Clinical trial NCT04159701
Conditions: Chronic Spontaneous Urticaria
Sponsor: Eli Lilly and Company
Start date: 2019-11-15; Completion date: 2021-02-24
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The reason for this study is to see if the study drug LY3454738 is safe and effective as treatment for participants with hives that are caused by chronic spontaneous urticaria (CSU) and that are not controlled with H1-antihistamines.

Detailed description:

Arms: arm 1: 500 milligram (mg) LY3454738 administered intravenously (IV). arm 2: Placebo administered IV.
Interventions: intervention 1: LY3454738 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol Number  (c ) J1B-MC-FRCF 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Crossover Study to 
Evaluate the Efficacy and Safety of LY3454738 in Adults with Chronic Spontaneous Urticaria 
Inadequately Controlled with H1-Antihistamines 
 
NCT04159701 
Approval Date: 10-Jun-2020 


CONFIDENTIAL
Protocol J1B-MC-FRCF(c)
LY3454738
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Title Page
Confidential Information
The information contained in this document is confidential and is intended for the use of clinical investigators.  It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3454738, unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Crossover Study to Evaluate the Efficacy and Safety of LY3454738 in Adults 
with Chronic Spontaneous Urticaria Inadequately Controlled with 
H1-Antihistamines
Protocol Number: J1B-MC-FRCF
Amendment Number:  C
Compound: LY3454738
Study Phase: Phase 2
Short Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Crossover 
Study to Evaluate the Efficacy and Safety of LY3454738 in Adults with Chronic 
Spontaneous Urticaria Inadequately Controlled with H1-Antihistamines
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Numbers:
IND: 143892
EudraCT:  2019-002495-13
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 10-Jun-2020 GMT


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Protocol J1B-MC-FRCF(c)
LY3454738
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Medical monitor name and contact information will be provided separately.


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Protocol J1B-MC-FRCF(c)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment B
29-Jan-2020
Amendment A
23-Aug-2019
Original Protocol
12-Aug-2019
Amendment C
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment: The rationale for the amendment is to enhance 
participant safety by decreasing the risk of enrolling or dosing a patient with COVID-19 disease.
Section # and Name
Description of Change
Brief Rationale
Section 1.3, Schedule of 
Activities
Changed visit tolerance interval 
from 2 days to 3 days. 
Minor change for added participant 
flexibility. 
Section 5.2, Exclusion Criteria
Clarified Exclusion Criteria 13.
Minor clarification to further 
define confirmed or suspected 
infections.
Section 5.2, Exclusion Criteria
Updated the time period for 
specified types of infection in 
Exclusion Criteria 14.
Minor clarification.
Section 5.2, Exclusion Criteria
Updated Exclusion Criteria 29 
to include first generation H1-
antihistamines.
Minor clarification.
Section 5.2, Exclusion Criteria
Removed “leukotriene-receptor 
antagonists” from Exclusion 
Criteria 32.
This was a duplication with 
Exclusion Criteria 29.
Section 6.5.3, Other Permitted 
Concomitant Therapy
Clarified the use of nasal 
steroids are permitted. 
Minor clarification.
Section 7.1.2, Criteria for 
Temporary Interruption 
(Withholding) of Study Drug
Clarified temporary withholding 
for confirmed or suspected 
infections. 
Minor clarification.
Section 8.1, Efficacy 
Assessments; Section 8.2, Safety 
Assessments; Section 8.2.6, 
Laboratory Tests
Clarified home or virtual visits 
along with local safety labs are 
permitted, under special 
circumstances.
Minor clarification for added 
participant flexibility. 
Section 9.2, Sample Size 
Updated the effect size
Clarified per ethics committee 


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Protocol J1B-MC-FRCF(c)
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Section # and Name
Description of Change
Brief Rationale
Determination
assumption for LY3454738 and 
updated the power. 
feedback. 
Section 9.5, Interim Analyses
Clarified unblinding details 
which are specified in the SAP 
and Unblinding Plan. 
Minor clarification.


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Protocol J1B-MC-FRCF(c)
LY3454738
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Table of Contents
Title Page...................................................................................................................................1
Protocol Amendment Summary of Changes Table ......................................................................3
Table of Contents ......................................................................................................................5
1.
Protocol Summary......................................................................................................9
1.1.
Synopsis.......................................................................................................................9
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................12
2.
Introduction..............................................................................................................21
2.1.
Study Rationale ..........................................................................................................21
2.2.
Background ................................................................................................................21
2.3.
Benefit/Risk Assessment ............................................................................................21
3.
Objectives and Endpoints.........................................................................................23
4.
Study Design .............................................................................................................24
4.1.
Overall Design............................................................................................................24
4.2.
Scientific Rationale for Study Design .........................................................................24
4.3.
Justification for Dose..................................................................................................25
4.4.
End-of-Study Definition .............................................................................................26
5.
Study Population ......................................................................................................27
5.1.
Inclusion Criteria........................................................................................................27
5.2.
Exclusion Criteria.......................................................................................................29
5.3.
Lifestyle Considerations .............................................................................................33
5.4.
Screen Failures...........................................................................................................33
5.4.1.
Rescreening of Individuals Who Failed Screening ......................................................34
6.
Study Intervention....................................................................................................35
6.1.
Study Interventions Administered...............................................................................35
6.2.
Preparation/Handling/Storage/Accountability.............................................................35
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................36
6.4.
Study Intervention Compliance...................................................................................37
6.5.
Concomitant Therapy .................................................................................................37
6.5.1.
Background Medications ............................................................................................37
6.5.2.
Rescue Therapy..........................................................................................................38
6.5.3.
Other Permitted Concomitant Therapy........................................................................38
6.5.4.
Prohibited Concomitant Therapy ................................................................................38
6.6.
Dose Modification......................................................................................................39
6.7.
Intervention after the End of the Study........................................................................39
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................40
7.1.
Discontinuation of Study Intervention ........................................................................40
7.1.1.
Criteria for Permanent Discontinuation of Study Drug................................................40
7.1.2.
Criteria for Temporary Interruption (Withholding) of Study Drug...............................42


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Protocol J1B-MC-FRCF(c)
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7.1.3.
Discontinuation of Inadvertently Enrolled Participants ...............................................42
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................43
7.3.
Lost to Follow-Up ......................................................................................................43
8.
Study Assessments and Procedures .........................................................................44
8.1.
Efficacy Assessments .................................................................................................44
8.1.1.
Primary Efficacy Assessment......................................................................................45
8.1.1.1. Urticaria Activity Score Over 7 Days (UAS7) ............................................................45
8.1.2.
Secondary Efficacy Assessments ................................................................................45
8.1.2.1. Itch Severity Score Over 7 Days (ISS7)......................................................................45
8.1.2.2. Hives Severity Score Over 7 Days (HSS7)..................................................................45
8.1.3.
Exploratory Assessments............................................................................................45
8.1.3.1. Dermatology Life Quality Index.................................................................................45
8.2.
Safety Assessments ....................................................................................................46
8.2.1.
Vital Signs..................................................................................................................47
8.2.2.
Physical Examinations................................................................................................47
8.2.3.
Electrocardiograms.....................................................................................................47
8.2.4.
Chest Radiography .....................................................................................................47
8.2.5.
Stool Testing ..............................................................................................................48
8.2.6.
Laboratory Tests.........................................................................................................48
8.2.6.1. Pregnancy Testing ......................................................................................................49
8.2.7.
Tuberculosis Testing and Monitoring..........................................................................50
8.2.8.
Hepatitis B Testing and Monitoring ............................................................................51
8.2.9.
Hepatitis C Testing and Monitoring ............................................................................51
8.2.10.
Hepatic Safety Monitoring..........................................................................................52
8.3.
Adverse Events and Serious Adverse Events ..............................................................52
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................53
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................53
8.3.3.
Follow-Up of AEs and SAEs ......................................................................................53
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................54
8.3.5.
Pregnancy...................................................................................................................54
8.3.6.
Study Endpoints Not Qualifying as Adverse Events....................................................54
8.3.7.
Adverse Events of Special Interest..............................................................................54
8.3.7.1. Infusion Reactions......................................................................................................55
8.3.7.2. Allergic Reactions and Hypersensitivity Events..........................................................55
8.3.7.3. Infections....................................................................................................................55
8.3.8.
Complaint Handling ...................................................................................................55
8.4.
Treatment of Overdose ...............................................................................................55
8.5.
Pharmacokinetics........................................................................................................56
8.6.
Pharmacodynamics.....................................................................................................56
8.7.
Genetics .....................................................................................................................57
8.8.
Biomarkers.................................................................................................................57
8.9.
Immunogenicity Assessments.....................................................................................58
8.10.
Health Economics or Medical Resource Utilization and Health 
Economics..................................................................................................................58
9.
Statistical Considerations.........................................................................................59


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Protocol J1B-MC-FRCF(c)
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9.1.
Statistical Hypotheses.................................................................................................59
9.2.
Sample Size Determination.........................................................................................59
9.3.
Populations for Analyses ............................................................................................59
9.4.
Statistical Analyses.....................................................................................................59
9.4.1.
General Considerations...............................................................................................60
9.4.1.1. Participant Disposition................................................................................................60
9.4.1.2. Participant Characteristics ..........................................................................................60
9.4.1.3. Missing Data Imputation ............................................................................................61
9.4.2.
Primary Endpoints......................................................................................................61
9.4.3.
Secondary Endpoints ..................................................................................................61
9.4.3.1. Change from Baseline in ISS7 at Week 12..................................................................61
9.4.3.2. Change from Baseline in HSS7 at Week 12 ................................................................62
9.4.3.3. Proportion of Patients with UAS7 ≤6 at Week 12 .......................................................62
9.4.3.4. Pharmacokinetic Analysis...........................................................................................62
9.4.4.
Exploratory Endpoints................................................................................................62
9.4.4.1. Evaluation of Immunogenicity....................................................................................62
9.4.5.
Safety Analyses ..........................................................................................................63
9.5.
Interim Analyses.........................................................................................................63
9.6.
Data Monitoring Committee (DMC)...........................................................................63
10.
Supporting Documentation and Operational Considerations ................................64
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................64
10.1.1.
Regulatory and Ethical Considerations........................................................................64
10.1.2.
Financial Disclosure ...................................................................................................64
10.1.3.
Informed Consent Process ..........................................................................................65
10.1.4.
Data Protection...........................................................................................................65
10.1.5.
Committee Structure...................................................................................................65
10.1.6.
Dissemination of Clinical Study Data .........................................................................66
10.1.7.
Data Quality Assurance ..............................................................................................66
10.1.8.
Source Documents......................................................................................................67
10.1.9.
Study and Site Start and Closure.................................................................................68
10.1.10. Publication Policy.......................................................................................................69
10.1.11. Information about Participating Investigators..............................................................69
10.1.12. Long-Term Sample Retention.....................................................................................69
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................70
10.3.
Appendix 3:  Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting......................................................73
10.3.1.
Definition of AE.........................................................................................................73
10.3.2.
Definition of SAE.......................................................................................................74
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................75
10.3.4.
Reporting of SAEs......................................................................................................77
10.4.
Appendix 4:  Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................78
10.5.
Appendix 5:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments ...............................................................................................................80


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Protocol J1B-MC-FRCF(c)
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10.6.
Appendix 6:  Examples of Infections That May Be Considered 
Opportunistic in the Setting of Biologic Therapy ........................................................81
10.7.
Appendix 7:  Definitions and Selected Abbreviations .................................................83
10.8.
Appendix 8:  Protocol Amendment History ................................................................87
11.
References.................................................................................................................89


