A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of LY3375880 in Adult Subjects With Moderate-to-Severe Atopic Dermatitis: The ADmIRe Study
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: Eli Lilly and Company

 
Protocol I9N-MC-FCAB(b) 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the 
Efficacy and Safety of LY3375880 in Adult Subjects with Moderate-to-Severe Atopic 
Dermatitis: The ADmIRe Study 
 
NCT03831191 
 
Approval Date: 25-Jul-2019 
 

I9N-MC-FCAB(b) Clinical Protocol
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LY3375880
Protocol I9N-MC-FCAB(b)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy 
and Safety of LY3375880 in Adult Subjects with 
Moderate-to-Severe Atopic Dermatitis: The ADmIRe Study
2018-002401-56
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
LY3375880, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3375880
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  11 December 2018
Protocol Amendment (a) Electronically Signed and Approved by Lilly:  
04 February 2019
Protocol Amendment (b) Electronically Signed and Approved by Lilly:  
Approval Date: 25-Jul-2019 GMT

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Table of Contents
Section
Page
Protocol I9N-MC-FCAB(b) A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and 
Safety of LY3375880 in Adult Subjects with Moderate-to-Severe 
Atopic Dermatitis:  The ADmIRe Study..............................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................23
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle Restrictions....................................................................................................35
6.4.
Screen Failures.............................................................................................................35
7.
Treatments........................................................................................................................36
7.1.
Treatments Administered .............................................................................................36
7.1.1.
Packaging and Labeling .......................................................................................36
7.2.
Method of Treatment Assignment ................................................................................37
7.2.1.
Selection and Timing of Doses.............................................................................37
7.3.
Blinding .......................................................................................................................37
7.4.
Dosage Modification....................................................................................................38
7.5.
Preparation/Handling/Storage/Accountability...............................................................38
7.6.
Treatment Compliance .................................................................................................38
7.7.
Concomitant Therapy...................................................................................................39
7.7.1.
Prohibited Medications and Procedures................................................................39

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7.7.2.
Permitted Medications..........................................................................................40
7.7.3.
Rescue Therapy....................................................................................................40
7.8.
Treatment after the End of the Study............................................................................41
8.
Discontinuation Criteria ....................................................................................................42
8.1.
Discontinuation from Study Treatment.........................................................................42
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................42
8.1.2.
Discontinuation of Inadvertently Enrolled Subjects..............................................42
8.2.
Discontinuation from the Study....................................................................................43
8.3.
Lost to Follow-Up........................................................................................................43
9.
Study Assessments and Procedures ...................................................................................44
9.1.
Efficacy Assessments...................................................................................................44
9.1.1.
Primary Efficacy Assessments .............................................................................44
9.1.1.1.
Validated Investigator’s Global Assessment for AD 
(vIGA-AD).....................................................................................................44
9.1.2.
Secondary Efficacy Assessments..........................................................................44
9.1.2.1.
Eczema Area and Severity Index Scores.........................................................44
9.1.2.2.
SCORing AD .................................................................................................44
9.1.3.
Health Outcomes and Quality-of-Life Measures...................................................44
9.1.3.1.
Patient-Oriented Eczema Measure ..................................................................45
9.1.3.2.
Itch Numeric Rating Scale..............................................................................45
9.1.3.3.
Skin Pain Numeric Rating Scale .....................................................................45
9.1.3.4.
Dermatology Life Quality Index.....................................................................45
9.1.4.
Appropriateness of Assessments ..........................................................................45
9.2.
Adverse Events ............................................................................................................45
9.2.1.
Serious Adverse Events........................................................................................46
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................47
9.2.2.
Adverse Events of Special Interest .......................................................................47
9.2.3.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Electrocardiograms ..............................................................................................48
9.4.2.
Vital Signs ...........................................................................................................48
9.4.3.
Physical Exam .....................................................................................................48
9.4.4.
Laboratory Tests ..................................................................................................49
9.4.5.
Columbia Suicide Severity Rating Scale...............................................................49
9.4.6.
Self-Harm Supplement and Follow-Up Forms......................................................49
9.4.7.
Chest X-ray and Tuberculosis Testing..................................................................49
9.4.8.
Hepatitis B Virus DNA Monitoring......................................................................50

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9.4.9.
Immunogenicity Assessments ..............................................................................50
9.4.10.
Safety Monitoring ................................................................................................50
9.4.10.1.
Hepatic Safety Monitoring..............................................................................51
9.5.
Pharmacokinetics .........................................................................................................51
9.6.
Pharmacodynamics ......................................................................................................52
9.7.
Pharmacogenomics ......................................................................................................52
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................52
9.8.
Biomarkers...................................................................................................................53
9.9.
Medical Resource Utilization and Health Economics ...................................................53
10.
Statistical Considerations ..................................................................................................54
10.1. Populations for Analyses..............................................................................................54
10.2. Statistical Analyses ......................................................................................................54
10.2.1.
General Statistical Considerations ........................................................................54
10.2.1.1.
Missing Data Imputation ................................................................................55
10.2.1.2.
Maintenance Period Considerations................................................................56
10.2.2.
Treatment Group Comparability...........................................................................56
10.2.2.1.
Subject Disposition.........................................................................................56
10.2.2.2.
Subject Characteristics....................................................................................56
10.2.2.3.
Concomitant Therapy .....................................................................................56
10.2.2.4.
Treatment Compliance....................................................................................56
10.2.3.
Efficacy Analyses ................................................................................................57
10.2.3.1.
Primary Analyses ...........................................................................................57
10.2.3.2.
Secondary Analyses........................................................................................57
10.2.3.3.
Exploratory Analyses .....................................................................................57
10.2.4.
Safety Analyses....................................................................................................57
10.2.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................58
10.2.6.
Evaluation of Immunogenicity .............................................................................58
10.2.7.
Other Analyses.....................................................................................................59
10.2.7.1.
Health Economics...........................................................................................59
10.2.7.2.
Subgroup Analyses.........................................................................................59
10.2.8.
Interim Analyses..................................................................................................59
11.
References ........................................................................................................................60
12.
Appendices .......................................................................................................................62

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List of Tables
Table
Page
Table FCAB.1.
I9N-MC-FCAB Schedule of Activities ..........................................................11
Table FCAB.2.
Objectives and Endpoints...............................................................................18
Table FCAB.3.
Exposure Multiples for Administration of LY3375880 Based on 
Administered Dose and Predicted Human Exposure ......................................24
Table FCAB.4.
Treatment Regimens......................................................................................36

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List of Figures
Figure
Page
Figure FCAB.1. Study design for Study I9N-MC-FCAB. ........................................................22

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................63
Appendix 2.
Clinical Laboratory Tests...............................................................................67
Appendix 3.
Study Governance Considerations..................................................................69
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................73
Appendix 5.
Examples of Infections That May Be Considered Opportunistic in the 
Setting of Biologic Therapy...........................................................................74
Appendix 6.
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis ...................................................................76
Appendix 7.
Protocol Amendment I9N-MC-FCAB(a) Summary:  Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to 
Evaluate the Efficacy and Safety of LY3375880 in Adult Subjects with 
Moderate-to-Severe Atopic Dermatitis:  The ADmIRe Study.........................80

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1.
Synopsis
Title of Study:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the 
Efficacy and Safety of LY3375880 in Adult Subjects with Moderate-to-Severe Atopic 
Dermatitis:  The ADmIRe study.
Rationale: 
Atopic dermatitis (AD) is the most common chronic skin disease with clinical hallmarks of
inflammatory lesions with an intense itch. In the World Health Organization (WHO) 2010 
Global Burden of Disease survey, AD ranked first among common skin diseases with respect to 
disability-adjusted life-years and years lived with a disease (Murray et al. 2012; Vos et al. 2012). 
Currently, there is no cure for AD; thus, the aim of disease management is to improve symptoms 
and achieve long-term disease control with a multistep approach. There is a need for more
efficacious therapies with a better safety profile than the standard of care for subjects with AD.
LY3375880 is a human immunoglobulin (Ig) G4-variant monoclonal antibody (mAb) that binds 
and neutralizes soluble human interleukin (IL)-33 cytokine. LY3375880 is being developed for 
the treatment of subjects with AD.  This study will evaluate the safety and efficacy of 
LY3375880 in subjects with moderate-to-severe AD.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of LY3375880 to placebo 
as measured by IGA at Week 16 in the treatment of 
subjects with moderate-to-severe AD.

Proportion of subjects achieving IGA of 0 or 
1 with a ≥2-point improvement at Week 16.
Secondary

To compare the efficacy of LY3375880 to placebo 
as measured by improvement in signs and symptoms 
at Week 16 and 52 in the treatment of subjects with 
moderate-to-severe AD.

To characterize the PK of LY3375880 in subjects 
with moderate-to-severe AD

Proportion of subjects achieving at Week 16:
o
EASI-50
o
EASI-75
o
EASI-90
o
SCORAD-75
o
SCORAD-90
o
IGA of 0

Mean change from baseline to Week 16 in:
o
EASI score
o
SCORAD

Proportion of subjects achieving IGA of 0 or 
1 at Week 52
Abbreviations:  AD = atopic dermatitis; EASI = Eczema Area and Severity Index; EASI-50/75/90 = 50%/75%/90%
reduction in the EASI score; IGA = Investigator’s Global Assessment; PK = pharmacokinetic(s); SCORAD = 
SCORing AD.

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LY3375880
Summary of Study Design:
Study I9N-MC-FCAB (FCAB) is a Phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient study evaluating the efficacy and safety of 
LY3375880 subcutaneous (SC) 600 mg every 4 weeks (Q4W), 150 mg Q4W, and 50 mg Q4W 
as compared to placebo Q4W in adult subjects with moderate-to-severe AD.  In addition, 
LY3375880 300mg Q4W will be evaluated during the maintenance period. 
The study duration will be up to 65 weeks over 4 study periods:

Period 1: Screening Period, lasting 8 to 35 days prior to Week 0 (baseline, Visit 2).

Period 2: Induction Period, lasting from Week 0 (baseline, Visit 2) through Week 16 
(Visit 8).

Period 3:  Maintenance Period, lasting from Week 16 (Visit 8) through Week 52 
(Visit 17, inclusive).

Period 4: Post-Treatment Follow-Up Period, lasting 8 weeks from Week 52 (after 
Visit 17) to Week 60 (Visit 801).
Treatment Arms and Duration:
Subjects will be randomized 1:1:1:1 at Week 0 to 1 of 4 treatment groups:  placebo SC Q4W, 
LY3375880 SC 600 mg Q4W, LY3375880 150 mg Q4W, or LY3375880 50 mg Q4W.  The 
study duration will be up to 65 weeks (Screening Period:  Up to 5 weeks; Induction Period:  
16 weeks; Maintenance Period: 36 weeks; Post-Treatment Follow-up Period: 8 weeks).
Number of Subjects:
Approximately 200 subjects will be randomized.
Statistical Analysis:
Efficacy will be conducted on the intent-to-treat population. Safety analyses will be conducted 
on the safety population.
Treatment comparisons of discrete efficacy variables between LY3375880 and placebo will be 
made using a logistic regression analysis with treatment, baseline disease severity (Investigator’s 
Global Assessment [IGA] [3 versus 4]), and geographic region in the model.  Treatment 
comparisons of the continuous efficacy variables will be made using a mixed-effects model of 
repeated measures (MMRM) analysis with treatment, baseline disease severity, geographic 
region, visit, and treatment-by-visit interaction as fixed categorical effects and, if a baseline score 
is available, baseline score and baseline score-by-visit interaction as fixed continuous effects.  
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, with no control 
for multiple comparisons.
Fisher’s exact test will be used for the adverse events (AEs), discontinuations, and other 
categorical safety data for between-treatment group comparisons.  Continuous vital signs, body 
weight, and other continuous safety variables including laboratory variables will be analyzed by 
an analysis of covariance with treatment and baseline value in the model.

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LY3375880
2.
Schedule of Activities

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LY3375880
Table FCAB.1.
I9N-MC-FCAB Schedule of Activities
Screening
Induction Period
Maintenance Period
Posttreatment 
Follow-Up
Period 1
Period 2
Period 3
Period 4
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
801
Weeks from 
randomization
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52 or 
ET
60
Days from 
randomization
0
7
14
28
56
84
112
140
168
196
224
252
280
308
336
364
420
Visit tolerance interval 
(days)
-8 to -35
±2
±2
±2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
Procedure
Inclusion and exclusion 
review
X
X
Informed consent
X
Clinical assessments
Demographics 
X
Medical history 
X
Previous and current AD 
treatments
X
Weight
X
Height
X
Vital signs (BP and 
Pulse)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X
Symptom-directed 
physical examinationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ePRO (patient diary) 
dispensed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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LY3375880
Screening
Induction Period
Maintenance Period
Posttreatment 
Follow-Up
Period 1
Period 2
Period 3
Period 4
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
801
Weeks from 
randomization
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52 or 
ET
60
Days from 
randomization
0
7
14
28
56
84
112
140
168
196
224
252
280
308
336
364
420
Visit tolerance interval 
(days)
-8 to -35
±2
±2
±2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
ePRO (patient diary) 
returned
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Xb
IWRS entry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP SC injections
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigator Scales
IGAc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EASIc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCORADc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Outcome 
Measures and Other 
Questionnaires
POEMc,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DLQIc,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Itch NRSe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin Pain NRSe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS 
“Baseline/Screening”
X
C-SSRS 
“Since Last Visit”
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Supplement 
Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Follow-up 
Formf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I9N-MC-FCAB(b) Clinical Protocol
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LY3375880
Screening
Induction Period
Maintenance Period
Posttreatment 
Follow-Up
Period 1
Period 2
Period 3
Period 4
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
801
Weeks from 
randomization
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
52 or 
ET
60
Days from 
randomization
0
7
14
28
56
84
112
140
168
196
224
252
280
308
336
364
420
Visit tolerance interval 
(days)
-8 to -35
±2
±2
±2
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±5
Laboratory Assessment
12-lead ECG (single)
X
Chest x-rayg (posterior–
anterior and lateral 
views)
X
TB testh
X
Read PPD if applicable 
(48–72 hours post-PPD)i
X
Skin punch biopsiesj
(lesional, nonlesional)
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipids (fasting)k
X
X
X
Serum pregnancyl
X
FSHm
X
HIV, HCV,n HBV 
screening tests
X
HBV DNAo
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine pregnancyl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacogenetics sample
X
Serum IgE (total)
X
X
X
X
Serum IgE (allergen 
X
X

