously completed or withdrawn from Study AMBG or any other 
study investigating mirikizumab, except for completion of 12 weeks of 
induction study AMAN. 
[23.] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the patient daily for the duration of Study AMBG,
or are unable to complete other study procedures. 

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6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study 
and for 20 weeks following their last dose (if last dose is given IV) or for 16 weeks following 
their last dose (if last dose is given SC).  In order to participate in the study, patients must agree 
to the contraception, reproduction and breastfeeding criteria detailed in inclusion criterion [4] 
and exclusion criterion [19].
6.4.
Screen Failures
As described in Section 6, patients will be entered into Study AMBG directly from 
Study AMAN, with a maximum 14-day window between start of the Visit 5 (Week 12) visit of 
the induction study AMAN and start of Visit 1 (Week 0) of Study AMBG. 
Data collected during the last visit of the induction trial will be used to review enrollment criteria 
and the suitability of an induction patient proceeding to Study AMBG. Patients who do not meet 
enrollment criteria may have one or more blood measures repeated one time, at the investigator’s 
discretion, prior to study entry as long as all testing is completed within 14 calendar days from 
the start of the last induction visit.

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7. Treatments
7.1.
Treatments Administered
The treatments to which patients will be randomized or assigned to will depend upon their 
clinical response at Visit 5 (Week 12) of induction study AMAN (Figure AMBG.5.1).  Patients 
who achieved clinical response during the induction study (defined in Table AMBG.9.1) will 
follow the treatment regimens described in Table AMBG.7.1.  Patients who did not achieve 
clinical response during the induction study will follow the treatment regimens described in 
Table AMBG.7.2. Importantly, to preserve the study blind:

All Study AMAN responders, regardless of Study AMBG treatment assignment, will be 
administered study drug in Study AMBG in the same manner:
o
Blinded SC study drug for maintenance dosing, and open-label 300 mg
mirikizumab IV rescue dosing if they develop secondary LOR.

All Study AMAN nonresponders will be administered study drug in Study AMBG in the 
same manner:
o
Open-label 300 mg mirikizumab IV, followed by open-label 200 mg 
mirikizumab SC dosing if they demonstrate delayed clinical response with 
extended induction. 
Patients who meet all criteria for enrollment and who have achieved clinical response to 
mirikizumab at the end of induction study AMAN will be randomized 2:1 to double-blind 
treatment with either 200 mg mirikizumab Q4W SC or placebo Q4W SC at Visit 1.  Patients who 
achieved clinical response to placebo at the end of the induction study AMAN will continue to 
receive blinded placebo Q4W SC during the maintenance study starting at Visit 1.
If the patient experiences LOR to either 200 mg mirikizumab Q4W SC or to placebo Q4W SC at 
or after Week 12 of Study AMBG, they will receive rescue with open-label 300 mg mirikizumab
IV Q4W for 3 doses.  Induction-study placebo responders who experience LOR on SC placebo 
will also receive open-label mirikizumab IV 300 mg Q4W for 3 doses. No further treatment 
adjustments are permitted. Once IV LOR dosing is complete, patients who, in the opinion of the 
investigator, are receiving clinical benefit from mirikizumab therapy may be considered for 
enrollment into the long term extension study AMAP to receive further SC dosing. Patients who 
are not considered by the investigator to be receiving clinical benefit from mirikizumab IV 
rescue therapy, will be discontinued and proceed to post-treatment follow-up. 
Patients who meet all enrollment criteria and who did not respond to study drug (either 
mirikizumab or placebo) in induction study AMAN will enter Study AMBG as nonresponders. 
All induction nonresponders will receive open-label extended induction dosing with 300 mg 
mirikizumab IV Q4W for 3 doses. Patients who achieve delayed clinical response to
mirikizumab IV extended induction therapy at Week 12, compared to induction baseline, will 
subsequently receive open-label 200 mg mirikizumab Q4W SC injections for the remainder of 
the 40-week treatment period. Patients who do not achieve clinical response to mirikizumab IV 
extended induction therapy at Week 12 will discontinue study drug and undergo early 
termination procedures and proceed to post-treatment follow-up.  

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Table AMBG.7.1.
Treatment Regimens: Induction Clinical Responders
Regimen
Dose
Weeks 0-8
Dose
Weeks 12-40
Responders to blinded mirikizumab in induction study
Randomized
2:1
Blinded 200 mg 
mirikizumab
Q4W SC
Weeks 0, 4, 8

Continue blinded 200 mg mirikizumab SC at 
Weeks 12, 16, 20, 24, 28, 32, 36
Or, if LOR anytime between Weeks 12 and 28 (inclusive):

Change to open-label 300 mg mirikizumab IV 
Q4W for 3 doses
If no clinical benefit after 3 doses of rescue IV 
induction with mirikizumab, then discontinue 
mirikizumab
If clinical benefit, may proceed to Study AMAP
Blinded Placebo
Q4W SC
Weeks 0, 4, 8

Continue blinded placebo at Weeks 12, 16, 20, 24, 
28, 32, 36
Or, if LOR anytime between Weeks 12 and 28 (inclusive):

Change to open-label 300 mg mirikizumab IV 
Q4W for 3 doses
If no clinical benefit after 3 doses of rescue IV 
induction with mirikizumab, then discontinue 
mirikizumab
If clinical benefit, may proceed to Study AMAP
Responders to blinded placebo in induction study
Blinded Placebo
Q4W SC
Weeks 0, 4, 8

Continue blinded placebo at Weeks 12, 16, 20, 24, 
28, 32, 36
Or, if LOR anytime between Weeks 12 and 28 (inclusive):

Change to open-label 300 mg mirikizumab IV 
Q4W for 3 doses
If no clinical benefit after 3 doses of rescue IV 
induction with mirikizumab, then discontinue 
mirikizumab
If clinical benefit, may proceed to Study AMAP
Abbreviations:  IV = intravenous; LOR = loss of response (defined as ≥2-point increase from maintenance baseline 
in the combined SF + RB scores, AND combined SF + RB score of ≥4 on 2 consecutive visits, AND confirmed by 
endoscopic subscore of 2 or 3); OL = open-label; Q4W = every 4 weeks; RB = rectal bleeding; SC = subcutaneous; 
SF = stool frequency.

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Table AMBG.7.2.
Treatment Regimens: Induction Clinical Nonresponders 
Regimen
Dose
Weeks 0-8
Dose
Weeks 12-40
Nonresponders to blinded mirikizumab IV in induction study
Open-label 300 mg mirikizumab IV
Weeks 0, 4, 8
Week 12 Extended Induction Responders

Open-label 200 mg mirikizumab SC at Weeks 12, 
16, 20, 24, 28, 32, 36; then may proceed to Study 
AMAP

If clinical benefit is lost, discontinue mirikizumab 
and enter post-treatment follow-up period
Week 12 Extended Induction Nonresponders:

Discontinue mirikizumab
Nonresponders to blinded placebo in induction study
Open-label 300 mg mirikizumab IV
Weeks 0, 4, 8
Week 12 Extended Induction Responders

Open-label 200 mg mirikizumab SC at Weeks 12, 
16, 20, 24, 28, 32, 36; then may proceed to Study 
AMAP

If clinical benefit is lost, discontinue mirikizumab 
and enter post-treatment follow-up period
Week 12 Extended Induction Nonresponders:

Discontinue mirikizumab
Abbreviations:  IV = intravenous; SC = subcutaneous.
Study Drug Administration
Subcutaneous administration of mirikizumab or placebo will be given in 2 injections (maximum 
volume is 1 mL per injection).  
Intravenous infusion of mirikizumab will occur over at least 30 minutes.  All patients should be 
monitored for 1 hour or longer after dosing, or longer according to investigator practice or local 
standard of care.  Sites must have resuscitation equipment, emergency medications, and 
appropriately trained staff available during the infusion and monitoring period.  Detailed 
instructions for investigational product administration will be provided separately by the sponsor.  
Investigational product will be prepared at the site by blinded pharmacists or other trained and 
qualified personnel as designated by the investigator. Investigational product will be 
administered at the site by a blinded nurse, pharmacist, or other trained and qualified personnel 
as designated by the investigator.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the investigational agent(s) to the site personnel 

Verifying that instructions are followed properly

Maintaining accurate records of investigational product dispensing and collection

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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
Mirikizumab and placebo will be supplied to the investigator by Lilly or its designee.  Clinical 
trial materials will be labeled according to the country’s regulatory requirements.  All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations.  Clinical trial materials are manufactured in accordance with current 
Good Manufacturing Practices (GMP).
Study drug will be supplied as: 

Single-use solution pre-filled syringe containing mirikizumab or placebo.  The 1-mL 
syringe of mirikizumab is manufactured to deliver 100 mg.  

Single-use solution vial containing mirikizumab.  The 15-mL vial of mirikizumab is 
manufactured to deliver 300 mg (20 mg/ml).  
Mirikizumab cannot be distinguished visually from placebo.
Study drug will be provided with study-specific labels.  Syringes and vials will be supplied in 
cartons, with the appropriate quantity specific to the planned dispensing schedule of the 
investigational product. No concomitant UC therapies will be provided by Lilly or its designee.
7.2.
Method of Treatment Assignment
Assignment to treatment groups for patients entering Study AMBG as clinical responders will be 
determined by a computer-generated random sequence using an interactive web-response system 
(IWRS) in a double-blind manner.  To achieve between-group comparability, patients will be 
stratified to these arms based upon biologic-failed status (yes or no), baseline corticosteroid use 
(yes or no), region (North America/Europe/Other), and induction remission status (yes or no).  
This stratification will be controlled by IWRS.  
7.2.1. Selection and Timing of Doses
The doses will be administered at each scheduled visit as described in the Schedule of Activities
(Section 2).  The actual time of all dose administrations will be recorded in the patient’s 
electronic case report form (eCRF). Doses, other than rescue mirikizumab IV doses, should not 
be administered during unscheduled visits, unless the unscheduled visit occurs during the next 
scheduled dosing window. Rescue mirikizumab IV doses may be administered during 
unscheduled visits if LOR has been confirmed and if it is ≥7 days from the most recent SC dose.  
Subsequent rescue mirikizumab IV doses will be given every 4 weeks (+/- 3 days) for total of 
3 doses.
7.3.
Blinding
This is a double-blind study.  To preserve the blinding of the study, a minimum number of Lilly 
personnel will have access to the randomization table and treatment assignments before the study 

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is complete. These personnel will not have communication with site personnel. No unblinding 
at the investigational site for investigational product preparation will be required.  A blinded 
study site pharmacist or other trained and qualified person will prepare the investigational 
product.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All notifications resulting in an unblinding event are recorded and reported by 
the IWRS.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study drug and must complete the ETV and post-treatment 
follow-up as per protocol.  In cases where there are ethical reasons to have the patient remain on 
study drug, the investigator must obtain specific approval from the sponsor or designee for the 
patient to continue in the study.
7.4.
Dosage Modification
Dose adjustments, other than the dose regimen change provided to patients who demonstrate a 
LOR, described in Section 7.1, are not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

Confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

Ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as, receipt, reconciliation, and final disposition 
records).

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Detailed instructions regarding supplies and preparation and handling of mirikizumab will be 
provided by the sponsor.
Investigational products will be supplied by Lilly or its designee, in accordance with current 
GMP and will be supplied with lot numbers, expiry dates, and certificates of analysis, as 
applicable.
Mirikizumab and placebo should be stored in refrigerated conditions 2̊C to 8̊C (36̊F to 46̊F).
7.6.
Treatment Compliance
All doses of study medication will be administered at the study site by site personnel.  Deviations 
from the prescribed dosage regimen should be recorded in the eCRF.
Every attempt will be made to select patients who have the ability to understand and comply with 
study instructions.  The investigator is responsible for discussing methods to ensure high 
treatment compliance with the patient before randomization.  
If a patient is noncompliant with study procedures and/or investigational product administration, 
the investigator should assess the patient to determine the reason for noncompliance and educate 
and/or manage the patient as appropriate to improve compliance. If, in consultation with Lilly or 
its designee, the noncompliance is deemed to be significant such that it affects the safety of the 
patient or the evaluation of the efficacy and safety data in this study, the patient may be 
discontinued from the study.
7.7.
Concomitant Therapy
All concomitant medications taken during the study must be recorded in the Concomitant 
Medication eCRF.  All patients are encouraged to maintain their usual medication regimens for 
concomitant conditions or diseases throughout the study, unless those medications are 
specifically excluded (Appendix 8).  
Patients taking permitted UC concomitant medications, other than oral corticosteroids, are to 
keep doses stable unless modifications are needed due to AEs, and follow the instructions 
regarding dose stabilization as detailed in Appendix 9.  Patients taking oral corticosteroids are to 
follow the corticosteroid taper instructions described below.  Administration of prohibited UC
medications, approved or investigational, constitutes treatment failure.  Use of such medications 
should not be withheld if, in the opinion of the investigator, failure to prescribe them would 
compromise patient safety.  Patients who require a prohibited medication to treat their UC (see 
Appendix 8) need to be discontinued from study drug and complete an ETV and post-treatment 
follow-up visits.
If a concomitant medication is needed to treat an AE or for appropriate medical management, the 
investigator should base decisions on the patient and clinical factors, considering prohibited 
medications.  Local administration of corticosteroids (for example, intranasal, inhaled, 
intraarticular) are allowed as required for the management of pre-existing conditions and AEs.  A 
patient who initiates a prohibited medication for a non-UC indication may either discontinue the 
study drug, or discontinue the prohibited medication.

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Use of BCG vaccination is prohibited throughout the duration of the study and for 12 months 
after discontinuation of study drug.  Use of nonlive (killed, inactivated or subunit) vaccinations 
are allowed for all patients; however, their efficacy with concomitant mirikizumab is unknown.  
Use of live, attenuated vaccines are prohibited during the study and for 3 months after 
discontinuation of study drug.  
The list of prohibited medications and the list of permitted medications with dose stabilization 
guidance are provided in Appendix 8 and Appendix 9, respectively.
Corticosteroid Taper
Patients who enter Study AMBG on corticosteroid therapy for treatment of their UC and who
achieved clinical response in the induction study AMAN will initiate corticosteroid tapering, as 
described below, at Week 0 of Study AMBG.  Clinical nonresponders who undergo extended IV 
induction with mirikizumab will begin corticosteroid tapering if clinical response is achieved at 
Week 12 of the extended induction dosing, or earlier if symptomatic improvement, based on 
investigator discretion, is evident at any time after starting extended IV induction dosing. 
For patients who cannot tolerate the corticosteroid taper without recurrence of clinical 
symptoms, corticosteroid taper may be paused and/or corticosteroid dose may be increased up to 
the original dose at induction baseline (should not exceed induction baseline dose). In such 
cases, attempts to reinitiate corticosteroid tapering should be made within 2 weeks of interruption 
of taper, with a goal to complete tapering no later than Week 12 of Study AMBG.
The recommended tapering schedule for oral corticosteroids (other than budesonide extended 
release tablets [budesonide MMX] or beclomethasone dipropionate [gastro-resistant prolonged-
release tablet]) is as follows:

Dose >10 mg/day prednisone or equivalent: taper daily dose by 5 mg/week until 
receiving 10 mg/day, and then continue tapering at 2.5 mg/week until 0 mg/day.

Dose ≤10 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week until 
0 mg/day.
The recommended tapering schedule for patients receiving oral budesonide MMX 9 mg/day is to 
reduce tablets to 9 mg every other day for 2 weeks, followed by 9 mg every third day for 
2 weeks, and then discontinue.
The recommended tapering schedule for patients receiving oral beclomethasone dipropionate 
(gastro-resistant prolonged-release tablet) 5 mg/day is to reduce tablets to 5 mg every other day 
for 4 weeks, and then discontinue.
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions 
Patients who complete Week 40 in Study AMBG will be assessed for eligibility to enter the 
open-label extension study (Study AMAP).  There is no extension period within Study AMBG.
If patients do not meet enrollment criteria for Study AMAP or opt not to continue into Study 

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AMAP, they will be asked to complete the post-treatment follow-up period, as described in the 
Schedule of Activities (Section 2), which will complete their study participation. 
7.8.2. Treatment after Study Completion
Mirikizumab will not be made available to patients after conclusion of the study.
7.8.3. Special Treatment Considerations 
7.8.3.1.
Premedication for Infusions
Premedication for the study drug infusions or injections is not planned. Any premedication for 
infusions or injections should be discussed with the medical monitor.  Any premedication given 
will be documented as a concomitant therapy.
7.8.3.2.
Management of Hypersensitivity, Infusion-Related Events, Infusion Site 
Reactions and Injection Site Reactions
During and after study drug administration, patients should be closely monitored for signs or 
symptoms of AEs, including hypersensitivity events, other infusion-related events, and infusion 
or injection site reactions.
Hypersensitivity Events
If a patient experiences a systemic hypersensitivity reaction involving the skin or mucous 
membranes, respiratory, cardiovascular, gastrointestinal, or urinary systems, during or up to 
6 hours after an infusion of study drug, the following guidance should be followed (see 
Appendix 10 for additional information): 

Study drug infusion should be stopped immediately and appropriate supportive care 
provided according to local standard practice (for example, administration of epinephrine, 
anti-histamine, systemic steroids, and/or bronchodilators).

After patient’s stabilization, an anti-drug antibody (ADA) and PK sample should be 
collected; additional samples should be obtained 4 and 12-16 weeks after the event.  
These samples will also be used for tryptase, complement (C3/C4), and cytokine panel 
assays.

The patient should be monitored until resolution or stabilization of the symptoms, as 
clinically appropriate. 

Study drug should be permanently discontinued after a systemic drug administration 
reaction.  The patient should undergo post-treatment follow-up procedures after study 
drug discontinuation.

The medical monitor should be notified as soon as feasible.
Other Infusion-Related Events and Infusion Site Reactions
If a patient experiences a reaction consisting of headache, rigors and/or temperature >38°C (in 
the absence of signs or symptoms of a systemic hypersensitivity reaction), or an infusion site
reaction, including urticaria, pruritus, or angioedema localized to the IV infusion site (in the 
absence of other systemic hypersensitivity signs or symptoms), during or up to 6 hours after an 
infusion of study drug, the following guidance should be followed:

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
Study drug infusion should be interrupted and appropriate medical care should be 
administered (for example, NSAIDS, anti-pyretics or antihistamines). 

An ADA and PK sample should be collected at the time of the event (or as soon as 
possible after the event occurs), and 4 and 12-16 weeks after the event. These samples 
will also be used for tryptase, complement (C3/C4), and cytokine panel assays.

Resumption of study drug infusion after interruption, possibly at a slower rate of 
administration, can be considered if symptoms resolve and it is deemed to be medically
appropriate based on the investigator’s discretion, and considering the risk/benefit of 
readminstration.

If the patient develops systemic hypersensitivity symptoms or signs, they should be 
managed as described above for a systemic hypersensitivity reaction.  Patient should 
remain in observation, as is clinically appropriate for the 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.  
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. 

If the patient develops systemic hypersensitivity symptoms, they should be managed as 
described above for a systemic hypersensitivity reaction.  

Premedication prior to subsequent study drug administration may be considered as 
appropriate for the individual patient.  