CONFIDENTIAL
Protocol J1B-MC-FRCF(c)
LY3454738
9
1.
Protocol Summary
1.1.
Synopsis
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Crossover Study to Evaluate the Efficacy and Safety of LY3454738 in Adults with Chronic 
Spontaneous Urticaria Inadequately Controlled with H1-Antihistamines
Rationale:  LY3454738 is a humanized immunoglobulin G (IgG) 4-variant monoclonal antibody 
(mAb) that binds to and agonizes the human inhibitory checkpoint CD200R.  Binding of
LY3454738 to CD200R induces a negative signal that results in functional inhibition of the 
target cell activity.  CD200R is expressed on mast cells and basophils, both of which are critical 
in the pathogenesis of chronic spontaneous urticaria (CSU).  Thus, LY3454738 is being 
developed for the treatment of CSU.  This proof-of-concept study will evaluate the safety and 
efficacy of LY3454738 in adults with CSU.
Objectives and Endpoints
Objectives
Endpoints
Primary
●  To test the hypothesis that treatment with 
LY3454738 is superior to placebo as 
measured by patient-assessed itch severity and 
hive count for the treatment of adult 
participants with CSU
●  Mean change from baseline to Week 12 in 
UAS7
Secondary
●  To compare the efficacy of LY3454738 to 
placebo as measured by improvement in signs 
and symptoms of CSU
●  Mean change from baseline to Week 12 in
○
ISS7
○
HSS7
●  Proportion of patients achieving UAS7 ≤6 
at Week 12
●  To characterize the pharmacokinetics (PK) of 
LY3454738
●  Cmax and AUC
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum plasma drug 
concentration; CSU = chronic spontaneous urticaria; HSS7 = Hives Severity Score Over 7 Days; ISS7 = Itch 
Severity Score Over 7 Days; UAS7 = Urticaria Activity Score Over 7 Days.
Overall Design:  Study J1B-MC-FRCF (FRCF) is a multicenter, randomized, double-blind, 
placebo-controlled, Phase 2 crossover study to evaluate the efficacy and safety of LY3454738 


CONFIDENTIAL
Protocol J1B-MC-FRCF(c)
LY3454738
10
500 mg given intravenously (IV) every 2 weeks (Q2W) versus placebo IV Q2W in adults with 
CSU inadequately controlled with H1-antihistamines.
The study duration will be up to approximately 39 weeks over 4 study periods:
Period 1:  Screening, starting up to 35 days before randomization
Period 2:  First 12-week treatment (LY3454738 or placebo), from randomization visit 
through Week 12
Period 3:  Second 12-week treatment (crossover), from Week 12 through Week 24
Period 4:  Post-treatment follow-up for approximately 10 weeks.
Throughout the study, participants will take a second-generation H1-antihistamine at a dose 
specified in approved product labeling.  Certain participants may receive rescue therapy.
Disclosure Statement: This is a crossover treatment study with 2 arms that is 
participant-blinded and investigator-blinded.
Number of Participants:
Approximately 85 patients will be screened to achieve approximately 60 randomized 
participants.  A total of approximately 52 evaluable participants are expected.
Intervention Groups and Duration:
Participants will be randomized in a 3:1 ratio to either Sequence Group 1 or Sequence Group 2:
Sequence Group 1: LY3454738 500 mg IV for 12 weeks followed by placebo for 12 weeks
Sequence Group 2: Placebo for 12 weeks followed by LY3454738 500 mg IV for 12 weeks
Data Monitoring Committee: No


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Protocol J1B-MC-FRCF(c)
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1.2.
Schema
Abbreviations: C = crossover visit; D = day; Q2W = every 2 weeks; R = randomization visit; W = study week relative to randomization visit; V = visit.
Figure 1.
Schema of Study J1B-MC-FRCF, a phase 2 study to evaluate the efficacy and safety of LY3454738 in adults 
with chronic spontaneous urticaria.


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Protocol J1B-MC-FRCF(c)
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1.3.
Schedule of Activities (SoA)
Note: Visit 1 procedures may be conducted over more than 1 day as long as all tasks are completed within the allowable visit 
tolerance.  The early termination visit (ETV) activities in Table 1 apply to early terminations occurring prior to Visit 16. See Table 2
for procedures in post-treatment follow-up period (Period 4).  
Table 1. Schedule of activities for the screening and treatment periods of Study J1B-MC-FRCF.
Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demographics
X
Preexisting 
conditions and 
medical history
X
Prespecified 
medical history 
(indication and 
history of interest)
X
Prior treatments 
for indication
X


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Protocol J1B-MC-FRCF(c)
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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Concomitant 
medications, 
including 
medications for 
indication
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
For AESIs, additional 
data are collected.
Substance use 
(alcohol, tobacco, 
caffeine)
X
Height
X
Weight
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure, body 
temperature, pulse rate
Physical 
examination
X
Includes assessment of 
skin (Section 8.2.2);
tuberculosis (TB) risk 
factors, symptoms or 
signs of TB, including 
assessment of 
peripheral lymph nodes 
(Section 8.2.7)
Symptom-directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Includes assessment of 
skin at every visit 
(Section 8.2.2)


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Protocol J1B-MC-FRCF(c)
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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
12-lead ECG
X
X
X
X
Locally read, performed 
before blood sampling
Chest x-ray 
(posterior–
anterior view)
X
Interpreted and 
reported by radiologist 
or pulmonologist.  Not 
performed at screening 
if performed within 6
months before 
screening and if
qualifying radiographs 
or equivalent imaging 
study and/or formal 
report are available for 
investigator’s review.  
Locally performed.
Patient Diary (Electronic)
Dispense 
electronic diary
X
Includes Urticaria 
Patient Daily Diary 
(UPDD).  The diary is 
completed daily.
Check electronic 
diary compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol J1B-MC-FRCF(c)
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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Return electronic 
diary
Participant should 
return the diary at 
Treatment Period ETV if 
the participant does not 
enter Post-Treatment 
Follow-Up period 
(Period 4).
Patient-Reported Outcomes (Paper)
DLQI
X
X
X
X
X
X
X
X
Laboratory Tests and Sample Collections
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
For the fasting lipid 
profile, participants 
should not eat or drink 
anything except water 
for 12 hours prior to 
the test.  Fasting is not 
required for the lipid 
panel at an ETV.
Urinalysis
X
X
X
X
X
Serum pregnancy
X
Only for women of 
childbearing potential
and women with 
history of tubal ligation


CONFIDENTIAL
Protocol J1B-MC-FRCF(c)
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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Urine pregnancy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Only for women of 
childbearing potential
and women with a 
history of tubal ligation; 
done locally and prior 
to dosing at dosing 
visits
Follicle-stimulating 
hormone (FSH)
X
Optional, 
performed to confirm 
postmenopausal status
Stool evaluation
X
Only for participants 
with certain risk factors 
and eosinophil count 
>2 times ULN (see 
Sections 5.2 and 8.2.5)
C-reactive protein, 
high-sensitivity 
(hs-CRP)
X
X
X
X
X
X


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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Tuberculosis (TB) 
test
X
Participants who had a 
TST will return 48 to 72 
hours after placement 
to have their test 
results read (Section 
8.2.7).  Samples may be 
sent to central lab or to
a local lab based on the 
type of test (Appendix 
10.2). Local laboratory
must be qualified by 
local regulations.
HIV screening tests
X
HCV screening 
tests
X
A positive hepatitis C 
antibody laboratory
assessment will be 
confirmed with an 
additional test method.
HBV screening 
tests
X
Serum 
immunoglobulins
(IgG, IgM, IgA, IgE)
X
X
X
X
Pharmacogenetics 
sample
X


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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Exploratory 
biomarker samples
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic 
(PK) samples
X
X
X
X
X
X
X
X
X
X
X
X
Visit 2: Samples are 
collected at four time 
points: 
1) before infusion starts
2) after infusion ends
3) 1 hour after infusion 
ends
4) 2 hours after infusion 
ends.
Other visits: Samples 
are collected before 
infusion starts.
Immunogenicity 
(ADA) samples
X
X
X
X
X
X
X
X
All samples for 
immunogenicity should 
be collected before 
infusion when 
applicable and possible.  
A time-matched PK 
sample should be 
collected at each 
immunogenicity sample 
time point.
TBNK panel
X
X
X
X
X
X
X


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Screening
Treatment Periods
Period 1
Period 2
Period 3
ETV
Comments
Visit number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
Weeks from 
randomization
5
—
1
2
4
6
8
10
12
13
14
16
18
20
22
24
Study day
35 
1
8
15
29
43
57
71
85
92
99
113
127
141
155
169
Visit tolerance 
interval (days)
—
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Fasting visit
X
X
X
Receptor 
occupancy assay
X
X
X
X
X
X
Visit 2:  Samples are 
collected at four time 
points:
1) before infusion starts
2) after infusion ends
3) 1 hour after infusion 
ends
4) 2 hours after infusion 
ends.
Other visits:  Samples 
are collected before 
infusion starts.
Randomization and Dosing
Randomization
X
Dosing
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  ADA = anti-drug antibody; AESI = adverse event of special interest; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; 
ETV = early termination visit; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; TBNK = T-cells, B-cells, and 
natural killer (NK) cells; TST = tuberculin skin test; ULN = upper limit of normal; V = visit.


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Table 2.  Schedule of activities post-treatment follow-up period (Period 4) of Study J1B-MC-FRCF.
Post-Treatment
Follow-Up
Comment
Period 4
Post-Treatment
ETV
Visit number
V801
V802
Weeks from randomization
28/
ETV+4
34/
ETV+10
Study day
197
239
Visit tolerance interval (days)
±7
±7
Fasting visit
No fasting in this period.
Concomitant medications, including 
medications for indication
X
X
X
Adverse events
X
X
X
For AESIs, additional data are collected.
Vital signs
X
X
X
Blood pressure, body temperature, pulse rate
Symptom-directed physical examination
X
X
X
Includes assessment of skin at every visit (Section 8.2.2)
Patient Diary (Electronic)
Check electronic diary compliance
X
The diary is completed daily.
Return electronic diary
X
X
Patient-Reported Outcomes (Paper)
DLQI
X
X
X
Laboratory Tests and Sample Collections
Hematology
X
X
X
Clinical chemistry
X
X
X
Urine pregnancy
X
X
X
Only for women of childbearing potential and women with a history of 
tubal ligation; done locally
Pharmacokinetic (PK) samples
X
X
Immunogenicity (ADA) samples
X
X
A time-matched PK sample should be collected at each immunogenicity 
sample time point.
Abbreviations:  ADA = anti-drug antibody, AESI = adverse event of special interest; DLQI = Dermatology Life Quality Index; ETV = early termination visit; 
V = visit.