I 9 N-M C -F C A B( b) Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 3 3 7 5 8 8 0
Scree ni n g
I n d ucti o n Peri o d
M ai nte n a nce Peri o d
P osttre at me nt 
F oll o w -U p
Peri o d 1
Peri o d 2
Peri o d 3
Peri o d 4
Visit N u m ber
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
8 0 1
Wee ks fr o m 
ra n d o mizati o n
0
1
2
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 2 or 
E T
6 0
Da ys fr o m 
ra n d o mizati o n
0
7
1 4
2 8
5 6
8 4
1 1 2
1 4 0
1 6 8
1 9 6
2 2 4
2 5 2
2 8 0
3 0 8
3 3 6
3 6 4
4 2 0
Visit t olera nce i nter val 
( da ys)
-8 t o -3 5
± 2
± 2
± 2
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 5
s pecific)p
E x pl o rat or y l o n g-ter m 
st ora ge sa m ples (ser u m, 
plas ma E D T A)
X  
X  
X  
X  
X
X
X  
X
X
E x pl o rat or y l o n g-ter m 
st ora ge sa m ples:  R N A 
a n d D N A (e pi ge netic)
X
X
X
X
L Y 3 3 7 5 8 8 0 P K 
Sa m ples q
X  
X  
X  
X  
X  
X
X
X
X  
X
I m m u n o ge nicit y 
sa m plesq
X
X
X
X
X
X  
X
Tar get e n ga ge me nt 
sa m ples ( T otal I L- 3 3)
X  
X  
X  
X  
X
X
X
X
I L-1 9, T A R C, Peri osti n
X  
X  
X  
X  
X
X
X  
X
X
Fl o w c yt ometr y  sa m ple
X
X
X
X
A b bre viati o ns: A D = at o pic der matitis; B P = bl o o d press ure; C- S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale (1 1 cate g ories of s uici dal i deati o n/s uici dal 
be ha vi or ); D L QI = Der mat ol o g y Life Q ualit y I n de x; D N A = d e o x yri b o n ucleic aci d; E A SI = Ecze ma Area a n d Se verit y I n de x; E C G = electr ocar di o gra m; 
E D T A = et h yle ne dia mi netetraacetic aci d; e P R O = electr o nic s u bject-re p orte d o utc o mes ( de vice); E T = earl y ter mi nati o n; F S H = f ollicle -sti m ulati n g 
h or m o ne; H Bc A b = he patitis B c ore a nti b o d y; H Bs A b = he patitis B s urface a nti b o d y; H Bs A g = he patitis B s urface a nti ge n; H B V = he patitis B vir us; 
H C V = he patitis C vir us; HI V = h u ma n i m m u n o deficie n c y  vir us; I G A = I n vesti gat or’s Gl o bal Assess me nt; I g E = i m m u n o gl o b uli n E; I L = i nterle u ki n; 
I P = i n vesti gati o nal pr o d uct; I W R S = i nteracti ve we b-res p o nse s ystem; N R S = N u meric R ati n g S cale; P K = p har mac o ki netic; P O E M = Patie nt -Orie nte d 
Ecze ma Meas ure; P P D = p urifie d pr otei n deri vati ve; R N A = ri b o n ucleic aci d; S C = s u bc uta ne o us; S C O R A D = S C O Ri n g A D ; T A R C = t h ym us a n d 
acti vati on -re g ulate d c he m o ki ne; T B = t u berc ul osis.

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LY3375880
a
The symptom-directed physical examination may be conducted at the investigator’s discretion any time a subject presents with physical complaints.
b
Subjects will be re-randomized/reassigned at Week 16 as described in Section 5.
c
Will be collected as electronic Clinical Outcome Assessment (eCOA) data.
d
The following measures (POEM and DLQI) should be completed by the subject prior to any clinical assessments being performed on days when study visits 
occur.
e
Will be collected daily via an electronic subject diary.
f
The Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form.
g
A posterior–anterior and lateral chest x-ray will be performed at screening unless one has been performed within the past 90 days, the x-ray and reports are 
available, and a repeat chest x-ray is not clinically indicated per investigator judgment.
h
TB test(s) including PPD, QuantiFERON®-TB Gold, and T SPOT®. See Exclusion Criterion [17] for description of TB testing.  In countries where the 
QuantiFERON-TB Gold test or T-SPOT is available, either test may be used instead of the PPD TB test.  The QuantiFERON-TB Gold test may be performed 
locally or centrally; the T-SPOT must be performed locally.  (Note:  Subjects who have a documented history of completing an appropriate TB treatment 
regimen for latent tuberculosis infection [LTBI] and with no risk of re-exposure since their treatments were completed are eligible to participate in the study if 
other criteria are met. These subjects should not undergo tuberculin skin test (TST) or interferon-gamma release assay (IGRA) testing unless advised to do so 
based on local guidelines, but must have a chest x-ray at screening.)
i
If PPD testing was chosen to test for TB, then the subject must return and PPD test read 48 to 72 hours after Visit 1 (post-PPD).
j
To be performed following investigator and subject disease assessments/scales.
k
Fasting lipid profile: Subjects should not eat or drink anything except water for 12 hours prior to sample collection.  If a subject attends these visits in a 
nonfasting state, this will not be considered a protocol violation.
l
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1.  Urine pregnancy tests (local laboratory) will 
be performed at Visit 2 and subsequent visits according to the study schedule.  If required per investigator judgment, local regulations, and/or institutional 
guidelines, additional pregnancy testing can occur during the study treatment period.
m For female subjects to confirm post-menopausal status according to Inclusion Criterion [9].
n
For subjects who are positive for HCV antibody, a follow-up test for HCV RNA will be performed automatically.  Subjects who are positive for HCV 
antibody and negative for HCV RNA may be enrolled.
o
Subjects who are HBsAg negative and positive for HBcAb (and/or HBsAb in Japan) will automatically have an HBV DNA performed at screening. Any 
patient positive for HBcAb and negative for HBV DNA may be enrolled and must undergo HBV DNA monitoring per the schedule (see Section 9.4.8).
p
Allergen-specific IgE testing could include, but is not limited to, Dermatophagoides pteronyssinus, Dermatophagoides farinae, Alternaria alternata.
q
PK and immunogenicity samples should be collected prior to dosing on days of dosing.  Sites may be prompted to draw an unscheduled PK and 
immunogenicity sample based on EASI score entered.  See Sections 9.4.9 and 9.5.

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3.
Introduction
3.1.
Study Rationale
LY3375880 is a human Ig G4-variant mAb that binds and neutralizes soluble human IL-33 
cytokine. LY3375880 is being developed for the treatment of subjects with AD.  This study will 
evaluate the safety and efficacy of LY3375880 in subjects with moderate-to-severe AD.
3.2.
Background
Atopic dermatitis (AD) is the most common chronic skin disease with clinical hallmarks of 
inflammatory lesions with an intense itch.  In the WHO 2010 Global Burden of Disease survey, 
AD ranked first among common skin diseases with respect to disability-adjusted life-years and 
years lived with a disease (Murray et al. 2012; Vos et al. 2012).  Currently, there is no cure for 
AD; thus, the aim of disease management is to improve symptoms and achieve long-term disease 
control with a multistep approach.  There is a need for more efficacious therapies with a better 
safety profile than the standard of care for subjects with AD.
Interleukin-33 is expressed in AD skin with increased numbers of IL-33-positive cells in areas 
with active lesions over nonlesional skin (Savinko et al. 2012).  Serum levels of IL-33 were 
significantly higher (approximately 7-fold) in subjects with AD compared to healthy control 
subjects and correlated with disease severity (Tamagawa-Mineoka et al. 2014).  IL-33 is a driver 
of type 2 helper T-cell (Th2)-mediated inflammation.  The effects of IL-33 cause the production 
of other pro-inflammatory mediators, including IL-4 and IL-5.  Therapeutic intervention has 
focused on neutralizing downstream effector cytokines such as IL-4, IL-13, or IL-5, with partial 
success.  Dupilumab (Dupixent®; Regeneron and Sanofi) blocks signaling from both IL-4 and 
IL-13 and was approved by the Food and Drug Administration (FDA) in March 2017 for 
moderate-to-severe AD.  However, in Phase 3 studies, over 60% of subjects did not achieve a 
high level of response (90% reduction in the Eczema Area and Severity Index score [EASI-90]), 
and the need for additional treatment approaches remains (Simpson et al. 2016).  Interleukin-33 
is upstream of IL-4 and IL-13 in the Th2 pathway, and neutralization of IL-33 would also reduce 
IL-5 production, leading to the hypothesis that LY3375880 has the potential for superior efficacy 
in AD than currently available treatments.
LY3375880 has been tested in humans in the Phase 1 study I9N-MC-FCAA (FCAA).  Single 
doses ranging from 3 mg to 400 mg SC and 100 mg and 700 mg intravenous (IV); and multiple 
doses of 150 mg SC, 300 mg IV and 700 mg IV, were administered to healthy volunteers.  No 
dose-limiting AEs were observed and dose escalation to the maximum dose of 700mg IV was 
achieved. As of 06 September 2018, no deaths, serious adverse events (SAEs), or 
discontinuations due to AEs were reported.  Based on analysis of data from single-dose 
administration between 3 mg to 400 mg SC and 100 mg IV, the average half-life was 24 days.
Study I9N-MC-FCAB (FCAB) is the first Phase 2 study for LY3375880 and will evaluate the 
safety and efficacy of LY3375880 in adults with moderate-to-severe AD.  Results from this 
study will lead to further development of LY3375880 in AD and other related diseases.

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3.3.
Benefit/Risk Assessment
There are currently no human data regarding the efficacy of LY3375880 in AD.  IL-33 is 
upstream of IL-4 and IL-13 in the Th2 pathway (both cytokines inhibited by dupilumab, an 
approved treatment  for moderate to severe AD); neutralization of IL-33 would also reduce IL-5 
production, leading to the hypothesis that LY3375880 has the potential for efficacy in AD.  
Nonclinical data and safety data in Phase 1 support further development of LY3375880 in AD at 
the proposed doses.
The safety profile for LY3375880 has been presented by the results from nonclinical toxicology 
and safety pharmacology studies and from the Phase 1 clinical study FCAA.  The primary 
adverse effects observed in animal studies included vasculopathy, glomerulopathy, anemia, 
and/or thrombocytopenia, which were attributable to immunogenicity of LY3375880.  All 
affected animals had detectable antidrug antibodies (ADA), and the immunohistochemical and 
electron microscopy evaluations demonstrated the presence of, or changes associated with, 
immune complex deposition.  Taken together, these findings suggest an immune-mediated 
response by the animals to the repeated administration of a humanized mAb and not attributable 
to LY3375880 pharmacology.  The observation of immunogenicity and immune-mediated 
toxicity findings in monkeys is generally not considered predictive for immunogenicity and 
sequelae in humans.  In terms of clinical safety observed in the Phase 1 Study FCAA, no dose-
limiting safety issues have been identified.  As of 06 September 2018, there have been no deaths, 
SAEs, or discontinuations due to AEs.  The majority of AEs have been mild with no severe AEs 
reported.  Furthermore, there were no renal, vascular, hematologic, or any other AEs suggestive 
of immune-complex disease.  ADA titers in subjects have generally been low with no clinically 
evident impact.
Although the immune-mediated findings in the animal studies are generally not considered 
predictive for humans and there have been no apparent clinical effects attributable to 
immunogenicity in Study FCAA, subjects in Study FCAB will continue to be closely monitored 
for safety events, including allergic/hypersensitivity reactions, injection site reactions, or other 
events plausibly related to drug immunogenicity.  Ongoing monitoring of safety data (including 
AEs, SAEs, and selected laboratory measurements) will continue throughout the study using 
blinded data.  Interim safety analyses will be conducted to review unblinded safety data if 
deemed appropriate based on the ongoing blinded monitoring; the unblinded analyses will be 
conducted and reviewed by an internal assessment committee composed of personnel who do not 
have direct site contact or data entry/validation responsibilities.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY3375880 will be found in the Investigator’s Brochure (IB).

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LY3375880
4.
Objectives and Endpoints
Table FCAB.2 shows the objectives and endpoints of the study.
Table FCAB.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare the efficacy of LY3375880 to 
placebo as measured by IGA at Week 16 in 
the treatment of subjects with moderate-to-
severe AD.

Proportion of subjects achieving IGA of 0 or 1 with a 
≥2-point improvement at Week 16.
Secondary

To compare the efficacy of LY3375880 to 
placebo as measured by improvement in signs 
and symptoms at Week 16 and 52 in the 
treatment of subjects with moderate-to-severe 
AD.

To characterize the PK of LY3375880 in 
subjects with moderate-to-severe AD

Proportion of subjects achieving at Week 16
o
EASI-50
o
EASI-75
o
EASI-90
o
SCORAD-75
o
SCORAD-90
o
IGA of 0

Mean change from baseline to Week 16 in
o
EASI
o
SCORAD

Proportion of subjects achieving IGA of 0 or 1 at 
Week 52

Serum PK Data
Exploratory Objectives/Endpoints

To evaluate signs and symptoms, health outcome measures, and QoL measures (total scores, item scores, and 
derivations) at each time point collected.

To explore relationships between LY3375880 exposure and study endpoints.

To characterize post-induction loss of response and maintenance of response.

To evaluate PD effects of LY3375880 in skin biopsies and peripheral blood.
Abbreviations:  AD = atopic dermatitis; EASI = Eczema Area and Severity Index; EASI-50/75/90 = 50%/75%/90%
reduction in the EASI score; IGA = Investigator’s Global Assessment; PD = pharmacodynamic; PK = 
pharmacokinetic(s); QoL = quality-of-life; SCORAD = SCORing AD.

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5.
Study Design
5.1.
Overall Design
Study I9N-MC-FCAB (FCAB) is a Phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient study evaluating the efficacy and safety of 
LY3375880 SC 600 mg Q4W, 150 mg Q4W, and 50 mg Q4W as compared to placebo Q4W in 
adult subjects with moderate-to-severe AD. In addition, LY3375880 300mg Q4W will be 
evaluated in the maintenance period as described below. 
The study duration will be up to 65 weeks over 4 study periods:

Period 1: Screening Period lasting from 8 to 35 days prior to Week 0 (baseline, Visit 2).