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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Study treatment may be permanently discontinued during the study.  Patients who discontinue 
study treatment early will undergo early termination procedures, which include an ETV and 
post-treatment follow-up visits.  The investigator will also complete any AE reporting and 
follow-up that may be required (if applicable, see Section 9.2).  
If a patient's study treatment is discontinued before the end of the Maintenance Study Dosing 
Period, the patient should complete the ETV and post-treatment follow-up period as follows:

Patients who discontinue investigational product during extended induction IV dosing
or before receiving any SC dosing will return for post-treatment follow-up visits
(Visit 801 and 802) 4 and 16 weeks after the end-of-treatment visit.

Patients who discontinue study drug after having received ≥1 SC dose will return for 
post-treatment follow-up visits (Visit 801 and 802) 4 and 12 weeks after the 
end-of-treatment visit.
Possible reasons leading to permanent discontinuation of investigational product include the 
following (list is not exhaustive):
Patient Decision

The patient requests to discontinue investigational product.
Discontinuation due to a hepatic event or liver test abnormality  

Patients who are discontinued from investigational product due to a hepatic event or liver 
test abnormality should have additional hepatic safety data collected via the hepatic 
eCRF packet.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly-designated medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>8x upper limit of normal (ULN)

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and total bilirubin level (TBL) >2xULN or 
international normalized ratio >1.5

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

Alkaline phosphatase (ALP) >3xULN

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
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%)
Discontinuation due to Lack of Clinical Benefit or Disease Worsening

Induction study responders who experience LOR and do not receive clinical benefit from 
mirikizumab IV rescue induction

Induction study nonresponders who do not achieve clinical response with 3 doses of 
mirikizumab IV extended induction

Induction study nonresponders who achieve clinical response with mirikizumab extended 
IV induction, but subsequently lose clinical benefit with open-label mirikizumab SC 
dosing, should be discontinued. Loss of clinical benefit may be based on demonstrating 
LOR criteria ( see Section 5.1) or by other criteria according to investigator discretion

Patients who require treatment with a prohibited UC medication (Appendix 8), an 
increase in immunomodulatory medication, or a course of corticosteroids that exceeds the 
baseline dose 

Patients who undergo surgery for UC
Safety Criteria for Study Drug Discontinuation

The patient requires a prohibited medication to treat their UC (Appendix 8). A patient 
who initiates a prohibited medication for a non-UC indication may either discontinue the 
study drug, or discontinue the prohibited medication.

The patient requires a colectomy, proctocolectomy, or partial colectomy during the study.

A diagnosis of cancer, other than squamous cell or basal cell carcinoma of the skin,
during the study.

Dysplasia occurring in flat mucosa or DALM.

A diagnosis of active TB during the study.

A diagnosis of HIV/AIDS during the study.

A diagnosis of hepatitis B during the study or development of detectable HBV DNA 
during the study (see Section 9.4.5.2).

A diagnosis of hepatitis C during the study or development of detectable hepatitis C virus 
(HCV) RNA during the study (see Section 9.4.5.4).

The patient becomes pregnant.  Pregnant patients will not undergo an endoscopy at 
the ETV. 

The participant has an AE or SAE which, in the opinion of the investigator or sponsor, 
would preclude the participant from continuing to receive study drug.

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
Systemic hypersensitivity event or anaphylaxis to study drug.
It is recommended that the patient be assessed by an appropriately trained professional to assist 
in deciding whether the patient is to be discontinued from the study if:

The patient scores a 3 for Item 12 (Thoughts of Death or Suicide) on the Quick Inventory 
of Depressive Symptomatology—Self-Report (16 Items ) (QIDS-SR16) at any time in the 
study, or

The patient reports suicidal ideation or suicide-related behaviors during the study
Other Reasons for Study Drug Discontinuation

If an investigator, site personnel performing assessments, or patient is unblinded, the 
patient must be discontinued from the study drug and continue to post-treatment 
follow-up.  In cases where there are ethical reasons to have the patient continue on study 
drug, the investigator must obtain specific approval from the sponsor or designee for the 
patient to continue in the study.

Inadvertent enrollment (see Section 8.1.3)
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Interruption (Withholding) of Study Treatment
Some possible reasons for temporarily withholding the investigational product include (but are 
not limited to):

Patient develops a clinically important intestinal or extraintestinal infection during the 
study, including latent tuberculosis infection (LTBI).

Patient requires major surgery (resume administration of the investigational product only 
after adequate wound healing).

Patient develops a confirmed absolute neutrophil count <1x109/L (<1x103/µL or <1 GI/L)
(2 assessments below this threshold).

Patient develops absolute lymphocyte count <500 cells/µL (<0.5x103/µL or <0.50 GI/L).  
Azathioprine, 6-MP or methotrexate must be discontinued, if applicable, for a confirmed 
absolute lymphocyte count <0.5x103/µL (2 assessments below this threshold). The 
hematology must be repeated in 2 weeks. If the absolute lymphocyte count remains 
<0.5x103/µL, the hematology will be repeated again in 2 weeks (that is, prior to the next 
dose of study drug).  If the absolute lymphocyte count remains <0.5x103/µL, the next 
dose of study drug will not be administered. The hematology will be repeated again in 2 
weeks. If the absolute lymphocyte count remains <0.5x103/µL, study drug will be 
permanently discontinued. White blood cell and lymphocyte counts will be followed for 
these patients until they return to an acceptable level.

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Cases that may merit temporary withholding of the study treatment will be discussed with the 
medical monitor.  The medical monitor, in consultation with the investigator, will determine 
when it is appropriate to recommence study treatment.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor agree it is medically appropriate to continue
on study treatment, the investigator must obtain documented approval from the sponsor to allow 
the inadvertently enrolled patient to continue in the study. Patients who are discontinued from 
study treatment should have safety follow-up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice 

Investigator decision
o
The investigator decides that the patient should be discontinued from the 
study
o
If the patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of 
the new agent

Patient decision
o
The patient requests to be discontinued from the study
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, 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.

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9.1.
Efficacy Assessments
Table AMBG.9.1.
Endpoint Definitions in Study AMBG
Endpoint
Definition
Clinical remission

Stool frequency (SF) subscore = 0, or SF = 1 with a ≥1-point decrease from 
induction baseline, and

Rectal bleeding (RB) subscore = 0; and

Endoscopic subscore (ES) = 0 or 1 (excluding friability)
Clinical remission (using 
a more stringent ES) 

SF subscore = 0, or SF = 1 with a ≥1-point decrease from induction baseline, and

RB subscore = 0; and

ES = 0 
Clinical response

A decrease in the modified Mayo score (MMS) of ≥2 points and ≥30% decrease 
from baseline, and 

A decrease of ≥1 point in the RB subscore from baseline or a RB score of 0 or 1
Corticosteroid-free 
remission without 
surgery at Week 40a

Clinical remission at Week 40, and

Symptomatic remission at Week 28, and 

No corticosteroid use for ≥12 weeks prior to Week 40
Endoscopic remission

ES = 0 or 1 (excluding friability)
Endoscopic response

A decrease in the ES of ≥1 point compared to baseline
Histologic remission 

This definition will be specified in the SAP
Mucosal healing

Histologic remission as described in the SAP and

endoscopic remission defined as ES = 0 or 1 (excluding friability)
Symptomatic remission

SF = 0, or SF = 1 with a ≥1-point decrease from induction baseline, and

RB = 0
Stable maintenance of 
symptomatic remissionb

Symptomatic remission for at least 7 out of 9 visits from Week 4 to Week 36 

Symptomatic in remission at Week 40
Bowel movement urgency 
improvement 

The definition will be specified in the study SAP
Abbreviations: ES = endoscopic subscore; MMS = modified Mayo score; RB = rectal bleeding; SAP = statistical 
analysis plan; SF = stool frequency.
a
Among patients induced into clinical response with mirikizumab during the induction study and who were 
receiving corticosteroids at induction baseline.
b
Among patients in symptomatic remission at Week 12 of Study AMAN.
9.1.1. Primary Efficacy Assessments
9.1.1.1.
Primary Endpoint
The primary endpoint is clinical remission at Week 40, among patients induced into clinical 
response with mirikizumab induction treatment (Study AMAN). Clinical remission is based on 
the MMS and is defined in Table AMBG.9.1.
9.1.1.2.
Mayo Score
This study utilizes components of the Mayo Score (Schroeder et al. 1987) to assess UC disease 
activity for the primary and major secondary endpoints (see Appendix 6).  Complete and 
accurate recording of the Mayo SF and RB subscores by patients in their daily electronic 
diary is necessary for the success of the study. Adequate bowel preparation and an endoscopy 
with adequate visualization of the mucosa will enable calculation of the Mayo ES.  

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

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9.1.1.3.
Endoscopy
Endoscopy will be used to determine the Mayo ES at the time points described in the Schedule 
of Activities (Section 2). 
Flexible sigmoidoscopy is the standard endoscopic procedure for assessment of endoscopic 
disease activity in this study.  However, colonoscopy can be performed instead of flexible 
sigmoidoscopy within this study in order to surveille for dysplasia, screen for colorectal cancer
(see Inclusion Criterion [5]), or for other clinically indicated reasons, in the judgement of the 
investigator and after discussion with the medical monitor as appropriate.   
Endoscopic disease activity assessed at Week 12 of Study AMAN will serve as the baseline 
assessment of endoscopic disease activity in Study AMBG. 
In patients who enter Study AMBG in clinical response or clinical remission, endoscopy will be 
performed at Week 40, ETV, UV, or if LOR is suspected in these patients based on SF/RB 
scores, endoscopy can be performed at or after Week 12 to confirm secondary LOR. Secondary 
LOR must be confirmed endoscopically before rescue mirikizumab IV induction dosing is 
initiated.  If endoscopy does not confirm secondary LOR, patients are encouraged to continue 
study drug dosing.  If study drug dosing is continued, an additional endoscopy would be 
performed at Week 40, ETV, or UV.
In patients who enter Study AMBG as induction study nonresponders, endoscopy will be 
performed at Week 12, following extended mirikizumab IV induction. An additional endoscopy 
will be performed at Week 40, ETV, or UV. Patients who plan to continue in the long term 
extension study AMAP and who require an annual surveillance colonoscopy to remain 
up-to-date in screening for colorectal cancer (see Inclusion Criterion [5]), will undergo
colonoscopy as the endoscopy method at Week 40.
If a patient becomes pregnant during the study, no additional endoscopies will be performed. 
If a patient undergoes early termination soon after baseline, loss of response, or at the end of 
extended induction endoscopy, the need for ETV endoscopy should be discussed with the 
medical monitor.
The endoscopy report and histopathology report (if biopsies are sent to a local histopathology 
laboratory) must be available in the source documents.
The endoscopist will be a licensed physician, who is qualified by education, training, and 
experience to perform colonoscopies.  Investigators may delegate endoscopy to other members 
of the study team.  However, all study staff performing endoscopy must receive training from the 
sponsor or designee in the determination and calculation of the Mayo ES.  The site endoscopist 
will determine the Mayo ES at each endoscopy and it will be recorded in the eCRF.  
All endoscopic procedures will be video recorded using a storage medium provided by the 
sponsor or designee.  The video images will be sent for independent central reading.  A detailed 
image review charter from the central reading laboratory will outline the standard study 
procedures used to capture and transmit video recordings of endoscopic procedures throughout 
the study, and the qualifications required of the central reader.

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The central reader will determine centrally-read Mayo ES at each colonoscopy in a blinded 
manner, as detailed in the image review charter.
Disagreement between the site and the central read will be adjudicated by an additional blinded 
central reader, as detailed in the image review charter. The adjudicated Mayo ES will be 
provided to the sites from the central reader vendor. 
9.1.1.4.
Endoscopic Biopsies
Biopsies will be obtained at each endoscopy to support assessment of the histopathology 
endpoints in this study, and where permitted, for the assessment of exploratory biomarkers.  
These will be sent to the central study laboratory for processing.  Histopathologic scoring of 
these biopsies will be performed by a blinded central reader.  A detailed histopathology charter 
will outline the procedures to be used for specimen transfer, processing, slide preparation, and 
digitization of slides for histopathologic scoring.  Centrally read histopathology results will not 
be made available to study sites. 
9.1.2. Secondary Efficacy Assessments
9.1.2.1.
Major Secondary Endpoints
The major secondary endpoints are as follows (see Table AMBG.9.1 for definitions):

Clinical remission at Week 40, among patients induced into clinical remission with 
mirikizumab at Week 12 of induction study (Study AMAN)

Endoscopic remission at Week 40, among patients induced into clinical response with 
mirikizumab at Week 12 of the induction study

Corticosteroid-free remission without surgery at Week 40, among patients induced into 
clinical response with mirikizumab at Week 12 of the induction study and were receiving 
corticosteroids at induction baseline  

Histologic remission at Week 40, among patients induced into clinical response with 
mirikizumab at Week 12 of induction study

Stable maintenance of symptomatic remission, among patients induced into clinical 
response with mirikizumab and were in symptomatic remission at Week 12 of induction 
study

Bowel movement urgency improvement among patients induced into clinical response
with mirikizumab at Week 12 of induction study
9.1.2.1.1. Histopathology Scoring Instruments 
The histopathology instruments that will be used for the evaluation of microscopic inflammation 
and histopathologic disease activity will be specified in the histopathology charter.
9.1.2.1.2. Patient Reported Outcome Instruments
The Urgency NRS (see Appendix 7 for description) is a PRO instrument used to collect bowel 
movement urgency data in the patient eDiary. The Urgency NRS will be used to determine the 
secondary endpoint for bowel movement urgency improvement (see Table AMBG.4.1 for 
definition).

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9.1.2.2.
Other Secondary Endpoints
Other secondary endpoints are found in Table AMBG.4.1.
9.1.2.2.1. Physician Reported Instrument
The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a physician reported instrument 
for measuring the endoscopic disease activity of UC on flexible sigmoidoscopy or colonoscopy, 
that includes 3 descriptors of vascular pattern, bleeding, and erosions/ulcerations (Arai et al. 
2016; Ikeya et al. 2016; Tontini et al. 2014).  Only blinded central reading of endoscopies will be 
used to determine the UCEIS score for each endoscopy.
9.1.2.2.2. PRO Instruments Used to Assess Secondary Endpoints
The following are additional PRO instruments collected using a patient electronic diary (eDiary).  
Please see Appendix 7 for additional descriptions.

Abdominal Pain Numeric Rating Scale (NRS)

Fatigue NRS (collected at site visits until Visit 10 when collected via electronic diary) 
The following are additional PRO instruments collected using a tablet device. Please see 
Appendix 7 for additional descriptions.

Inflammatory Bowel Disease Questionnaire (IBDQ)

European Quality of Life 5-Dimension 5 Level (EQ-5D 5L)

Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Version 2

Work Productivity and Activity Impairment Questionnaire: Ulcerative Colitis
(WPAI:UC)
9.1.3. Exploratory Endpoints
Exploratory endpoints are defined in the SAP.
9.1.3.1.
Inflammatory Biomarkers
C-reactive protein (CRP): CRP is an acute phase protein expressed by hepatocytes in response 
to inflammatory cytokines, particularly IL-6, tumor necrosis factor, and IL-1β (Sands 2015).  C-
reactive protein will be obtained at the time points described in the Schedule of Activities
(Section 2).  Investigators will be blinded to CRP results. 
Fecal calprotectin: Fecal calprotectin is a complex consisting of the calcium-binding proteins 
S100A8 and S100A9 (Sands 2015).  It is expressed by activated neutrophils (and to a lesser 
extent by macrophages and monocytes) and fecal levels correlate with the number of neutrophils 
in the gut.  It is used as a biomarker of intestinal inflammation in clinical practice.  Fecal 
calprotectin will be obtained at time points described in the Schedule of Activities (Section 2).  
Investigators will be blinded to fecal calprotectin results. 
9.1.3.2.
Extraintestinal Manifestations
Review of extraintestinal manifestations (EIMs) will be performed at the time points described in 
the Schedule of Activities (Section 2).  If new events are reported or ongoing events change in 
severity, they are to be reported as AEs.  Extraintestinal manifestations include, but are not 
limited to:  uveitis, episcleritis, peripheral arthritis, dactylitis, enthesitis, sacroileitis, ankylosing 

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spondylitis, erythema nodosum, pyoderma gangrenosum, primary sclerosing cholangitis, and 
oral aphthous ulcers.
9.1.3.3.
PRO Instruments Used to Assess Exploratory Endpoints
The Patient UC Symptom Diary is a set of 8 items that assess UC-related symptoms in the past 
24 hours (Appendix 7).  In addition to the SF, RB, abdominal pain, and urgency items mentioned 
above, the diary also includes items that asks the patient to report stool consistency, the 
frequency of night-time stools, and overall disease severity.
The following exploratory endpoints will be assessed via the electronic diary tool and/or at 
applicable study visits using the tablet device:

Nocturnal Stool (collected at site visits until Visit 10 when collected via electronic diary)

Patient’s Global Rating of Severity (PGRS) (collected via electronic diary)

Bristol Stool Scale (collected at site visits until Visit 10 when collected via electronic 
diary)
In addition to those exploratory endpoints assessed by the Symptom Diary, the PGRC will be 
administered at applicable study visits using the tablet device. Additional descriptions of these 
PRO instruments can be found in Appendix 7.
9.1.4. Appropriateness of Assessments
The clinical safety parameters in this study are routine elements of clinical health assessment and 
Phase 3 drug development.  The disease activity measurements are used in clinical practice and 
UC clinical trials.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.

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After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  
In addition, site personnel will record any change in the condition(s), including exacerbation of 
UC, and any new conditions as AEs.
Investigators should record their assessment of the potential relatedness of each AE to protocol 
procedure or investigational product via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.  The investigator 
answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in any of the following outcomes:

Death

Initial or prolonged inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 

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reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic AE should have additional data collected using the 
hepatic eCRF packet.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the 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 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Adverse Events of Special Interest
Adverse events of special interest are AEs which the sponsor specifies as being of special 
interest based on standard drug registration topics, safety findings from previous studies in 
development program, potential risks associated with biologic immunomodulators as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations.  The AESIs for this study are defined in the SAP, and may include but not 
be limited to:

Opportunistic infections

Hypersensitivity events, including anaphylaxis 

Injection site events

Cerebro-cardiovascular events

Malignancies

Depression, or suicidal ideation and behavior

Hepatic AEs.