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2.
Introduction
2.1.
Study Rationale
LY3454738 is a humanized immunoglobulin G (IgG) 4-variant monoclonal antibody (mAb) that
binds to and agonizes the human inhibitory checkpoint CD200R.  Binding of LY3454738 to
CD200R induces a negative signal that results in functional inhibition of the target cell activity.  
CD200R is expressed on mast cells and basophils, both of which are critical in the pathogenesis
of chronic spontaneous urticaria (CSU).  Thus LY3454738 is being developed for the treatment 
of CSU.  This proof-of-concept study will evaluate the safety and efficacy of LY3454738 in 
adults with CSU.
2.2.
Background
Chronic spontaneous urticaria is an immune-mediated skin disease that causes pruritic hives 
(wheals) and/or soft tissue swelling (angioedema).  Histamine release from mast cells and 
basophils is critical in the pathogenesis of CSU (Saini and Kaplan 2018).  The unpredictability of 
the symptoms of CSU has a negative effect on quality of life similar to that caused by ischemic 
heart disease (O’Donnell et al. 1997) and moderate-to-severe psoriasis (Balp et al. 2018).  
Antihistamines are the first-line treatment for CSU, but only about 45% to 60% of patients 
respond, even at higher-than-licensed doses (Maurer et al. 2011, 2017; Guillén-Aguinaga et al.
2016).  Omalizumab was approved in March 2014 by the Food and Drug Administration (FDA)
for the treatment of CSU, but fewer than 50% of patients treated with omalizumab have 
symptoms that resolve completely (Maurer et al. 2013; Saini et al. 2015).  Omalizumab also has 
a warning for anaphylaxis in its label, so it should be administered to patients under direct 
medical supervision by health care workers (Xolair package insert, 2019).  For patients with 
CSU inadequately controlled by antihistamines, there is a need for additional therapies.
Activation of CD200R may be effective in the treatment of CSU because CD200R is an 
inhibitory receptor that is expressed on the mast cells and other immune cell types thought to be 
important in the disease pathogenesis. LY3454738 binds to and agonizes CD200R.
Study J1B-MC-FRCF (FRCF) will be the first clinical study to evaluate the safety and efficacy 
of LY3454738 in patients with CSU.
2.3.
Benefit/Risk Assessment
There are currently no human data regarding the efficacy of LY3454738 in CSU.  CD200R is an 
inhibitory receptor that is expressed on mast cells and other immune cells that are important in 
CSU pathogenesis.  A surrogate antibody suppressed mast cell activation in a nonclinical model.  
These findings support the hypothesis that LY3454738 has the potential for efficacy in CSU.  
Nonclinical data and safety data from the Phase 1 clinical study J1B-MC-FRCC (FRCC) support 
development of LY3454738 in CSU at the proposed dose.
No dose-limiting safety issues were identified in healthy volunteers receiving single or repeat 
doses of LY3454738 in Study FRCC.  See the Investigator’s Brochure (IB) for additional 
information.


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The toxicological potential of LY3454738 was assessed in cynomolgus monkeys, a 
pharmacologically relevant species, that were administered the molecule for 3 months; 
additionally, the potential for cytokine release syndrome was evaluated in vitro with human 
whole blood and peripheral blood mononuclear cells, and the data generated support a low risk 
of cytokine release in the clinic.  Although LY3454738 has agonist action on CD200R to achieve 
immunosuppressive effects, it is notable that nonclinical toxicology studies of immune-
enhancing molecules that act by antagonizing inhibitory checkpoint receptors (for example,
programmed cell death protein 1 [PD-1], programmed death ligand 1 [PD-L1], cytotoxic 
T-lymphocyte-associated protein 4 [CTLA-4]) have underpredicted adverse events (AEs)
experienced clinically (Naidoo et al. 2015; Saber et al. 2016).
LY3454738 binding to CD200R does not block binding of the ligand (CD200).  Both
LY3454738 and ligand can bind at the same time and induce activity through CD200R, resulting 
in the inhibitory signaling cascade.  All of the preclinical data support LY3454738 as an agonist 
to CD200R resulting in induction of the inhibitory cascade, and there is no evidence of any 
immune activation due to LY3454738 binding to CD200R.
Ongoing monitoring of safety data (including AEs, serious adverse events [SAEs], and selected 
laboratory measurements) will continue throughout the study using blinded data.  Interim safety 
analyses may be conducted to review unblinded safety data, as described in Section 9.5 and 
Appendix 10.1, Section 10.1.5.
This protocol has been designed to be conducted in accordance with applicable regulations and 
guidances, including “Guideline on strategies to identify and mitigate risks for first-in-human 
and early clinical trials with investigational medicinal products” (EMA 2017).  All participants 
will be monitored for AEs at every visit and managed appropriately as needed.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY3454738 is presented in the IB.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
●  To test the hypothesis that treatment with 
LY3454738 is superior to placebo as measured 
by patient-assessed itch severity and hive count 
for the treatment of adult participants with CSU
●  Mean change from baseline to Week 12 
in UAS7
Secondary
●  To compare the efficacy of LY3454738 to 
placebo as measured by improvement in signs 
and symptoms of CSU
●  Mean change from baseline to Week 12 
in
○
ISS7
○
HSS7
●  Proportion of patients achieving
UAS7 ≤6 at Week 12
●  To characterize the pharmacokinetics (PK) of 
LY3454738
●  Cmax and AUC
Exploratory
Exploratory objectives and endpoints may include the following:
  To evaluate signs and symptoms and measures of quality of life at various time points in 
Period 2 (first 12-week treatment period) and in Period 3 (second 12-week treatment period, 
after crossover) using the DLQI and the UPDD items.
  To assess the potential development of anti-LY3454738 antibodies and their impact on the 
safety profile and PK of LY3454738.
  To explore relationships between LY3454738 exposure and select biomarkers and clinical 
efficacy endpoints.
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum plasma drug 
concentration; CSU = chronic spontaneous urticaria; DLQI = Dermatology Life Quality Index; HSS7 = Hives 
Severity Score Over 7 Days; ISS7 = Itch Severity Score Over 7 Days; UAS7 = Urticaria Activity Score Over 
7 Days; UPDD = Urticaria Patient Daily Diary.


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4.
Study Design
4.1.
Overall Design
Study J1B-MC-FRCF (FRCF) is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 2 crossover study to evaluate the efficacy and safety of LY3454738 500 mg given
intravenously (IV) every 2 weeks (Q2W) versus placebo IV Q2W in adults with CSU 
inadequately controlled with H1-antihistamines.
The study duration will be up to approximately 39 weeks over 4 study periods, as shown below:
Period 1:  Screening, lasting up to 35 days before Week 0 (Visit 2, baseline)
Period 2:  First 12-week treatment, from Week 0 (Day 1) through Week 12:
Participants will be randomized in a 3:1 ratio to receive 
either LY3454738 500 mg IV or placebo IV Q2W
Period 3:  Second 12-week treatment (crossover), from Week 12 through Week 24:
Participants who received LY3454738 500 mg IV in Period 2 will receive 
placebo IV Q2W in Period 3.
Participants who received placebo IV in Period 2 will receive 
LY3454738 500 mg IV Q2W in Period 3.
Period 4:  Post-treatment follow-up for approximately 10 weeks.
Participants will not receive study drug in Period 4.
The last dose of study drug is given at Week 22, which is 6 weeks before the 
first post-treatment follow-up visit (Visit 801).  Thus, participants will have 
been withdrawn from study drug for a total of 12 weeks at the last
post-treatment follow-up visit (Visit 802).
The study schema is presented in Section 1.2.
Throughout the study, participants will take a second-generation H1-antihistamine at a dose 
specified in approved product labeling.  Certain participants may receive rescue therapy as 
described in Section 6.5.2.
Participants who permanently discontinue the study drug early (Section 7.1) will undergo early 
termination procedures, including an early termination visit (ETV) and the post-treatment 
follow-up visits specified in the Schedule of Activities (SoA) (Section 1.3).
4.2.
Scientific Rationale for Study Design
Patients with CSU whose symptoms are not well controlled by licensed doses of antihistamines 
are appropriate for a novel investigational product (IP) with immunomodulating properties.  A 
double-blind, placebo-controlled design limits bias for both patient and investigator assessments 
and enables a clearer interpretation of the effects of active drug.  One active dose level of 


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LY3454738 will allow for an evaluation of safety and efficacy and will provide information to 
guide dose selection in future studies.
Study treatment will be provided during two study periods (Period 2 and Period 3).  Study 
treatment in Period 2 is designed to evaluate the primary endpoint, which is the mean change 
from baseline in the Urticaria Activity Score (UAS) at the Week 12 visit.  The Urticaria Activity 
Score Over 7 Days (UAS7) assesses the burden of itch and hives in CSU.  It is used widely in 
CSU trials and has been accepted by the FDA as a primary endpoint for trials conducted for 
approval of new drugs.  Evaluation of the primary endpoint at the Week 12 time point is 
appropriate, based on previous clinical trials of systemic therapies in CSU (Maurer et al. 2013; 
Saini et al. 2015).
The crossover in Period 3 allows for an evaluation of safety and durability of efficacy in 
participants who received LY3454738 in Period 2.  This study period also allows participants
who were randomized to placebo in Period 2 to receive LY3454738 in Period 3 for an equal 
treatment duration as in Period 2.
The post-treatment follow-up in Period 4 will allow for continued safety monitoring after the last 
dose of LY3454738.  The last dose given in Period 3 is at Week 22.  This is 2 weeks before the 
last visit in Period 3 (Week 24, Visit 16) and a total of 12 weeks before the last post-treatment 
follow-up visit (Week 34, Visit 802).  A follow-up period of a similar duration was used after the 
last dose of LY3454738 in the single- and multiple-dose cohorts in Phase 1 Study FRCC.  
LY3454738 is expected to be undetectable in the serum after 5 half-lives.  The terminal half-life 
of LY3454738 is approximately 2 weeks, based on pharmacokinetic (PK) data from the Phase 1 
Study FRCC.  Therefore, for the present study, the planned duration of safety follow-up is 
adequate, as this duration covers approximately 6 half-lives.
4.3.
Justification for Dose
The planned dose of 500 mg IV Q2W for patients with CSU was chosen based on an analysis 
with preliminary human PK and receptor occupancy data from healthy subjects who received 
single (1 to 1000 mg) or repeat (200 mg x 2 doses) IV doses of LY3454738 in the Phase 1 Study 
FRCC.  Based on the preliminary analysis, the half-life of LY3454738 is approximately 2 weeks,
and a Q2W dose of 500 mg is expected to achieve approximately 90% saturation of the receptor 
at the trough drug concentration at steady state (Cmin,ss).  Receptor occupancy is used as a 
surrogate of pharmacological activity, and receptor saturation is desired to maximize the 
probability of achieving clinical efficacy.
This 500 mg IV Q2W dose was predicted to achieve a steady-state exposure that is similar to the 
maximum exposure achieved after the highest dose tested as a single dose in Study FRCC (that 
is, 1000 mg).  In the single-ascending dose portion of Study FRCC, there were no dose-limiting 
safety findings.  See the IB for additional information.
Dose selection is further supported by preclinical toxicity data.  LY3454738 was evaluated in 
cynomolgus monkeys over a 3-month dosing period, during which LY3454738 was administered 
once weekly at doses of 0, 15, or 50 mg/kg subcutaneous or 170 mg/kg IV (13 total doses).  The 
no-observed-adverse-effect level (NOAEL) in this study was 170 mg/kg, and this provides a
margin of safety of ≥33-fold (based on mg/kg dose or estimated human exposure) to a repeated 
dose of 500 mg Q2W.  See the IB for additional information supportive of the dose selection.