Period 2: Induction Period, lasting from Week 0 (baseline, Visit 2) through Week 16 
(Visit 8).

Period 3:  Maintenance Period, lasting from Week 16 (Visit 8) through Week 52 (Visit 
17, inclusive). At Week 16, the following will occur:
o
Responders (defined as having achieved a 50% reduction in the Eczema Area and 
Severity Index score [EASI-50] response, regardless of whether rescue therapy 
has been initiated) will undergo the following re-randomizations:

Subjects on any dose of LY3375880 will be re-randomized at a 2:1 ratio to 
either maintain their current regimen or to receive placebo until loss of 
response (not achieving a 25% reduction in the EASI score [EASI-25] at a 
scheduled visit), at which point they will restart their induction period 
regimen.

Subjects on placebo will continue receiving placebo until loss of response, 
at which point they will be reassigned to receive LY3375880 at 300 Q4W.
o
Nonresponders will undergo the following reassignments:

Subjects on 50 mg Q4W will be reassigned to 150 mg Q4W.

Subjects on 150 mg Q4W will be reassigned to 300 mg Q4W.

Subjects on 600 mg Q4W will remain on their current regimen.

Subjects on placebo will be reassigned to receive 300 mg Q4W.
o
Subjects with persistent disease activity, defined as not achieving EASI-25 for 3 
consecutive scheduled maintenance period visits, not already on 600 mg Q4W
will be reassigned to 600 mg Q4W for the remainder of the study.

Period 4: Post-Treatment Follow-Up Period, spanning approximately 8 weeks from
Week 52 (after Visit 17) to Week 60 (Visit 801).
Rescue therapy is permitted starting at Week 8 for subjects who do not achieve an EASI-25 
response. Refer to Section 7.7.3 for details.
Treatment Arms and Duration:
Approximately 200 subjects will be randomized 1:1:1:1 at Week 0 to 1 of 4 treatment groups in 
the induction period:  placebo SC (Q4W), LY3375880 SC 600 mg (Q4W), LY3375880 150 mg 
(Q4W), or LY3375880 50 mg (Q4W).  The study duration will be up to 65 weeks (Screening 

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LY3375880
Period: Up to 5 weeks; Induction Period: 16 weeks; Maintenance Period: 36 weeks; Follow-up 
Period: 8 weeks).
Subjects will be stratified at randomization according to disease severity (IGA [3 versus 4]) and 
geographic region (Japan versus non-Japan).
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Section 2).  Appendix 2 describes collection of laboratory samples
with the list of specific laboratory tests that will be performed for this study.  Study governance 
considerations are described in detail in Appendix 3.
Figure FCAB.1 illustrates the study design.

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W1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
W60
W0
-35 to -8 
days
Placebo until loss of response, then 300 mg q4w
50 mg q4w 
PBO q4w 
Screening 
Period
Induction 
Period
Maintenance 
Period
Follow-up 
Period
Randomization
1:1:1:1
Primary
Endpoint
NR
R
300 mg q4w
150 mg q4w
R 2:1
50 mg q4w
NR
Placebo until loss of response, then 50 mg q4w
150 mg q4w 
300 mg q4w
R 2:1
150 mg q4w
NR
Placebo until loss of response, then 150 mg q4w
600 mg q4w 
600 mg q4w
R 2:1
600 mg q4w
NR
Placebo until loss of response, then 600 mg q4w
W2

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LY3375880
Abbreviations: R = Responders. 
Response to study drug is defined as achieving an EASI-50. At Week 16, responders
on LY3375880 will be re-randomized to either maintain current dosing regimen or 
placebo until disease recurrence (EASI-25). Placebo responders will continue on 
placebo until disease recurrence.
NR = Nonresponders.  At Week 16, nonresponders will be reassigned to 600 mg Q4W, 
300mg Q4W, or 150 mg Q4W depending on treatment group.
Note: Subjects with persistent disease activity, defined as not achieving EASI-25 for 3 
consecutive scheduled maintenance period visits, not already on 600 mg Q4W will be
reassigned to 600 mg Q4W for the remainder of the study.
Figure FCAB.1.
Study design for Study I9N-MC-FCAB.
5.2.
Number of Participants
Approximately 200 participants will be randomized.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
Study FCAB is the first clinical trial evaluating the safety and efficacy of LY3375880 in subjects 
with moderate-to-severe AD. A moderate-to-severe subject population is appropriate for a novel 
investigational product (IP) with immunomodulating properties. Three active dose levels of 
LY3375880 to evaluate the primary endpoint will allow the evaluation of safety and efficacy 
across a broad dose range to fully characterize the benefit/risk profile of LY3375880 and provide 
information on dose selection in future studies.  A double-blind, placebo-controlled design limits 
bias for both subject and investigator assessments and enables a clearer interpretation of active 
drug effect.
The treatment period includes an induction and maintenance period.  The induction period of the 
study is designed to evaluate the primary endpoint, which is the proportion of subjects achieving 
IGA of 0 or 1 with a ≥2-point improvement at Week 16.  The IGA is a global disease severity 
scale that is widely used in AD trials, and is accepted by the FDA as a primary endpoint for trials 
conducted for approval of new drugs (Futamura et al. 2016; Simpson et al. 2016).  A time point 
at Week 16 to evaluate the primary endpoint is appropriate, based on previous clinical trials of 
systemic therapies in AD (Simpson et al. 2016).  A maintenance period spanning Weeks 16 to 52 
allows for an evaluation of safety and efficacy over a longer duration.  In addition to the dose 
regimens being tested in the induction period, an additional dosing regimen of 300mg Q4W will 
be evaluated during the maintenance period to obtain safety and efficacy data of an intermediate 
dose.  Given the broad dose range being evaluated in this study, data regarding this dose will 
further aid in exposure–response modeling and dose selection for future studies.  During the 
maintenance period, subjects taking LY3375880 who respond to study drug at Week 16 will be 
re-randomized to either maintain their current regimen or administered placebo until disease 
recurrence to understand durability of disease response.  This information will provide the dose 

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and frequency of administration in future studies.  Nonresponders on LY3375880 on 50 mg and 
150 mg will be reassigned to the next highest dose level to evaluate whether disease activity will 
respond to a higher dose of active study drug.  Placebo nonresponders will be reassigned to 300 
mg to efficiently obtain safety and efficacy data on the intermediate dose of 300 mg Q4W not 
tested in the induction period.
5.5.
Justification for Dose
The LY3375880 dose range of 50 mg to 600 mg SC is based on clinical safety data from the 
Phase 1 Study FCAA, pharmacokinetic/pharmacodynamic (PK/PD) modeling, and nonclinical 
toxicology data. 
In the Phase 1 study FCAA, single and multiple doses of up to 700 mg IV of LY3375880 were 
tested in healthy subjects.  As of the cutoff date of 06 September 2018, all cohorts have 
completed dosing.  There have been no dose-limiting AEs identified and dose escalation to the 
highest possible dose of 700 mg IV in both the single ascending and multiple ascending dose 
portions was achieved.  No deaths, SAEs, or discontinuations due to AEs were reported.  
Overall, the frequency of treatment-emergent AEs was 8/20 (40%) for subjects dosed with 
placebo and 11/58 (19%) for subjects dosed with LY3375880.  There were no dose-related 
changes in AE frequency across single doses of 3 to 700 mg LY3375880 or multiple doses of 
150 to 700 mg LY3375880. To date, the most commonly reported AEs in LY3375880 treated 
subjects have been upper respiratory tract infection reported by 3 (5.2%) subjects who received 
LY3375880 and 0 subjects who received placebo, headache reported by 2 (3.4%) subjects who 
received LY3375880 and 1 (5.0%) subject who received placebo, and skin abrasion reported by 
2 (3.4%) subjects who received LY3375880 and 1 (5%) subject who received placebo.  The 
majority of the AEs have been mild and no severe AEs have been reported.  There were no 
clinically significant changes in clinical safety laboratory results in subjects administered 
LY3375880.
The available PK and target engagement data from the first 6 cohorts of the SAD portion of 
FCAA (3mg to 400 mg SC and 100 mg IV) as well as data from the first cohort of the multiple 
ascending dose (150 mg SC) were used to develop a PK/PD model.  The model described the 
time course of the relationship of serum concentrations of LY3375880 and inhibition of IL-33.  
Based on simulations conducted with this model, doses between 50 mg and 600 mg administered 
once monthly are expected to cover a minimal–maximal effect range, assuming that maximum 
inhibition of IL-33 throughout the dosing interval would be required for efficacy.
The nonclinical toxicity profile of LY3375880 has been characterized in 6-week and 6-month 
Good Laboratory Practice-compliant general toxicology studies in cynomolgus monkeys, the 
only pharmacologically relevant species based on binding to human and cynomolgus IL-33.  No 
adverse effects considered related to IL-33 neutralization were observed in monkeys.  However, 
histologic or hematologic effects, considered related to systemic inflammation attributable to 
immunogenicity of LY3375880, were observed in all treated animals in the 6-month study. In 7 
of the 22 treated animals, the immunogenicity-associated inflammation caused adverse 
histopathological or hematological findings that are most likely a consequence of immune 

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LY3375880
complex-associated type III hypersensitivity. These adverse findings included immune-mediated 
hemolytic anemia and/or thrombocytopenia, protein-losing glomerulopathy, and vasculopathy; 
clinical decline associated with these findings resulted in the euthanasia prior to scheduled 
termination in 3 animals and a suspension of dosing in another animal.  In addition, non-adverse 
increased incidence and/or severity of mononuclear cell infiltrates was observed in 1 or more 
tissues in all treated animals. The observation of immunogenicity and immune-mediated toxicity 
findings in monkeys is generally not considered predictive for immunogenicity and sequelae in 
humans, and no safety signals suggestive of immune-complex disease have been reported in 
Phase 1 trial subjects.  In the 6-week toxicology study, LY3375880-related effects were limited 
to non-dose-related decreases in circulating natural killer (NK) cells (with no impact on NK cell 
function); this effect was not observed in the 6-month toxicology study, suggesting these effects 
were not related to LY3375880.  Because none of the adverse effects in the 6-month study are 
considered attributable to LY3375880 pharmacology, the high dose (400 mg/kg/wk) is 
appropriate to derive dose and exposure multiples to intended clinical doses and projected 
exposures supportive of the margin of safety in clinical trials.  Exposure at the dose of 400 
mg/kg/wk in the 6-month monkey study supports the currently planned highest clinical Phase 2 
dose of 600 mg with a 224-fold multiple based on predicted human exposure (Table FCAB.3).
Table FCAB.3.
Exposure Multiples for Administration of LY3375880 Based on 
Administered Dose and Predicted Human Exposure
Species
Dose level
Dose 
(mg/kg)
Dose Multiple
Average Plasma 
Concentration 
(g/mL)a
Exposure 
Multipleb
Human Minimum Dosec
50 mg (SC) Q4W
0.71
7.2d
Monkey Maximum Dosee
200 mg/kg (IV) BIW
400
563×
22813f
3168×
Human Maximum Dosec
600 mg (SC) Q4W
8.6
102d
Monkey Maximum Dosee
200 mg/kg (IV) BIW
400
47×
22813f
224×
Abbreviations:  AUC = area under the concentration versus time curve; BIW = twice per week; IV = intravenous; 
kg = kilogram; mg = milligram; mL = milliliters; Q4W = every 4 weeks SC = subcutaneous; g = microgram.
a
AUC value expressed as average plasma concentration to normalize for differences in dosing frequency.
b
Exposure multiple is the calculated average plasma concentration in animals, divided by the predicted average 
plasma concentration in humans.

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c
Assume human body weight = 70 kg.
d
Value from pharmacokinetic data from Study FCAA, obtained by dividing predicted steady state AUC(0-672hr)
values by 672 hours. At 50 mg, AUC(0-672hr) = 4810 µghr/mL; at 600 mg AUC(0-672hr) = 68700 µghr/mL.
e
Study 20125378.  At the dose of level 200 mg/kg, no adverse effects attributable to the pharmacology of 
LY3375880 were observed.
f
Value calculated as average of male and female steady-state AUC(0-96hr) (ghr/mL), divided by 96 hours.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
Study investigator(s) will review subject history and screening test results at Visit 1 and Visit 2 
to determine if the subject meets all inclusion and none of the exclusion criteria to qualify for 
randomization in the study.  All screening activities must be completed and reviewed before the 
subject is randomized.
6.1.
Inclusion Criteria
Informed Consent
[1]
Are at least 18 years of age at the time of informed consent.
Note:  Use local requirements to provide consent if the age of adulthood is 
defined as >18 years.
[2]
Are able to read, understand, and give documented informed consent.
Disease Characteristics
[3]
Have a diagnosis of AD at least 12 months prior to screening, as defined by 
the American Academy of Dermatology:  Guidelines of care for the 
management of AD; Section 1. Diagnosis and assessment of AD (see
Appendix 6).
[4]
Have moderate-to-severe AD, including all of the following:
a.
Eczema Area and Severity Index (EASI) score ≥16 at randomization 
(Visit 2).
b. IGA score of ≥3 at randomization (Visit 2).
c.
≥10% of body surface area (BSA) involvement at randomization 
(Visit 2).
[5]
Have a documented history provided by a physician and/or investigator of 
inadequate response to existing topical medications within 6 months 
preceding screening, or history of intolerance to topical therapy as defined by 
at least 1 of the following:
a.
Inability to achieve good disease control defined as mild disease or better 
(e.g., IGA ≤2) after use of at least a medium-potency topical 
corticosteroid (TCS) for at least 4 weeks, or for the maximum duration 
recommended by the product prescribing information (e.g., 14 days for 
super-potent TCS), whichever is shorter.  Topical corticosteroids may be 
used with or without topical calcineurin inhibitors (TCNIs).