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For some AESIs, sites should provide additional information regarding the event, as instructed 
on the eCRF.
Opportunistic Infections
Infections will be categorized by Lilly as opportunistic according to Opportunistic Infections and 
Biologic Therapies in Immune-Mediated Inflammatory Diseases: Consensus Recommendations 
for Infection Reporting during Clinical Trials and Postmarketing Surveillance by Winthrop et al. 
(2015).
Hypersensitivity Events 
Site personnel should educate patients and/or caregivers about the symptoms and signs of 
hypersensitivity events and provide instructions on dealing with these events. For 
recommendations on the management and follow-up of hypersensitivity events, see 
Section 7.8.3.2.
Cerebro-Cardiovascular Event Adjudication
Data collected regarding a potential or actual cerebro-cardiovascular AE will be provided to, and 
adjudicated by, an independent, external adjudication committee.  The role of the committee is to 
adjudicate the reported cardiovascular AEs in a blinded, consistent, and unbiased manner 
throughout the course of the study, thereby ensuring that all such reported events are evaluated 
uniformly.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
In case of suspected overdose, hematology, chemistry, vital signs, and oxygen saturation should 
be monitored and supportive care provided as necessary.  There is no known antidote for 
mirikizumab.
9.4.
Safety
When multiple safety assessments are scheduled for the same time point, the preferred order of 
completion is as follows:  vital signs, electrocardiogram (ECG), and then blood sampling. 
9.4.1. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  

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Sitting blood pressure and pulse rate should be measured after the patient has been sitting for at 
least 5 minutes.  Any clinically significant findings from vital signs measurement that result in a 
diagnosis and that occur after the patient receives the first dose of study treatment should be 
reported to Lilly or its designee as an AE via eCRF. 
9.4.2. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).  
Electrocardiograms should be completed prior to any blood draw.  Patients should be supine for 
approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG 
collection.  Electrocardiograms will be read locally. Any clinically significant findings from 
ECGs that result in a diagnosis and that occur after the patient receives the first dose of the 
investigational treatment should be reported to Lilly or its designee as an AE via eCRF. 
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). Retesting is allowed 1 time between the last induction visit 
and Visit 1 of Study AMBG.
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial. The investigator or designee is expected to review 
laboratory reports in a timely manner throughout the study.
Any clinically significant findings from laboratory tests that result in a diagnosis and require 
medical or surgical intervention or result in study treatment discontinuation, and that occur after 
the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.3.1.
Pregnancy Testing
Pregnancy testing is to be performed on all females ≤60 years old, unless they meet the criteria 
describing women not of childbearing potential, outlined in Inclusion Criterion [4b].
Urine pregnancy testing will be performed locally during designated scheduled visits, as 
described in the Schedule of Activities (Section 2).  The urine pregnancy test must be “negative”
within 24 hours prior to administration of investigational product.  
Urine pregnancy testing may be performed at additional time points during the treatment period 
and/or follow-up period, at the discretion of the investigator or if this is required by local 
regulations.
If a urine pregnancy test is not available, a serum pregnancy test is an acceptable alternative.
Assessment of FSH levels can assist in determining if a woman meets the definition of 
“postmenopausal,” as outlined in Inclusion Criterion [4b]. Follicle-stimulating hormone can also 
be optionally obtained at any visit during the study, as indicated in the Schedule of Activities

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(Section 2), to determine if a woman meets the definition of “postmenopausal,” as outlined in 
Inclusion Criterion [4b].
9.4.4. Immunogenicity Assessments 
Venous blood samples will be collected to determine antibody production against mirikizumab at 
the visits and times specified in the Schedule of Activities (Section 2).  To aid interpretation of 
these results, a blood sample for PK analysis will be collected at the same time points.  Samples 
for ADA and accompanying PK analysis should be taken prior to dosing.  
In the event of a drug hypersensitivity event (immediate or nonimmediate), additional samples 
for ADA and PK will be collected as close to the onset of the event as possible, and at 4 and 
12-16 weeks after the event. These samples will also be used for tryptase, complement (C3/C4), 
and cytokine panel assays. Instructions for the collection and handling of blood samples will be 
provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will be 
recorded.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to mirikizumab.  Any samples 
remaining after 15 years will be destroyed.
9.4.5. Other Tests
9.4.5.1.
Physical Examination
Physical examination will be performed as specified in the Schedule of Activities (Section 2).  
Physical examination should include a symptom-directed evaluation as well as examination of 
heart, lungs, abdomen, and visual examination of the skin, and exclude pelvic, rectal, and breast 
examinations.  Physical examination is mandated at Week 40 (or ETV), and must also be 
performed at Week 0 if not performed at Week 12 of induction study.  Physical examination can 
also be performed at the discretion of the investigator at any additional time points, for example, 
to assist in the evaluation of a new symptom during the study. Any clinically significant findings 
from physical examination that result in a diagnosis, and that occur after the patient receives the 
first dose of investigational product, should be reported to Lilly or its designee as an AE via 
eCRF.
9.4.5.2.
Tuberculosis
Diagnosis of LTBI during Study
Patients diagnosed with LTBI during the study must have study drug interrupted.  If treatment 
for LTBI is considered to be appropriate, the patient must complete at least 4 weeks of 
appropriate therapy for LTBI, based on the United States Centers for Disease Control and 
Prevention guidance (CDC [WWW]) for the United States or the World Health Organization 
guidance for the treatment of LTBI for all countries outside of the United States (WHOa
[WWW]), and have no evidence of hepatotoxicity (ALT and AST levels must remain ≤2xULN) 
upon retesting of serum ALT and AST levels after at least 4 weeks of LTBI treatment.  Such 

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patients may then resume study drug treatment and must continue with and complete a full 
course of treatment for LTBI in order to continue on study drug.  Noncompliance with LTBI 
treatment during the study is a reason for permanent discontinuation from study drug.  
Household Contact
Patients who have had household contact with a person with active TB must be evaluated for TB 
infection.
Active TB 
If a patient is diagnosed with active TB during the study, the study drug will be discontinued, the 
patient will undergo an ETV and then enter the post-treatment follow-up period.  The patient 
should also be referred by the investigator for appropriate TB treatment and follow-up.
9.4.5.3.
Hepatitis B
Patients who are HBsAg- anti-HBc+ will be allowed to enter Study AMBG if the following 
criteria are fulfilled:

HBV DNA is not detected at Visit 5 (Week 12) of Study AMAN and

If HBV DNA was tested at other times in Study AMAN, HBV DNA was not detected
and

The other inclusion/exclusion criteria of Study AMBG are met.
Such patients will undergo HBV DNA testing at the following time points:

Weeks 12, 24, and 40 (or ETV) per the Schedule of Activities (Section 2) and

If an elevated ALT or AST level >3xULN is detected.  In this circumstance, if 
HBV DNA is not detected, the investigator should consult with the Lilly-designated 
medical monitor regarding further management of the patient.  
If HBV DNA is detected during Study AMBG, the study drug will be discontinued, an early 
termination visit will take place and the patient will then enter the post-treatment follow-up 
period.  The sponsor recommends that a hepatologist (or a physician with a specialist interest in 
viral hepatology) is consulted and that it is determined whether it is appropriate to start antiviral 
therapy prior to discontinuation of any immunosuppressant or immunomodulatory therapy, or the 
study drug.  Such patients should also receive appropriate follow-up medical care  
If HBV DNA is detected during the study, the investigator should consider using one of the 
following terms to report the AE:

“Detectable HBV DNA”, if HBV DNA is detected without an increase in 
aminotransferase levels.  

“Reactivation of hepatitis B”, if HBV DNA is detected with an increase in 
aminotransferase levels.
Anyone with a new diagnosis of hepatitis B made during this study will be discontinued from 
study treatment, undergo ETV and post-treatment follow-up, and receive appropriate follow-up 
medical care. 

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9.4.5.4.
Hepatitis C 
Patients who test positive for HCV RNA during the induction study AMAN will be excluded.
Any patient with a history of HCV infection who develops elevated ALT >3xULN will be tested 
for HCV RNA (see Section 9.4.6.1).
Patients diagnosed with hepatitis C during the study (test positive for HCV RNA) will be 
discontinued from study treatment, undergo ETV and post-treatment follow-up, and receive 
appropriate follow-up medical care. 
9.4.5.5.
Depression and Suicidality
Suicide-related events (behavior and/or ideations) will be assessed and evaluated at Week 0 with 
the administration of the C-SSRS, the Self-Harm Supplement Form, and the Self-Harm “Follow-
Up” Form (if applicable).  Depressive symptomology will be assessed with the QIDS-SR16 at 
Week 0, Week 12, Week 24, and Week 40 or ETV.  These assessments are described below, and 
further information is provided in Appendix 11.
Columbia Suicide Severity Rating Scale:  The C-SSRS (Columbia University Medical 
Center [WWW]) is a scale that captures the occurrence, severity, and frequency of 
suicide-related ideations and behaviors during the assessment period.  The scale includes 
suggested questions to solicit the type of information needed to determine if suicidal 
ideation and/or behavior occurred.  The C-SSRS is administered by an appropriately 
trained health care professional with at least 1 year of patient care/clinical experience.  
Patient data for the C-SSRS will be recorded in the eCRF.
Self-Harm Supplement Form:  The Self-Harm Supplement Form is a single question to 
enter the number of suicidal behavior events, possible suicide behaviors, or nonsuicidal 
self-injurious behaviors the patient has experienced since the last assessment. For each 
unique event identified, a questionnaire (Self-Harm “Follow-Up” Form) that collects 
supplemental information on the self-injurious behavior is to be completed. This 
information is then documented in the eCRF. 
Quick Inventory of Depressive Symptomatology—Self-Report (16 Items):  The 
QIDS-SR16 is a self-administered, 16-item instrument intended to assess the existence 
and severity of symptoms of depression as listed in the American Psychiatric 
Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) (APA 2013).  Patients will record their responses to the QIDS-SR16 
electronically as source data in the tablet device according to the Schedule of Activities 
(Section 2).
Spontaneous AE collection should occur prior to the collection of the C-SSRS or QIDS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
spontaneous AE collection at Week 0, sites should not change the AE form.  If an event is 
serious or leads to discontinuation, this is an exception where the SAE and/or AE leading to 
discontinuation should be included on the AE form and the process for reporting SAEs should be 
followed.

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9.4.5.6.
Stool Testing
In assessing secondary LOR, a stool sample for C. difficile toxin will be obtained at the first of 
the LOR assessments.  C. difficile testing will also be performed at UVs and ETV when UC
disease exacerbation is suspected. 
This assay tests for the presence of C. difficile toxin protein, followed by a confirmatory test for 
C. difficile toxin gene expression in the stool sample.  C. difficile testing must be negative for 
patients to be eligible to receive IV mirikizumab rescue dosing.  If the C. difficile test confirms 
active C. difficile infection, patients should be treated as considered appropriate by the 
investigator, and study treatment dosing may be withheld if infection is assessed to be clinically 
important (Section 8.1.2).  An AE should be reported if, in the judgement of the investigator, the 
patient’s signs, symptoms, and positive C. difficile test results are consistent with a C. difficile 
infection.
In the event of a positive test, re-testing is allowed if, in the judgement of the investigator, the 
patient’s symptoms or signs are not consistent with C. difficile infection.
Additional local stool culture/testing is allowed at the investigator’s discretion at the time of
LOR evaluation or as deemed appropriate by the investigator.
9.4.6. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by 
appropriate methods.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring board (an advisory group for this study 
formed to protect the integrity of data; refer to Interim Analyses section [Section 10.3.8]) can 
conduct additional analyses of the safety data.
9.4.6.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3xULN, ALP ≥2xULN, or elevated TBL ≥2xULN, 
liver testing (Appendix 4) should be repeated within 3 to 5 days, including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase, to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected via the hepatic eCRF packet if 1 or more of the 
following conditions occur: 

Elevation of serum ALT to ≥5xULN on 2 or more consecutive blood tests

Elevated serum TBL to ≥ 2xULN (except for cases of known Gilbert’s syndrome)

Elevation of serum ALP to ≥2xULN on 2 or more consecutive blood tests

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 8 3
L Y 3 0 7 4 8 2 8

P atie nt disc o nt i n ue d fr o m treat me nt d ue t o a he patic e ve nt or a b n or malit y of 
li ver t ests

H e patic e ve nt c o nsidere d t o be a n S A E

P ati e nt wit h a hist or y of H C V i nfecti on de vel o ps ele vate d A L T > 3 x U L N.  Patie nt 
will be teste d f or H C V R N A

P ati e nt e x perie nces a n A L T or A S T > 3 x U L N a n d T B L > 2 x U L N or i nter nat i onal 
n or m alize d ratio > 1. 5.  T he st u d y  me dical m o nit or s h o ul d be c o ns ul te d as s o o n as 
p ossi ble f or f urt her g ui da nce 
9. 5.
P h ar m a c o ki n eti c s
At  t he visits a n d ti mes s pecifie d i n t he Sc he d ule of Act i vities ( Sectio n 2 ), ve n o us bl o o d sa mples 
of  a p pr o xi matel y 2 m L eac h will  be c ollecte d t o deter mi ne t he ser u m c o nce ntratio ns of 
mir i kiz u ma b.
S a m ples will  be a nal yzed at a l a b orat or y a p pr o ve d b y t he s p o ns or a n d st ore d at a facility 
desi g nate d b y  t he s p o ns or.  Ser u m c o nce ntratio ns of mir i kiz u ma b will be deter mi ne d usi n g a 
vali date d e nz y me -li n ke d i m m u n os or be nt assa y. It is n ot i nte n de d t hat sa m ples c ollecte d fr om 
pl ace b o -treate d patie nts will be a nal yze d. A d dit i onal sa m ples ma y be c ollecte d a n d use d f or 
e x pl orat or y a nal yses s uc h as bi oa nal ytical met h o d de vel o p me nt or vali dat i on e xercises.
A ma xi m u m of 3 sa m ples ma y be c ollecte d at a d diti o nal t i me p oi nts d uri n g t he st u d y if 
warra nte d a n d a gree d u p o n bet wee n b ot h t he i n vesti gat or a n d s p o ns or.  I nstr ucti o ns f or t he 
c ollect i on a n d ha n dli n g of bl o o d sa m ples will be pr o vi de d b y t he s p o ns or .  T he act ual date a n d
ti me ( 2 4-h o ur cl oc k ti me ) of  eac h sa m pli n g will be rec or de d.
Dr u g c o nce ntrati o n i nf or mat i on t hat m a y u n bli n d t he st u d y will n ot be re p orte d t o i n vesti gati ve 
sites or bli n de d pers o n nel.
Bi oa nal y tic al sa m ples c ollecte d t o meas ure i n vest i gati o nal pr o d uct c o nce ntratio n will be retai ne d 
f or a ma xi m u m of 1 year f oll o wi n g last patie nt visit f or t he st u d y.  
 
 
 
 
 
9. 6.
P h ar m a c o d y n a mi c s
S ee S ectio n 9. 8 .
C CI

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L Y 3 0 7 4 8 2 8
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
9. 9.
M e di c al R e s o ur c e Utili z ati o n a n d H e alt h E c o n o mi c s
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics para meters are n ot e val uate d i n t his st u d y .
C CI

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10. Statistical Considerations 
10.1. Sample Size Determination 
Assuming that 90% of patients complete Study AMAN (which is expected to randomize 
approximately 1160 patients), Eli Lilly and Company (Lilly) anticipates approximately 
1044 patients will enroll in Study AMBG.  It is expected that approximately 470 of these patients 
will enter Study AMBG as clinical responders to mirikizumab and then will be randomized 2:1 
to 200 mg mirikizumab SC (approximately 313 patients) and placebo (approximately 
157 patients).  Among the expected 470 mirikizumab clinical responders, approximately 
180 mirikizumab clinical remitters will be randomized to 200 mg mirikizumab SC 
(approximately 120 patients) and placebo (approximately 60 patients).  This assumes that: 
 The induction study (AMAN, which has a mixed population with approximately 50% 
biologic-failed patients) is expected to have an overall clinical remission rate of 23% and 
response rate of 60% with mirikizumab. 
 75% of induction patients receive treatment with mirikizumab, based on a 3:1 
randomization ratio for the induction study. 
 10% dropout rate from induction to maintenance. 
 
The primary endpoint, clinical remission at Week 40, will be assessed on patients who achieved 
clinical response to mirikizumab induction treatment.  Assuming mirikizumab and placebo 
clinical remission rates of 47% and 27%, respectively, this study based on the 470 mirikizumab 
induction responders is expected to have >95% power to demonstrate that mirikizumab is 
superior to placebo by using a chi-square test with a 2-sided significance level of 0.05.  In 
addition, the sample size is expected to provide adequate power (>80%) to demonstrate that 
mirikizumab is superior to placebo for endoscopic remission, histologic remission, and 
corticosteroid-free remission at Week 40, among responders to mirikizumab induction treatment 
by using a chi-square test with a 2-sided significance level of 0.05. 
10.2. Populations for Analyses 
For purposes of analysis, the populations described in Table AMBG.10.1 are defined. 

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Table AMBG.10.1.
Analysis Populations in Study AMBG
Population
Description
Intent-to-treat (ITT) Population
All randomized/assigned patients. Patients will be analyzed according to the 
treatment to which they were assigned
Modified Intent-to-treat (mITT) 
Population
All randomized/assigned patients who received at least 1 dose of study 
treatment in Study AMBG, regardless of whether correct treatment was 
administered or whether protocol was followed, will be analyzed according to 
the treatment to which they were assigned.
Safety Population
Same as mITT Population
Per-Protocol (PP) Population
All mITT patients who are not deemed noncompliant with treatment, who do 
not have significant protocol deviations (defined in the SAP), and whose 
investigator site does not have significant GCP deviations that require a report to 
regulatory agencies (regardless of study period).  Qualifications and 
identification of the specific significant protocol deviations that result in 
exclusion from the PP population will be determined while the study remains 
blinded, prior to the database lock
Pharmacokinetic Evaluable
All patients who received at least 1 dose of investigational product and have 
sufficient blood sampling to allow for pharmacokinetic evaluation
Abbreviations:  GCP = good clinical practice; SAP = statistical analysis plan.
Four analysis cohorts have been defined (Table AMBG.10.2).
Table AMBG.10.2.
Analysis Cohorts in Study AMBG
Cohort ID
Cohort
Description
1
Main cohort 
(mirikizumab induction 
responders)
Patients who are randomized and responded to mirikizumab
induction dosing and then are rerandomized to 200 mg 
mirikizumab SC or placebo
2
Mirikizumab induction 
nonresponders
Patients who are randomized and did not respond to 
mirikizumab induction dosing and then are enrolled into 
Study AMBG
3
Placebo induction 
responders
Patients who are randomized and responded to placebo in 
induction study and then enrolled into Study AMBG
4
Placebo induction 
nonresponders
Patients who are randomized and did not respond to placebo 
in induction study and then enrolled into Study AMBG
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  
Both efficacy and safety analysis will be conducted on the modified intent-to-treat (mITT) 
population.  The efficacy analysis of the primary endpoint and major secondary endpoints will be 
repeated for intent-to treat population and the per-protocol population in the main cohort 
(mirikizumab induction responders). Additional analyses may be performed as deemed 
appropriate.