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4.4.
End-of-Study Definition
A participant is considered to have completed the study if he or she has completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the SoA 
(Section 1.3).
The end of the study is defined as the date of the last visit or last scheduled procedure shown in 
the SoA (Section 1.3) for the last participant in the trial globally.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria.
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.
For screen failures and rescreening activities within the screening period, see Section 5.4.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if they meet all of the following criteria 
during screening, unless otherwise specified below:
Informed consent
[1]
Have provided signed informed consent as described in Appendix 10.1 and are capable of 
compliance with the requirements and restrictions listed in the informed consent form and 
in this protocol.
Participant characteristics
[2]
Are male or female participants from 18 to 65 years of age, inclusive, at the time of 
signing the informed consent document.
[2a] Female participants:
Women of childbearing potential (WOCBP)
Women of childbearing potential who are abstinent (if this is complete abstinence, as 
their preferred and usual lifestyle) or in a same-sex relationship (as part of their 
preferred and usual lifestyle) must agree to either remain abstinent or stay in a same-sex 
relationship without sexual relationships with males. Periodic abstinence (for example, 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence 
just for the duration of the trial, and withdrawal are not acceptable methods of 
contraception.
Otherwise, WOCBP who participate in the study must agree to use two forms of 
effective contraception, where at least one form is highly effective (less than 1% failure 
rate) for the entirety of the study.
Abstinence or contraception must continue following completion of study drug
administration until their plasma concentrations are below the level that could result in a 
relevant potential exposure to a possible fetus, predicted to be 90 days following last 
dose of study drug.
A.  Women of childbearing potential participating must test negative for pregnancy 
prior to initiation of treatment as indicated by a negative serum pregnancy test at the 


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screening visit followed by a negative urine pregnancy test within 24 hours prior to 
exposure. Women must also test negative for pregnancy prior to each dose.
B.  Two forms of effective contraception, where at least one form is highly effective
(such as combination oral contraceptives, implanted contraceptives, or intrauterine 
devices) will be used. Effective contraception (such as male or female condoms 
with spermicide, diaphragms with spermicide or cervical sponges) may be used as 
the second therapy. Barrier protection methods without concomitant use of a 
spermicide are not a reliable or acceptable method. Thus, each barrier method must 
include use of a spermicide (that is, condom with spermicide, diaphragm with 
spermicide, female condom with spermicide). It should be noted that the use of 
male and female condoms as a double-barrier method is not considered acceptable 
due to the high failure rate when these methods are combined.
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.  post-menopausal – defined as either
i.  A woman at least 40 years of age with an intact uterus, not on hormone therapy, 
who has cessation of menses for at least 1 year without an alternative medical 
cause and a follicle-stimulating hormone (FSH) >40 IU/mL; or
ii.  A woman at least 55 years of age not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea; or
iii.  A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
[2b] Male participants: 
Men, regardless of their fertility status, with nonpregnant WOCBP partners must agree 
to either remain abstinent (if this is their preferred and usual lifestyle) or use condoms as 
well as one additional highly effective (less than 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 90 days following the last dose of study drug.
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 (for example, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are 
not acceptable methods of contraception.


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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 WOCBP,
predicted to be 90 days following the 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 90 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.
CSU-related inclusion criteria
[3]
Have a diagnosis of CSU for at least 6 months before the screening visit.
Note: CSU is as defined by the 2018 revision of the EAACI/GA2LEN/EDF/WAO 
guideline for the definition, classification, diagnosis, and management of urticaria 
[Zuberbier et al. 2018]).
[4]
Have hives associated with itching at any time for at least 8 consecutive weeks before the 
baseline (randomization) visit, despite current use of H1-antihistamines.
[5]
Are taking an approved (marketed) 24-hour oral dose of a second-generation 
H1-antihistamine (cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, 
rupatadine, mizolastine, bilastine) for CSU for at least 10 consecutive days before the 
baseline (randomization) visit, and agree to continue taking this medication at the same 
dose every day throughout the study (Section 6.5.1).
Note:  If the participant is not already taking this medication at the screening visit, he or 
she may be eligible for the study if he or she agrees to take this medication for at least 
10 consecutive days before the baseline (randomization) visit, agrees to continue taking 
this medication every day throughout the study at same dose, and meets all other study 
eligibility criteria.
[6]
Are willing and able to complete the scheduled study assessments, including twice daily 
diary entry.
[7]
Have an urticaria activity score during a 7-day period (UAS7 score) of 16 or more during 
the 7 consecutive days prior to the baseline (randomization) visit.
[8]
Have no more than 5 missing diary entries for the 7 days before the baseline 
(randomization) visit.
[9]
If the participant’s CSU symptoms are triggered or worsened by aspirin and/or 
nonsteroidal anti-inflammatory drugs (NSAIDs), the participant must agree not to use the 
triggering agent during the study.
5.2.
Exclusion Criteria
Participants will be excluded from study enrollment if they meet any of the following criteria 
within the screening period.


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Skin diseases and skin conditions other than CSU
[10]
Have a clearly defined underlying cause for chronic urticaria other than CSU.  Such 
causes can include, but are not limited to, the following: symptomatic dermatographism 
(urticaria factitia); cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, 
cholinergic-, or contact-urticaria.
[11]
Have diseases, other than chronic urticaria, with urticarial or angioedema symptoms.  
These diseases include, but are not limited to, urticarial vasculitis, urticaria pigmentosa, 
erythema multiforme, mastocytosis, hereditary, or acquired angioedema (for example, 
due to C1 inhibitor deficiency), lymphoma, leukemia, or generalized malignancy.
[12]
Have any other skin disease associated with chronic itching that, in the investigator’s 
opinion, might influence the study evaluations and results (including, but not limited to, 
prurigo nodularis, atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, and 
senile pruritus).
Infections
[13]
Have a current or recent acute, active infection. For at least 30 days prior to screening, 
participants must have no significant symptoms including fever of 100.5°F (38°C) or 
above, at screening or baseline, and/or signs of confirmed or suspected infection, and 
must have completed any appropriate anti-infective treatment.
[14]
Have had, within 6 months of screening, any of the following types of infection:

Serious infections (requiring hospitalization, and/or intravenous antibiotic treatment)

Opportunistic infections (as defined in Winthrop et al. 2015)

Herpes zoster that is considered active and ongoing until all vesicles are dry and 
crusted over

Chronic infections (duration of symptoms, signs, and/or treatment of 6 weeks or
longer)

Recurring infection (including, but not limited to, herpes simplex, herpes zoster,
recurring cellulitis, chronic osteomyelitis)
o
Participants with only recurrent, mild, and uncomplicated orolabial and/or genital 
herpes may be discussed with the Lilly-designated medical monitor for possible 
exemption from this exclusion criterion.
[15]
Have human immunodeficiency virus (HIV) infection.
[16]
Have a current or past infection with hepatitis B virus (HBV) (that is, positive for 
hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody) (see Section 8.2.8).
[17]
Have a current infection with hepatitis C virus (HCV) (that is, positive for HCV 
ribonucleic acid [RNA]) (see Section 8.2.9).
[18]
Have current or past active tuberculosis (TB) (see Section 8.2.7).
[19]
Have or have had latent TB infection (LTBI) that has not been treated with a complete 
course of appropriate therapy as defined by the World Health Organization (WHO) 
and/or the United States Centers for Disease Control and Prevention (CDC), unless such 
treatment is underway (see Section 8.2.7).


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[20]
Have received a Bacillus Calmette-Guerin (BCG) vaccination or treatment within 
12 months of screening, or received any other live vaccines (that is, live attenuated),
within 3 months before the screening visit, or intend to receive a live vaccine (or live 
attenuated vaccine) during the study or within 90 days after the last dose of study drug.
Note:  Use of nonlive (inactivated) vaccinations is allowed for all participants.
[21]
Have evidence of parasitic infection, defined as meeting any of the following three 
criteria:
1) risk factors for parasitic disease (living in an endemic area, chronic gastrointestinal 
symptoms, travel within the last 6 months to an endemic area and/or chronic 
immunosuppression)
2) an absolute eosinophil count >2 times the upper limit of normal (ULN)
3) evidence of parasitic colonization or infection on stool evaluation for ova and 
parasites.
Note:  Stool evaluation for ova and parasites will be conducted only in participants 
with risk factors (#1 above) and an eosinophil count >2 times ULN (#2 above).
Other medical conditions/history
[22]
Have an unstable or uncontrolled illness, including but not limited to 
cerebrocardiovascular (for example, 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 the participant’s safety in the study or confound efficacy and 
safety assessments.
[23]
Have a diagnosis or history of malignancy within 5 years prior to the baseline 
(randomization) visit, with the following exceptions:
a.  Basal cell or squamous epithelial carcinomas of the skin that have been resected with 
no evidence of metastatic disease for 3 years,
b. Cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to 
baseline (randomization) visit.
[24]
Have a history of anaphylaxis.
[25]
Have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug abuse within 
1 year prior to the screening visit.
Note:  Marijuana is considered an illicit drug for the purposes of this study, regardless of 
local laws. Cannabidiol (CBD) products may be used during the study if they are derived 
exclusively from hemp.  Participants who use hemp-based CBD products must be on a 
stable dose for at least 10 days prior to the baseline visit, and participants must remain on 
that stable dose during the study.
[26]
Have a history of asthma with severity classified greater than intermittent asthma.


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Note: Intermittent asthma is defined according to “Expert Panel Report 3:  Guidelines for 
the Diagnosis and Management of Asthma Summary Report 2007 (EPR-3)” (2007 Expert 
Panel).
Diagnostic assessments
[27]
Have any of the following specific abnormalities on screening laboratory tests:
a. Serum creatinine, aspartate aminotransferase (AST), or alanine aminotransferase 
(ALT) ≥2 times ULN
b. Alkaline phosphatase (ALP) ≥2 times ULN
c. Total bilirubin level (TBL) ≥1.5 times 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 (platelet count <100,000 cells/L) (<100x103/L or <100 GI/L)
Note: For each aforementioned test, 1 repeat testing is allowed during screening, and 
values resulting from repeat testing may be accepted for a participant’s enrollment 
eligibility if the other eligibility criteria are met (see Section 5.4.1).
[28]
Have screening electrocardiogram (ECG) abnormalities that, in the opinion of the 
investigator, are clinically significant and indicate an unacceptable risk for the 
participant’s safety in the study.
Prior or concomitant therapy
[29]
Have used any first generation H1-antihistamine, H2-antihistamine or leukotriene-
receptor antagonist within 10 days before the baseline (randomization) visit.
Note:  The first generation H1-antihistamine diphenhydramine is allowed as rescue 
medication before the baseline (randomization) visit per Section 6.5.2.
Note:  Participants taking H2-antihistamines for gastroesophageal reflux disease (GERD) 
during the screening period may be eligible for the study if the other study eligibility 
criteria are met; such participants may continue to take this medication at a stable dose 
during the study.
[30]
Have received routine administration (that is, daily or every other day for 5 or more 
consecutive days) of systemic glucocorticoids, hydroxychloroquine, methotrexate, 
cyclosporine, cyclophosphamide, doxepin, or IV immunoglobulin for any indication 
within 30 days before the baseline (randomization) visit.
[31]
Have received prior treatment with omalizumab, ligelizumab, or any other approved or
investigational biologic compound for CSU.


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Note:  Participants with prior use of investigational antihistamines may be eligible for the 
study if the other study eligibility criteria are met and if the investigational antihistamines 
are discontinued within 30 days or 5 half-lives, whichever is longer, before the baseline 
(randomization) visit.
[32]
Have received within 30 days of the baseline (randomization) visit, corticosteroids 
(inhaled or oral), long-acting beta agonists, cromolyn, theophylline, zileuton, or 
monoclonal antibodies targeting interleukin-13 (IL-13), IL-4/IL-13 receptor (dupilumab), 
IL-5 (mepolizumab, reslizumab), or IL-5 receptor (benralizumab).
Prior or concurrent clinical study experience
[33]
Are currently enrolled in any other clinical study involving an investigational product
(IP) or any other type of medical research judged not to be scientifically or medically 
compatible with Study FRCF.
[34]
Have participated within the last 30 days in a clinical study involving an IP.  If the 
previous IP has a long half-life, at least 5 half-lives or 30 days (whichever is longer) 
should have passed before the baseline (randomization) visit of Study FRCF.
Other exclusions
[35]
Are pregnant or breastfeeding, or intend to become pregnant or breastfeed during the 
study.
[36]
Have donated more than a single unit of blood within 4 weeks prior to the screening visit 
or intend to donate blood during the course of the study.
[37]
Have a contraindication to diphenhydramine.
[38]
Have an inability to swallow medication in tablet form.
[39]
Have significant allergies to humanized monoclonal antibodies or any components of the 
LY3454738 product formulation.
[40]
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.
[41]
Are employees of Eli Lilly and Company (Lilly).
5.3.
Lifestyle Considerations
Not applicable.
5.4.
Screen Failures
Individuals are described as having failed screening (“screen failures,” “screen failed”) if they 
consent to participate in the clinical study but are not subsequently randomized. A minimal set 
of information about such individuals is required to ensure transparent reporting consistent with
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. The minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs.