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b. Subjects who failed systemic therapies intended to treat AD within 
6 months preceding screening, such as cyclosporine, methotrexate
(MTX), azathioprine, and mycophenolate mofetil (MMF), will also be 
considered as a surrogate for having inadequate response to topical 
therapy.
c.
Documented history of clinically significant adverse reactions with the 
use of TCS such as skin atrophy, allergic reactions, and systemic effects 
that in the opinion of the investigator outweigh the benefits of 
retreatment.
[6]
Have applied emollients daily for at least 14 days prior to randomization and 
agree to use emollients daily throughout the treatment period.
[7]
Are willing and able to undergo punch biopsies according to the Schedule of 
Activities (Section 2).
Other Subject Characteristics
[8]
Women of childbearing potential:
a.
Agree not to breastfeed from the start of screening until 120 days after 
the last dose of study drug, and must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative serum pregnancy test at 
the screening visit followed by a negative urine pregnancy test within 24 
hours prior to exposure.
AND
b. Must agree to either remain abstinent, if complete abstinence is their 
preferred and usual lifestyle, or remain in same-sex relationships, if part 
of their preferred and usual lifestyle, without sexual relationships with 
males.  Periodic abstinence (e.g., 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
c.
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 120 days after the last dose of study 
drug.

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
Two effective methods of contraception (such as male or female 
condoms with spermicide, diaphragms with spermicide, or cervical 
sponges) will be used. The subject may choose to use a double 
barrier method of contraception. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable 
method. Thus, each barrier method must include use of a spermicide. 
It should be noted that the use of male and female condoms as a 
double barrier method is not considered acceptable because of the 
high failure rate when these methods are combined.

Of note, 1 of the 2 methods of contraception may be a highly 
effective (<1% failure rate) method of contraception (such as 
combination oral contraceptives, implanted contraceptives, or 
intrauterine devices).
[9]
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:

a woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either
o
cessation of menses for at least 1 year or
o
at least 6 months of spontaneous amenorrhea (or longer if 
required by local regulatory requirements) with a 
follicle-stimulating hormone level >40 mIU/mL; or

a woman 55 years or older not on hormone therapy, who has had 
at least 6 months of spontaneous amenorrhea; or

a woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy.
[10] Men, regardless of their fertility status, with nonpregnant women partners of 
childbearing potential must agree to either remain abstinent (if that is their 
preferred and usual lifestyle) or use condoms as well as 1 additional highly 
effective (<1% failure rate) method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) or effective 
method of contraception (such as diaphragms with spermicide or cervical 
sponges) for the duration of the study and until their plasma concentrations are 
below the level that could result in a relevant potential exposure to a possible 
fetus (predicted to be 120 days following the last dose of study drug).

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
Men and their partners may choose to use a double–barrier method of 
contraception. (Barrier protection methods without concomitant use of a 
spermicide are not an effective or acceptable method of contraception. 
Thus, each barrier method must include use of a spermicide. It should be 
noted, however, 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 barrier methods are combined.)

Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence just for the duration of 
a trial, and withdrawal are not acceptable methods of contraception.

Men with pregnant partners should use condoms during intercourse for 
the duration of the study and until the end of estimated relevant potential 
exposure in women of childbearing potential (120 days following last 
dose of study drug).

Men should refrain from sperm donation for the duration of the study and 
until their plasma concentrations are below the level that could result in a 
relevant potential exposure to a possible fetus (predicted to be 120 days 
following the last dose of study drug).

Men who are in exclusively same-sex relationships (as their preferred and 
usual lifestyle) are not required to use contraception.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria within 
the screening period, unless specifically defined otherwise.
Medical Conditions Related to AD
[11] Have received any of the following therapies within the time frames specified 
below:
a.
Topical treatments:
Topical corticosteroids or topical immune modulators (e.g., 
tacrolimus or pimecrolimus) within 2 weeks prior to randomization 
(Visit 2) and throughout the study.
Topical phosphodiesterase type 4 (PDE-4) inhibitor (crisaborole)
within 2 weeks prior to randomization (Visit 2) and throughout the 
study.
b. Systemic treatments:

Systemic corticosteroids
Oral systemic corticosteroids within 4 weeks prior to 
randomization (Visit 2) and throughout the study.

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Parenteral corticosteroids administered by intramuscular, 
intra-articular, or IV injection within 2 weeks prior to study entry
(Visit 1) or within 6 weeks prior to planned randomization
(Visit 2) or are anticipated to require parenteral injection of 
corticosteroids during the study.
Note:  Intranasal or inhaled steroid use is allowed during the trial.

Other systemic treatments
Synthetic (oral) immunomodulators, including but not limited to
Janus kinase (JAK) inhibitors (e.g., tofacitinib, ruxolitinib), 
cyclosporine, MTX, MMF, and azathioprine within 4 weeks prior 
to randomization (Visit 2) and throughout the study.
Biologics: Any prior treatment with dupilumab, or an agent 
directly targeting IL-13 or IL-33 (marketed or investigational), is 
exclusionary. Other immunomodulating mAbs (e.g.,
ustekinumab, omalizumab, etc.) are prohibited within 5 half-lives 
prior to randomization and throughout the study.
Leukotriene inhibitors within 4 weeks prior to randomization 
(Visit 2) and throughout the study.
Any other systemic therapy used to treat AD or symptoms of AD 
(approved or off-label use) within 4 weeks prior to randomization, 
unless allowed as a concomitant therapy in Section 7.7.
c.
Phototherapy, including therapeutic phototherapy (psoralen plus 
ultraviolet-A, ultraviolet-B), excimer laser, as well as self-treatment 
with tanning beds within 4 weeks prior to randomization (Visit 2) and 
throughout the study.
[12] Are currently experiencing or have a history of other concomitant skin 
conditions (e.g., psoriasis or cutaneous lupus) that would interfere with 
evaluations of the effect of study medication on AD.
[13] Subjects who, in the opinion of the investigator, are currently experiencing or
have a history of erythrodermic, refractory, or unstable skin disease that 
requires frequent hospitalizations and/or IV treatment for skin infections that 
may interfere with participation in the study.
[14] A history of eczema herpeticum within 12 months prior to screening or a 
history of 2 or more episodes of eczema herpeticum in the past.
[15] Have any serious concomitant illness that is anticipated to require the use of
systemic corticosteroids or otherwise interfere with study participation or
require active frequent monitoring (e.g., unstable chronic asthma).
Diagnostic Assessments
[16] Have any of the following specific abnormalities on screening laboratory 
tests:

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a.
Serum creatinine, aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) ≥2x upper limit of normal (ULN)
b. alkaline phosphatase (ALP) ≥2x ULN
c.
total bilirubin (TBL) ≥1.5x ULN
d. hemoglobin <10.0 g/dL (<100.0 g/L)
e.
total white blood cell count <2500 cells/L (<2.50x103/L or 
<2.50 GI/L)
f.
neutropenia (absolute neutrophil count <1200 cells/L) (<1.20x103/L or 
<1.20 GI/L)
g. lymphopenia (lymphocyte count <750 cells/L) (<0.75x103/L or 
<0.75 GI/L)
h. thrombocytopenia (platelets <100,000/L) (<100x103/L or <100 GI/L)
Note:  For each aforementioned test, a single repeat analysis is allowed during 
screening, and values resulting from repeat testing may be accepted for 
enrollment eligibility if they meet the eligibility criterion.
Infectious Disease Exclusion Criteria
[17] Have any history or evidence of active tuberculosis (TB) disease as 
determined on the basis of a positive medical history, physical examination, or 
chest radiography (per local standard of care), and regardless of previous or 
current TB treatments; or are diagnosed with latent tuberculosis infection 
(LTBI) at screening, defined as:

a positive tuberculin skin test (TST, also called a purified protein 
derivative [PPD] or Mantoux test) result (skin induration ≥5mm) at 48 to 
72 hours after the test date, or 

a positive interferon-gamma release assay (IGRA, e.g., QuantiFERON®-
TB Gold or T-Spot®.TB).
If the QuantiFERON-TB Gold is indeterminate or the T-Spot®.TB is invalid 
or borderline, 1 retest is allowed according to investigator judgment. Subjects 
with 2 indeterminate QuantiFERON-TB Gold or 2 invalid or borderline T-
Spot®. TB assays are excluded, unless they complete appropriate therapy for 
LTBI (defined as below).

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Subjects diagnosed with LTBI at screening may be rescreened once and 
enrolled if they have received at least 4 weeks of appropriate ongoing 
prophylactic therapy for LTBI (i.e., according to WHO or US Centers for 
Disease Control and Prevention LTBI treatment guidelines), meet all other 
inclusion and exclusion criteria for participation, and also continue and 
complete appropriate LTBI therapy during the course of the study to remain 
eligible for participation in the study. The choice to perform either a TST or 
an IGRA test must be made by the investigator according to local licensing 
and standard of care. Interferon-gamma release assay test is a preferred 
method in subjects with a history of Bacillus Calmette–Guérin (BCG) 
vaccination, given the rate of false-positive TST results in this population.
Subjects who have a documented history of completing an appropriate TB 
treatment regimen for LTBI and with no risk of re-exposure since their 
treatments were completed are eligible to participate in the study if they meet 
all other inclusion and exclusion criteria for participation. These subjects 
should not undergo TST or IGRA testing unless advised to do so based on 
local guidelines.
Subjects with documentation of a “negative” IGRA or TST testing within 3 
months before initial screening may not need to repeat TB testing at 
screening, based on judgment of the investigator. Source documentation must 
include the original laboratory report for IGRA or a record to size in 
millimeters of the induration response (for TST). A TST recorded as 
“negative” without documenting the size of induration in millimeters will not 
be acceptable and will require a retest.
[18] Have known hepatitis B or test positive for hepatitis B virus (HBV) at 
screening, defined as:  (1) positive for hepatitis B surface antigen (HBsAg+) 
or (2) positive for hepatitis B core antibody (HBcAb+) and positive 
confirmatory polymerase chain reaction (PCR) for HBV deoxyribonucleic 
acid (DNA), regardless of hepatitis B surface antibody status or (3) for sites in 
Japan only, positive for HBcAb and/or positive for anti-hepatitis B surface 
antibody (HBsAb), and a confirmatory PCR for HBV DNA.
Subjects whose results are HBcAb positive (and/or HBsAb positive in Japan)
and HBV DNA negative may be eligible to continue screening, according to
investigator judgment.  Such subjects will be monitored for HBV during the 
study as detailed in Section 9.4.8.
[19] Have known hepatitis C or test positive for hepatitis C virus (HCV) at 
screening, defined as a positive test result for hepatitis C virus antibody 
(anti-HCVAb) plus a positive confirmatory test result for HCV (e.g., HCV 
ribonucleic acid [RNA]).
Subjects whose results are anti-HCVAb positive and HCV RNA negative are 
eligible to continue screening, according to investigator judgment.

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Note:  Subjects who have documented anti-HCV treatment for a past HCV 
infection AND are HCV RNA negative are eligible to continue screening per 
investigator judgment.
[20] Have evidence of human immunodeficiency virus/acquired immune 
deficiency syndrome (HIV/AIDS) and/or test positive for HIV antibodies at 
screening.
[21] Have received a BCG vaccination within 12 months or received live/live
attenuated vaccine(s) within 3 months of baseline or intend to receive such 
during the study. Live/live attenuated vaccines should be avoided for at least 
5 drug half-lives after the last dose of study drug.
Note: Use of nonlive (inactivated) vaccinations are allowed for all subjects.
[22] History of an endoparasitic, opportunistic, chronic/recurring, or clinically 
serious infections (such as infections requiring IV antibiotics, hospitalization, 
or prolonged treatment) within 6 months prior to screening, or deemed by the 
investigator to be immunocompromised or at high risk of infectious 
complications (e.g., indwelling urinary catheter), such that participation in the 
study would pose an unacceptable risk to the subject. Refer to Appendix 5 for 
examples of opportunistic infections to consider.
[23] Active skin infection that requires treatment with topical OR systemic 
antibiotics within 4 weeks prior to randomization.
[24] Any other active infection treated with systemic anti-infectives within 4 weeks 
prior to randomization.
Note: Subjects with an active upper respiratory infection that is only being 
treated symptomatically and does not require anti-infectives may be 
considered for enrollment if other eligibility criteria are met.
[25] Have evidence of active/infectious herpes zoster infection ≤12 weeks prior to 
screening (herpes zoster lesions remain active until all vesicles are crusted 
over), or any history of disseminated/complicated herpes zoster (e.g., 
multidermatomal involvement, ophthalmic zoster, central nervous system, or 
other internal organ involvement).
Medical Conditions in General
[26] Are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden.
[27] Have significant allergies to humanized mAbs or any components of the 
LY3375880 product formulation.

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[28] Have an unstable or uncontrolled illness, including but not limited to 
cerebrocardiovascular (e.g., unstable angina, unstable arterial hypertension, 
moderate-to-severe heart failure [New York Heart Association Class III/IV]), 
respiratory, gastrointestinal, hepatic, renal, endocrine, hematologic, or 
neurologic disorders that would potentially affect subject safety within the 
study or confound efficacy and safety assessments.
[29] Have screening electrocardiogram (ECG) abnormalities that, in the opinion of 
the investigator, are clinically significant and indicate an unacceptable risk for 
the subject’s participation in the study.
[30] Have active malignancy or have been in remission from a malignancy for less 
than 5 years, with the following exceptions:
a.
Cervical carcinoma in situ that has been appropriately treated with no 
evidence of recurrence or metastatic disease for at least 3 years.
b. Basal cell or squamous epithelial carcinoma of the skin that has been 
appropriately treated with no evidence of recurrence for at least 3 years.
c.
In situ colon cancer or noninvasive malignant colon polyps that had been 
appropriately removed with no evidence of recurrence for at least 3 years.
[31] Presence of significant uncontrolled neuropsychiatric disorder or judged by 
the investigator to be at risk for suicide;
OR
marked “yes” to Columbia-Suicide Severity Rating Scale (C-SSRS) Question 
4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or 
Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the 
“Suicidal Ideation” portion
OR
marked “yes” to suicide-related behavior questions on the “Suicidal Behavior 
portion of the C-SSRS 
AND
the ideation or behavior occurred within the past 6 months prior to Visit 1 or 
anytime during the screening period prior to randomization.
Note:  A subject does not necessarily have to be excluded if they have 
self-injurious behavior that would be classified as nonsuicidal self-injurious 
behavior.  If this situation arises, the subject should be referred to a 
psychiatrist or appropriately trained professional as indicated.
[32] Have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug 
abuse within the 2 years prior to screening. Subjects who partake in legal 
marijuana use, whether recreational or medical, must agree to refrain from use 
during the study.