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For efficacy analysis, the baseline will be defined as the initial baseline value before the patient 
is randomized into the induction study (Study AMAN), unless otherwise specified. For safety 
analysis, the baseline will be defined as the visit at Week 12 value in the induction study and 
prior to enrollment in Study AMBG, unless otherwise specified.
Unless otherwise specified, the main efficacy and safety analyses will be conducted on the main 
cohort for patients who respond to mirikizumab induction dosing and then are rerandomized to 
200 mg mirikizumab SC dosing or placebo. For other cohorts of patients, efficacy and safety 
will be descriptive without statistical testing.
Summary statistics for continuous variables may include mean, standard deviation, median, and 
minimum and maximum values.  Categorical variables will be presented as counts and 
percentages.  Unless otherwise specified, variables will be analyzed in the original scale on 
which they are measured.  The parametric approach will be employed by default for statistical 
analysis, except when nonparametric analysis, such as by a rank-based method, is assessed to be 
more fitting.  Additional exploratory analyses of the data may be conducted as deemed 
appropriate.  All hypothesis tests of treatment effects will be 2-sided, unless otherwise stated.
For assessments of the primary endpoint and other categorical efficacy endpoints among induced 
responders, the CMH chi-square test will be used to compare mirikizumab and placebo with 
stratification factors:  (a) previous biologic therapy failure (yes or no), (b) baseline corticosteroid 
use (yes or no), (c) region (North America/Europe/Other), and (d) induction remission status 
(yes/no).  The CMH chi-square p-value and the relative risk along with its 95% 2-sided 
confidence interval (CI) will be provided.  In addition, the absolute treatment difference in 
proportions will be provided along with the 95% 2-sided CI estimate. The differences between 
mirikizumab and placebo will also be tested separately using a logistic regression model that 
controls for the stratification factors.  If deemed necessary, additional analyses of categorical 
efficacy variables may be conducted to address sparse data and/or small sample sizes.  
Treatment comparisons of continuous efficacy and health outcome variables will be made using 
mixed-effects model of repeated measures (MMRM) analysis.  When the MMRM model is used, 
the model includes:  (a) treatment group, (b) previous biologic therapy failure (yes or no), (c) 
corticosteroid use (yes or no), (d) region (North America/Europe/Other), (e) baseline value in the 
model, (f) visit, (g) induction remission status (if analysis is among induced responders), and (h) 
the interactions of treatment-by-visit and baseline-by-visit as fixed factors.  The covariance 
structure to model the within-patient errors will be unstructured.  If the unstructured covariance 
matrix results in a lack of convergence, the heterogeneous Toeplitz covariance structure, 
followed by the heterogeneous autoregressive covariance structure will be used.  The 
Kenward-Roger method will be used to estimate the denominator degrees of freedom.  Type III 
sums of squares for the least squares (LS) means will be used for the statistical comparison; the 
95% CI will also be reported.
Treatment comparisons of continuous efficacy and health outcome variables with a single 
post-baseline time point will be made using analysis of covariance with:  (a) treatment group, 
(b) previous biologic therapy failure (yes or no), (c) corticosteroid use (yes or no), (d) region 

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(North America/Europe/Other), (e) baseline value in the model, and (f) induction remission 
status.  Type III sums of squares for LS means will be used for statistical comparison between
treatment groups.  The LS mean difference, standard error, p-value, and 95% CI, unless 
otherwise specified, will also be reported.  
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.
10.3.1.1. Missing Data Imputation: 
While every effort will be made to reduce missing data, the missing data imputation methods 
described below will be used to provide a conservative approach for assessing efficacy endpoints 
when patients are permanently discontinued from study drug or otherwise have missing data.

Nonresponder imputation (NRI): For analysis of categorical efficacy and health 
outcomes variables, missing data will be imputed using an NRI method.  Patients will be 
considered a nonresponder for the NRI analysis if they do not meet the categorical 
response criteria, have missing clinical response data at a time point of interest, or take 
rescue dosing with mirikizumab prior to the time point of interest. 

Mixed-effects model of repeated measures: For continuous variables, the primary 
analysis will be MMRM with the missing at random assumption for handling missing 
data.  This analysis takes into account both missingness of data and the correlation of the 
repeated measurements.  The data collected after rescue medication will be censored in 
the primary analysis. No additional imputation methods will be applied to the MMRM 
analysis.
Sensitivity analyses, including additional methods of handling missing data or analyzing the data 
that may be required to satisfy regulatory needs will be specified in the SAP.
10.3.1.2. Multiplicity Control
A prespecified multiple testing scheme based on graphical approach (Bretz et al. 2009, 2011) 
will be used to test the primary and major secondary hypotheses at overall family wise type 1 
error rate (FWER) of 0.05.  The graphical approach is a closed testing procedure; hence, it 
strongly controls the FWER across all endpoints (Alosh et al. 2014).  Details of the specific 
graphical testing scheme (including testing order, interrelationships, type I error allocation for 
the major secondary endpoints, and the associated propagation) will be prespecified in the SAPs 
prior to first unblinding of efficacy.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number of enrolled patients will be summarized by cohort and by treatment. Frequency 
counts and percentages of all patients who are enrolled and complete the study or discontinue the 

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study drug/study early will be presented.  Reasons for discontinuing the study drug/study will be 
summarized.
10.3.2.2. Patient Characteristics
Year of birth, sex, weight, smoking habits, prior biologic therapy, and other demographic and 
disease characteristics will be summarized for all enrolled patients.  Age and body mass index 
will be calculated.  Demographic and baseline disease characteristics will be summarized for 
each treatment group and by cohort. 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 drug dictionary.  Medications started prior to randomization and 
medications started on study after randomization will be presented separately in frequency tables 
by drug name and by cohort for all enrolled patients.  
Patients who are noncompliant will be listed by treatment and by cohort. The details of 
noncompliance will be defined in SAP. A contingency table of numbers of noncompliant 
patients by treatment and by cohort will be provided.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary endpoint is the proportion of patients with clinical remission at Week 40 (Week 52 
of continuous therapy) among the patients who are responders to 300 mg mirikizumab IV at 
12 weeks of induction dosing.
For study visits that include endoscopy as a study procedure (for example, Visit 11 [Week 40]), 
the SF and RB subscores of the Mayo score will be calculated from daily electronic diary data by 
averaging the most recent 3 valid days (possibly nonconsecutive) in the 7 days prior to 
commencing bowel preparation for endoscopy. At other study visits, where endoscopy is not 
performed, SF and RB subscores will be calculated from the daily electronic diary data by 
averaging the most recent 3 valid days (possibly nonconsecutive) in the 7 days prior to that study 
visit. If data for fewer than 3 valid days are available, the subscores will be considered missing.  
Patient diary data obtained on the following days will be excluded: (i) days when bowel 
preparation was taken prior to endoscopy, (ii) the day of the endoscopy, and (iii) the day after the 
endoscopy.  
Rates of clinical remission at Week 40 among induction responders will be analyzed.  Patients 
who do not achieve clinical remission or who do not reach the Week 40 assessment will be 
considered to be nonremitters. In addition, patients who take rescue dosing with mirikizumab
will be considered nonremitters.
The primary endpoint analysis will utilize the CMH test as described in Section 10.3.1.
Additional analyses of the primary endpoint may be considered and will be fully detailed in 
the SAP.

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10.3.3.2. Secondary Analyses
The secondary efficacy and health outcome endpoints of the trial are presented in 
Table AMBG.4.1 and details of the analysis methods that will be utilized are provided in 
Section 10.3.1.
The endpoints for the major secondary objectives will be analyzed using the similar CMH test 
used for the primary endpoint. Multiplicity adjustment for type 1 error control to the major 
secondary endpoints is described in Section 10.3.1.2.
Additional analyses of the secondary efficacy and health outcome endpoints may be considered 
and will be fully detailed in the SAP.
10.3.3.3. Exploratory Analyses
Details of the analysis of exploratory endpoints will be fully detailed in the SAP. Additional 
analyses of exploratory health outcome endpoints may be considered and will be fully detailed in 
the SAP.
10.3.4. Safety Analyses
Safety will be assessed by evaluating exposure, AE (for example, treatment-emergent AE
[TEAE], SAE, treatment related AE, discontinuation due to AE), AESI (for example, infection, 
MACE, injection site event, hypersensitivity event, etc.), laboratory analytes, vital signs, ECGs, 
C-SSRS, etc.
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities and 
summarized by system organ class, preferred term, severity, and relationship to investigational 
product. A TEAE is defined as an event that first occurred or worsened in severity after 
baseline, which is the on-study AE recorded at Week 12 in the induction study. For each event 
classification term, the number of patients experiencing a TEAE with that classification term will 
be tabulated. 
The safety analyses for the main cohort will compare mirikizumab to placebo during the 
maintenance treatment. For other cohorts, the safety data will be summarized without treatment 
comparison.
The Fisher exact test will be used to perform the between-treatment group comparisons for AEs, 
discontinuations, and other categorical safety data.  The change from baseline in continuous vital 
signs, physical characteristics, and other continuous safety variables, including laboratory 
variables, will be summarized by visit and treatment. The change from baseline to last 
observation value will be analyzed with the ANOVA model with baseline as a covariate. The 
last non-missing observation in the treatment period will be used as the last observation.
Shift tables for categorical safety analyses (for example, “high” or “low” laboratory results) will 
also be produced. 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
The PK of mirikizumab will be characterized using graphical evaluations and mixed-effect 
(population PK) modeling approaches.  Various structural and error models will be evaluated 

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during development of the mixed-effect model.  Intrinsic factors (such as, age, body weight, 
gender, ADAs, etc.) and extrinsic factors (such as, co-medications) will be investigated to assess 
their influence on model parameters.  Model evaluation will include a visual predictive check.  
Estimates of PK model parameters and covariate effects and the corresponding 90% CIs will be 
reported.
Analyses of exposure-response relationships will be conducted using both exploratory graphical 
approaches and model based approaches.  Exploratory graphical analysis approaches may consist 
of graphs showing the percentage of patients who achieve clinical response, clinical remission, 
and endoscopic remission at different percentiles (for example, quartiles) of exposure of 
mirikizumab at Week 40.  Measures of exposure may include population PK estimated average 
concentrations (Cavg) between Week 0 and Week 40, or estimated or observed trough 
concentrations at Week 40.  Model based analyses will utilize population exposure-response 
logistic regression models, where maximum effect (Emax) or other model structures may be used 
to relate exposure to the probability of achieving clinical response, clinical remission, and 
endoscopic remission. These models may be used to evaluate patient factors that may impact the 
relationship between exposure and the probability of achieving the endpoint. Longitudinal 
exposure-response models for SF and RB subscores may be developed, which relate the time 
course and magnitude of mirikizumab exposure to the time course of these subscores.
Additional analyses may be conducted if they are deemed appropriate.  Data from this study may 
be combined with other study data, if appropriate.  Further details on PK and PK/PD analyses 
will be provided in the PK/PD analysis plan.
10.3.6. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting (baseline) ADA, ADA at any time 
post baseline, and with treatment-emergent (TE)-ADA to mirikizumab will be tabulated.  If no 
ADAs are detected at baseline, TE-ADA are defined as those with a titer 2-fold (1 dilution) 
greater than the minimum required dilution of the assay.  For samples with ADA detected at 
baseline, TE-ADA are defined as those with a 4-fold (2 dilutions) increase in titer compared to 
baseline.  For patients who have TE-ADA, the distribution of maximum titers will be described.  
The frequency of neutralizing antibodies will also be tabulated.
The relationship between the presence of antibodies and the PK parameters and PD response,
including safety and efficacy to mirikizumab, may be assessed.
10.3.7. Other Analyses
10.3.7.1. Subgroup Analyses 
Subgroup analyses will be conducted for the primary endpoint and selected major secondary 
endpoints.  Subgroups to be evaluated will include sex, age category, body weight, race, 
geographic region, baseline disease severity, duration of disease, previous biologic-failed status 
(yes or no), corticosteroid use (yes or no), UC concomitant therapy use (corticosteroid, 
immunomodulators), induction remission status (yes or no) for endpoints among induction 
responders. The treatment-by-subgroup interaction will be tested at the significance level 

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of 0.10.  If any treatment group within the subgroup is less than 10% of the total mITT
population for the main cohort, only summaries of the efficacy data will be provided (that is, no 
inferential testing will be done). 
Detailed subgroup analysis will be defined in the SAP.
10.3.8. Interim Analyses
One DMC consisting of members external to Lilly will be established for periodic monitoring of 
clinical trial data across all Phase 3 trials for the UC adult program.  This committee will consist 
of a minimum of 3 members, including a physician with expertise in gastroenterology and a 
statistician.  No member of the DMC may have contact with study sites.  A statistical analysis 
center (SAC) will prepare and provide unblinded data to the DMC. The SAC members may be 
Lilly employees or from third-party organizations designated by Lilly. However, they will be 
external to the study team and will have no contact with sites and no privileges to influence 
changes to the ongoing studies. The timing and frequency of the periodic clinical trial data 
review by the DMC will be detailed in the DMC charter for the UC adult program.
A primary database lock is planned after all patients complete the Week 40 visit or the ETV. 
The analysis based on data from the primary database lock will be conducted by the sponsor or a 
designee and no further multiplicity adjustment will be implemented. The final database lock 
will occur after all patients complete the entire study, including safety follow-up. 
The DMC is authorized to evaluate unblinded interim efficacy and safety analyses during the 
periodic safety review. The DMC will make recommendation to the Lilly Research Laboratories 
Senior Management Designee, who may order the immediate implementation of the DMC 
recommendation, or may convene an internal review committee (IRC), which is independent 
from the study team, to review the recommendation according to standard Lilly policy.  Study 
sites will receive information about interim results ONLY if they need to know for the safety of 
their patients.
In addition to DMC, SAC, and potential IRC, 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 shared to the study sites or the blinded study team until the study has been 
unblinded.  Unblinding details will be specified in the unblinding plan section of the SAP or a 
separate unblinding plan document.

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11.
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recommendations for infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis. 2015;74(12):2107–2116.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions

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

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

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ICH
International Council for Harmonisation
IgG4
immunoglobulin G4
IL
interleukin
IRC
internal review committee
IV
intravenous
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study after having been informed of all aspects of the study that are relevant to 
the patient decision to participate.  Informed consent is documented by means of a written, 
signed, and dated informed consent form.
interim analysis
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.
IWRS
interactive web-response system
LOR
Loss of Response
LS
least squares
LTBI
latent tuberculosis infection 
mITT
All randomized/enrolled patients who received at least 1 dose of study treatment, do not 
receive the correct treatment, or otherwise do not follow the protocol. Patients will be 
analyzed according to the treatment to which they were assigned
MMRM
mixed-effects model of repeated measures
MMS
modified Mayo Score
MOS
margin of safety
NOAEL
no-observed-adverse-effect level
NRI
nonresponder imputation
NRS
numeric rating scale
PASI
Psoriasis Area and Severity Index
PD
pharmacodynamic(s)

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PGA
Physician’s Global Assessment
PGRC
Patient’s Global Rating of Change
PGRS
Patient’s Global Rating of Severity
PK
pharmacokinetic(s)
PRO
patient-reported outcomes
Q4W
every 4 weeks
QIDS-SR16
Quick Inventory of Depressive Symptomatology —Self-Report (16 Items)
RB
rectal bleeding
SAE
serious adverse event
SAC
statistical analysis center
SAP
statistical analysis plan
SC
subcutaneous
SF
stool frequency
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study. 
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TBL
total bilirubin level
TE-ADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event
UC
ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
ULN
upper limit of normal
UV
unscheduled visit 
WPAI:UC
Work Productivity and Activity Impairment Questionnaire Ulcerative Colitis

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Appendix 2.
Clinical Laboratory Tests

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 1 0 6
L Y 3 0 7 4 8 2 8
He m at ol o g y
a, b
Cli nic al C he mistr y
a, b
He m o gl o bi n
Ser u m C o nce ntr ati o ns of:
He mat ocrit
S o di u m
Er y t hr oc yte c o u nt ( R B C)
C hl ori de
Mea n cell v ol u me 
Bicar b o nate
Mea n cell he m o gl o bi n
P otassi u m
Mea n cell he m o gl o bi n c o nce ntrati o n 
T otal bilir u bi n
Le u k oc ytes ( W B C)
T otal pr otei n
Cell m or p h ol o g y
Direct bilir u bi n
Ne utr o p hils, se g me nte d
Al kali ne p h os p hatase ( A L P)
L y m p h oc y t es
Ala ni ne a mi n otra nsferase ( A L T)
M o n oc ytes
As partate a mi n otra nsferase ( A S T)
E osi n o p hils
Ga m ma -Gl uta m yl Tra nsferase ( G G T)
Bas o p hils
Bl o o d urea nitr o ge n ( B U N)
Platelets
Creati ni ne
Ur ic aci d
Calci u m
Gl uc ose
Al b u mi n
C h olester ol (t otal)
Tri gl yceri des
Li pi d Pa nel (fasti n g) c
H D L ch olester ol
L D L ch olester ol
Creati ne ki nase ( C K)
Ot her Tests a
He patitis B D N A P C R (if i n dicate d)
b, d
Pre g na nc y test ( ur i ne
e)
F S H
b, e
 
A nti- miri kiz u ma b a nti b o dies (i m m u n o ge nicit y)
Ser u m miri kiz u ma b c o nce ntrati o n ( P K)
C- reacti ve pr otei n, hi g h-se nsiti vit y
Cl ostri di u m difficile
f,g a n d St o ol C ult ure g
Fecal cal pr otecti n
E x pl o rat or y c yt oki nes
T r yptase h
C o m ple me nt ( C 3/ C 4) h
C y t o ki ne pa nelh
F o ot n otes o n next p a ge.
C CI

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Abbreviations:  ADA = anti-drug antibody; anti-HBc+  = positive anti-hepatitis B core antibody; 
DNA = deoxyribonucleic acid; FSH = follicle-stimulating hormone; HBsAg- = negative hepatitis B surface 
antigen; HBV = hepatitis B virus; HDL = high density lipoprotein; LDL = low density lipoprotein 
PCR = polymerase chain reaction; PK = pharmacokinetic; RBC = red blood cell; RNA = ribonucleic acid; 
SC = subcutaneous; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b
Results will be confirmed by the Central Laboratory/other at the time of initial testing.
c
For the fasting lipid profile, patients should not eat or drink anything except water for 12 hours prior to test.
d
Hepatitis B PCR testing will be performed in patients known from induction study to be HBsAg-, anti-HBc+, 
and in whom HBV DNA was not detected.
e
Urine pregnancy test will be evaluated locally.  FSH test can be performed to confirm that women ≥50 years of
age with spontaneous amenorrhea for at least 6 months lack childbearing potential, see Inclusion Criteria [4b].
f
To be performed only for patients with secondary loss of response after at least 3 maintenance SC doses to 
determine eligibility for rescue dosing.
g
Can be done locally by investigator as needed
h
Performed only in the event of systemic allergic/hypersensitivity events, along with ADA and PK.