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5.4.1.
Rescreening of Individuals Who Failed Screening
Informed consent for rescreening
Individuals who are rescreened must sign a new informed consent form (ICF) (Appendix 10.1, 
Section 10.1.3) and will be assigned a new identification number.
Allowed rescreening for an administrative reason
An individual may be rescreened one time for an administrative reason, including, for example, 
but not limited to, falling out of the screening window because of scheduling conflicts.  The 
sponsor does not need to approve rescreening for an administrative reason.
Allowed rescreening after failure to meet certain study eligibility criteria
An individual who has failed screening because of one or more of the following eligibility 
criteria may be rescreened one time if the reason for screen failure has resolved and if the 
sponsor has approved the rescreening:
[2a/B], specifically for women not of childbearing potential who are rescreening for 
postmenopausal status
[3], [4], [5], [7], to satisfy requirements for disease activity/duration
[13], [14], to satisfy requirements for infection-free time
[20], to satisfy requirement for timings of vaccination
[23], to satisfy requirement for cancer-free time
[27], to address requirements for specific abnormalities on screening laboratory tests
[29], [30], [32], [34], to satisfy medication washout periods
[36], to satisfy requirement for timing of blood donations.
Allowed retesting of screening investigations
Repeating of laboratory tests during the screening period does not constitute rescreening.  
See Section 8.2.7 for retesting for LTBI.
Procedures not required to be repeated during rescreening
Individuals in rescreening who have already completed the protocol-required ECG, screening 
chest x-ray (CXR), or TB tests are not required to repeat these procedures if these procedures 
were performed within 90 days before the date of signing the ICF for rescreening.  However, 
these procedures can be repeated at the discretion of the investigator.
All other screening procedures must be repeated during rescreening to ensure that all the study 
eligibility criteria are met.


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6.
Study Intervention
Study intervention is defined as any investigational intervention, marketed product, placebo, or 
investigational device intended to be administered to a study participant according to the study 
protocol.
6.1.
Study Interventions Administered
Study interventions
This study involves a single dose level of LY3454738 and placebo, as shown below.
Treatment Name
LY3454738
Placebo
Dosage Formulation
Lyophilized powder
0.9% sodium chloride
Dosage Level
500 mg
not applicable
Routes of Administration
IV infusion 
IV infusion
Dosing Instructions
One dose every 2 weeks
One dose every 2 weeks
Abbreviation:  IV = intravenous.
LY3454738 is supplied for clinical trial use as a lyophilized powder formulation in a glass vial.  
Vials will be supplied in cartons, with the appropriate quantity specific to the planned dispensing 
schedule of the IPs.
When the IPs are prepared for dosing according to instructions (Section 6.2) it will not be 
possible to distinguish LY3454738 from placebo.
All participants should be monitored for 30 minutes or longer after dosing, according to 
investigator practice or local standard of care.  Sites must have resuscitation equipment, 
emergency drugs, and appropriately trained staff available during the infusion and monitoring 
period, or until completion of all required post-dosing activities (whichever is longer).
Packaging and labeling
Study interventions (LY3454738 and placebo) will be supplied by the sponsor or its designee in 
accordance with current Good Manufacturing Practice (cGMP).  Clinical trial materials will be 
labeled according to the country’s regulatory requirements.  All IPs will be stored, inventoried, 
reconciled, and destroyed according to applicable regulations.
6.2.
Preparation/Handling/Storage/Accountability
Detailed instructions for the preparation and handling of the administered products will be 
provided by the sponsor in the Pharmacy Manual.  Investigators should consult the study drug 
information provided in the Pharmacy Manual or label for the specific administration 
information (including warnings, precautions, contraindications, adverse reactions, and dose 
modifications).


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Preparation
The IPs must be prepared by an unblinded pharmacist (or other unblinded qualified individual) 
who is not involved in any other study-related procedures.
Handling and storage
Follow storage and handling instructions on the IP packaging.
Site responsibilities and accountability
The following are responsibilities of the investigator or his or her designee:
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all study intervention received and any discrepancies 
are reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention 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 authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record 
maintenance (that is, receipt, reconciliation, and final disposition records).
The investigator or designee is also responsible for
explaining the correct use of the study interventions
verifying that instructions are followed properly
maintaining accurate records of IP dispensing and collection, and
returning all unused medication to Lilly or its designee at the end of the study.
Note:  In some cases, sites may destroy the material if, during the investigative site 
selection, the evaluator has verified and documented that the site has appropriate 
facilities and written procedures to dispose of clinical materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Blinding will be maintained throughout the conduct of the study as described in the separate 
Unblinding Plan.
Method of treatment assignment
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).
Unblinded pharmacist
Investigators and all individuals involved in administering the blinded treatment or performing 
assessments will remain blinded to each participant’s assigned study intervention throughout the 
course of the study.  To maintain this blind, an otherwise uninvolved party (unblinded 


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pharmacist or other unblinded qualified individual) will be responsible for the reconstitution and 
dispensation of all study intervention.  Blinded site personnel will administer the intervention to 
the participant.
Emergency unblinding
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the participant’s well-being requires knowledge of the participant’s treatment 
assignment.  All actions resulting in an unblinding event are recorded and reported by the IWRS.
If a participant’s study treatment assignment is unblinded, the participant must be discontinued 
from the study, unless the investigator obtains specific approval from the sponsor’s medical 
monitor for the study participant to continue in the study (Section 7.1.1).
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that unblinding is 
warranted, it is the responsibility of the investigator to promptly document the decision and 
rationale and notify the sponsor as soon as possible.
6.4.
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee at the study 
site, under medical supervision.  The date and time of each dose administered in the clinic will 
be recorded in the source documents and recorded in the electronic case report form (eCRF).  
Deviations from the prescribed dosage regimen should be recorded in the eCRF.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with
Reason for use
Dates of administration including start and end dates, and
Dosage information, including dose for concomitant therapy of special interest
(background H1-antihistamine and rescue treatments).
Participants will be instructed to consult the investigator or other appropriate study site personnel 
before taking any new medications or supplements during the study.
The sponsor’s medical monitor should be contacted if there are any questions.
6.5.1.
Background Medications
Throughout the study, participants will continue taking the second-generation H1-antihistamine 
that they were taking prior to the baseline (randomization) visit.  The choice of background 
medication will be made by the participant and his or her relevant physician. Once the choice is 
made, the same background medication should be continued for the duration of the study.


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The doses and regimens of background medications should be as follows, unless locally
approved product labeling specifies another dose or regimen for CSU:
cetirizine 10 mg once daily
levocetirizine dihydrochloride 5 mg once daily
fexofenadine 180 mg once daily
loratadine 10 mg once daily
desloratadine 5 mg once daily
rupatadine (not available in the United States of America [USA]) 10 mg once daily
mizolastine (not available in the USA) 10 mg once daily, and
bilastine (not available in the USA) 20 mg once daily.
6.5.2.
Rescue Therapy
Participants may be eligible for rescue therapy based on the following considerations:
  Therapy used as rescue therapy can start as soon as the background medication is 
started.
  The need for rescue therapy is determined by the participant, although a conversation 
between the participant and the investigator on parameters for use of rescue therapy is 
encouraged. The decision to use rescue therapy is based on the individual
participant’s tolerance of pruritus and angioedema.
  Rescue therapy is either diphenhydramine 25-mg tablets or the addition of a second 
second-generation H1-antihistamine that the participant is currently NOT taking. This
may be cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, or (outside 
the USA) rupatadine, mizolastine, or bilastine with the 24-hour oral dose as specified 
in approved product labeling.
If the participant chooses diphenhydramine, dosing is as follows for this study: 25-mg 
tablets, with 1 tablet every 4 to 6 hours as needed up to a maximum of 3 tablets (75 mg) 
in a 24-hour period of time.
The date of rescue medication administration as well as the name and dosage regimen of the 
rescue medication must be recorded on the eCRF.
6.5.3.
Other Permitted Concomitant Therapy
Unless prohibited in Section 6.5.4 or in the study entry criteria (Section 5), concomitant therapies 
are permitted, including, for example, ophthalmic steroids, nasal steroids, and inhaled short-
acting beta-2-selective adrenergic agonists.
6.5.4.
Prohibited Concomitant Therapy
The following table lists medications that are prohibited as concomitant therapy during the study, 
unless an exception is noted in the “Exceptions” column.  Of note, patients who have received 
monoclonal antibodies that target IgE (for example, omalizumab, ligelizumab) are not eligible 


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for study enrollment (Section 5.2), and the use of such medications during the study is 
prohibited.
Prohibited as Concomitant Therapy
Exceptions
Aspirin, if participant has history of CSU symptoms triggered or worsened by 
aspirin
Allowed if participant has no such 
history
Bacillus Calmette-Guerin (BCG) vaccine
Cromolyn
Cyclophosphamide
Cyclosporine
Doxepin
H2-antihistamines (for example, ranitidine, famotidine, etc.)
Allowed for treatment of GERD
Hydroxychloroquine
Investigational biologic for CSU
IV immunoglobulin
Leukotriene-receptor antagonists (for example, montelukast, zafirlukast, etc.)
Live or live attenuated vaccine
Long-acting beta agonists (for example, salmeterol, formoterol, etc.)
Methotrexate
Monoclonal antibodies targeting 
IL-13 (for example, tralokinumab)
IL-4/IL-13 receptor (for example, dupilumab)
IL-5 (for example, mepolizumab, reslizumab)
IL-5 receptor (for example, benralizumab), or
IgE (for example, omalizumab, ligelizumab)
NSAIDs, if participant has history of CSU symptoms triggered or worsened by 
NSAIDs (for example, ibuprofen, naproxen, etc.)
Allowed if participant has no such 
history
Systemic corticosteroids/glucocorticoids (inhaled or oral), for example:
beclomethasone
budesonide
ciclesonide
flunisolide
fluticasone
mometasone
methylprednisolone
prednisone, etc.)
Theophylline
Zileuton
Abbreviations: CSU = chronic spontaneous urticaria; GERD = gastroesophageal reflux disease; IgE = 
immunoglobulin E; IL = interleukin; IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug.
6.6.
Dose Modification
Modification of the dose of the study intervention is not permitted in this study.
6.7.
Intervention after the End of the Study
LY3454738 will not be available to participants following completion of the study.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
These sections describe reasons for
permanent or temporary discontinuation of study drug, or
participant’s discontinuation (withdrawal) from the study.
Discontinuation of the study as a whole or of particular study sites is described in Appendix 10.1, 
Section 10.1.9.
7.1.
Discontinuation of Study Intervention
Study drug may be permanently discontinued or temporarily withheld during the study.
Participants who permanently discontinue study drug early will undergo early termination 
procedures, which include
an ETV 
   AND,
post-treatment follow-up visits (V801, V802).
The investigator will complete any AE reporting and necessary follow-up (Section 8.3).
7.1.1.
Criteria for Permanent Discontinuation of Study Drug
Possible reasons leading to permanent discontinuation of study drug include, but are not limited 
to the following:
Participant Decision
The participant requests to discontinue the study drug.
Prohibited Concomitant Medication Use
The participant requires treatment with a prohibited medication (Section 6.5.4).
The participant changes the background H1-antihistamine.
Safety Considerations
The participant develops any of the following during the study:
  malignancy (except for successfully treated basal or squamous cell skin carcinoma)
  HIV/acquired immune deficiency syndrome (AIDS) infection
active TB or untreated LTBI (Section 7.1.2; Section 8.2.7)
  HCV RNA positive
The investigator determines that a clinically significant hypersensitivity reaction has 
occurred.  A clinically significant systemic hypersensitivity reaction is one that occurs 
after administration of the investigational intervention (for example, drug-related 


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symptomatic bronchospasm or hypotension) and is different from the participant’s 
baseline CSU symptoms, requires parenteral medication, does not respond to 
symptomatic medication, results in clinical sequelae, or is an anaphylactic reaction 
(Section 8.3.7.2).  Study drug should be discontinued after a systemic hypersensitivity 
event or anaphylaxis.
The participant experiences any 1 of the following events on 2 consecutive samples 
taken at least 48 hours apart:
  Total white blood cell count (WBC) <1000 cells/L
  Absolute neutrophil count (ANC) <500 cells/L
  Absolute lymphocyte count (ALC) <200 cells/L
The participant becomes pregnant (see Section 8.2.6.1).
Noncompliance with LTBI treatment (see Section 8.2.7).
The participant has an AE or SAE that, in the opinion of the investigator or sponsor, 
would preclude the participant from continuing to receive study drug.
Hepatic Event or Liver Test Abnormality
Participants who are discontinued from study drug because of a hepatic event or liver 
test abnormality should have additional hepatic safety data collected via the hepatic 
eCRF packet.
Discontinuation of study drug because of abnormal liver tests should be considered by 
the investigator when a participant meets one of the following conditions after 
consultation with the medical monitor (see Section 8.2.10):
  ALT or AST >8 times ULN
  ALT or AST >5 times ULN sustained for more than 2 weeks
  ALT or AST >3 times ULN and TBL >2 times ULN or international normalized 
ratio (INR) >1.5
  ALT or AST >3 times ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
  ALP >3 times ULN
  ALP >2.5 times ULN and TBL >2 times ULN, or
  ALP >2.5 times ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
Other Reasons
Unblinding:  If an investigator, site personnel performing assessments, or participant is 
unblinded, the participant must be discontinued from the study drug and continue to 
post-treatment follow-up.  In cases where there are ethical reasons to have the 
participant continue on study drug, the investigator must obtain specific approval from 
the sponsor or designee for the participant to continue.