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[33] Have donated more than a single unit of blood within 4 weeks prior to 
screening or intend to donate blood during the course of the study.
Other Exclusions
[34] Are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures.
[35] Are currently enrolled in any other clinical trial involving an IP or any other 
type of medical research judged not to be scientifically or medically 
compatible with this study or have received any of the following IPs under the 
defined conditions:

any nonbiologic IP within 5 half-lives prior to screening

any biologic IP (not directly targeting IL-13 or IL-33) within 90 days or 5 
drug half-lives (whichever is longer) prior to screening.
[36] Have previously been randomized in this study or any other study 
investigating LY3375880.
[37] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[38] Are Eli Lilly and Company (Lilly) employees or their designee.
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Subjects who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once under certain circumstances (e.g., having previously failed criteria [4], 
[11], [16], [23], [24]) and with sponsor approval. Subjects may be rescreened once for 
administrative reasons (e.g., falling out of the screening window because of scheduling reasons).  
When rescreening is performed after being screen failed, the individual must sign a new 
informed consent form (ICF) and will be assigned a new identification number.  Subjects in 
rescreening who have previously completed screening chest radiography and/or TB tests 
according to the protocol do not need to repeat these procedures if they were performed within 
90 days before their rescreening date of consent but may do so at the discretion of the 
investigator. All other screening procedures must be conducted at rescreen to ensure all 
eligibility criteria are met.

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7.
Treatments
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
7.1.
Treatments Administered
The study involves a comparison of each LY3375880 dosing regimen (600 mg, 300 mg in 
Maintenance period, 150 mg, and 50 mg SC Q4W) with placebo.  Table FCAB.4 shows the 
treatment regimens. Subcutaneous LY3375880 should be administered as 3 to 4 injections 
(maximum volume: 2 mL per injection) preferably in the abdomen in separate quadrants,
whenever possible. All subjects should be monitored after dosing according to investigator 
practice or local standard of care.  Detailed instructions for IP administration will be provided 
separately by the sponsor.
Table FCAB.4.
Treatment Regimens
Treatment Name
LY3375880
Placebo
Dosage Formulation
LY3375880 for clinical trial use supplied 
as solution in vial, manufactured to contain 
200 mg/2 mL of LY3375880 (100 mg/mL)
0.9% Sodium chloride
Dosage Levels
600 mg SC Q4W,
300 mg SC Q4W (In Maintenance period 
only)
150 mg SC Q4W,
50 mg SC Q4W
NA
Route of Administration
SC injection(s)
SC injection(s)
Abbreviations:  NA = not applicable; Q4W = every 4 weeks; SC = subcutaneous.
The investigator or designee is responsible for:

explaining the correct use of the IP to the site personnel.

verifying that instructions are followed properly.

maintaining accurate records of IP dispensing and collection.

at the end of the study returning all unused medication to Lilly, or its designee, unless the 
sponsor and sites have agreed all unused medication is to be destroyed by the site, as 
allowed by local law.
7.1.1. Packaging and Labeling
Clinical study materials will be labeled according to the country’s regulatory requirements.
LY3375880 is supplied for clinical trial use as solution in vial with study-specific labels.  The 
2-mL vial is manufactured to contain 200 mg of LY3375880 (100 mg/mL).

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Commercially available 0.9% sodium chloride solution will be used as a placebo for this study.
When prepared for dosing according to instructions, it will not be possible to distinguish between 
LY3375880 and placebo.
Detailed instructions for the preparation and handling of LY3375880 will be provided by the 
sponsor.
The IP must be prepared by an unblinded site personnel qualified to prepare study drug who is 
not involved in any other study-related procedures to protect the blinding.
7.2.
Method of Treatment Assignment
Subjects who meet all criteria for enrollment will be randomized 1:1:1:1 to double-blind 
treatment at Visit 2.  Assignment to treatment groups will be determined by a 
computer-generated random sequence using an interactive web-response system (IWRS).  The 
IWRS will be used to assign packages containing double-blind IP to each subject.  Site personnel 
will confirm that they have located the correct packages by entering a confirmation number 
found on the packages into the IWRS.
To achieve between-group comparability, the randomization will be stratified by IGA (3 versus
4) and by geographic region (Japan versus non-Japan).
7.2.1. Selection and Timing of Doses
Study visits at which IP is administered are preferred, if possible, to occur on the same day of the 
week. In any case, the study visits should occur within the visit window specified on the 
Schedule of Activities (see Section 2). The actual time of all dose administrations will be 
recorded in the subject’s electronic case report form (eCRF).
7.3.
Blinding
The induction period of the study is double blind. The maintenance period of the study is double 
blind unless a subject has persistent disease activity defined as not achieving EASI-25 for 3 
consecutive scheduled maintenance period visits. In this circumstance, the subject is reassigned 
to 600 mg Q4W for the remainder of the study unless they were already on that regimen.
Therefore, the treatment regimen can be inferred in this scenario, but will not be considered as an 
unblinding event as described in procedures in this section.
To preserve the blinding of the study, the unblinded site personnel qualified to prepare study 
drug should not be involved in any study-related procedures, and a minimum number of Lilly 
personnel will have access to the randomization table and treatment assignments before the study 
is complete.
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 subject’s well-being requires knowledge of the subject’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS.

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If an investigator, site personnel performing assessments, or subject is unblinded, the subject
must be discontinued from the study.  In cases where there are ethical reasons to have the subject
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the subject to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
safety of the subject must always be the first consideration in making such a determination.  If a 
subject’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.
7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
IPs will be supplied by Lilly or its representative, in accordance with current good manufacturing 
practices, and will be supplied with lot numbers, expiry dates, and certificates of analysis, as 
applicable.
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).
Follow storage and handling instructions stated on the IP label. Detailed instructions regarding 
preparation and handling of IPs will be provided by the Sponsor.
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 subjects who have the ability to understand and comply 
with study instructions. The investigator is responsible for discussing methods to ensure high 
treatment compliance with the subject before randomization.

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If a subject is noncompliant with study procedures and/or IP administration, the investigator 
should assess the subject to determine the reason for noncompliance and educate and/or manage 
the subject, as appropriate, to improve compliance. Overall compliance with therapy is defined 
to be missing no more than 20% of the expected doses within the protocol-defined dosing 
interval and not missing 2 consecutive doses.  If, in consultation with Lilly or its designee, the 
noncompliance is deemed to be significant or if further noncompliance occurs, the subject may
be discontinued from the study.
7.7.
Concomitant Therapy
All concomitant medication, whether prescription or over the counter, used at baseline and/or
during the course of the study, must be recorded on the Concomitant Medication eCRF.  Subjects 
will be instructed to consult the investigator or other appropriate study personnel at the site 
before taking any new medications or supplements during the study.  For AD therapies permitted 
as part of rescue therapy, see Section 7.7.3.
7.7.1. Prohibited Medications and Procedures
The following therapies will not be allowed during the course of the study (Refer to Exclusion 
Criteria [11], [21], [23], [24], and [36] for details regarding washout periods for study 
eligibility):

Topical Treatments:  TCS, topical immune modulators (e.g., tacrolimus or 
pimecrolimus) or topical PDE-4 inhibitor (e.g., crisaborole) except when 
given as rescue therapy as described in Section 7.7.3.

Systemic corticosteroids:  oral or parenteral corticosteroids (intramuscular, 
intra-articular or IV) Note:  Intranasal or inhaled steroid use is allowed during 
the trial.

Other Systemic treatments:
o
Synthetic (oral) immunomodulators, including, but not limited to, JAK 
inhibitors (e.g. tofacitinib, ruxolitinib), cyclosporine, MTX, MMF, and 
azathioprine.
o
Biologics: Immunomodulating mAbs (including but not limited to
dupilumab, ustekinumab, omalizumab, etc.).
o
Leukotriene inhibitors

Phototherapy, including therapeutic phototherapy (psoralen ultraviolet-A, 
ultraviolet-B), excimer laser as well as self-treatment with tanning beds.

Any investigational therapy that is not LY3375880.

Bleach baths

Allergen immunotherapy.

Live vaccines.

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7.7.2. Permitted Medications
Treatment with concomitant AD therapies during the study is permitted only as described below:

Daily use of emollients is required as background treatment.  Moisturizers with 
additives such as antipruritics or antiseptics are not permitted.  If daily 
applications are missed, it will not be considered a protocol violation.

Oral and topical antihistamines including, but not limited to, diphenhydramine, 
hydroxyzine, acrivastine, bilastine, cetirizine, desloratadine, fexofenadine, 
levocetirizine, loratadine, mizolastine, and rupatadine are allowed.

Topical anesthetics
Note:  Subjects should not apply emollients or other topical treatments on the day of 
their study visit prior to the procedures to allow adequate assessment of skin dryness.
Any changes in concomitant medications must be recorded in the Concomitant Therapy of 
Special Interest eCRF.
7.7.3. Rescue Therapy
Rescue therapy is permitted starting at Week 8 for subjects who do not achieve an EASI-25
response. If the subject meets criteria, the decision to implement rescue is according to 
investigator judgment and is not a requirement. Rescue therapy should only be initiated at a visit 
at which an EASI-25 is not met. 
Choice of rescue therapy treatment

Triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment.  In the event where 
either of these topical formulations is not available, an alternate, equivalent potency TCS 
cream and/or ointment may be used.

Investigators may also select to use TCNIs and/or crisaborole where approved.  If TCNIs 
are prescribed, use should be limited to problem areas only (e.g., face, neck, skin folds, 
genital areas, etc.).

On the days of study visits, topical therapy should not be applied before the subject has 
undergone all study procedures and clinical evaluations in order to allow adequate 
assessment of skin dryness.

Subjects rescued to topical therapy will continue to take IP and use of rescue therapy will 
be documented in the eCRF.
In subjects who do not improve sufficiently with the prescribed provided rescue topical therapy
after 7 days, a higher potency TCS may be used and IP may continue.  It is recommended that if 
a subject reaches “clear” to “almost clear” skin after topical rescue, then medium- and/or 
high-potency TCS and TCNI should be stopped, and low–potency TCS (e.g., hydrocortisone 
2.5% ointment) should be used once daily for an additional 7 days, then stopped.  If lesions 
return, subjects can be retreated with TCS with or without TCNIs and/or crisaborole as before at 
the discretion of the investigator.

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If topical rescue therapy as described above fails to sufficiently control AD symptoms 
and if the investigator determines that a subject requires treatment with another 
therapeutic agent that has been demonstrated to be effective for treatment of AD but is 
contraindicated in this study, the subject should be discontinued from the study. In such 
cases, discontinuation from the study occurs prior to introduction of the new agent.
Note that subjects who receive rescue therapy during the induction period will be considered 
nonresponders for the primary analysis, but will undergo re-assignment/re-randomization at 
Week 16 based on EASI-50 response according to Section 5.1, and will not automatically be 
considered nonresponders for purposes of treatment assignment.
Investigators should make every attempt to conduct efficacy and safety assessments immediately 
before administering any rescue treatment. An unscheduled visit can be used for this purpose if 
necessary.
7.8.
Treatment after the End of the Study
Study drug is experimental and will be provided to study subjects only according to the protocol; 
it will not be made available to subjects after they have completed or discontinued from the study 
unless the subject qualifies to continue study drug in another protocol.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1.
Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP:

Subject Decision
o
the subject requests to discontinue IP.

Discontinuation due to a hepatic event or liver test abnormality: Subjects who are 
discontinued from IP due to a hepatic event or liver test abnormality should have 
additional hepatic safety data collected via designated data transmission methods.
Discontinuation of the IP for abnormal liver tests should be considered by the 
investigator when a subject meets one of the following conditions after consultation with 
the Lilly-designated medical monitor:
o
ALT or AST >8x upper ULN
o
ALT or AST >5x ULN for more than 2 weeks.
o
ALT or AST >3x ULN and TBL level >2x ULN or international 
normalized ratio (INR) >1.5.
o
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).
o
ALP >3x ULN
o
ALP >2.5x ULN and TBL >2x ULN
o
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

Discontinuation due to HBV DNA results
o
Subjects who are HBcAb positive (and/or HBsAb positive in Japan) at 
screening and are enrolled in the study will be discontinued from the IP if 
the result of the HBV DNA testing becomes detectable at any time during 
the study.
Subjects who discontinue the IP early will continue in the study according to the Schedule of 
Activities (Section 2), unless there is a reason to discontinue from the study (Section 8.2).
8.1.2.
Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor’s medical monitor and the 
investigator to determine if the subject may continue in the study.  If the investigator and the 
sponsor CRP agree that it is medically appropriate to continue, the investigator must obtain 

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documented approval from the sponsor CRP to allow the inadvertently enrolled subject to 
continue in the study with or without treatment with IP. Safety follow-up is as outlined in 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this 
protocol.
8.2.
Discontinuation from the Study
Subjects may choose to withdraw from the study for any reason at any time, and the reason for 
early withdrawal will be documented.
Some possible reasons that may lead to permanent discontinuation include the following:

enrollment in any other clinical study involving an IP or enrollment in any other 
type of medical research judged not to be scientifically or medically compatible 
with this study.

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and Good Clinical 
Practice (GCP).

investigator decision
o
The investigator decides that the subject should be discontinued from the 
study.
o
If the subject, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of 
the new agent.

Subject decision
o
The subject requests to be withdrawn from the study.
Subjects 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 subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1.
Primary Efficacy Assessments
9.1.1.1.
Validated Investigator’s Global Assessment for AD (vIGA-AD)
The IGA used in this study, the vIGA-AD (referred to as the IGA throughout the protocol) 
measures the investigator’s global assessment of the subject’s overall severity of their AD, based 
on a static, numeric 5-point scale from 0 (clear skin) to 4 (severe disease). The score is based on 
an overall assessment of the degree of erythema, papulation/induration, oozing/crusting, and 
lichenification.
9.1.2.
Secondary Efficacy Assessments
9.1.2.1.
Eczema Area and Severity Index Scores
The EASI assesses extent of disease at 4 body regions and measures 4 clinical signs:  
(1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification each on a scale of 
0 to 3.  The EASI confers a maximum score of 72.  The EASI evaluates 2 dimensions of AD:  
disease extent and clinical signs (Hanifin et al. 2001).
Body surface area affected by AD will be derived from data collected as part of the EASI 
assessment.
9.1.2.2.
SCORing AD
The SCORing AD (SCORAD) index uses the rule of nines to assess disease extent and evaluates 
6 clinical characteristics to determine disease severity:  (1) erythema, (2) edema/papulation, 
(3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness.  The SCORAD index also 
assesses subjective symptoms of pruritus and sleep loss.  These 3 aspects:  extent of disease, 
disease severity, and subjective symptoms combine to give a maximum possible score of 103 
(Stalder et al. 1993; Kunz et al. 1997; Schram et al. 2012).
9.1.3. Health Outcomes and Quality-of-Life Measures
The subject self-reported questionnaires will be administered via either an electronic subject
diary or via an electronic tablet and in countries where the questionnaires have been translated 
into the native language of the region and linguistically validated.