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Appendix 3.
Study Governance Considerations

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

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

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

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

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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality

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Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.  These tests will be performed at a Lilly-designated laboratory.
Hepatic Monitoring Tests
Hepatic Hematology
Haptoglobin
Hemoglobin
Hematocrit
Hepatic Coagulation
RBCs
Prothrombin Time
WBCs
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologies
a
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody 
Hepatic Chemistry
Hepatitis C antibody 
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody
AST
GGT
Alkaline phosphatase isoenzymes
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cell; WBC = white blood cell.
a
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Risk Factors for Latent Tuberculosis Infection 

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Risk Factors for Latent Tuberculosis Infection
Household contact or recent exposure to an active case
Birth or residency in a high burden country (>20/100,000)
Residents and employees of high risk congregate settings, for example, prisons, homelessness, intravenous drug use
Source:  Adapted from Horsburgh and Rubin (2011) and Lewinsohn et al. (2017).
Risk Factors for Increased Likelihood of Progression from LTBI to Active TB
Household contact or close contact with an active case
HIV
Radiographic evidence of old, healed TB that was not treated
Silicosis
Treatment with ≥15 mg prednisone (or equivalent) per day
Children <5 years of age
Chronic renal failure
Treatment with an anti-TNF antibody
Poorly controlled diabetes
Intravenous drug use
Weight ≥10% below normal
Smoking
Abbreviations:  HIV = human immunodeficiency virus; LTBI = latent tuberculosis infection; TB = tuberculosis; 
TNF = tumor necrosis factor.
Source:  Adapted from Horsburgh and Rubin (2011).
WHO List of High Burden Countries (as at 28 Oct 2015, includes but may not be limited to)
Angola
India
Peru
Azerbaijan
Indonesia
Philippines
Bangladesh
Kenya
Russian Federation
Belarus
Kazakhstan
Sierra Leone
Botswana
Democratic People’s Republic of Korea
Somalia
Brazil
Kyrgyzstan
South Africa
Cambodia
Lesotho
Swaziland
Cameroon
Liberia
Tajikistan
Central African Republic
Malawi
United Republic of Tanzania
Chad
Republic of Moldova
Thailand
China
Mozambique
Uganda
Congo
Myanmar
Ukraine
Democratic Republic of the Congo
Namibia
Uzbekistan
Ethiopia
Nigeria
Vietnam
Ghana
Pakistan
Zambia
Guinea-Bissau
Papua New Guinea
Zimbabwe
Source: WHOb [WWW]

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

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

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Appendix 7.
Patient-Reported Outcome Instruments

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Daily Diary Review
Rectal Bleeding
a
Stool Frequency
a
Urgency NRS
a
Abdominal Pain NRS
a
PGRS
a
Nocturnal Stool
b
Fatigue NRS
b
Bristol Stool Scale
b
Abbreviations: NRS = numeric rating scale; PGRS = Patient’s Global Rating of Severity
a
Question will be administered daily through Week 40 or early termination visit.
b
Question will be administered at Visits 2 through 10 (Weeks 4 through 36), and daily between Visit 10 and 
Visit 11.
The following are descriptions of additional patient-reported outcome instruments used in Study 
AMBG using Patient eDiary or tablet device:

Urgency Numeric Rating Scale (NRS):  A single item that measures the severity of the 
urgency (sudden or immediate need) to have a bowel movement in the past 24 hours,
using an 11-point NRS ranging from 0 (no urgency) to 10 (worst possible urgency).  
Patients will be provided with an electronic diary tool during screening to record 
information daily pertaining to their severity of urgency.

Abdominal Pain NRS: A single item that measures the “worst abdominal pain in the 
past 24 hours” using an 11-point NRS ranging from 0 (no pain) to 10 (worst possible 
pain).  Patients will be provided with an electronic diary tool during screening to record 
information daily pertaining to their worst abdominal pain experience.

Patient’s Global Rating of Severity (PGRS): The PGRS is a 1-item patient-rated 
questionnaire designed to assess the patients’ rating of their disease symptom severity 
over the past 24 hours. Responses are graded on a 6-point scale in which a score of 1 
indicates that the patient has no symptoms (that is, “none”) and a score of 6 indicates that 
the patient’s symptom(s) are “very severe.” Patients will be provided with an electronic 
diary tool during screening to record information daily pertaining to their disease 
experience. 

Nocturnal Stool: The Nocturnal Stool instrument is a single item asking the patient to 
record the number of stools they had during the night (or day, for shift workers), causing 
them to waken from sleep. Patients will be provided with an electronic diary tool during 
screening to record information daily pertaining to their nocturnal stool count during 
appropriate time periods. Patients will also record their response to the nocturnal stool 
count electronically as source data in the tablet device at appropriate visits.

Fatigue NRS:  The Fatigue NRS is a single item that measures the “worst fatigue 
(weariness, tiredness) in the past 24 hours” using an 11-point NRS ranging from 0 (no 
fatigue) to 10 (fatigue as bad as you can imagine). Patients will be provided with an 
electronic diary tool during screening to record information daily pertaining to their worst 
fatigue experience during appropriate time periods.  Patients will also record their 

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response to the Fatigue NRS electronically as source data in the tablet device at 
appropriate visits.

Bristol Stool Scale: The Bristol Stool Scale is a single item that provides a pictorial and 
verbal description of stool consistency and form, ranging from Type 1 (hard lumps) to 
Type 7 (watery/liquid).  Patients will be provided with an electronic diary tool during 
screening to record information daily pertaining to their stool during appropriate time 
periods. Patients will also record their response to the Bristol Stool Scale electronically 
as source data in the tablet device at appropriate visits.

Patient’s Global Rating of Change (PGRC): The PGRC scale is a patient-rated 
instrument designed to assess the patients’ rating of change in their symptom(s).  
Responses are graded on a 7-point Likert scale, in which a score of 1 indicates that the 
subject’s symptom(s) is “very much better,” a score of 4 indicates that the subject’s 
symptom(s) has experienced “no change,” and a score of 7 indicates that the subject’s 
symptom(s) is “very much worse.” Patients will record their response to the PGRC 
electronically as source data in the tablet device at appropriate visits.

Inflammatory Bowel Disease Questionnaire (IBDQ):  A 32-item patient-completed 
questionnaire that measures 4 aspects of patients’ lives:  symptoms directly related to the 
primary bowel disturbance, systemic symptoms, emotional function, and social function 
(Guyatt et al.1989; Irvine et al. 1994, 1996).  Responses are graded on a 7-point Likert 
scale, in which 7 denotes “not a problem at all” and 1 denotes “a very severe problem.” 
Scores range from 32 to 224; a higher score indicates a better quality of life. Patients will 
record their responses to the IBDQ electronically as source data in the tablet device at 
appropriate visits.

European Quality of Life 5-Dimension 5 Level (EQ-5D 5L):  A widely used, generic 
questionnaire that assesses health status (Herdman et al. 2011; EuroQol Group 2015).  
The questionnaire consists of 2 parts.  The first part assesses 5 dimensions (mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression) that have 5 possible levels 
of response (no problems, slight problems, moderate problems, severe problems, extreme 
problems).  This part of the EQ-5D can be used to generate a health state index score, 
which is often used to compute quality-adjusted life years (QALY) for utilization in 
health economic analyses.  The health state index score is calculated based on the 
responses to the 5 dimensions, providing a single value on a scale from less than 0 (where 
zero is a health state equivalent to death; negative values are valued as worse than dead) 
to 1 (perfect health), with higher scores indicating better health utility (EuroQol Group 
[WWW]).  The second part of the questionnaire consists of a visual analog scale (VAS) 
on which the patient rates their perceived health state from 0 (the worst health you can 
imagine) to 100 (the best health you can imagine).  Patients will record their responses to 
the EQ-5D 5L electronically as source data in the tablet device at appropriate visits.

Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Version 2:  A
patient-reported, generic, health-related quality of life instrument originally published in 
1992, with some item wordings and response options revised in 2000 (Ware and 
Sherbourne 1992; Ware 2000). It consists of 36 questions measuring 8 health domains:  
physical functioning, bodily pain, role limitations due to physical problems, role 

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limitations due to emotional problems, general health perceptions, mental health, social 
function, and vitality. The patient’s responses are solicited using Likert scales that vary 
in length, with 3 – 6 response options per item. The SF-36 can be scored into the 8 health 
domains named above and 2 overall summary scores:  physical component summary 
(PCS) and mental component summary (MCS) scores.  The domain and summary scores 
range from 0 to 100; higher scores indicate better levels of function and/or better health. 
The SF-36 version 2 (standard version) will be used, which utilizes the recall period of 
“the past 4 weeks” (Ware and Sherbourne 1992; Maruish 2011).  Patients will record 
their responses to the SF-36 Version 2 electronically as source data in the tablet device at 
appropriate visits.

Work Productivity and Activity Impairment Questionnaire: Ulcerative Colitis 
(WPAI:UC):  A patient-reported instrument developed to measure the impact on work 
productivity and regular activities attributable to a specific health problem (WPAI:UC). 
It contains 6 items that measure: 1) employment status, 2) hours missed from work due 
to the specific health problem, 3) hours missed from work for other reasons, 4) hours 
actually worked, 5) degree health affected productivity while working, and 6) degree 
health affected productivity in regular unpaid activities. Four scores are calculated from 
the responses to these 6 items: absenteeism, presenteeism, work productivity loss, and 
activity impairment (Reilly Associates [WWW]). Scores are calculated as impairment 
percentages (Reilly et al. 1993), with higher numbers indicating greater impairment and 
less productivity, that is, worse outcomes (Reilly Associates [WWW]).  Patients will 
record their responses to the WPAI:UC electronically as source data in the tablet device 
at appropriate visits.

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Appendix 8.
Prohibited Medications

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This section outlines medications that are prohibited during the treatment phase of the study, if 
applicable.  Use of the medications listed in this appendix is allowed at the discretion of the 
investigator after a patient discontinues study drug and completes the early termination visit.
Drug Class
Comments
Anti-TNF antibodies (for example, infliximab, adalimumab, or 
golimumab)
Prohibited throughout treatment period
Anti-integrin antibodies (for example, vedolizumab)
Prohibited throughout treatment period
Agents depleting B or T cells (for example, rituximab, 
alemtuzumab, or visilizumab)
Prohibited throughout treatment period
Immunomodulatory medications, including oral cyclosporine, 
IV cyclosporine, tacrolimus, mycophenolate mofetil, 
thalidomide or JAK inhibitors (for example, tofacitinib) 
Prohibited throughout treatment period
Rectally administered 5-ASAs (enemas or suppositories)
Prohibited throughout treatment period
Rectally administered corticosteroids (enemas or suppositories)
Prohibited throughout treatment period
Rectally administered investigational preparations for UC such 
as arsenic preparations
Prohibited throughout treatment period
Intravenous corticosteroids for UC
A course of IV corticosteroids for UC is 
prohibited
Systemic corticosteroids for non-UC indications (oral or IV) 
Patients requiring systemic 
corticosteroids for non-UC conditions 
are excluded.  Exceptions include
corticosteroids to treat adrenal 
insufficiency, premedication for IP 
infusion, or locally administered 
corticosteroids (e.g., inhaled, intranasal, 
intra-articular, topical) (see Appendix 
10)
Oral budesonide standard formulation (that is, not the oral 
budesonide extended release tablet formulation [budesonide 
MMX])
Prohibited throughout treatment period.  
Any investigational therapy (biologic or nonbiologic) 
Prohibited throughout treatment period
Interferon therapy
Prohibited throughout treatment period
Leukocyte apheresis (leukopheresis, for example, Adacolumn)
Prohibited throughout treatment period
Anti-IL12p40 antibodies (for example, ustekinumab [Stelara®]) 
or anti-IL-23p19 antibodies (for example, risankizumab 
[BI-655066], brazikumab [MEDI-2070], guselkumab 
[CNTO1959], tildrakizumab [MK-3222]) for any indication, 
including investigational use
Prohibited throughout treatment period
Bacillus Calmette-Guerin (BCG) vaccine
BCG vaccination prohibited throughout the 
duration of the study and for 12 months after 
discontinuation of study drug.
Live attenuated vaccines
Live attenuated vaccines are prohibited 
throughout the duration of the study and for 
3 months after discontinuation of study drug.

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Abbreviations:  5-ASA = 5-aminosalicyclic; IL = interleukin; IV = intravenous; JAK = Janus Kinase; TNF = tumor 
necrosis factor; UC = ulcerative colitis.

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Appendix 9.
Permitted Medications with Dose Stabilization

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Drug Class
Comments
Oral 5-ASAs (for example, mesalamine, 
balsalazide, olsalazide) and sulfasalazine 
for UC 
May continue during study with stable doses encouraged
Oral corticosteroids for UC (prednisone 
≤20 mg/day or equivalent, budesonide 
MMX 9 mg/day, or beclomethasone 
dipropionate [gastro-resistant prolonged-
release tablet] 5 mg/day)
Responder patients who are receiving oral corticosteroids at the start of 
Study AMBG will start corticosteroid taper at the beginning of the 
study.  Clinical nonresponders who undergo extended IV induction with 
mirikizumab will begin corticosteroid tapering if symptomatic response 
or symptomatic improvement based on investigator discretion is 
achieved at any time after starting extended induction (see 
Corticosteroid Taper in Section 7.7).
Corticosteroids for non-UC indications: 
corticosteroids to treat adrenal 
insufficiency, as premedication for IP 
infusion, or locally administered 
corticosteroids (e.g. inhaled, intranasal, 
intra-articular, topical).
May continue corticosteroids to treat adrenal insufficiency or locally 
administered corticosteroids during study with stable dose encouraged.  
Single doses of oral or IV corticosteroids as premedication to IP 
administration are allowed in patients with prior IP or other previous 
biologic injection reactions.
Immunomodulators (for example, AZA, 
6-MP, or methrotrexate
Prescribed dose will remain stable throughout the study unless 
medication is discontinued due to a toxicity related to the medication. 
Antidiarrheals (for example, loperamide, 
diphenoxylate with atropine)
May continue during study with stable doses encouraged
Low-dose or baby aspirin (75 mg to
162.5 mg)
Daily use for cardiovascular prophylaxis permitted
Non-live (killed, inactivated or subunit) 
vaccines
Allowed during the study.  The efficacy of non-live vaccinations with 
concomitant mirikizumab treatment is unknown.
Abbreviations:  5-ASA = 5-aminosalicyclic acid; 6-MP = 6-mercaptopurine; AZA = azathioprine; IV = intravenous; 
IP = investigational product; UC = ulcerative colitis.

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Appendix 10.
Additional Information on Systemic Drug 
Administration Reactions

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

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Appendix 11.
Additional Information on the Columbia 
Suicide Severity Rating Scale, and Quick Inventory of 
Depressive Symptomatology (Self Report)

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

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Appendix 12.
Protocol Amendment I6T-MC-AMBG(a)
Summary A Phase 3, Multicenter, Randomized, Double-
Blind, Parallel-Arm, Placebo-Controlled Maintenance 
Study of Mirikizumab in Patients with Moderately to 
Severely Active Ulcerative Colitis
LUCENT 2
Overview
Protocol I6T-MC-AMBG, A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Arm, 
Placebo-Controlled Maintenance Study of Mirikizumab in Patients with Moderately to Severely 
Active Ulcerative Colitis LUCENT 2 has been amended.  The new protocol is indicated by 
amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Amendment Summary for Protocol I6T-MC-AMBG Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 1 Synopsis, Objective(s), 
Endpoints
Added/modified/removed Primary, 
Major secondary and Other 
secondary objectives/endpoints
Match Section 4 Objectives and 
Endpoints
Section 1 Synopsis, Statistical 
Analysis
Clarified primary endpoint statistics
Match Section 10 Statistical 
Considerations 
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  Informed consent
Added that patients may consent 
between the start of V5 of Study 
AMAN 
Clarification of consent window
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders, FSH
Added that FSH is optional in 
women to confirm nonchild-bearing 
potential
Clarification of the patient for whom 
FSH should be performed
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  PK Assessment and 
ADA Assessment
Clarified that patients with potential 
hypersensitivity or infusion-related 
event should have sample taken as 
soon as possible after event occurs 
and at 4 and 12 to 16 weeks after 
the event.
Clarification to be consistent with 
management of hypersensitivity and 
infusion related event section 
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  C. Difficile Testing 
and 
Fecal Calprotectin and Exploratory 
Fecal Biomarkers
Expanded the timeframe for C. 
Difficile, Fecal Calprotectin and 
Exploratory Fecal Biomarkers 
testing to as early as V3 during the 
loss of response assessment 
Since loss of response assessment can 
start as early as V3, the window for 
C. Difficile, Fecal Calprotectin and 
Fecal Biomarkers were expanded to 
facilitate this assessment 
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Clarified that loss of response has to 
be confirmed with endoscopy and 
Clarification of Table AMBG.2.2
Schedule of Activities comment for 

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Section # and Name
Description of Change
Brief Rationale
Responders,  Endoscopy with 
biopsies
added clarification to refer to 
Section 9.1.1.3 of the protocol for 
specification of what endoscopic 
procedure can be performed when
Endoscopy with biopsies
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  IBDQ, EQ-5D 5L, and 
PGRC
Added that health outcome 
assessments are to be performed for 
patients who have LOR confirmed 
by endoscopy before rescue dosing 
instead of for those with secondary 
LOR at the second of 2 LOR 
assessments
Clarification of when health outcome 
assessments for LOR should be 
performed
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  Abbreviations
Added abbreviation: DNA = 
deoxyribonucleic acid
Clarification of acronym in Table
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  Footnote section 
Clarified the options that patients 
have after completing the last visit 
in AMBG or the ETV in AMBG
Clarification provided since Study
AMBG does not have an open label 
extension period but patients may 
qualify for the long term extension 
Study I6T-MC-AMAP
Section 2 Table AMBG.2.1
Schedule of Activities, Induction 
Responders,  footnote a
Changed that V1 (Week 0) should 
occur no more than 14 days instead 
of 10 days from the start of the Visit 
5/Week 12 visit of Study AMAN 
Changes make the transition from 
AMAN to AMBG operationally 
acceptable while enabling AMAN 
Week 12 endoscopy to represent 
baseline status of disease severity in 
AMBG
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders  
Footnote letters reordered
Editorial change 
Section 2 Table AMBG.2.2 
Schedule of Activities
Updated window for V4
Allow more time for V4
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, Informed consent
Added that patients may consent 
between the start of V5 of AMAN 
and before any procedures at 
V1/Week 0 are performed instead of 
between the time of induction 
consent and before any procedures 
at V1/Week 0 are performed
Clarification of consent window
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, FSH
Added that FSH is optional in 
women to confirm nonchild-bearing 
potential
Clarification of the patient for whom 
FSH should be performed
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, PK and ADA
Clarified that patients with potential 
hypersensitivity or infusion-related 
event should have sample taken as 
soon as possible after event occurs 
and at 4 and 12 to 16 weeks after 
the event
Clarification to be consistent with 
management of hypersensitivity and 
infusion related event section 

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Section # and Name
Description of Change
Brief Rationale
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, C. difficile testing
Clarified that V1 C. difficile testing 
does not need to be completed 
before the patient can start study 
drug therapy
Clarification of C. difficile testing 
procedure at V1
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, Endoscopy with 
biopsies
Added clarification to refer to 
Section 9.1.1.3 of the protocol for 
specification of what procedure can 
be performed when  
Clarification for Endoscopy with 
biopsies 
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non- responders,  Footnote section
Added “Notes” section describing 
when study procedures should be 
performed and patient options post 
study completion or early 
termination 
Information added to be consistent 
with the induction responder path of 
Study AMBG 
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, footnote a
Added that for patients who cannot 
continue beyond V4 because they 
did not achieve delayed clinical 
response, ETV activities that are 
performed as part of V4 do not need 
to be repeated.  Only those ETV 
activities that are not part of V4 
should be completed during the 
ETV
Clarification to minimize study 
procedures for patients who 
discontinue AMBG soon after 
completing V4
Section 2 Table AMBG.2.2
Schedule of Activities, Induction 
Non-responders, footnote b
Clarified that V1 (Week 0) should 
occur no more than 14 days instead 
of 10 days from the start of the Visit 
5/Week 12 visit of Study AMAN
Changes make the transition from 
AMAN to AMBG operationally 
acceptable while enabling AMAN 
Week 12 endoscopy to represent 
baseline status of disease severity in 
AMBG
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Moved “To test the hypothesis that 
mirikizumab is superior to placebo 
in achieving clinical remission at 
Week 40 among patients induced 
into clinical response with 
mirikizumab in Study AMAN” 
from first Major Secondary 
Objective/Endpoints to Primary 
Objective/Endpoints
In order to align with recent external 
biologic clinical trials in UC, primary 
endpoint changed to clinical 
remission among responders, and 
clinical remission among remitters 
moved to a Major secondary 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
To evaluate the efficacy of 
mirikizumab compared to placebo 
in maintaining clinical remission at 
Week 40 (Week 52 of continuous 
therapy) among patients induced 
into clinical remission with 
mirikizumab has been moved from 
primary to first major secondary 
In order to align with recent external 
biologic clinical trials in UC, primary 
endpoint changed to clinical 
remission among responders, and 
clinical remission among remitters 
moved to a Major secondary. 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Moved “Clinical remission at Week 
40 in the subgroup of patients in 
whom biologic agents have failed or 
In order to align with recent external 
biologic clinical trials in UC and 
associated enrollment trends, this 