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Participants discontinuing from the study drug prematurely for any reason will complete AE and 
other follow-up procedures as specified in the SoA (Section 1.3), Section 8.2 (“Safety 
Assessments”), and Section 8.3 (“Adverse Events and Serious Adverse Events”), including ETV 
and post-treatment follow-up visits (V801, V802).
7.1.2.
Criteria for Temporary Interruption (Withholding) of Study Drug
Dosing may be interrupted and resumed in participants who experience the following reductions 
in WBC counts, but do not meet the criteria for permanent discontinuation (Section 7.1.1):
interrupt if total WBC count is <2000 cells/L (leukopenia) and resume when total 
WBC count is ≥2000 cells/L
interrupt if ANC is <1000 cells/L (neutropenia) and resume when ANC is 
≥1000 cells/L
interrupt if ALC is <500 cells/L (lymphopenia) and resume when ALC is 
≥500 cells/L.
Temporary withholding of study intervention is allowed when the participant has positive 
microbial lab results or clinical signs of a confirmed or suspected infection (Section 5.2) after 
consultation with the sponsor’s medical monitor.
Temporary withholding of study intervention is required for the development of any of the 
following infection-related criteria during the study:
Serious or opportunistic infections, as defined in Exclusion Criteria (Section 5.2).  
Study intervention is to be withheld until resolution of all acute clinical signs and 
symptoms, and completion of all appropriate anti-infective treatment (exception for 
LTBI, noted below).
Participants diagnosed with LTBI during the study are to be permanently discontinued 
from study intervention unless a participant is a candidate for LTBI treatment, and is 
treated for LTBI as follows:
  Study intervention is temporarily held for at least the first 4 weeks of LTBI 
treatment.
  After receiving at least 4 weeks of appropriate LTBI therapy (as per World Health 
Organization and/or the United States Centers for Disease Control guidelines), if 
there is no evidence of hepatotoxicity (ALT/AST must remain ≤2 times ULN) or 
other treatment intolerance, study intervention may be resumed.
  The participant must complete appropriate LTBI therapy to remain eligible to 
receive study intervention.
7.1.3.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment 
unless there are extenuating circumstances that make it medically necessary for the participant to 
continue study treatment.  If the investigator and the sponsor agree that it is medically 


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appropriate to continue, the investigator must obtain documented approval from the sponsor to 
allow the inadvertently enrolled participant to continue in the study with or without treatment 
with IP. Safety follow-up is as outlined in the SoA (Section 1.3), Section 8.2 (“Safety 
Assessments”), and Section 8.3 (“Adverse Events and Serious Adverse Events”), including ETV 
and post-treatment follow-up visits (V801, V802).
7.2.
Participant Discontinuation/Withdrawal from the Study
Participants will be discontinued (withdrawn) from the study in the following circumstances:
  enrollment in any other clinical study involving an 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
  the investigator decides that the participant should be discontinued from the study
  the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication.  In this 
case, discontinuation from the study occurs before introduction of the new agent.
  participant decision
  the participant requests to be withdrawn from the study.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records.
Participants discontinuing from the study prematurely for any reason should have AE and other 
safety follow-up specified for the ETV.  See safety follow-up as outlined in the SoA 
(Section 1.3), Section 8.2 (“Safety Assessments”), and Section 8.3 (“Adverse Events and Serious 
Adverse Events”), including ETV and post-treatment follow-up visits (V801, V802).
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
Site personnel are expected to make diligent attempts to contact participants who fail to return 
for a scheduled visit or were otherwise unable to be followed up by the site.  Contact attempts 
should be documented in the participant’s medical record.
If the participant continues to be unreachable, he or she will be considered to have withdrawn 
from the study.


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8.
Study Assessments and Procedures
Study procedures and the study visits at which they are performed, including tolerance limits for 
the study visits, are listed in the SoA (Section 1.3).  Adherence to the study design requirements, 
including those specified in the SoA, is essential and required for study conduct.
8.1.
Efficacy Assessments
Visits and order of efficacy assessments
Efficacy assessments occur as specified in the SoA (Section 1.3).  Procedures at study visits 
should be timed so that participants’ self-assessments, including Urticaria Patient Daily Diary 
(UPDD) and Dermatology Life Quality Index (DLQI), are completed before any clinical 
assessments or sample collections are performed.
Home or virtual health visits are permitted to evaluate clinical efficacy under special 
circumstances (for example, site closure or other restrictions), after consultation with the 
sponsor’s medical monitor. The home or virtual health visits should be documented in the CRF.
If required under special circumstances and after consultation with the sponsor’s medical 
monitor, the DLQI can be read over the phone exactly as it is written, in the patient’s native 
language, without any additional words or explanations.  Responses should be documented by 
site staff, retained as source documentation, and entered into the CRF
Urticaria Patient Daily Diary (UPDD)
The UPDD is a daily diary completed twice per day (morning and evening) via an electronic, 
handheld device. Items asking about itch severity and number of hives pertain to the past 12 
hours and are asked twice per day. The remaining items are asked once per day and pertain to 
the past 24 hours: interference with sleep, interference with daily activities, use of rescue 
medication (number of tablets), presence (and treatment) of angioedema, and any calls placed to 
healthcare professionals.  While developed originally on paper, the electronic version of the 
UPDD has been shown to be equivalent to the paper version from a measurement perspective, 
and is considered a valid and reliable assessment of urticaria symptoms (Flood et al. 2013).
Pruritus, angioedema, and hives are monitored as clinical endpoints in the UPDD and would not 
constitute AEs.  However, if any of these events is an SAE as defined in Appendix 10.3, Section 
10.3.2, the event should be reported as an SAE.  See Section 8.3.6 for more information.
There is no overall UPDD score calculation. The primary endpoint assessment (Urticaria 
Activity Score Over 7 Days [UAS7]) and key secondary endpoint assessments (Itch Severity 
Score Over 7 Days [ISS7] and Hives Severity Score Over 7 Days [HSS7]) are derived from data 
collected via the UPDD, as described below (Sections 8.1.1 and 8.1.2, respectively).
Appropriateness and devices/questionnaires for assessments
The UAS7, which is derived from the UPDD, has been used in previous CSU trials and is being 
used as the primary endpoint for trials conducted for registration (Xolair package insert, 2019; 
ligelizumab studies NCT03580369 and NCT03580356 [ClinicalTrials.gov]).
The secondary and exploratory measures of disease activity and quality of life in this study are 
also generally recognized as reliable, accurate, and relevant.


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The self-reported questionnaires will be administered via either an electronic participant diary
(UPDD) or on paper (DLQI), and in countries where the questionnaires have been translated into 
the native language of the region and linguistically validated.
8.1.1.
Primary Efficacy Assessment
8.1.1.1.
Urticaria Activity Score Over 7 Days (UAS7)
The weekly UAS7 is calculated using data from the UPDD. The UAS7 is the sum of the daily 
urticaria activity scores (UAS) over a 7-day period and ranges from 0 to 42.  The daily UAS is 
the sum of the daily itch severity score (ISS) and daily number of hives score, and ranges from 0 
to 6. The baseline UAS7 is the sum of the daily UAS over the 7 days prior to the first treatment. 
A higher UAS or higher UAS7 indicates greater urticaria disease activity.
The minimally important difference (MID) for UAS7 is defined as a reduction from baseline in 
weekly Urticaria Activity Score of 9.5 to 10.5 points or more (Mathias et al. 2015).
8.1.2.
Secondary Efficacy Assessments
8.1.2.1.
Itch Severity Score Over 7 Days (ISS7)
The weekly ISS7 is calculated using data from the UPDD. The ISS7 is the sum of the daily ISS
over a 7-day period and ranges from 0 to 21. The daily ISS is the average of the morning and 
evening ISS on a 4-point scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe). The baseline 
ISS7 is the sum of the daily ISS over the 7 days prior to the first treatment. A higher ISS or 
higher ISS7 indicates more severe itching.
The MID for ISS7 is defined as a reduction from baseline in weekly itch severity score of 4.5 to 
5.0 points or more (Mathias et al. 2015).
8.1.2.2.
Hives Severity Score Over 7 Days (HSS7)
The weekly HSS7 is calculated using data from the UPDD. The HSS7 is the sum of the daily 
number of hives over a 7-day period and ranges from 0 to 21.  The daily number of hives score 
(also called HSS) is the average of the morning and evening number of hive scores on a four-
point scale of 0 (none), 1 (between 1 and 6 hives, inclusive), 2 (between 7 and 12 hives, 
inclusive), and 3 (greater than 12 hives). The baseline weekly HSS7 is the sum of the HSS over 
the 7 days prior to the first treatment. A higher HSS or higher HSS7 indicates a greater number 
of hives.
The MID for HSS7 is defined as a reduction from baseline in weekly number of hives score of 
5.0 to 5.5 points or more (Mathias et al. 2015).
8.1.3.
Exploratory Assessments
8.1.3.1.
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a participant-rated, 10-item 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 “a little,” “a lot,” and “very much,” with corresponding scores of 1, 


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2, and 3, respectively, and “not at all,” or unanswered (“not relevant”) responses scored as 0.  
Scores range from 0 to 30, with higher scores indicating greater impairment of quality of life.  A 
DLQI total score of 0 to 1 is considered as having no effect on a participant’s health-related 
quality of life (Hongbo et al. 2005), and a 4-point change from baseline is considered the 
minimal clinically important difference threshold (Basra et al. 2015).
8.2.
Safety Assessments
Visits and order of safety assessments
Safety assessments occur at visits specified in the SoA (Section 1.3). Home or virtual health 
visits are permitted to assess the safety of the participant under special circumstances (for 
example, site closure or other restrictions), after consultation with the sponsor’s medical monitor. 
The home or virtual health visits should be documented in the CRF.
If multiple safety assessments are scheduled for the same visit, the preferred order of completion 
is
1) ECG (if applicable) and vital signs first
2)  other safety assessments, including physical examinations and AE collection, and finally
3) blood sample collection for clinical laboratory, PK, pharmacodynamic (PD), 
pharmacogenetic, biomarker, and immunogenicity testing.
Data collection and reporting
The AE data collection and reporting requirements are described in Section 8.3 and 
Appendix 10.3.  Any clinically significant findings that result in a diagnosis and that occur after 
the participant receives the first dose of study drug should be reported to Lilly or its designee as 
an AE via eCRF.  Additional requirements regarding adverse events of special interest are 
described in Section 8.3.
Safety monitoring
The principle investigator will monitor safety and laboratory data throughout the study and 
should discuss safety concerns with the sponsor immediately upon occurrence or awareness of 
the concern in order to determine whether the participant should continue or discontinue study 
drug.
The sponsor will periodically review evolving safety data, including AEs and SAEs, 
discontinuations, vital signs, concomitant medications, and medical history in monthly blinded 
reviews and via other appropriate methods.  These methods include review by a functionally 
independent safety physician and/or clinical research scientist who regularly reviews SAE 
reports in real time and across studies, and reviews applicable clinical safety and epidemiological 
publications from the literature.  If this safety monitoring uncovers an issue that needs to be 
addressed by unblinding at the individual or group level, additional analyses of the safety data 
can be performed by the sponsor’s independent internal safety review committee.
Appropriateness of safety assessments
The safety assessments used in this study are routine elements of clinical health assessment and 
Phase 2 drug development.