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9.1.3.1.
Patient-Oriented Eczema Measure
The Patient-Oriented Eczema Measure (POEM) is a simple, 7-item, patient-administered scale 
that assesses disease severity in children and adults.  Subjects respond to questions about the 
frequency of 7 symptoms (itching, sleep disturbance, bleeding, weeping/oozing, cracking, 
flaking, and dryness/roughness) over the last week.  Response categories include “No days,” 
“1-2 days,” “3-4 days,” “5-6 days,” and “Every day,” with corresponding scores of 0, 1, 2, 3, and 
4, respectively.  Scores range from 0 to 28, with higher total scores indicating greater disease 
severity (Charman et al. 2004).
9.1.3.2.
Itch Numeric Rating Scale
The Itch Numeric Rating Scale (NRS) is a patient-administered, 11-point horizontal scale 
anchored at 0 and 10, with 0 representing “no itch” and 10 representing the “worst itch 
imaginable.”  Overall severity of a subject’s itching is indicated by selecting the number that best 
describes the worst level of itching in the past 24 hours (Naegeli et al. 2015; Kimball et al. 2016).
9.1.3.3.
Skin Pain Numeric Rating Scale
Skin Pain NRS is a subject-administered, 11-point horizontal scale anchored at 0 and 10, with 
0 representing “no pain” and 10 representing the “worst pain imaginable.”  Overall severity of a 
subject’s skin pain is indicated by selecting the number that best describes the worst level of skin 
pain in the past 24 hours.
9.1.3.4.
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a simple, patient-administered, 10-item, 
validated, quality-of-life (QoL) questionnaire that covers 6 domains including symptoms and 
feelings, daily activities, leisure, work and school, personal relationships, and treatment.  The 
recall period of this scale is over the “last week.”  Response categories include “not at all,” “a 
lot,” and “very much,” with corresponding scores of 1, 2, and 3, respectively, and unanswered 
(“not relevant”) responses scored as 0.  Scores range from 0 to 30, with higher scores indicating 
greater impairment of QoL.  A DLQI total score of 0 to 1 is considered as having no effect on a 
subject’s health-related QoL (Hongbo et al. 2005), and a 4-point change from baseline is 
considered as the minimal clinically important difference threshold (Khilji et al. 2002; Basra et 
al. 2015).
9.1.4.
Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant except Skin Pain NRS, which is currently being developed and 
validated according to regulatory guidances.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.

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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 IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs.  Investigators should record their assessment of the 
potential relatedness of each AE to IP, 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 IP, study device, and/or study procedure and the AE.  
The investigator answers “yes/no” when making this assessment.  The investigator will record all 
relevant AE and SAE information in the eCRF.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a subject’s IP 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 1 of the following outcomes:

death

initial or prolonged insubject hospitalization

a life-threatening experience (i.e., immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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
important medical events that may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in insubject 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 subject has signed the ICF and has 
received IP.  However, if an SAE occurs after signing the ICF, but prior to receiving IP, the SAE 
should be reported to the sponsor as per SAE reporting requirements and timelines 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.  Subjects with a serious hepatic AE should have additional data collected using the 
hepatic safety eCRF.
Pregnancy (during maternal or paternal exposure to IP) 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 subjects once they have 
discontinued and/or completed the study (the subject disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or 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 IP 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
Injection site reactions and allergic/hypersensitivity reactions are AEs of special interest. In the 
event of an injection site reaction or allergic/hypersensitivity reaction, additional questions will
be triggered in the eCRF to provide further details regarding the reaction.

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In the event of anaphylaxis or generalized urticaria, additional laboratory samples should be 
collected after the subject has been stabilized (ideally 1 to 2 hours, and no more than 12 hours
after the event), whenever possible. Follow-up samples should be obtained at the next scheduled 
visit or after 4 weeks, whichever is later. Specific instructions for the collection and handling of 
samples will be provided by the sponsor.
9.2.3.
Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical studies to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP 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 clinically indicated.  There is no known antidote 
for LY3375880.
9.4.
Safety
Any clinically significant findings from ECG testing, physical examination, vital signs 
measurements, or laboratory measurements that result in a diagnosis and that occur after the 
subject receives the first dose of study treatment should be reported to Lilly or its designee as an 
AE via eCRF.
9.4.1.
Electrocardiograms
A single 12-lead standard ECG will be obtained locally at Visit 1 and read by a qualified 
physician (the investigator or qualified designee) at the site to determine whether the subject
meets entry criteria.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.
9.4.2.
Vital Signs
For each subject, vital signs should be measured according to the Schedule of Activities 
(Section 2).
9.4.3.
Physical Exam
For each subject, a complete physical examination (excluding pelvic and rectal examinations
unless clinically indicated) will be performed at Visit 1 (Screening).  A symptom-directed 
physical examination may be performed at other visits as specified in the Schedule of Activities 
(Section 2) as clinically indicated.

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9.4.4.
Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  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.
9.4.5.
Columbia Suicide Severity Rating Scale
The C-SSRS captures the occurrence, severity, and frequency of suicidal ideation and/or 
behavior during the assessment period.  The scale includes suggested questions to solicit the type 
of information needed to determine if suicidal ideation and/or behavior occurred.  The C-SSRS is 
administered by appropriately trained site personnel.  The tool was developed by the National 
Institute of Mental Health 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.
The nonleading AE collection should occur prior to the collection of the C-SSRS.  If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.  If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed.
9.4.6.
Self-Harm Supplement and Follow-Up Forms
Suicide-related events (behavior and/or ideations) will be assessed and evaluated with each
administration of the C-SSRS.  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.  If the number of behavioral events is greater than zero, it will lead to the completion 
of the self-harm follow-up form.  The Self-Harm Follow-up form is a series of questions that 
provides a more detailed description of the behavior cases.
9.4.7.
Chest X-ray and Tuberculosis Testing
Posteroanterior and lateral chest radiography will be performed at screening for all subjects 
unless these have been obtained within 90 days prior to initial screening and the radiographs or 
report is available for investigator review.  Variations on the chest radiography view 
requirements will only be permitted if the country/local guidelines of care for standard TB 
screening differ from these protocol specifications.
All subjects will undergo a TB test at screening (TST or interferon release test).  Refer to 
Exclusion Criterion [17] for details regarding TB testing.
See Section 6.4 for subjects who are rescreening for this study and have undergone radiography 
and/or TB testing as part of their initial screening.

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9.4.8.
Hepatitis B Virus DNA Monitoring
Subjects whose results are HBsAg negative and HBcAb positive (and/or HBsAb positive in 
Japan) at screening, will have an HBV DNA test performed by the central laboratory.  Subjects 
whose results are HBV DNA negative (undetectable) may be enrolled into the study, according 
to investigator judgment, with HBV DNA monitoring as detailed in the Schedule of Activities 
(Section 2). If the result of the HBV DNA testing becomes positive at any time during the study, 
the subject will be permanently discontinued from IP (see Section 8.1) and should receive 
appropriate follow-up medical care, including consideration for antiviral therapy.  A specialist 
physician in the care of subjects with hepatitis (for example, infectious disease physician or 
hepatologist) should be consulted.  The timing of discontinuation from the study drug and any 
other immunosuppressant therapy should be based on the recommendations of the consulting 
specialist physician in conjunction with the investigator and medical guidelines/standard of care.
9.4.9.
Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against the LY3375880.  To interpret the 
results of immunogenicity, a PK sample will be collected at the same time points as the 
immunogenicity sample. All samples for immunogenicity should be taken predose.  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.  
In addition, subjects who were deemed responders at Week 16 may be prompted to collect an 
immunogenicity sample at the first scheduled visit where loss of response is observed (i.e., 
EASI-25 was not achieved) in the maintenance period. This will allow an evaluation of ADA 
status at the time of retreatment for subjects randomized to placebo until loss of response during 
the maintenance period. To prevent unblinding of treatment regimen, all subjects who are 
deemed responders at Week 16 will have PK and immunogenicity collected upon loss of 
response.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
the LY3375880 at a laboratory approved by the sponsor.  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of LY3375880.
Treatment-emergent ADA positive (TE ADA+) are defined in Section 10.2.6.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
LY3375880.  Any samples remaining after 15 years will be destroyed.
9.4.10. 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 

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unblinding at the group level, members of an internal assessment committee can view unblinded 
data and conduct additional analyses of the unblinded safety data. The internal assessment 
committee is composed of personnel who do not have direct site contact or data entry/validation 
responsibilities. Details are specified in the statistical analysis plan (SAP). In addition, the 
Safety Internal Review Committee and the Global Subject Safety expedited reporting team can 
also unblind at the individual SAE case level, when appropriate.
9.4.10.1. Hepatic Safety Monitoring
If a study subject experiences elevated ALT ≥3x ULN, ALP ≥2x ULN, or elevated TBL 
≥2x ULN, liver testing 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.
Discontinuation criteria of IPs, either temporary interruption or permanent discontinuation, due 
to abnormal ALT, AST, TBL, or ALP, are detailed in Section 8.
Hepatic Safety Data Collection
Additional safety data should be collected via the hepatic eCRF if 1 or more of the following 
conditions occur:

elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2x ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE.
See Appendix 4 for a description of selected tests that may be obtained in the event of a 
treatment-emergent hepatic abnormality.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 4 mL each will be collected to determine the plasma concentrations of 
LY3375880. The actual date and time (24-hour clock time) of each dose and PK sampling blood 
draw will be recorded. It is essential that the actual times of dosing and sampling are recorded 
accurately. In addition, subjects who were deemed responders at Week 16 may be prompted to 
collect a PK sample at the first scheduled where loss of response is observed (i.e., EASI-25 was 
not achieved) in the maintenance period. This will support the evaluation of ADA status at the 
time of retreatment for subjects randomized to placebo until loss of response during the 
maintenance period.  To prevent unblinding of treatment regimen, all subjects who are deemed 
responders at Week 16 will have PK and immunogenicity collected upon loss of response.

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In addition to the planned PK sampling as described, a maximum of 2 samples may be collected
at additional time points during the study if warranted and agreed upon between both the 
investigator and sponsor.  Instructions for the collection and handling of blood samples will be 
provided by the sponsor.  The actual date and time [24-hour clock time] of each sampling will be 
recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure IP concentration will be retained for a maximum of 
1 year following the last subject visit for the study.
9.6.
Pharmacodynamics
Samples collected (as specified in the schedule of activities) to measure TARC, Periostin, IL-19
will be identified by the subject number (coded) and retained at a facility selected by Lilly or its 
designee for a maximum of 1 year following the last subject visit for the study at a facility 
selected by Lilly or its designee.
9.7.
Pharmacogenomics
9.7.1.
Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3375880 and to 
investigate genetic variants thought to play a role in AD or associated diseases.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last subject visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards impose shorter time limits.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of LY3375880 or after LY3375880
becomes commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.

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9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics (PD), mechanism of action, variability of subject response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules including DNA, 
RNA, proteins, lipids, and other cellular elements.
Samples for biomarker research (serum, plasma, whole blood RNA, whole blood for epigenetics, 
and skin biopsies for mRNA expression profiling and immunohistochemistry) will be collected 
at the times specified in the Schedule of Activities (Section 2) where local regulations allow.
Blood samples for nonpharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3375880, pathways associated with AD or associated diseases, mechanism of action of 
LY3375880, and/or research method or in validating diagnostic tools or assay(s) related to AD or 
associated diseases.
Skin biopsy samples from AD lesions and adjacent nonlesional tissue will be collected and used 
to study biomarkers related to AD and/or related to the mechanism of action of LY3375880. 
Techniques used may include but are not limited to immunohistochemistry and microarray 
expression profiling. Samples may be used for exploratory microarray expression profiling or 
transcriptome sequencing. Detailed instructions for sample collection and handling will be 
provided by the sponsor. Samples will be sent to a sponsor-designated laboratory for
immunohistochemistry.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last subject visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3375880 or after LY3375880 becomes commercially available.
9.9.
Medical Resource Utilization and Health Economics
Health Economics and Medical Resource Utilization parameters will not be evaluated in this 
study.