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Section # and Name
Description of Change
Brief Rationale
caused intolerance.” and definition 
of “clinical remission” from Major 
Secondary Objective/Endpoints to 
Other Secondary 
Objectives/Endpoints
objective/endpoints was moved to 
other secondary objective/endpoints 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Moved “Endoscopic remission at 
Week 40 in the subgroup of patients 
in whom biologic agents have failed 
or caused intolerance.” and 
definition of ”endoscopic 
remission” from Major Secondary 
Objective/Endpoints to Other 
Secondary Objectives/Endpoints
In order to align with recent external 
biologic clinical trials in UC and 
associated enrollment trends, this 
objective/endpoints was moved to 
other secondary objective/endpoints
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Added “The proportion of patients 
in symptomatic remission defined as 
being in symptomatic remission for 
at least 7 out of 9 visits from Week 
4 to Week 36 and in symptomatic 
remission at Week 40 among 
patients in symptomatic remission at 
Week 12 of AMAN.” and definition 
of “Symptomatic remission” to 
Major Secondary 
Objective/Endpoints
This endpoint (and associated 
objective) was added in order to 
assess the stability of efficacy with 
mirikizumab throughout the 
maintenance period 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Moved and modified “The 
proportion of patients with bowel 
movement urgency improvement at 
Week 40 as defined in the study 
SAP” to Major Secondary 
Objective/Endpoints
Moved and modified endpoint to 
assess improvement in urgency.  
Published literature shows that 
improvement in urgency is a 
clinically meaningful endpoint and 
supports urgency as one of the most 
bothersome symptoms experienced 
by patients with UC.  Therefore, this 
endpoint has been moved from an 
Other Secondary endpoint to a Major 
secondary endpoint
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Deleted from Other Secondary 
Objective/Endpoints: The 
percentage of the total time (in 
weeks) during maintenance study 
treatment that patients achieve: SF = 
0, or SF = 1 with a ≥1-point 
decrease from induction baseline, 
and RB subscore = 0
Other Secondary Objective/Endpoints 
for symptom free duration removed 
and replaced with new Major 
Secondary Objective/Endpoints of 
stable maintenance of symptomatic 
remission 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Removed redundant text in Other 
Secondary Objective/Endpoints: 
“…among subgroup of patients on 
corticosteroids at induction study 
baseline” from Corticosteroid-free 
Editorial change 

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Section # and Name
Description of Change
Brief Rationale
remission without surgery at Week 
40 endpoint.
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Deleted from Other Secondary 
Objective/Endpoints related to 
patient reported outcomes the 
reference to Urgency NRS score 
following change from induction 
baseline at Week 40 
Other Secondary Objective/Endpoints
for bowel movement urgency
removed and replaced with new 
Major Secondary 
Objective/Endpoints bowel 
movement urgency improvement
endpoint was added to Major 
secondary endpoints. This 
objective/endpoint now focuses on 
the patient reported outcome of 
abdominal pain only
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Added to Other Secondary 
Objective/Endpoints:
The proportion of patients with a 
UCEIS score of ≤1 at Week 40
The UCEIS is considered to be an 
important endpoint assessing 
endoscopic disease activity and thus 
has been added as an other secondary 
endpoint.  The UCEIS has been 
included in all endoscopy central 
readings from the onset of the study  
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Added “The proportion of patients 
with mucosal healing at Week 40, 
defined as achieving both histologic 
remission and endoscopic 
remission” and their definitions to 
Other Secondary 
Objective/Endpoints
In order to align with recent UC 
clinical trials and FDA guidance, 
protocol definition of mucosal 
healing was updated to include 
histologic and endoscopic healing. 
This is the same endpoint – note that 
histologic remission is already and 
has always been a secondary 
endpoint. The location of the 
histologic remission/response 
definition has been clarified 
throughout the protocol amendment 
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Other Secondary 
Objectives/Endpoints added
Fatigue is a common symptom for 
patients with active disease and 
published literature supports fatigue 
as an important symptom experienced 
by patients with UC. Therefore, this 
endpoint has been added to Other 
Secondary Endpoint
Section 4 Objectives and Endpoints, 
Table AMBG.4.1
Abbreviations have been added 
under the table
Editorial change
Section 5 Study Design
Added “baseline” to corticosteroid 
use stratification criteria
Clarified that baseline corticosteroid 
use (yes or no) will be used to stratify 
patients 
Section 5 Study Design
Clarified definition of “loss of 
response”
Clarification that the loss of response  
assessment can start as early as Week 
8/V3 but the endoscopic confirmation 
of loss of response cannot occur any 

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Section # and Name
Description of Change
Brief Rationale
earlier than Week 12/V4 
Section 6.0 Study population 
Changed the duration for the 
maximum window from the start of 
AMAN Week 12/V5 to the start of 
Week 0/V1 from 10 to 14 days 
Changes make the transition from 
AMAN to AMBG operationally 
acceptable while enabling AMAN 
Week 12 endoscopy to represent 
baseline status of disease severity in 
AMBG
Section 6.1 Inclusion Criteria, 
Patient Characteristics
Added text to clarify that patients 
require a Visit 5/Week 12 of Study
AMAN MMS, not just an 
endoscopy
Clarification that not only is an 
endoscopy required but a MMS is 
needed in order to enroll in AMBG 
from AMAN
6.2 Exclusion Criteria, General 
Exclusion Criteria
The term “malignancy” was added 
to Exclusion Criterion [17]
Added to be consistent with exclusion 
criteria in induction study AMAN 
Section 6.4 Screen Failures 
Changed the duration for the 
maximum window from the start of 
AMAN Week 12/V5 to the start of 
Week 0/V1 from 10 to 14 days 
Changes make the transition from 
AMAN to AMBG operationally 
acceptable while enabling AMAN 
Week 12 endoscopy to represent 
baseline status of disease severity in 
AMBG
Section 7.1 Treatments 
Administered, Study Drug 
Administration 
Added that intravenous infusion of 
mirikizumab (not placebo) will 
occur over at least 30 minutes  
Clarification that placebo will not be 
administered IV
Section 7.2 Method of Treatment 
Assignment
Added “baseline” to corticosteroid 
use stratification criteria
Clarified that baseline corticosteroid 
use (yes or no) will be used to stratify 
patients 
Section 7.7 Concomitant Therapy, 
Corticosteroid Taper
Added “or beclomethasone 
dipropionate (gastro-resistant 
prolonged-release tablet)” including 
tapering schedule 
Based on wide use of this 
corticosteroid in certain countries, 
tapering instructions were added 

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Section # and Name
Description of Change
Brief Rationale
Section 7.8.3.2. Management of 
Hypersensitivity, Infusion Related 
Events, Infusion Site Reactions and 
Injection Site Reactions
Added “These samples will also be 
used for tryptase, complement 
(C3/C4), and cytokine panel 
assays.”
Additional assessments added to 
better understand the possible 
etiology if a drug hypersensitivity 
event is observed, including markers 
of basophil/mast cell activation (i.e. 
tryptase), immune complex formation 
(i.e. C3/C4 levels) and cytokine 
release (i.e., cytokine panel). No 
additional blood is required for this 
sample collection.
Section 7.8.3.2. Management of 
Hypersensitivity, Infusion Related 
Events, Infusion Site Reactions and 
Injection Site Reactions
Under “Other Infusion-Related 
Events and Infusion Site 
Reactions”: added the word “other” 
in sentence describing reaction 
consisting of headache, rigors 
and/or temperature >38°C
Clarification of reaction consisting of 
headache, rigors and/or temperature 
>38°C 
Section 8.1.1. Permanent 
Discontinuation from Study 
Treatment, Safety Criteria for Study 
Drug Discontinuation
Added to safety criteria for study 
drug discontinuation:  
“proctocolectomy or partial 
colectomy”.
Clarification of safety criteria for 
drug discontinuation
Section 8.1.1. Permanent 
Discontinuation from Study 
Treatment, Safety Criteria for Study 
Drug Discontinuation
Added to safety criteria for study 
drug discontinuation that the patient 
has an AE or SAE which, in the 
opinion of the investigator or 
sponsor, would preclude the 
participant from continuing to 
receive study drug.
Study drug discontinuation related to 
AEs or SAEs is now consistent with 
wording in AMAN
Section 8.1.1. Permanent 
Discontinuation from Study 
Treatment, Safety Criteria for Study 
Drug Discontinuation
Mirikizumab changed to “study 
drug”
Clarification since study drug may be 
blinded
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Added endpoint, definition, and 
footnote for corticosteroid-free 
remission without surgery at Week 
40
Defined corticosteroid-free remission 
without surgery at Week 40
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Term mucosal healing deleted from 
histologic remission endpoint 
definition
Clarification of term “histologic 
remission”
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Added mucosal healing endpoint 
definition 
Defined mucosal healing endpoint 
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Added stable maintenance of 
symptomatic remission 
This endpoint was added in order to 
assess the stability of efficacy with 
mirikizumab throughout the 
maintenance period
Section 9.1 Efficacy Assessments: 
Added bowel movement urgency 
Now included as a major secondary 

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Section # and Name
Description of Change
Brief Rationale
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
improvement
endpoint because of unmet patient 
needs and the symptom being one of 
the most meaningful and important 
symptoms from patient perspective
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Added footnote: “ aAmong patients 
induced into clinical response with 
mirikizumab during the induction 
study and who were receiving 
corticosteroids at induction 
baseline.”
Added footnote clarifying the 
applicable patient population for this 
endpoint
Section 9.1 Efficacy Assessments: 
Table AMBG.9.1 Endpoint 
Definitions in Study AMBG
Added footnote: “bAmong patients 
in symptomatic remission at Week 
12 of AMAN” 
Added footnote clarifying the 
applicable patient population for this 
endpoint
Section 9.1.1.1. Primary Endpoint
Terminology changed from 
“durable clinical remission” to 
“clinical remission”; “remission”
changed to “response” with 
mirikizumab induction treatment.
Change made due to change in 
primary endpoint of the study
9.1.1.2. Mayo Score
Deleted from SF Subscore and 
expanded to its own sub-section: 
‘Normal SF for that patient is based 
on reported SF when the patient was 
in remission or reported SF before 
initial onset of signs and symptoms 
of UC.”  
Sentence moved to new description of 
Normal SF and to provide additional 
detail regarding the definition
Section 9.1.1.3. Endoscopy
Wording added to clarify when 
colonoscopy can be performed 
instead of flexible sigmoidoscopy in 
the judgement of the investigator 
and after discussion with the 
medical monitor as appropriate
Clarification of importance to discuss 
with medical monitor the need for 
colonoscopy vs. flexible 
sigmoidoscopy to assure appropriate 
consideration for patient safety
Section 9.1.1.3. Endoscopy
Added that allowances may be 
made for not performing ETV 
endoscopy if ETV occurs soon after 
a recent study required endoscopy, 
based on approval by the medical 
monitor
Change made to assure patient safety 
by not performing unnecessary repeat 
endoscopies soon after a recent 
endoscopy procedure 
9.1.2.1. Major Secondary 
Endpoints
Multiple changes made in major 
secondary endpoints to match 
Section 1 and Section 4 
To align with Section 1 Synopsis and 
Section 4 Objectives and Endpoints. 
9.1.2.1.2. Patient Reported Outcome 
Instruments
Description of Urgency NRS added 
under major secondary endpoints 
section 
Moved definition of Urgency NRS to 
major secondary endpoints to be 
consistent with changes in objective 
and endpoint sections (Section 1 and 
Section 4) 
9.1.2.2.1. Physician Reported 
Instrument
Added description of UCEIS
Due to the addition of the 
objective/endpoint, added description 

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 1 4 0
L Y 3 0 7 4 8 2 8
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
of t he i nstr u me nt
9. 1. 2. 2. 2 . P R O I nstr u me nts Use d t o 
Assess Sec o n dar y E n d p oi nts
Ur ge nc y N R S delete d fr o m P R O 
i nstr u me nts use d t o assess ot her 
sec o n dary e n d p oi nts; Fati g ue N R S 
a d de d
M o ve d defi niti o n of Ur ge nc y N R S 
o ut of ot her sec o n dar y e n d p oi nts a n d 
a d de d Fati g ue N R S t o be c o nsiste nt 
wit h c ha n ges i n o bjecti ve s
9. 1. 3. 3. P R O I nstr u me nts Use d t o 
Assess E x pl orat or y E n d p oi nts
C ollecti o n c o n diti o ns f or t he 
f oll o wi n g a d de d: 

N oct ur nal St o ol

Patie nt’s Gl o bal Rati n g of 
Se verit y  

Br ist ol St o ol Scale 
Fati g ue N R S delete d 
Clarificati o n of data c ollecti o n 
c o n diti ons
Secti o n 9. 4. 4. I m m u n o ge nicit y 
Assess me nts
A d de d t hat tr y ptase, c o m p le me nt 
( C 3/ C 4), a n d c yt o ki ne pa nel 
sa m ples will be c ollecte d i n t he 
e ve nt of a dr u g h y perse nsiti vit y 
e ve nt, ot her i nf usi o n relate d e ve nts 
a n d i nf usi o n site reacti o ns
A d diti o nal assess me nts a d de d t o 
better u n dersta n d t he p ossi ble 
eti ol o g y if a dr u g h y perse nsiti vit y 
e ve nt is o bser ve d, i ncl u di n g mar kers 
of bas o p hil/ mast cell acti vati o n (i.e. 
tr yptase), i m m u ne c o m ple x f or mati o n 
(i.e. C 3/ C 4 le vels) a n d c yt o ki ne 
release (i.e., c yt o ki ne pa nel ). N o 
a d diti o nal bl o o d is re q uire d f or t his 
sa m ple c ollecti o n.
Secti o n 9. 4. 5. 2. T u berc ul osis, 
Dia g n osis of L T BI d uri n g St u d y
F or t he treat me nt of L T BI, a d de d 
t hat C D C g ui deli nes are t o be use d  
f or t he U S A a n d t he W H O 
g ui deli nes  are t o b e f oll o we d  f or 
c o u ntries o utsi de of t he U S A
Clarificati o n of g ui da nce f or L T BI 
treat me nt
Secti o n 9. 5 P har mac o ki netics
 
 
 
 
 
 
 
Secti o n 1 0. 1 Sa m ple Size 
Deter mi nati o n
Pri mar y  e n d p oi nt statistical c ha n ges
Matc h wit h Secti o n 1 S y n o psis a n d 
Secti o n 4 O bjecti ves a n d E n d p oi nts. 
D ue t o c ha n ges i n pri mar y a n d maj or 
sec o n dar y en d p oi nts, sa m ple size has 
bee n recalc ulate d.
1 0. 2. P o p ulati o ns f or A nal yses, 
Ta ble A M B G. 1 0. 1 A nal ysis 
P o p ulati o ns i n St u d y A M B G
I nte nt-t o-treat (I T T) P o p ulati o n 
c ha n ge d fr o m e nr olle d t o 
ra n d o mize d/assi g ne d
Clarificati o n of t he defi niti o n of 
“e nr olle d” i n t he I T T p o p ulati o n
1 0. 2. P o p ulati o ns f or A nal yses, 
Ta ble A M B G. 1 0. 1 A nal ysis 
P o p ulati o ns i n St u d y A M B G
M o difie d I nte nt -t o-treat ( mI T T) 
P o p ulati o n c ha n ge d t o “ All 
ra n d o mize d/assi g ne d patie nts w h o 
recei ve d at least 1 d ose of st u d y 
treat me nt, re gar dless of w het her 
Defi niti o n clarifie d of t he mI T T 
p o p ulati o n
C CI
C CI

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Section # and Name
Description of Change
Brief Rationale
correct treatment was administered 
or whether protocol was followed.”
10.3.1. General Statistical 
Considerations
Changed that induced responders 
instead of induced remitters were 
among those assessed. Induction 
remission status of yes or no was 
added. “Baseline” was added to 
corticosteroid use.
Change made due to change in 
primary endpoint of the study. 
Clarified that baseline corticosteroid 
use (yes or no) will be used to stratify 
patients
10.3.1.1.Missing Data Imputation
Deleted “In addition, the patients 
who require UC surgery, increase 
UC medication dose from baseline, 
or initiate new UC medications will 
be considered as nonresponders” 
from the description of 
nonresponder imputation.
Modifications made to align with 
other recent UC clinical trials and to 
clarify that patients who require UC 
surgery, require an increase in UC 
medication dose from baseline, or 
require treatment with new UC 
medications should be discontinued 
from the trial as described in Section 
8.1.1 of the protocol. Therefore, 
imputing such patients as non-
responders will be performed because 
the data will be missing
10.3.2.3 Concomitant Therapy
Changed description of how 
concomitant therapy will be 
presented in frequency tables
Clarification 
10.3.3.1.Primary Analyses
Primary analysis was changed from 
“durable clinical remission” to 
“clinical remission” and “remitters” 
to “responders.” 
Change made due to change in 
primary endpoint of the study.
10.3.3.1.Primary Analyses
Nonremitter description changed
Change made due to clarification of 
NRI 
10.3.7.1 Subgroup Analyses
Removed “The major subgroup 
analysis is for the primary and 
major secondary endpoints for 
biologic-failed patients described in 
Section 9.1.2.1.  Multiplicity 
adjustment described in Section 
10.3.1.2. will be used to control type 
I error.” 
Change made due to changes in the 
major secondary endpoints 
Section 11. References
References added
Editorial change
Appendix 1. Abbreviations and 
Definitions
Term added
Editorial Change
Appendix 2. Clinical Laboratory 
Tests
Other tests along with their 
associated footnote added
Clarification of procedures. Updates 
made to align with Section 7.8.3.2 of 
the protocol
Appendix 3.1.7. Final Report 
Signature
Deleted that the investigator with 
most enrolled patients will be 
selected by the study team to act as 
the CSR coordinating investigator
This change reflects that the selection 
of CSR coordinating investigator is 
not dependent on number of patients 
enrolled
Appendix 6. Mayo Scoring System 
Note added to table for stool 
Definition of normal stool frequency 