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As noted in Section 8.1, pruritus, angioedema, and hives are monitored as clinical endpoints and 
would not constitute AEs.  However, if any of these events is an SAE as defined in Appendix 
10.3, Section 10.3.2, the event should be reported as an SAE.  See Section 8.3.6 for more 
information.
8.2.1.
Vital Signs
Measurements of vital signs (body temperature, blood pressure, and pulse rate) will be conducted 
at the study visits specified in the SoA (Section 1.3) and as clinically indicated.  Additional vital 
signs may be measured during each study period as per judgment of the investigator.
Blood pressure and pulse rate should be measured after the participant has been sitting for at 
least 5 minutes. Orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms.  If orthostatic measurements are required, participants 
should be supine for at least 5 minutes and stand for at least 3 minutes.  If the participant feels 
unable to stand, only supine vital signs will be recorded.
8.2.2.
Physical Examinations
One complete physical examination will be performed at Visit 1.  This examination includes a 
visual examination of the skin and an assessment of peripheral lymph nodes but excludes pelvic, 
rectal, and breast examinations.
A symptom-directed physical examination that includes a visual examination of the skin will be 
performed at other visits, as specified in the SoA (Section 1.3) or as clinically indicated.
8.2.3.
Electrocardiograms
For each participant, 12-lead electrocardiograms (ECGs) will be collected as specified in the 
SoA (Section 1.3).  Participants must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.
Electrocardiograms should be taken before collecting any blood for safety or PK tests; however, 
aberrations to this specified time will not be considered protocol deviations as long as the ECGs 
are taken and the actual recording time is documented.  Electrocardiograms may be obtained at 
additional visits and times when deemed clinically necessary.  Collection of additional ECGs is 
allowed to ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the study site as soon after the time of ECG collection as possible, and ideally while 
the participant is still present, to determine whether the participant meets the study entry criteria 
and for immediate participant management, should any clinically relevant findings be identified.
8.2.4.
Chest Radiography
A posterior–anterior (PA) chest x-ray CXR, interpreted and reported by a radiologist or 
pulmonologist, will be obtained at screening, as specified in the SoA (Section 1.3).  A lateral 
CXR can also be obtained if, in the opinion of the investigator, a lateral view is indicated.
Note:  Participants do not need to have a CXR at screening if, based on the judgment of 
the investigator, both of the following two conditions are met:


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  the CXR was performed within 6 months before initial screening, and
  documentation of the CXR, read by a qualified radiologist or pulmonologist, is 
sufficient for TB evaluation according to local standard of care.
For each participant, the CXR films or images or a radiology report must be available to the 
investigator for review before the participant is randomized.  Certain findings from CXR may be 
consistent with a condition that excludes a participant from the study; see Section 5.2.
Note: Results of a chest computerized tomography (CT) scan or other imaging study 
similar to a CXR may be substituted in place of the CXR as described above, in 
consultation with the sponsor’s medical monitor.
8.2.5.
Stool Testing
The stool evaluation will be conducted only for participants with certain risk factors and an 
eosinophil count >2 times ULN (Section 5.2).  To be randomized, these participants must have a 
negative stool culture indicating no enteric pathogens (ova or parasites) are isolated.
Retesting is allowed within the screening period if there is a technical difficulty in performing or 
reporting the stool culture assay (Section 5.4.1).
8.2.6.
Laboratory Tests
Appendix 10.2 lists the clinical laboratory tests to be performed, and the SoA (Section 1.3) 
specifies the study visits at which samples are routinely collected for clinical laboratory tests.
Under special circumstances (for example, site closure or other restrictions), local laboratory 
testing is permitted after consultation with the sponsor’s medical monitor as specified if 
indicated per PI to evaluate AEs .
If a participant elects, or is advised by the site, to have local labs drawn via home health or by 
presenting to a local lab, the lab analytes to be tested for safety assessment must be ordered at the 
local lab by the PI/site. The specific lab analytes for safety assessment will be determined in 
consultation with the sponsor’s medical monitor.  These analytes will be drawn, sampled, tested, 
and reported back to the PI/site. The PI must sign and date review of safety labs as per normal 
process.
Additional samples for laboratory testing will be obtained in the event of anaphylaxis or systemic 
allergic/hypersensitivity reactions, as described in Section 8.3.7.2 and Appendix 10.2.  
Additional tests may be performed at any time during the study as deemed necessary by the 
investigator or as required by local regulations.
All protocol-required laboratory assessments, as defined in Appendix 10.2, must be conducted in 
accordance with the laboratory manual and the SoA.
Reviewing and recording test results
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents.


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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (for example, SAE or AE or dose modification), the 
results must be recorded in the CRF.
Repeat testing after clinically significant abnormal findings
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  Laboratory tests with values that are clinically significantly abnormal 
during participation in the study or within 12 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.  If the values do not return to 
normal/baseline within a period of time judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
Blinding of laboratory test results
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel (Appendix 10.2).
Sample retention
Unless otherwise specified in the subsections of Section 8 or in Appendix 10.1, Section 10.1.12
(“Long-Term Sample Retention”), all samples collected for specified laboratory tests will be 
destroyed within 60 days of receipt of confirmed test results.  Certain samples may be retained 
for a longer period, if necessary, to comply with applicable laws, regulations, or laboratory 
certification standards.
8.2.6.1.
Pregnancy Testing
Pregnancy testing is to be performed on women of childbearing potential and women with a 
history of tubal ligation (see Section 5.1). Participants who are pregnant will be discontinued 
from the study (Section 7.1.1).
Visits and times
Serum pregnancy test will be done at screening only, and results will be confirmed by the central 
laboratory.
Urine pregnancy testing will be performed locally at visits specified in the SoA (Section 1.3).  
The urine pregnancy test must be “negative” within 24 hours prior to administration of study 
drug at every study visit.
Urine pregnancy testing may be performed at additional time points during the treatment period 
and/or follow-up period, at the discretion of the investigator or if this is required by local 
regulations.
If a urine pregnancy test is not available, a serum pregnancy test is an acceptable alternative.
Optional FSH Testing
Assessment of FSH levels can assist in determining if a woman meets the definition of 
“postmenopausal” as described in Section 5.1.  The participant’s FSH level can be obtained 


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during screening at the discretion of the investigator.  The FSH level can also be optionally 
obtained during the study to determine the participant’s postmenopausal status (see Section 1.3
and Appendix 10.2).
8.2.7.
Tuberculosis Testing and Monitoring
Tuberculosis Testing
During screening, all participants are to be assessed for risk factors, symptoms, and signs of TB 
with all of the following:
Thorough history to determine the lifetime risk factors for TB infection, for TB 
progression, and for symptoms and/or signs of active TB, and
Signs of previous or active TB by means of
Thorough physical examination for signs of active TB, including measurement of 
body temperature and assessment of peripheral lymph nodes (Section 8.2.2), and
PA CXR interpreted and reported by radiologist or pulmonologist (Section 8.2.4).
All participants with no history of LTBI or active TB, and no history of positive Mantoux 
tuberculin skin test (TST) using purified protein derivative (PPD) or positive Mycobacterium
tuberculosis interferon gamma release assay (IGRA) must have one of the following:
Purified Protein Derivative (PPD) TST
The TST is performed by injecting 0.1 mL of tuberculin PPD into the inner surface 
of the forearm. The injection should be made with a tuberculin syringe, with the 
needle bevel facing upward. The TST is an intradermal injection. When placed 
correctly, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 
mm in diameter.  Measure induration at site of intradermal injection 48 to 72 hours 
after intradermal injection. Test must be read during this window of time.  The 
reaction should be measured in millimeters of induration (palpable, raised, hardened 
area or swelling). The reader should not measure erythema (redness). The diameter 
of the indurated area should be measured across the forearm (perpendicular to the 
long axis).
An induration of 5 or more millimeters is considered positive in
¤ HIV-infected persons
¤ A recent contact of a person with TB disease
¤ Persons with fibrotic changes on chest radiograph consistent with prior TB
¤ Persons with organ transplants
¤ Persons who are immunosuppressed for other reasons (for example, taking 
the equivalent of >15 mg/day of prednisone for 1 month or longer, taking 
tumor necrosis factor-α antagonists)
An induration of 10 or more millimeters is considered positive in all other potential 
clinical trial participants.


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Two-step testing (repeat TST 1 to 3 weeks after the first TST) is recommended for 
certain participant groups, including: 
¤ persons receiving immunosuppressant treatment
¤ persons with a history of temporally remote increased risk of TB infection 
¤ persons for whom the first test is negative, as per local public health and/or 
professional medical society recommendations.
Interferon Gamma Release Assay (IGRA) for M tuberculosis.  Ensure that specimen 
handling, transport, timing, and laboratory procedures meet all requirements per 
package insert.  If the investigator suspects a false-positive IGRA result in a participant 
with no increased risk of TB infection during lifetime, and no evidence of prior or 
current TB on physical examination and/or on CXR interpreted by radiologist and/or 
pulmonologist (investigator assessment by history and physical examination, and 
CXR report documented in eCRF), the investigator may discuss retesting with the 
sponsor’s designated medical monitor.
Retesting
One retest is allowed for participants with an “indeterminate” QuantiFERON-TB Gold assay or
“borderline” T-SPOT assay. Participants with 2 indeterminate QuantiFERON-TB Gold assays
or 2 borderline T-SPOT assays will be excluded.
Diagnosed LTBI
Participants diagnosed with LTBI are excluded unless they are candidates for LTBI treatment, 
are treated for LTBI, and the following criteria are met:
After receiving at least 4 weeks of appropriate LTBI therapy (as per World Health 
Organization and/or the United States Centers for Disease Control guidelines), there is 
no evidence of hepatotoxicity (ALT/AST must remain ≤2 times ULN) or other 
treatment intolerance.  The participant may be rescreened, and is not excluded due to 
LTBI.
The participant must continue and complete appropriate LTBI therapy in order to 
remain eligible to continue to receive study intervention.
8.2.8.
Hepatitis B Testing and Monitoring
Initial testing for HBV infection includes hepatitis B surface antigen (HBsAg) and antibody to 
hepatitis B core antigen (anti-HBc).
  If HBsAg is positive, the participant is excluded.
  If HBsAg is negative and anti-HBc is negative, the participant is not excluded.
  If HBsAg is negative and anti-HBc is positive, the participant is excluded.
8.2.9.
Hepatitis C Testing and Monitoring
Initial testing for HCV infection includes testing for antibodies to HCV.
If anti-HCV is positive, a serum test for circulating HCV RNA is required.