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10.
Statistical Considerations
Approximately 200 subjects will be randomized at a 1:1:1:1 ratio in the blinded induction dosing 
period to LY3375880 50 mg, 150 mg, 600 mg, and placebo (50 subjects per dosing regimen). 
Assuming 36% and 8% of subjects achieve an IGA score of 0 or 1 (clear or almost clear skin) 
and ≥2-point improvement from baseline at Week 16 for LY3375880 and placebo, respectively, 
pairwise comparisons to placebo have at least 90% power using a 2-sided Fisher’s exact test at 
the 0.05 significance level, with no adjustment for multiple comparisons.
10.1. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign informed consent.
Safety
All randomized participants who take at least 1 dose of their assigned 
double-blind study treatment. Participants will be included in the treatment
group they were randomized to.
Intent-to-Treat (ITT)
All randomized subjects, even if the subject does not take the assigned 
treatment, does not receive the correct treatment, or otherwise does not follow 
the protocol.
Maintenance Period
All ITT subjects who received at least 1 dose of study treatment and have 
entered the maintenance period at Week 16 (Visit 8).
10.2. Statistical Analyses
10.2.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  A detailed 
SAP describing the statistical methodologies will be developed by Lilly or its designee.
Efficacy analyses will be conducted on the intent-to-treat (ITT) population.  This set includes all 
randomized subjects, even if the subject does not take the assigned treatment, does not receive 
the correct treatment, or otherwise does not follow the protocol.
Safety analyses will be conducted on the safety population.  This set includes all data from all 
randomized subjects receiving at least 1 dose of the IP according to the treatment to which the
subjects were randomized.
When reported, descriptive statistics will include the number of subjects, mean, standard 
deviation, median, minimum, and maximum for continuous measures, and frequency counts and 
percentages for categorical measures.
Treatment comparisons of discrete efficacy variables between LY3375880 and placebo will be 
made using a logistic regression analysis with treatment, baseline disease severity (IGA 3 versus
4), geographic region, and, if applicable, baseline scores (such as baseline EASI score for a 
comparison of EASI-75) in the model.  The percentages, difference in percentages, and 95% 
confidence interval (CI) of the difference in percentages will be reported.  Treatment-by-region
interaction will be added to the logistic regression model of the primary and key secondary 

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variables as a sensitivity analysis.  If this interaction is significant at a 2-sided 0.1 level, further 
inspection will be used to assess whether the interaction is quantitative (i.e., the treatment effect 
is consistent in direction but not size of effect) or qualitative (the treatment is beneficial for some 
but not all regions).
When evaluating continuous measures over time, a restricted maximum likelihood-based 
mixed-effects model of repeated measures (MMRM) will be used.  The model will include 
treatment, baseline disease severity, geographic region, visit, and treatment-by-visit interaction 
as fixed categorical effects and, if a baseline score for the measure is available, baseline score 
and baseline score-by-visit interaction as fixed continuous effects.  An unstructured (co)variance 
structure will be used to model the between- and within-subject errors.  If this analysis fails to 
converge, other structures will be tested.  The Kenward–Roger method will be used to estimate 
the degrees of freedom.  Type III sums of squares for the least squares means will be used for the 
statistical comparison; 95% CI will also be reported.  Contrasts will be set up within the model to 
test treatment groups at specific time points of interest.  Further details on the use of MMRM 
will be described in the SAP.
Fisher’s exact test will be used for the AEs, discontinuation, and other categorical safety data for 
between-treatment group comparisons.  Continuous vital signs and other continuous safety 
variables including laboratory variables will be analyzed by an analysis of covariance with 
treatment and baseline value in the model.
The Kaplan–Meier product limit method will be used to estimate the survival curves for 
time-to-event variables.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05 with no control 
for multiple comparisons, unless otherwise stated.
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.
10.2.1.1. Missing Data Imputation

Nonresponder imputation (NRI):  All subjects who discontinue the study or the study 
treatment at any time for any reason will be defined as nonresponders for the analysis of 
categorical efficacy variables at discontinuation and subsequent visits.  Subjects who 
receive rescue therapy will be analyzed as nonresponders at rescue and subsequent visits.

MMRM:  Continuous variables will be assumed to be missing after rescue or 
discontinuation for which an MMRM analysis will be performed.

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10.2.1.2. Maintenance Period Considerations
For maintenance period efficacy measures, unless otherwise stated, baseline will be the last 
available value before the initial randomization in the induction period, which in most cases will 
be the value recorded at Week 0 (Visit 2).
For maintenance period safety measures, unless otherwise stated, baseline will be the last 
available value before the initial dose in the maintenance period, which in most cases will be the 
value recorded at Week 16. Additional information on baseline for efficacy and safety analyses 
will be available in the SAP.
Maintenance phase analyses are exploratory; therefore, only descriptive statistics will be 
provided.  Change from baseline and 95% CI will be calculated by treatment for continuous 
variables. The proportion and 95% CI will be reported by treatment for categorical variables.
Additional sensitivity analyses for the primary and key secondary endpoints may be done and 
will be specified in the SAP.
10.2.2. Treatment Group Comparability
10.2.2.1. Subject Disposition
All subjects who discontinue from the study or the study treatment will be identified, along with 
their reason for discontinuation.  Reasons for discontinuation from the study will be summarized 
by treatment group.
10.2.2.2. Subject Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Descriptive statistics including number of subjects, mean, standard deviation, median, minimum, 
and maximum will be provided for continuous measures, and frequency counts and percentages 
will be tabulated for categorical measures.
10.2.2.3. Concomitant Therapy
Concomitant medications will be summarized for subjects who enter each treatment period and 
will be presented by anatomical therapeutic chemical drug classes using the latest version of the 
WHO drug dictionary.
10.2.2.4. Treatment Compliance
Treatment compliance with IP will be summarized for subjects who enter the Induction and 
Maintenance periods.  A subject will be considered as having missed the visit if he or she fails to 
attend for administration of the IP within the required treatment window as defined in the 
Schedule of Activities (Section 2).  Overall compliance with therapy is defined to be missing no 
more than 20% of the expected doses within the protocol-defined dosing interval and not missing 
2 consecutive doses.  The proportion of subjects who demonstrate overall compliance during the 
Induction Period will be compared between treatment groups using Fisher’s exact test.

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10.2.3. Efficacy Analyses
10.2.3.1. Primary Analyses
The primary efficacy measure is the binary outcome of response defined as IGA score of 0 or 1 
(clear or almost clear skin) and ≥2-point improvement from baseline at Week 16.  Primary 
analysis will be conducted using the previously described logistic regression model.
10.2.3.2. Secondary Analyses
The previously described logistic regression model will be used to analyze the proportion of 
subjects achieving the following:

IGA of 0 at Week 16

EASI-50, EASI-75, and EASI-90 at Week 16, where EASI-75 and EASI-90 are
defined as having an improvement of at least 75% and 90% from baseline, 
respectively.

SCORAD75 and SCORAD90 at Week 16, where SCORAD75 and SCORAD90 
are defined as having an improvement of at least 75% and 90% from baseline, 
respectively.

IGA of 0 or 1 at Week 52
The previously described MMRM model will be used to analyze mean change from baseline for:

EASI score

SCORAD score
10.2.3.3. Exploratory Analyses
Improvement in signs and symptoms, health outcome measures, and QoL measures (total scores, 
item scores, and derivations) at each time point collected (induction and maintenance) will be 
summarized using descriptive statistics and the previously described models for discrete and 
continuous endpoints.  The Kaplan–Meier product limit method will be used to estimate the 
survival curves for time-to-event variables such as loss of response and maintenance of response.
10.2.4. Safety Analyses
All safety data will be descriptively summarized for the safety population by treatment group and 
analyzed using the methods described in Section 10.2.1.
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 IP. A TEAE is 
defined as an event that first occurred or worsened in severity after baseline. For each event 
classification term, the number of subjects experiencing a TEAE with that classification term 
will be tabulated.
Treatment-related TEAEs are defined as events that are indicated by the investigator on the 
eCRF to be related to treatment. For events that are gender specific, the denominator and 
computation of the percentage will include only subjects from the given gender.

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10.2.5. Pharmacokinetic/Pharmacodynamic Analyses
Analyses of PK/PD data will be performed using a nonlinear mixed-effect modeling approach as 
implemented in NONMEM software on a computer that meets or exceeds the minimum system 
requirements for this program. It is possible that other validated equivalent software programs 
may be used if appropriate. The version of any software used for the analysis will be 
documented. Population PK analyses will be performed to characterize the PK of LY3375880.  
These analyses will include model-based and graphical evaluations of the data. Estimates of PK 
model parameters and covariate effects and corresponding 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 for categorical clinical 
endpoints (e.g., IGA, EASI, etc.) may consist of graphs showing the percentage of subjects that 
achieve the clinical endpoint at different percentiles (e.g., quartiles) of exposure of LY3375880 
at Week 16. Measures of exposure may include population PK estimated average steady-state 
concentrations (Css, avg) or observed trough concentrations at the time of the clinical endpoint.  
Model-based analyses of the categorical clinical endpoints will utilize population exposure–
response logistic regression models, where maximum effect (Emax) or other model structures may 
be used to relate exposure to the probability of achieving the endpoint. These models may be 
used to evaluate subject factors that may impact the relationship between exposure and the 
probability of achieving the endpoint. Longitudinal exposure–response models for EASI scores 
or response rates may be developed, which relate the time course and magnitude of LY3375880 
exposure to the time course and magnitude of EASI response.
Exploratory analyses examining the relationships between LY3375880 exposure and PD 
biomarker responses may be conducted. Additional analyses may be conducted if they are 
deemed appropriate. Further details on PK and PK/PD analyses will be provided in the PK/PD 
analysis plan.
10.2.6. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE ADA+ to 
LY3375880 will be tabulated. TE ADA+ are defined as those with a titer 2-fold (1 dilution) 
greater than the minimum required dilution if no ADA were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADA were detected at baseline (treatment-boosted ADA). For the TE ADA+ subjects, 
time to first TE ADA+ result, distribution of maximum titers, and titer evolution over time will 
be described. The frequency of neutralizing antibodies will be tabulated in TE ADA+ subjects.  
The relationship between the presence of antibodies to LY3375880, IL-33 target engagement, 
PK parameters, efficacy, and safety parameters will be assessed, as well as the potential impact 
of rechallenge on ADA responses.

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10.2.7. Other Analyses
10.2.7.1. Health Economics
The health outcome measures will be analyzed using methods described for continuous or 
categorical data as described for efficacy measures in Section 9.1. 
10.2.7.2. Subgroup Analyses
Subgroup analyses will be conducted for the primary endpoint defined as IGA score of 0 or 1 
(clear or almost clear skin) and ≥2-point improvement from baseline at Week 16 using NRI for 
the ITT Population. Subgroups to be evaluated may include region, age, sex, race, baseline IgE 
levels, baseline levels of type II immune response analytes, etc.
A logistic regression model with treatment, subgroup, and the interaction of 
subgroup-by-treatment included as factors will be used. The subgroup-by-treatment interaction 
will be tested at the significance level of 0.10. If the interaction is statistically significant at =
0.10, the nature of the interaction will be explored.
Definitions for the levels of the subgroup variables, the analysis methodology, and any additional 
subgroup analyses will be defined in the SAP. This study is not powered for subgroup analyses; 
therefore, all subgroup analyses will be treated as exploratory.
10.2.8. Interim Analyses
Analysis for the primary database lock will be conducted when all patients have completed the 
induction phase (or discontinued induction treatment).  At least 1 interim analysis prior to 
analysis for the primary database lock will be conducted when approximately 40% to 60% 
patients have completed the induction phase (or discontinued induction treatment). All interim 
analyses will be used to support planning activities associated with the development program and 
to aid development of PK/PD modeling. No adjustment of Type I error will be performed.
The assessment will be conducted by an internal assessment committee with a limited number of 
prespecified team members who do not have direct site contact or data entry/validation 
responsibilities. 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. To minimize bias, the SAP and PK/PD analysis plan will be finalized and approved 
before unblinding. Unblinding details are specified in the SAP. Information that may unblind 
the study during the analyses will not be reported to study sites or the blinded study team until 
the study has been unblinded.
Ongoing monitoring of safety data (including AEs, SAEs, and selected laboratory 
measurements) will continue throughout the study using blinded data. Interim safety analyses 
may be conducted to review unblinded safety data; the analyses will be conducted and reviewed 
by an internal assessment committee composed of personnel who do not have direct site contact 
or data entry/validation responsibilities. Details are specified in the SAP.

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11.
References
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index (DLQI): 
further data. Dermatology. 2015;230(1):27-33.
Charman CR, Venn AJ, Williams, HC. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuring atopic eczema severity from the patients' 
perspective. Arch Dermatol. 2004;140(12):1513-1519.
Dupixent [prescribing information]. Bridgewater, NJ: Sanofi Aventis US LLC, and Tarrytown, 
NY: Regeneron Pharmaceuticals, Inc.; 2017. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761055lbl.pdf
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, Berger TG, 
Bergman JN, Cohen DE, Cooper KD, Cordoro KM, Davis DM, Krol A, Margolis DJ, Paller 
AS, Schwarzenberger K, Silverman RA, Williams HC, Elmets CA, Block J, Harrod CG, Smith 
Begolka W, Sidbury R. Guidelines of care for the management of atopic dermatitis: Section 1. 
Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351.
Futamura M, Leshem YA, Thomas KS, Nankervis H, Williams HC, Simpson EL. A systematic 
review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many 
options, no standards. J Am Acad Dermatol. 2016;74(2):288-294.
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-18.
Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality 
of life into practice: What do dermatology life quality index scores mean? J Invest Dermatol. 
2005;125(4):659-664.
Khilji FA, Gonzalez M, Finlay AY. Clinical meaning of change in Dermatology Life Quality 
Index scores. Br J Dermatol. 2002;147(suppl 62):25-54.
Kimball AB, Naegeli AN, Edson-Heredia E, Lin CY, Gaich C, Nikai E, Yosipovitch G. 
Psychometric properties of the Itch Numeric Rating Scale in patients with moderate-to-severe 
plaque psoriasis. Br J Dermatol. 2016;175(1):157-162.
Kunz B, Oranje AP, Labrèze L, Stadler JF, Ring J, Taїeb A. Clinical validation and guidelines 
for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. 
Dermatology. 1997;195(1):10-19.
Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted 
life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–2223.
Naegeli AN, Flood E, Tucker J, Devlen J, Edson-Heredia E. The worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. Int J 
Dermatol. 2015;54(6):715-722.