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Section # and Name
Description of Change
Brief Rationale
for the Assessment of Ulcerative 
Colitis Activity
frequency
when in remission from UC to align 
with Section 9.1.1.2 of the protocol
Appendix 7. Patient Reported 
Outcome Instruments
Replaced language in definition of 
Abdominal Pain Numeric Rating 
Scale (NRS) and Fatigue NRS   
Clarification of definitions of ranges
Appendix 8. Prohibited Medications
Added rectally administered 
investigational preparations for UC 
and restrictions 
Arsenic and other therapies were 
added because it was recognized that 
there are other treatments for UC in 
certain countries that need to be 
considered as prohibited medications
Appendix 8. Prohibited Medications
Added “for UC” to Intravenous 
corticosteroids category
Clarification of restrictions for IV 
corticosteroid use for UC vs. non UC 
indication
Appendix 8. Prohibited Medications
Added that patients requiring 
systemic corticosteroids for non-UC 
indications are “excluded”. Added 
“Exceptions include: premedication 
for IP infusion, or locally”.  
Added allowance for single limited 
dose for study drug administration 
premedication.  This would be a 
single limited dose that would not be 
expected to affect efficacy. Other 
minor editorial changes were made. 
Appendix 9. Permitted Medications 
with Dose Stabilization
Added to Drug Class: oral 5-ASAs 
“and sulfasalazine for UC” 
Clarification of drug class
Appendix 9. Permitted Medications 
with Dose Stabilization
Added to Drug Class: oral 
corticosteroids “for UC” indications 
clarification
Clarified that oral corticosteroids are 
allowed for UC indication
Appendix 9. Permitted Medications 
with Dose Stabilization
Added beclomethasone dipropionate 
[gastro-resistant prolonged-release 
tablet] 5 mg/day
Based on wide use of this 
corticosteroid in certain countries, 
this medication was added as 
permitted medication during the study 
along with prednisone or equivalent 
or budesonide MMX
Appendix 9. Permitted Medications 
with Dose Stabilization
Added to Drug Class: 
“corticosteroids for non-UC 
indications” that are allowed
Added clarification to reinforce the 
exception to the prohibited 
concomitant medications

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1.
Synopsis
Objective(s)/Endpoints:
Objectives
Endpoints
Primarya

To test the hypothesis that mirikizumab is superior 
to placebo in achieving maintaining clinical 
remission at Week 40 (Week 52 of continuous 
therapy) among patients induced into clinical
response remission with mirikizumab in Study 
AMAN

The proportion of patients who were in clinical 
remission at Week 12 in AMAN and are in 
clinical remission at Week 40, that is, with 
durable clinical remission, defined as:
o
Stool frequency (SF) subscore = 0 or SF = 1 
with a ≥1-point decrease from induction 
baseline, and
o
Rectal bleeding (RB) subscore = 0, and
o
Endoscopic subscore (ES) = 0 or 1 (excluding 
friability)
Major Secondarya,b

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving maintaining clinical 
remission at Week 40 (Week 52 of continuous 
therapy) among patients induced into clinical 
remission response with mirikizumab 

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e., 
durable clinical remission). Clinical remission is
defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES subscore = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on endoscopic remission at Week 40
among patients induced into clinical response with 
mirikizumab

The proportion of patients in endoscopic 
remission at Week 40, defined as:

ES = 0 or 1 (excluding friability)

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
To evaluate the efficacy of mirikizumab compared 
to placebo in achieving corticosteroid-free remission 
without surgery among patients induced into 
clinical response with mirikizumab and receiving 
corticosteroids at induction baseline

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 

No corticosteroid use for ≥12 weeks prior to 
Week 40 

To evaluate, in the subgroup of patients in whom 
biologic agents have failed or caused intolerance, 
clinical remission at Week 40 among patients 
induced into clinical response with mirikizumab

Clinical remission at Week 40 in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.  Clinical remission is defined 
as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate, in the subgroup of patients in whom 
biologic agents have failed or caused intolerance,
endoscopic remission at Week 40 among patients 
induced into clinical response with mirikizumab

Endoscopic remission at Week 40 in the subgroup 
of patients in whom biologic agents have failed or 
caused intolerance.  Endoscopic remission is 
defined as:
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo on histologic remission (mucosal healing) 
at Week 40 among patients induced into clinical 
response with mirikizumab

Proportion of patients in histologic remission at 
Week 40, as defined in the histopathology charter
SAP

To evaluate the efficacy of mirikizumab compared 
to placebo on stable maintenance of symptomatic 
remission among patients who were induced into 
clinical response and symptomatic remission with 
mirikizumab

The proportion of patients in symptomatic 
remission defined as being in symptomatic 
remission for at least 7 out of 9 visits from Week 
4 to Week 36 and being in symptomatic remission 
at Week 40 among patients in symptomatic 
remission at Week 12 of Study AMAN.

Symptomatic remission is defined as:
o
SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline and
o
RB = 0

To evaluate the efficacy of mirikizumab compared 
to placebo on bowel movement urgency 
improvement at Week 40, among patients who: (1) 
had bowel urgency symptoms at induction baseline 
and (2) were induced into clinical response with  
mirikizumab 

The proportion of patients with bowel movement 
urgency improvement at Week 40 as defined in 
the study SAP.
Other Secondary

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission at Week 
40 among patients induced into clinical response 
with mirikizumab, in the subgroup of patients in 
whom biologic agents have failed or caused 
intolerance,. clinical remission at Week 40 among 
patients induced into clinical remission with 

The proportion of patients who were in clinical 
remission at Week 12 in AMAN and are in
cClinical remission at Week 40 , that is, with 
durable clinical remission, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.  Clinical remission is defined 
as:

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mirikizumab
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving on maintaining endoscopic 
remission at Week 40 among patients induced into 
clinical response endoscopic remission with 
mirikizumab, in the subgroup of patients in whom 
biologic agents have failed or caused intolerance.

The proportion of patients in durable eEndoscopic 
remission at Week 40 in the subgroup of patients 
in whom biologic agents have failed or caused 
intolerance.  Endoscopic remission is defined as: 
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab as 
compared to placebo in maintaining clinical 
remission at Week 40 (Week 52 of continuous 
therapy) among patients induced into clinical 
remission with mirikizumab, in the subgroup of 
patients in whom biologic agents have failed or 
caused intolerance.

The proportion of patients who were in clinical 
remission at Week 40 among patients in clinical 
remission at Week 12 in Study AMAN (i.e., 
durable clinical remission) in whom biologic 
agents have failed or caused intolerance.  Clinical 
remission is defined as:
o
SF subscore = 0 or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0, and
o
ES = 0 or 1 (excluding friability)

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving clinical remission (using a 
more stringent ES) at Week 40  among patients 
induced into clinical responsemission with  
mirikizumab 

The proportion of patients with clinical remission 
(using a more stringent ES) at Week 40, with 
clinical remission defined as:
o
SF subscore = 0, or SF = 1 with a ≥1-point 
decrease from induction baseline, and
o
RB subscore = 0; and
o
ES = 0

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving an endoscopic response at 
Week 40 among patients induced into clinical 
response with mirikizumab

The proportion of patients in endoscopic 
response at Week 40 defined as:
o
A decrease in ES of ≥1 point from induction 
baseline.

To evaluate mirikizumab compared with placebo on 
symptom-free duration among patients induced into 
clinical response with mirikizumab 

The percentage of the total time (in weeks) 
during maintenance study treatment that patients 
achieve:

SF = 0, or SF = 1 with a ≥1-point decrease 
from induction baseline, and

RB subscore = 0

To evaluate the efficacy of mirikizumab compared 
to placebo in achieving 24-week corticosteroid-free 
remission without surgery among patients induced 
into clinical response with mirikizumab and 
receiving corticosteroids at induction baseline 

Corticosteroid-free remission without surgery at 
Week 40, defined as:
o
Clinical remission at Week 40, and 
o
Symptomatic remission at Week 28, and 
o
No corticosteroid use for ≥24 weeks prior to 
Week 40 among subgroup of patients on 
corticosteroids at induction study baseline

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
To evaluate the effect of mirikizumab compared to 
placebo on changes in patient-reported outcome 
endpoints Abdominal pain at Week 40 

Change from induction baseline at Week 40 in the 
following:
o Urgency NRS score
Abdominal pain NRS score

To evaluate the efficacy of mirikizumab compared 
to placebo in UCEIS endoscopic remission at Week 
40 among patients induced into clinical response
with  mirikizumab 

The proportion of patients with a UCEIS score of 
≤1 at Week 40

To evaluate the efficacy of mirikizumab compared
to placebo in mucosal healing at Week 40 among 
patients induced into clinical response with 
mirikizumab

The proportion of patients with mucosal healing 
at Week 40, defined as achieveing both:  
o
Histologic remission, as described in the 
histopathology charter, and
o
Endoscopic remission,  defined as ES = 0 or 
1 (excluding friability)

To evaluate the effect of mirikizumab compared to 
placebo on change in fatigue at Week 40

Change from induction baseline at Week 40 in the 
Fatigue NRS score
Abbreviations:  SAP = statistical analysis plan; UCEIS = Ulcerative Colitis Endoscopic Index of Severity.
Statistical Analysis
It is expected that approximately 459470 of these patients will enter Study AMBG as clinical 
responders to mirikizumab and then will be randomized 2:1 to 200 mg mirikizumab SC 
(306approximately 313 patients) and placebo (153approximately 157 patients).  Among the 
approximately expected 459470 mirikizumab clinical responders, approximately 169180
mirikizumab clinical remitters will be randomized to 200 mg mirikizumab SC 
(113approximately 120 patients) and placebo (56approximately 60 patients).  This assumes that:

The induction study (AMAN, which has a mixed population with approximately 6050% 
biologic-failed patients) is expected to have an overall clinical remission rate of 21.623% 
and response rate of 58.660% with mirikizumab.

75% of induction patients receive treatment with mirikizumab, based on a 3:1 
randomization ratio for the induction study.

10% dropout rate from induction to maintenance.
The primary endpoint, maintenance of clinical remission at Week 40, will be assessed on patients 
who achieved remissionclinical response to mirikizumab induction treatment.  Assuming 
mirikizumab and placebo maintenance of clinical remission rates of 58.447% and 23.627%, 
respectively(biologic-failed patients:  44% and 13%; conventional-failed patients:  70% and 
32%), this study based on the 169470 mirikizumab induction remitters responders is expected to 
have >950% power to demonstrate that mirikizumab is superior to placebo by using a chi-square 
test with a 2-sided 0.05 significance level of 0.05.  This sample size also provides 80% power to 
evaluate clinical remission among induction remitters in the biologic-failed subgroup of patients
. In addition, 459 mirikizumab induction clinical responders arethe sample size is expected to 
provide adequate power (>80%) to demonstrate that mirikizumab is superior to placebo for the 

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major secondary endpoints (clinical remission [among patients induced into clinical response 
with mirikizumab], endoscopic remission, histologic remission, andor corticosteroid-free 
remission) at Week 40, among responders to mirikizumab induction treatment by using a chi-
square test with a 2-sided 0.05 significance level of 0.05. 
For assessments of the primary endpoint and other categorical efficacy endpoints among induced 
remittersresponders, the Cochran-Mantel-Haenszel (CMH) chi-square test will be used to 
compare mirikizumab and placebo with stratification factors:  (a) previous biologic therapy 
failure (yes or no), (b) baseline corticosteroid use (yes or no), and (c) region (North 
America/Europe/Other), (d) induction remission status (yes/no).  The CMH chi-square p-value 
and the relative risk along with its 95% 2-sided confidence interval will be provided.
Treatment comparisons of continuous efficacy and health outcome variables with a single 
post-baseline time point will be made using analysis of covariance with:  (a) treatment group, 
(b) previous biologic therapy failure (yes or no), (c) corticosteroid use (yes or no), (d) region 
(North America/Europe/Other), (e) baseline value in the model, and (f) induction remission 
status(if analysis is among induced responders).
2.
Schedule of Activites 
Table AMBG.2.1.
Schedule of Activities – Responders from Induction Study
Informed Consent Notes: Patients may consent between the start of V5 of Study AMAN time of 
induction consent and before any procedures at V1/Week 0 are performed.
Procedure: FSH (optional in women to confirm nonchild-bearing potential)e
PK Assessment: In addition, patients with potential hypersensitivity or infusion-related event 
should have sample taken as soon as possible after event occurs,
ADA Assessment: In addition, patients with possible hypersensitivity or infusion-related event 
should have sample taken as soon as possible after event occurs,
C. Difficile Testing: Table cell expaneded to include V3
Fecal Calprotectin and Exploratory Fecal Biomarkers: Table cell expaneded to include V3
Endoscopy with biopsies: Flexible sigmoidoscopy is recommended for all patients. Colonoscopy 
can be performed instead of flexible sigmoidoscopy for clinically indicated reasons after 
discussion with the medical monitor (See section 9.1.1.3.)  
Xd:  At least 1 endoscopy is performed at Week 40/ETV or if LOR is confirmed.  LOR 
assessments confirmation based on endoscopy can only occur at a scheduled or unscheduled visit 
between V4 and V8. Please refer to Section 9.1.1.3 for procedure clarification.

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IBDQ and EQ-5D 5L Xd:  To be performed for patients who have LOR confirmed by endoscopy 
before rescue dosingTo be performed for patients with secondary LOR at the second of 2 LOR 
assessments.
PGRC: Xd:  To be performed for patients who have LOR confirmed by endoscopy before rescue 
dosingTo be performed for patients with secondary LOR at the second of 2 LOR assessments.
Abbreviations: DNA = deoxyribonucleic acid;
Notes:  Last visit or ETV is last visit prior to entering long term extension Study AMAP open-
label extension or post-treatment follow-up. 
Footnote: a
V1 (Week 0) should occur no more than 10 14 days from the start of the Visit 
5/Week 12 visit of Study AMAN.
Table AMBG.2.2.
Schedule of Activities – Nonresponders from Induction Study
Visit 4:  85 ± 4 7
Informed Consent Notes: Patients may consent between the start of V5 of Study AMAN time of 
induction consent and before any procedures at V1/Week 0 are performed.
Procedure:  FSH (optional in women to confirm nonchild-bearing potential)f
PK Assessment: In addition, patients with potential hypersensitivity or infusion-related event 
should have sample taken as soon as possible after event occurs,
ADA Assessment: In addition, patients with possible hypersensitivity or infusion-related event 
should have sample taken as soon as possible after event occurs,
C. difficile testing: V1 C. difficile testing does not need to be completed before the patient can 
start study drug therapy.
Endoscopy with biopsies: See Please refer to Section 9.1.1.3. for procedure clarification.
Notes: All activities should be completed prior to any study drug administration unless otherwise 
stated.  Last visit or ETV is last visit prior to entering long term extension Study AMAP or 
post-treatment follow-up.  Post-treatment follow-up visits should only occur if the patient is 
not proceeding to long term extension Study AMAP or if they discontinue treatment in Study 
AMBG early (i.e. patients who do not achieve delayed clinical response).
Footnotea: For patients who cannot continue beyond V4 because they did not achieve delayed 
clinical response, ETV activites that are performed as part of V4 do not need to be repated. 
Only those ETV activities that are not part of V4 should be completed during the ETV.
Footnoteb: V1 (Week 0) should occur no more than 10 14 days from the start of the Visit 5/Week 
12 visit of Study AMAN.
Various footnotes re-lettered

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4.
Objectives and Endpoints 
See Section 1 Synopsis Objective(s)/Endpoints above
5.1.
Overall Design
Mirikizumab Responders from Study AMAN
Randomization will be stratified to achieve between-group comparability, based on biologic-
failed status (yes or no), induction remission status (yes or no), baseline corticosteroid use (yes 
or no), and region (North America/Europe/Other).
Loss of Response (LOR) is defined as:
≥2-point increase from Study AMBG baseline in the combined SF + RB scores AND combined 
SF + RB score of ≥4, on 2 consecutive visits (≥7 days apart, and with confirmation of negative 
C. difficile testing) (first assessment can start as early as Week 8/Visit 3),
AND

Confirmed by centrally read endoscopic subscore (ES) of 2 or 3 not sooner than 
Week 12/Visit 4. 
6.
Study Population 
Besides a maximum 1014-day window between the start of the Visit 5 (Week 12) visit of the 
induction study AMAN and the start of Visit 1 (Week 0) of Study AMBG, no screening period is 
allowed for Study AMBG.  Data collected during the last visit of the induction study AMAN, 
including laboratory evaluations, endoscopy, and PRO data, will be used to review enrollment 
criteria for Study AMBG.  A visit window (1014 days) is provided to allow laboratory results 
and central reading of the endoscopy to be available for the investigator to appropriately evaluate 
a patient and to ensure compliance with enrollment criteria.  Patients who do not meet one or 
more hepatic or hematologic laboratory enrollment criteria may have these blood measures 
repeated one time at the investigator’s discretion prior to study entry, as long as all testing is 
completed within 1014 calendar days from the start of the Visit 5 (Week 12) visit of Study 
AMAN.  
6.1.
Inclusion Criteria
Patient Characteristics
[2.] Have completed Study AMAN through the Week 12 visit (Visit 5) and have a 
Visit 5 MMS and have , received at least 1 study drug administration without 
early termination of study drug., and underwent a Visit 5 (Week 12) 
endoscopy.
6.2.
Exclusion Criteria
General Exclusion Criteria

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[17.]  Have an unstable or uncontrolled illness, including, but not limited to, 
cerebro-cardiovascular, respiratory, gastrointestinal (excluding UC), hepatic, 
renal, endocrine, hematologic or neurological disorders or malignancy that 
would potentially affect patient safety within the study or confound efficacy 
assessment.
6.4.
Screen Failures
As described in Section 6, patients will be entered into Study AMBG directly from Study 
AMAN, with a maximum 1014 day window between start of the Visit 5 (Week 12) visit of the 
induction study AMAN and start of Visit 1 (Week 0) of Study AMBG.  
Patients who do not meet enrollment criteria may have one or more blood measures repeated one 
time, at the investigator’s discretion, prior to study entry as long as all testing is completed 
within 10 14 calendar days from the start of the last induction visit.
7.1.
Treatments Administered
Study Drug Administration
Subcutaneous administration of mirikizumab or placebo will be given in 2 injections (maximum 
volume is 1 mL per injection).  
Intravenous infusion of mirikizumab or placebo will occur over at least 30 minutes.  
7.2.
Method of Treatment Assignment
To achieve between-group comparability, patients will be stratified to these arms based upon 
biologic-failed status (yes or no), baseline corticosteroid use (yes or no), region (North 
America/Europe/Other), and induction remission status (yes or no).  This stratification will be 
controlled by IWRS.  
7.7.
Concomitant Therapy
The recommended tapering schedule for oral corticosteroids (other than budesonide extended 
release tablets [budesonide MMX] or beclomethasone dipropionate [gastro-resistant prolonged-
release tablet]) is as follows:
The recommended tapering schedule for patients receiving oral beclomethasone dipropionate 
(gastro-resistant prolonged-release tablet) 5 mg/day is to reduce tablets to 5 mg every other day 
for 4 weeks, and then discontinue.
7.8.3.2.
Management of Hypersensitivity, Infusion-Related Events, Infusion Site 
Reactions and Injection Site Reactions

After patient’s stabilization, an anti-drug antibody (ADA) and PK sample should be 
collected; additional samples should be obtained 4 and 12-16 weeks after the event.  

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These samples will also be used for tryptase, complement (C3/C4), and cytokine panel 
assays.
Other Infusion-Related Events and Infusion Site Reactions
If a patient experiences a reaction consisting of headache, rigors and/or temperature >38°C (in 
the absence of signs or symptoms of a systemic hypersensitivity reaction), or an infusion site 
reaction, including urticaria, pruritus, or angioedema localized to the IV infusion site (in the 
absence of other systemic hypersensitivity signs or symptoms), during or up to 6 hours after an 
infusion of study drug, the following guidance should be followed:

An ADA and PK sample should be collected at the time of the event (or as soon as 
possible after the event occurs), and 4 and 12-16 weeks after the event. These samples 
will also be used for tryptase, complement (C3/C4), and cytokine panel assays.
8.1.1. Permanent Discontinuation from Study Treatment
Safety Criteria for Study Drug Discontinuation

The patient requires a colectomy, proctocolectomy, or partial colectomy during the study.

The patient experiences an AE or SAE that would preclude him/her from participating in 
the trial.The participant has an AE or SAE which, in the opinion of the investigator or 
sponsor, would preclude the participant from continuing to receive study drug.

Systemic hypersensitivity event or anaphylaxis to mirikizumab study drug.
9.1.
Efficacy Assessments
Table AMBG.9.1.
Endpoint Definitions in Study AMBG
Endpoint 
Definition 
Corticosteroid-free 
remission without 
surgery at Week 40a

Clinical remission at Week 40, and

Symptomatic remission at Week 28, and 

No corticosteroid use for ≥12 weeks prior to Week 40
Histologic remission 
(mucosal healing)

This definition will be specified in the histopathology charterSAP
Mucosal healing

Histologic remission as described in the SAP and

endoscopic remission defined as ES = 0 or 1 (excluding friability)
Stable maintenance of 
symptomatic remissionb

Symptomatic remission for at least 7 out of 9 visits from Week 4 to Week 36 

Symptomatic in remission at Week 40
Bowel movement urgency 
improvement 
The definition will be specified in the study SAP
Abbreviations:  SAP = statistical analysis plan;
Note: The term “mucosal healing” may be used in study reports to describe histologic remission or to describe a 
Mayo ES of 0-1, and the definition will be clarified in the study report.
a
Among patients induced into clinical response with mirikizumab during the induction study and who were 
receiving corticosteroids at induction baseline.
b
Among patients in symptomatic remission at Week 12 of Study AMAN.

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9.1.1.1.
Primary Endpoint
The primary endpoint is durable clinical remission at Week 40, among patients induced into 
clinical remission response with mirikizumab induction treatment (Study AMAN).  
9.1.1.2.
Mayo Score
SF Subscore:  The reference “normal” SF for that patient will be recorded electronically 
at the induction study screening visit.  Normal SF for that patient is based on reported SF 
when the patient was in remission or reported SF before initial onset of signs and 
symptoms of UC.  Study software will use the patient-reported daily SF and the reference 
normal SF to automatically calculate the Mayo SF subscore.  
Normal SF: The Normal SF is a patient-reported measure. This item reports the number 
of stools in a 24-hour period when the patient was in remission or, if the patient has never 
achieved remission, the reported SF before initial onset of signs and symptoms of UC.  
Remission refers to a period of time since being diagnosed with UC when the patient is 
not experiencing any signs or symptoms relating to UC. This period of time may last a 
few weeks or a few months or may even last several years. The patient will record this 
electronically as source data in the tablet device at the screening study visit of Study 
AMAN.
9.1.1.3.
Endoscopy
However, colonoscopy can be performed instead of flexible sigmoidoscopy within this study in 
order to surveille for dysplasia, screen for colorectal cancer (see Inclusion Criterion [5]), or for 
other clinically indicated reasons, in the judgement of the investigator., and after discussion with 
the medical monitor as appropriate.  
If a patient becomes pregnant during the study, no additional endoscopies will be performed. 
If a patient undergoes early termination soon after baseline, loss of response, or at the end of 
extended induction endoscopy, the need for ETV endoscopy should be discussed with the 
medical monitor.
9.1.2.1.
Major Secondary Endpoints

Clinical remission at Week 40, among patients induced into clinical responseremission
(that is, demonstrating clinical response or clinical remission) with mirikizumab at Week 
12 of induction study (Study AMAN)

Corticosteroid-free remission without surgery at Week 40, among patients induced into 
clinical response with mirikizumab at Week 12 of the induction study during the
induction study and who were receiving corticosteroids at induction baseline.  For Week 
40, this endpoint is defined as:

Clinical remission at Week 40, and

Symptomatic remission at Week 28, and 

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
No corticosteroid use for ≥12 weeks prior to Week 40

Evaluate, in the subgroup of patients in whom biologic agents have failed or caused 
intolerance, clinical remission at Week 40 among patients induced into clinical response
with mirikizumab

Evaluate, in the subgroup of patients in whom biologic agents have failed or caused 
intolerance, endoscopic remission at Week 40 among patients induced into clinical 
response with mirikizumab

Histologic remission at Week 40, among patients induced into clinical response with 
mirikizumab at Week 12 of induction study

Stable maintenance of symptomatic remission, among patients induced into clinical 
response with mirikizumab and were in symptomatic remission at Week 12 of induction 
study

Bowel movement urgency improvement among patients induced into clinical response
with mirikizumab at Week 12 of induction study

9.1.2.1.2.
Patient Reported Outcome Instruments
The Urgency NRS (see Appendix 7 for description) is a PRO instrument used to collect bowel 
movement urgency data in the patient eDiary. The Urgency NRS will be used to determine the 
secondary endpoint for bowel movement urgency improvement (see Table AMBG.4.1 for 
definition).
9.1.2.2.1.
Physician Reported Instrument
The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a physician reported instrument 
for measuring the endoscopic disease activity of UC on flexible sigmoidoscopy or colonoscopy, 
that includes 3 descriptors of vascular pattern, bleeding, and erosions/ulcerations (Arai et al. 
2016; Ikeya et al. 2016; Tontini et al. 2014).  Only blinded central reading of endoscopies will be 
used to determine the UCEIS score for each endoscopy.
9.1.2.2.2.
PRO Instruments Used to Assess Secondary Endpoints
The following are additional PRO instruments collected using a patient electronic diary (eDiary).  

Abdominal Pain Numeric Rating Scale (NRS)

Fatigue NRS (collected at site visits until Visit 10 when collected via electronic diary) 

Urgency NRS
9.1.3.3.
PRO Instruments Used to Assess Exploratory Endpoints
The following exploratory endpoints will be assessed via the electronic diary tool and/or at 
applicable study visits using the tablet device:

Nocturnal Stool (collected at site visits until Visit 10 when collected via electronic diary)

Fatigue NRS 

Patient’s Global Rating of Severity (PGRS) (collected via electronic diary)

I 6 T-M C -A M B G( a) Cli ni c al Pr ot o c ol
P a g e 1 5 4
L Y 3 0 7 4 8 2 8

Bri st ol St o ol Scale (c ollecte d at site visits u ntil Visit 1 0 w he n c ollecte d via electr o nic 
di ar y)
9. 4. 4.
I m m u n o g e ni cit y A s s e s s m e nt s 
I n t he e ve nt of a dr u g h yperse nsi tivi t y e ve nt (i m me diate or n o ni m me diate), a d diti o nal sa m ples 
f or A D A a n d P K will be c ollecte d as cl ose t o t he o nset of t he e ve nt as p ossi ble, a n d at 4 a n d 
1 2- 1 6 wee ks after t he e ve nt.  T hese sa m ples will als o be use d f or tr y ptase, c o m ple me nt ( C 3/ C 4), 
a n d c yt o ki ne pa nel assa ys.
9. 4 . 5. 2.
T u b er c ul o si s
Di a g n osis of L T BI d uri n g St u d y
P ati e nts dia g n ose d wit h L T BI d uri n g t he st u d y must ha ve st u d y  dr u g i nterr u pte d.  If treat me nt 
f or L T BI is c o nsi dere d t o be a p pr o priate, t he patie nt m ust c o m plete at least 4 wee ks of 
a p pr o priate t hera p y for L T BI, base d o n nat i onal or i nter nat i onal g ui deli ne s (for e xa m ple, t he 
U nite d States Ce nters f or Disease C o ntr ol a n d Pre ve nt i on g ui da nce ( C D C [ W W W]) f or t he 
U nite d States ; or t he W orl d Heal t h Or ga nizati on g ui da nce f or t he treat me nt of L T BI f or all 
c o u ntries o utside of t he U nite d States ( W H Oa [ W W W]), a n d ha ve n o e vi de nce of he pat ot o xicit y 
( A L T a n d A S T le vels m ust re mai n ≤2 x U L N) u p o n retesti n g of ser u m A L T a n d A S T le vels after 
at least 4 wee ks of L T BI treat me nt.  
9. 5.
P h ar m a c o ki n eti c s
 
 
 
 
 
 
1 0. 1.
S a m pl e Si z e D et er mi n ati o n
It is e x pecte d t hat a p pr o xi matel y 4 5 9 4 7 0 of  t hese patie nts will e nter St u d y AM B G as cli nical 
res p o n ders t o miri kiz u ma b a n d t he n will be ra n d o mize d 2: 1 t o 2 0 0 m g miri kiz u ma b S C 
(a p pr o xi matel y 3 1 3 0 6 patie nts) a n d place b o ( a p pr o xi mat el y 1 5 7 3 pat ient s).  A mo n g t he 
a p pr o xi matel y e x pecte d 4 7 0 4 5 9 mir i kiz u ma b cli nical res p o n ders, a p pr o xi matel y 1 6 9 
1 8 0 mir i kiz u ma b cli nical re mitters will be ra n d omize d t o 2 0 0 m g miri kiz u ma b S C 
(a p pr o xi matel y 1 1 3 1 2 0 patie nts) a n d place b o ( a p pr o xi matel y 5 6 6 0 pat ient s).  T his ass u mes t hat:

T he i n d uct i on st u d y  ( A M A N, w hic h has a mi xe d p o p ulati on wi t h a p pr o xi matel y 6 0 5 0 % 
bi o l ogic -faile d patient s) is e x pecte d t o ha ve a n o verall cli nical re missi o n rate of 2 3 2 1. 6 % 
a n d res p o nse rate of 6 0 5 8. 6 % wit h miri kiz u ma b.
T he pri mar y  e n d p oi nt, ma i nte na nce of cli nical re missi o n at Wee k 4 0 , will be assesse d o n patie nts 
w h o ac hie ve d cli nical re missio n  res p o nse t o miriki z u m a b i n d uct i on treat me nt.  Ass u mi n g 
C CI

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mirikizumab and placebo maintenance of clinical remission rates of 58.447% and 23.627%, 
respectively(biologic-failed patients:  44% and 13%; conventional-failed patients:  70% and 
32%), this study based on the 169 470 mirikizumab induction remittersresponders is expected to 
have >950% power to demonstrate that mirikizumab is superior to placebo by using a chi-square 
test with a 2-sided 0.05 significance level of 0.05.  This sample size also provides 80% power to 
evaluate clinical remission among induction remitters in the subgroup of biologic-failed patients.  
In addition, 459 mirikizumab induction clinical responders are the sample size is expected to 
provide adequate power (>80%) to demonstrate that mirikizumab is superior to placebo for the 
major secondary endpoints (clinical remission, endoscopic remission, histologic remission, and
or corticosteroid-free remission) at Week 40, among responders to mirikizumab induction 
treatment by using a chi-square test with a 2-sided 0.05 significancet level of 0.05.
10.2.
Populations for Analyses
Table AMBG.10.1.
Analysis Populations in Study AMBG
Population
Description
Intent-to-treat (ITT) Population
All enrolledrandomized/assigned patients.  Patients will be analyzed according 
to the treatment to which they were assigned
Modified Intent-to-treat (mITT) 
Population
All enrolled patients who received at least 1 dose of study treatment, does not 
receive the correct treatment, or otherwise does not follow the protocol.All 
randomized/assigned patients who received at least 1 dose of study treatment, 
regardless of whether correct treatment was administered or whether protocol 
was followed,.Patients will be analyzed according to the treatment to which they 
were assigned
10.3.1. General Statistical Considerations
For assessments of the primary endpoint and other categorical efficacy endpoints among induced 
remittersresponders, the Cochran-Mantel-Haenszel (CMH) chi-square test will be used to 
compare mirikizumab and placebo with stratification factors:  (a) previous biologic therapy 
failure (yes or no), (b) baseline corticosteroid use (yes or no), and(c) region (North 
America/Europe/Other),. and (d) induction remission status (yes/no). For other major secondary 
endpoints and categorical efficacy endpoints among induced responders, similar CHM chi-
square test will be used.  Another stratification factor of induction remission status will be added 
in the analysis.  
Treatment comparisons of continuous efficacy and health outcome variables with a single 
post-baseline time point will be made using analysis of covariance with:  (a) treatment group, 
(b) previous biologic therapy failure (yes or no), (c) corticosteroid use (yes or no), (d) region 
(North America/Europe/Other), (e) baseline value in the model, and (f) induction remission 
status (if analysis is among induced responders).  Type III sums of squares for LS means will be 
used for statistical comparison between treatment groups.  The LS mean difference, standard 
error, p-value, and 95% CI, unless otherwise specified, will also be reported.  

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10.3.1.1.
Missing Data Imputation:

Nonresponder imputation (NRI):  For analysis of categorical efficacy and health 
outcomes variables, missing data will be imputed using an NRI method.  Patients will be 
considered a nonresponder for the NRI analysis if they do not meet the categorical 
response criteria, have missing clinical response data at a time point of interest, or take 
rescue dosing with mirikizumab prior to the time point of interest. In addition, the 
patients who require UC surgery, take rescue dosing with mirikizumab, increase UC 
medication dose from baseline, or initiate new UC medications will be considered as 
nonresponders.  
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 drug dictionary.  Medications started prior to randomization and 
medications started on study after randomization Previous concomitant therapy (reported before 
randomization) and current concomitant therapy (reported after randomization) will be presented 
separately in frequency tables by drug name and by cohort for all enrolled patients.  
10.3.3.1.
Primary Analyses
The primary endpoint is the proportion of patients with durable clinical remission at Week 40 
(Week 52 of continuous therapy) among the patients who are remittersresponders to 300 mg 
mirikizumab IV at 12 weeks of induction dosing.
Rates of clinical remission at Week 40 among induction responders remitters will be analyzed.  
Patients who do not achieve clinical remission or who do not reach the Week 40 assessment will 
be considered to be nonremitters.  In addition, patients who undergo UC surgery, take rescue 
dosing with mirikizumab, increase their concomitant UC medication, or initiate new UC 
medications will be considered nonremitters.
10.3.7.1.
Subgroup Analyses 
The major subgroup analysis is for the primary and major secondary endpoints for biologic-
failed patients described in Section 9.1.2.1.  Multiplicity adjustment described in Section 
10.3.1.2. will be used to control type I error.
Additional sSubgroup analyses will be conducted for the primary endpoint and selected major 
secondary endpoints.  
11.
References
Arai M, Naganuma M, Sugimoto S, Kiyohara H, Ono K, Mori K, Saigusa K, Nanki K, 
Mutaguchi M, Mizuno S, Bessho R, Nakazato Y, Hosoe N, Matsuoka K, Inoue N, Ogata H, 
Iwao Y, Kanai T. The Ulcerative Colitis Endoscopic Index of Severity is useful to predict 
medium- to long-term prognosis in ulcerative colitis patients with clinical remission. J Crohns 
Colitis. 2016;10:1303-1309.

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Ikeya K, Hanai H, Sugimoto K, Osawa S, Kawasaki S, Iida T, Maruyama Y, Watanabe F. The 
ulcerative colitis endoscopic index of severity more accurately reﬂects clinical outcomes and 
long-term prognosis than the Mayo endoscopic score. J Crohns Colitis. 2016;10:286-295.
Tontini GE, Bisschops R, Neumann H. Endoscopic scoring systems for inﬂammatory bowel 
disease: Pros and cons. Expert Rev Gastroenterol Hepatol. 2014;8:543-554. 
Appendix 1.
Abbreviations and Definitions
UCEIS   Ulcerative Colitis Endoscopic Index of Severity
Appendix 2.
Clinical Laboratory Tests
Other testsa
Tryptaseh
Complement (C3/C4)h
Cytokine panelh
Abbreviations:  ADA = anti-drug antibody
h
Performed only in the event of systemic allergic/hypersensitivity events, along with ADA and PK.
Appendix 3.1.7.
Final Report Signature
The investigator with the most enrolled patients will serve as the CSR coordinating investigator
will be selected by the study team.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the CSR coordinating investigator.
Appendix 6.
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Stool frequency reports the number of stools in a 24-hour period, relative to the normal number of stools for that 
patient. The reference “normal” stool frequency for that patient will be recorded electronically at the screening visit
in Study AMAN.  The Normal SF refers to when the patient was in remission or, if the patient has never achieved 
remission, the reported SF before initial onset of signs and symptoms of ulcerative colitis.  Remission refers to a 
period of time since being diagnosed with ulcerative colitis when the patient is not experiencing any signs or 
symptoms relating to ulcerative colitis.  This period of time may last a few weeks or a few months or may even last 
several years. The patient will record this electronically as source data in the tablet device at the screening study 
visit in Study AMAN.
Appendix 7.
Patient-Reported Outcome Instruments
Abdominal Pain NRS: A single item that measures the “worst abdominal pain in the past 24 
hours” using an 11-point NRS ranging from 0 (no pain) to 10 (pain as bad as can imagineworst 
possible pain).  
Fatigue NRS:  The Fatigue NRS is a single item that measures the “worst fatigue (weariness, 
tiredness) in the past 24 hours” using an 11-point NRS ranging from 0 (no fatigue) to 10 (fatigue 
as bad as you can imagine).

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Appendix 8.
Prohibited Medications
Drug Class
Comments
Rectally administered investigational preparations for UC such 
as arsenic preparations
Prohibited throughout treatment period
Intravenous corticosteroids for UC
A course of IV corticosteroids for UC is 
prohibited
Systemic corticosteroids for non-UC indications (oral or IV) 
Patients requiring systemic 
corticosteroids for non-UC conditions 
are excluded.  Exceptions
(exceptinclude corticosteroids to treat 
adrenal insufficiency, premedication for 
IP infusion, or lare excluded.  Locally 
administered corticosteroids (e.g., 
inhaled, intranasal, intra-articular, 
topical) (see Appendix 10).are allowed.
Appendix 9.
Permitted Medications with Dose Stabilization
Drug Class
Comments
Oral 5-ASAs (for example, mesalamine, 
balsalazide, olsalazide) and sulfasalazine 
for UC (for example, mesalamine, 
balsalazide, olsalazide)
May continue during study with stable doses encouraged
Oral corticosteroids for UC (prednisone 
≤20 mg/day or equivalent, or budesonide 
MMX 9 mg/day, or beclomethasone 
dipropionate [gastro-resistant prolonged-
release tablet] 5 mg/day)
Responder patients who are receiving oral corticosteroids at the start of 
Study AMBG will start corticosteroid taper at the beginning of the 
study.  Clinical nonresponders who undergo extended IV induction with 
mirikizumab will begin corticosteroid tapering if symptomatic response 
or symptomatic improvement based on investigator discretion is 
achieved at any time after starting extended induction (see 
Corticosteroid Taper in Section 7.7).
Corticosteroids for non-UC indications: 
corticosteroids to treat adrenal 
insufficiency, as premedication for IP 
infusion, or locally administered 
corticosteroids (e.g. inhaled, intranasal, 
intra-articular, topical).
May continue corticosteroids to treat adrenal insufficiency or locally 
administered corticosteroids during study with stable dose encouraged.  
Single doses of oral or IV corticosteroids as premedication to IP 
administration are allowed in patients with prior IP or other previous 
biologic injection reactions.
Abbreviations:  IP = investigational product; UC = ulcerative colitis

Leo Document ID = 8776699c-01e8-4a66-b52c-c63190ba695e
Approver: 
Approval Date & Time: 12-Sep-2019 20:08:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Sep-2019 20:48:02 GMT
Signature meaning: Approved
PPD
PPD