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Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimäki S, Karisola P, 
Reunala T, Wolff H, Lauerma A, Alenius H. IL-33 and ST2 in atopic dermatitis: expression 
profiles and modulation by triggering factors. J Invest Dermatol. 2012;132(5):1392–400.
Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) 
SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important 
difference. Allergy. 2012;67(1):99-106.
Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, 
Deleuran M, Kataoka Y, Lacour JP, Kingo K, Worm M, Poulin Y, Wollenberg A, Soo Y, 
Graham NM, Pirozzi G, Akinlade B, Staudinger H, Mastey V, Eckert L, Gadkari A, Stahl N, 
Yancopoulos GD, Ardeleanu M; SOLO 1 and SOLO 2 Investigators. Two Phase 3 trials of 
dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
Stalder JF, Taïeb A, Atherton DJ, Bieber P, Bonifazi E, Broberg A, Calza A, Coleman R, De 
Prost Y, Stalder JF, Gelmetti C, Cuannetti A, Harper J, Künz B, Lachapelle JM, Langeland T, 
Lever R, Oranje AP, Oueille-Roussel C, Revuz J, Ring J, Roujeau JC, Saurat JH, Song M, 
Tennstedt D, Van Neste D, Vieluf D, Poncet M; for the European Task Force on Atopic 
Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of 
the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.
Tamagawa-Mineoka R, Okuzawa Y, Masuda K, Katoh N. Increased serum levels of interleukin 
33 in patients with atopic dermatitis. J Am Acad Dermatol. 2014;70(5):882-888.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196.
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, Bartalesi F, 
Lipman M, Mariette X, Lortholary O, Weinblatt ME, Saag M, Smolen J. Opportunistic 
infections and biologic therapies in immune-mediated inflammatory diseases: consensus 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
AD
atopic dermatitis
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the subject are not.
A double-blind study is one in which neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BSA
body surface area
CI
confidence interval
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
clinical study report
DLQI
Dermatology Life Quality Index
DNA
deoxyribonucleic acid
EASI
Eczema Area and Severity Index
EASI-25
25% reduction in the Eczema Area and Severity Index score
EASI-50
50% reduction in the Eczema Area and Severity Index score
EASI-75
75% reduction in the Eczema Area and Severity Index score

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EASI-90
90% reduction in the Eczema Area and Severity Index score
ECG
electrocardiogram
eCOA
electronic Clinical Outcome Assessment
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Ig
immunoglobulin
IGA
Investigator’s Global Assessment
IL
interleukin
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
INR
international normalized ratio
IP
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.

I 9 N-M C -F C A B( b) Cli ni c al Pr ot o c ol
P a g e 6 5
L Y 3 3 7 5 8 8 0
I V
i ntra ve n o us
I W R S
i nteracti ve we b-res p o nse s yste m
J A K
Ja n us ki nase
L S M
least s q uares mea n
L T BI
late nt t u berc ul osis i nfecti o n
m A b
m o n ocl o nal a nti b o d y
M M F
m yc o p he n olate m ofetil
M M R M
mi xe d -effects m o del of re peate d meas ures
M T X
met h otre xate
N RI
n o nres p o n der i m p utati o n
N R S
N u meric Rati n g Scale
P C R
p ol y merase c hai n reacti o n
P D
p har mac o d y na mics(s)
P D E -4 i n hi bit or
p h os p h o diesterase t y pe 4 i n hi bit or
P K
p har mac o ki netic(s)
P O E M
Patie nt- Orie nte d Ecze ma Meas ure
P P D
p urifie d pr otei n deri vati ve
Q 4 W
e ver y 4 wee ks
Q o L
q ualit y - of-life
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C
s u bc uta ne o us
S C O R A D
S C O Ri n g A D
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T A R C
t h ym us a n d acti vati o n -re g ulate d c he m o ki ne
T B
t u berc ul osis
T B L
t otal bilir u bi n

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TCNI
topical calcineurin inhibitor
TCS
topical corticosteroids
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, which does not necessarily have to have a causal relationship 
with this treatment.
Th2
type 2 helper T-cell
TST
tuberculin skin test
ULN
upper limit of normal
vIGA-AD
validated Investigator’s Global Assessment for atopic dermatitis
WHO
World Health Organization

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Appendix 2.
Clinical Laboratory Tests
Hematologya,b
Hemoglobin
Clinical Chemistrya,b
Serum Concentrations of:
Hematocrit
Erythrocyte count (RBC)
Mean cell volume
Mean cell hemoglobin
Mean cell hemoglobin concentration
Leukocytes (WBC)
Platelets
Absolute counts of:
Sodium
Potassium
Bicarbonate
Chloride
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Neutrophils, segmented
Neutrophils, juvenile (bands)
Lymphocytes
Monocytes
Blood urea nitrogen (BUN)
Creatinine with calculated eGFR
Calcium
Phosphorus
Eosinophils
Glucose (random, fasting)
Basophils
Albumin
Total protein
Urinalysisa,b,c
Fasting lipid profiled
Specific gravity
Other Testsa
pH
Hepatitis B surface antigen (HBsAg)e
Protein
Anti-Hepatitis B core antibody (HBcAb)e
Glucose
HBV DNAf
Ketones
Bilirubin
Anti-Hepatitis B surface antibody (HBsAb)e
Human immunodeficiency virus (HIV)e
Urobilinogen
Blood
Nitrite
Hepatitis C antibodye,g
Exploratory (Long Term) storage samples (serum, plasma)
DNA for epigenetics, and mRNA)
Pharmacogenetic sample
Pregnancy Testh
Follicle-stimulating hormonee,i
Serum immunoglobulin (total and allergen-specific IgE)
QuantiFERON®-TB Gold or T-SPOT®.TBj
PPD (local testing)
LY3375880 plasma levels
Target engagement (Total IL-33)
Immunogenicity
IL-19
TARC
Periostin

I 9 N-M C -F C A B( b) Cli ni c al Pr ot o c ol
P a g e 6 8
L Y 3 3 7 5 8 8 0
A b bre viati o ns:  e G F R = esti mate d gl o mer ular filtrati o n rate; H B V = he patitis B vir us; I g E = i m m u n o gl o b uli n E; I L 
= i nterle u ki n; P P D = p urifie d pr otei n deri vati ve; R B C = re d bl o o d cell; T A R C = t h ym us a n d acti vati o n -re g ulate d 
c he m o ki ne; T B = t u berc ul osis; W B C = w hite bl o o d cell.
a
Assa y e d b y s p o ns or-desi g nate d la b orat or y.
b
U n sc he d ule d or re peat bl o o d c he mistr y, he mat ol o g y, a n d uri nal ysis pa nels ma y be perf or me d at t he discreti o n of 
t he i n vesti gat or, as nee de d.
c
Micr osc o pic e xa mi nati o n of se di me nt perf or me d o nl y if a b n or malities are n ote d o n t he r o uti ne uri nal ysis.
d
Fasti n g li pi d pr ofile.  S u bjects s h o ul d n ot eat or dri n k a n yt hi n g e xce pt water f or 1 2 h o urs pri or t o test.  If a 
s u bject atte n ds t hese visits i n a n o nfasti n g state, t his will n ot be c o nsi dere d a pr ot oc ol vi olati o n.
e
Test re q uire d at Visit 1 o nl y t o deter mi ne eli gi bilit y of s u bject f or t he st u d y.
f
F or s u bjects w h o meet criteria f or H B V D N A testi n g at scree ni n g a n d H B V D N A m o nit ori n g i n t he st u d y 
( Secti o n 9. 4. 8 ).
g
A p ositi ve he patitis C a nti b o d y res ult will be c o nfir me d wit h a n alter nate he patitis C met h o d.
h
F or all w o me n of c hil d beari n g p ote ntial, a ser u m pre g na nc y test will be perf or me d at Visit 1 a n d a l ocal uri ne 
pre g na n c y test will be perf or me d at Visit 2 a n d s u bse q ue nt visits acc or di n g t o t he st u d y sc he d ule.  If re q uire d per 
i n vesti gat or j u d g me nt, l ocal re g ulati o ns, a n d/ or i nstit uti o nal g ui deli nes, pre g na nc y testi n g ca n occ ur at ot her 
ti mes d uri n g t he st u d y treat me nt peri o d.
i
F or fe male s u bjects t o c o nfir m p ost -me n o pa usal stat us acc or di n g t o I ncl usi o n Criteri o n [ 9] .
j
T he Q ua nti F E R O N -T B G ol d test ma y be perf or me d l ocall y or ce ntrall y; t he T -S P O T m ust be perf or me d l ocall y.

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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring the following:

that the subject understands the potential risks and benefits of participating in 
the study.

that informed consent is given by each subject.  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.  A new ICF and subject number must be obtained if a 
subject will be rescreened after being screen failed from the study.

answering any questions the subject may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
subject’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator must give assurance that the 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 ERBs, before it is used at the investigative site(s). All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent form

relevant curricula vitae.
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

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
consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines.

applicable ICH GCP Guidelines.

applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.4.
Investigator Information
Physicians with an appropriate specialty and training will participate as investigators in this 
clinical trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
Lilly will select a qualified investigator from among investigators participating in the design, 
conduct, and/or analysis of the study to serve as the CSR coordinating investigator.  If this 
investigator is unable to fulfill this function, another investigator will be chosen by Lilly to serve 
as the CSR coordinating investigator.
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The 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.

Provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax.

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
Review and verify data reported to detect potential errors.
In addition, Lilly or its representatives will periodically check a sample of the subject data
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, electronic Clinical Outcome Assessment (eCOA) data (questionnaires, scales, 
self-reported diary data, rating scales, etc.) must be directly recorded by the subject/investigator 
site personnel, into an instrument (hand-held smart phone or tablet). The eCOA data will serve 
as the source documentation and the investigator must not maintain a separate written or 
electronic record of these data.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure

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

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

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Appendix 5.
Examples of Infections That May Be 
Considered Opportunistic in the Setting of Biologic Therapy
Bacterial
Bartonellosis (disseminated disease only)
Campylobacteriosis (invasive disease only)
Legionellosis
Listeria monocytogenes (invasive disease only)
Nocardiosis
Tuberculosis
Non-tuberculous mycobacterial disease 
Salmonellosis (invasive disease only) 
Shigellosis (invasive disease only)
Vibriosis (invasive disease due to Vibrio vulnificus)
Viral
BK virus disease including polyomavirus-associated nephropathy
Cytomegalovirus disease
Hepatitis B virus reactivation
Hepatitis C virus progression
Herpes simplex (invasive disease only)
Herpes zoster (any form)
Post-transplant lymphoproliferative disorder (Epstein–Barr virus)
Progressive multifocal leukoencephalopathy (PML), John Cunningham (JC) virus [excluded from the study]
Fungal
Aspergillosis (invasive disease only)
Blastomycosis
Candidiasis (invasive disease or pharyngeal)
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Paracoccidioides infections
Penicillium marneffei
Pneumocystis jirovecii (formerly Pneumocystis carinii)
Sporothrix schenckii
Other invasive fungi:  Mucormycosis (zygomycosis) (Rhizopus, Mucor, and Lichtheimia), 
Scedosporium/Pseudallescheria boydii, Fusarium
Protozoan
Leishmaniasis (visceral only)
Microsporidiosis
Toxoplasmosis
Trypanosoma cruzi infection (Chagas disease) (disseminated disease only)

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This table is provided to aid the investigator in recognizing infections that may be considered opportunistic in the 
context of biologic therapy, for the purposes of Exclusion Criterion [22].  This list is not exhaustive.  
Investigators should use their clinical judgment, as well as discussion with the Lilly-designated medical monitor, 
in determining if other infections may be considered opportunistic, for the purposes of Exclusion Criterion [22].
Consider tuberculosis (TB) and non-TB mycobacterial disease to be opportunistic infections in the context of 
biologic therapy.  See Section 6.2 for the approach to screening for latent TB infection within the study.  Subjects 
with any history of active TB are excluded from the study, regardless of previous or current TB treatments.
Source:  Adapted from Winthrop et al. (2015).

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Appendix 6.
American Academy of Dermatology:  Criteria 
for the Diagnosis and Assessment of Atopic Dermatitis
Features to be considered in diagnosis of subjects with AD:
Essential Features—Must be present:

pruritus

eczema (acute, subacute, chronic)
o
typical morphology and age-specific patterns*
o
chronic or relapsing history
*Patterns include the following:
1. Facial, neck, and extensor involvement in infants and children
2. Current or previous flexural lesions in any age group
3. Sparing of the groin and axillary regions
Important Features—Seen in most cases, adding support to the diagnosis:

early age of onset

atopy
o
personal and/or family history
o
Immunoglobulin E reactivity

xerosis
Associated Features—These clinical associations help to suggest the diagnosis of AD but 
are too nonspecific to be used for defining or detecting AD for research and epidemiologic 
studies:

atypical vascular responses (e.g., facial pallor, white dermographism, delayed blanch 
response)

keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis

ocular/periorbital changes

other regional findings (e.g., perioral changes/periauricular lesions)

perifollicular accentuation/lichenification/prurigo lesions
Exclusionary Features—It should be noted that a diagnosis of AD depends on excluding 
conditions, such as:

scabies

seborrheic dermatitis

contact dermatitis (irritant or allergic)

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
ichthyoses

cutaneous T-cell lymphoma

psoriasis

photosensitivity dermatoses

immune deficiency diseases

erythroderma of other causes
Source:  Eichenfield et al. (2014).

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Appendix 7.
Protocol Amendment I9N-MC-FCAB(b) 
Summary:  Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy 
and Safety of LY3375880 in Adult Subjects with 
Moderate-to-Severe Atopic Dermatitis:  The ADmIRe Study
Overview
Protocol I9N-MC-FCAB Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to 
Evaluate the Efficacy and Safety of LY3375880 in Adult Subjects with Moderate-to-Severe 
Atopic Dermatitis:  The ADmIRe Study has been amended.  The new protocol is indicated by 
amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The major overall changes and rationale for the changes made to this protocol are as follows:
Section
Change
Rationale
6.1 Inclusion Criteria 
For Inclusion Criterion
[4].  Disease activity 
requirements of IGA ≥3, 
EASI ≥16, and 
BSA ≥10% will be 
required at randomization 
only instead of requiring 
them at both screening 
and randomization.
The protocol requires a washout period 
during screening for patients currently 
using TCS and other treatments for AD, 
which can result in an increase in disease 
activity over the course of the screening 
period. Therefore, the disease activity 
criteria requirements were removed at 
screening to eliminate unnecessary 
restrictions to enrollment. This will not 
affect interpretation of efficacy data since 
the requirements remain the same as at 
baseline. Patient safety is not impacted 
by this change.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Inclusion Criteria: 
[4]
Have moderate-to-severe AD, including all of the following:
a.
Eczema Area and Severity Index (EASI) score ≥16 at screening (Visit 1) 
and at randomization (Visit 2).
b. IGA score of ≥3 at screening (Visit 1) and at randomization (Visit 2).
c.
≥10% of body surface area (BSA) involvement at screening (Visit 1) and
at randomization (Visit 2). 

Leo Document ID = aee78d2f-9aca-44e2-ac34-0bbbe5b7341a
Approver: 
Approval Date & Time: 25-Jul-2019 13:15:04 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Jul-2019 14:02:04 GMT
Signature meaning: Approved