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If HCV RNA test is negative, the participant is not excluded.
If HCV RNA test is positive, the participant is excluded (see Section 5.2).
Participants who have had HCV infection and been successfully treated, defined as a sustained 
virologic response (HCV RNA by polymerase chain reaction (PCR) negative for at least 24 
weeks following treatment completion) are not excluded on the basis of HCV as long as HCV 
RNA test is negative at screening.
If HCV RNA is detected during the study, the study drug will be discontinued (Section 7.1.1),
and the participant should receive appropriate follow-up medical care.
8.2.10.
Hepatic Safety Monitoring
If a study participant experiences elevated ALT ≥3 times ULN, ALP ≥2 times ULN, or TBL 
≥2 times ULN, liver testing (described in Appendix 10.5) 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 and evaluation for possible 
causes of abnormal liver tests should be initiated by the investigator in consultation with the 
study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should continue until levels 
normalize or return to approximate baseline levels.
Hepatic Safety Data Collection
Additional safety data should be collected via the hepatic eCRF packet if 1 or more of the 
following conditions occur: 
elevation of serum ALT to ≥5 times ULN on 2 or more consecutive blood tests
elevated serum TBL to ≥2 times ULN (except for cases of known Gilbert’s syndrome)
elevation of serum ALP to ≥2 times ULN on 2 or more consecutive blood tests
participant discontinued from treatment due to a hepatic event or abnormality of liver tests, 
or
hepatic event considered to be an SAE.
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the study participant or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative.
The investigator and qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE (Appendix 10.3, Section 10.3.1) or SAE 
(Appendix 10.3, Section 10.3.2) and remain responsible for follow-up of AEs through an 
appropriate health care option (Section 8.3.3).
As noted in Section 8.1, pruritus, angioedema, and hives are monitored as clinical endpoints and 
would not constitute AEs.  However, if any of these events is an SAE as defined in 
Appendix 10.3, Section 10.3.2, the event should be reported as an SAE.  See Section 8.3.6 for 
more information.


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Pregnancy after maternal or paternal exposure to IP does not meet the definition of an AE.  
However, to fulfill regulatory requirements, any pregnancy should be reported using the SAE 
process described in Appendix 10.3, Section 10.3.4, to collect data on the outcome for both 
mother and fetus.  See also Section 8.3.5.
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received 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 (see 
Appendix 10.3, Section 10.3.3 and Section 10.3.4) if the SAE is considered reasonably possibly 
related to study procedure.
All SAEs will be recorded and reported to the sponsor or designee immediately upon investigator 
awareness of the event; under no circumstance should this exceed 24 hours from the time of 
awareness, as indicated in Appendix 10.3. The investigator will likewise submit any updated 
SAE data to the sponsor within 24 hours of its availability.
Investigators are not obligated to actively seek AEs or SAEs in study participants once the 
participants have discontinued and/or completed the study (the Participant Study Disposition 
eCRF has been completed).  However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and the investigator considers 
the event reasonably possibly related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3, Section
10.3.3 and Section 10.3.4.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each event at 
subsequent visits and/or contacts with the participant.
All SAEs and AEs that are otherwise medically important, or that are considered related to the IP
or study procedures, or that caused the participant to discontinue the IP before completing the 
study, will be followed up until the event is resolved, stabilized, or otherwise explained, or until 
the participant is lost to follow-up (as defined in Section 7.3).  The frequency of follow-up 
evaluations is at the discretion of the investigator.
Further information on follow-up procedures is provided in Appendix 10.3, Section 10.3.3.


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8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE, as stated in Section 8.3.1, is 
essential so that legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements related to safety reporting to 
the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review and 
then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
For all pregnancies in female participants and female partners of male participants, details will 
be collected for pregnancies that begin at any point after the start of study drug and until at least 
12 weeks after the participant’s last dose of study drug.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 10.3, Section 10.3.3 and 
Section 10.3.4; and Appendix 10.4.
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Study Endpoints Not Qualifying as Adverse Events
The following events are being captured as study endpoints and will not be reported as AEs:
  Pruritus (itching)
  Angioedema
  Hives (wheals)
Information on these events will be captured via the UPDD (patient electronic diary).
However, if any of these events is an SAE as defined in Appendix 10.3, Section 10.3.2, the event 
should be reported as an SAE.
8.3.7.
Adverse Events of Special Interest
Adverse events of special interest for this study include anaphylaxis, infusion reactions, and 
infections.  If such AEs are reported, sites will be prompted to collect additional data as 
described in the following subsections.


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8.3.7.1.
Infusion Reactions
Symptoms of a local infusion site reaction may include erythema, induration, pain, and edema.  
Worsening of CSU symptoms present at baseline does not necessarily constitute an infusion 
reaction, per the investigator’s determination (see Section 8.3.6).  If an infusion site event is 
reported, the AE will be recorded, and additional data will be provided to the sponsor in the 
eCRF.
8.3.7.2.
Allergic Reactions and Hypersensitivity Events
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include but are not limited to:
skin rash
dyspnea
hypotension, and
anaphylactic reaction (Sampson et al. 2006).
Participants with clinical manifestations of systemic allergic/hypersensitivity reactions should be 
treated per local standard of care.  Additional data describing each symptom should be provided 
to the sponsor in the eCRF.
Blood sample collection for systemic allergic/hypersensitivity events
In case of anaphylaxis or a systemic hypersensitivity event, additional blood samples should be 
collected as close as possible to the onset of the event.  Follow-up samples should be obtained at 
the next regularly scheduled visit or 4 weeks after the event, whichever is later.  The laboratory 
test results are provided to the sponsor via the central laboratory.  See Appendix 10.2 for selected 
tests for which samples should be collected in the event of anaphylaxis or generalized urticaria.
8.3.7.3.
Infections
Completion of the Infection eCRF page is required for each infection reported as an AE/SAE.  
The sponsor will identify infections considered to be opportunistic based on the article by 
Winthrop et al. (2015) (Appendix 10.6).
8.3.8.
Complaint Handling
Lilly collects product complaints on investigational medicinal products used in clinical trials in 
order to ensure the safety of study participants, monitor quality, and facilitate process and 
product improvements.  Participants should be instructed to contact the investigator as soon as 
possible if he or she has a complaint or problem with the investigational medicinal product so 
that the situation can be assessed.
8.4.
Treatment of Overdose
For the purposes of this study, an overdose of LY3454738 is considered any dose higher than the 
dose assigned through randomization.
The treatment for overdose is supportive care (see the IB for LY3454738).


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8.5.
Pharmacokinetics
Visits and times
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the serum concentrations of LY3454738.  The actual date and time (24-hour clock 
time) of dosing and sample collection will be recorded.
Blood samples for PK are requested to be collected at the specified times.  However, deviations 
from the specified sampling times will not be considered protocol deviations as long as the 
samples are collected and the actual sampling time is recorded.  It is essential that the actual 
times of doses and samples are recorded accurately on the appropriate forms.
Collection, handling, and storage of samples
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3454738 will be determined using a validated enzyme-linked 
immunosorbent (ELISA) assay method.  Analyses of samples collected from placebo-treated 
participants are not planned.
Additional and unused samples
A maximum of 3 additional samples for exploratory analyses such as bioanalytical method 
development or validation exercises may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.
In the case of systemic allergic/hypersensitivity reactions, additional blood samples will be 
obtained for PK analysis (Section 8.3.7.2).
Any excess samples collected for PK testing may be pooled and used for exploratory analyses 
such as bioanalytical assay validation or cross-validation exercise.
Blinding
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.
Sample retention
Samples collected to measure IP concentration will be retained at a facility selected by the 
sponsor or its designee.  These samples will be retained for the purposes and maximum duration 
specified in Appendix 10.1, Section 10.1.12.
8.6.
Pharmacodynamics
In addition to exploratory biomarker sample collections described below (Section 8.8), samples 
for other PD evaluations will be collected for exploratory analyses at the visits and times 
specified in the SoA (Section 1.3), where local regulations allow.  These evaluations may include 
high-sensitivity C-reactive protein (hs-CRP), characterization of white blood cell differential 
counts, and soluble CD200R levels.


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8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA
(Section 1.3), where local regulations allow.
Sample use
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3454738 and to investigate genetic variants thought to play a role in CSU.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.
Molecular technologies are expected to improve during 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 
protocol.
Confidentiality
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  The sponsor will 
store the blood and/or deoxyribonucleic acid (DNA) samples in a secure storage space with 
adequate measures to protect confidentiality.
Sample retention
Samples will be retained at a facility selected by the sponsor or its designee.  These samples will 
be retained for the purposes and maximum duration specified in Appendix 10.1, Section 10.1.12, 
or for a shorter period if local regulations and/or Ethical Review Boards (ERBs)/IRBs impose 
shorter time limits.
8.8.
Biomarkers
Serum, plasma, whole blood RNA, and whole blood for nonpharmacogenetic biomarker research 
will be collected at the visits and times specified in the SoA (Section 1.3), where local 
regulations allow.
Sample use
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of participant response 
(including safety), and/or 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 will be used for research on the drug target, CSU disease process, variable response 
to LY3454738, pathways associated with CSU, mechanism of action of LY3454738, and/or 
research method or in validating diagnostic tools or assays related to CSU or to LY3454738.
Confidentiality
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.


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Sample retention
Samples will be retained at a facility selected by the sponsor or its designee.  These samples will 
be retained for the purposes and maximum duration specified in Appendix 10.1, Section 10.1.12, 
or for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits.
8.9.
Immunogenicity Assessments
Visits and times
At the visits and times specified in the SoA (Section 1.3), predose venous blood samples will be 
collected to determine antibody production against LY3454738.  The actual date and time 
(24-hour clock time) of each sample collection will be recorded.
To aid interpretation of these results, a predose blood sample for PK analysis will be collected at 
the same time points.
Sample collection, handling, and use
Instructions for the collection and handling of blood samples will be provided by the sponsor.
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies 
(ADAs) in the presence of LY3454738 at a laboratory approved by the sponsor.  Antibodies will 
be further evaluated for their ability to neutralize the activity of LY3454738, when available.
Sample retention
Samples will be retained at a facility selected by the sponsor or its designee.  These samples will 
be retained for the purposes and maximum duration specified in Appendix 10.1, Section 10.1.12, 
or for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits.
8.10.
Health Economics or Medical Resource Utilization and Health 
Economics
This section is not applicable.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The study will compare LY3454738 with placebo in adults with CSU. The primary study
objective is to demonstrate superior efficacy of LY3454738 over placebo.
The primary comparison of interest is the mean change of the UAS7 from baseline to Week 12. 
Secondary comparisons include the mean change of the ISS7 and the HSS7 from baseline to 
Week 12 as well as the proportion of participants achieving a UAS7 ≤6 at Week 12.
Efficacy comparisons will be made regardless of treatment discontinuation and without regard to 
changes to any background therapies. No adjustments for multiplicity will be made across the 
efficacy assessments.
9.2.
Sample Size Determination
Assuming a 30% screen fail rate, approximately 85 participants will be screened to achieve 
60 participants randomly assigned to study intervention for an estimated total of 52 evaluable 
participants.
The sample of 52 evaluable participants provides about 87% power to the primary endpoint.  
This calculation is based on a 2-sample t-test, assuming a mean change from baseline to 
Week 12 in the UAS7 for LY3454738 and for placebo of 17 points and 10 points, respectively, a 
standard deviation of 7 points for the change from baseline, and a 0.05 two-sided significance 
level.
9.3.
Populations for Analyses
The following populations are defined for this study:
Population
Description
Entered
All participants who sign the informed consent form
Modified Intent-to-Treat (mITT)
All participants randomly assigned to study intervention and who take at 
least 1 dose of study intervention. Participants will be analyzed according 
to the intervention to which they were assigned.
Safety
All participants randomly assigned to study intervention and who take at 
least 1 dose of study intervention. Participants will be analyzed according 
to the intervention they actually received within each study period.
Pharmacokinetic (PK) Analysis
All participants randomly assigned to study intervention and who take at 
least 1 dose of study intervention and have PK data available.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee.
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 


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in the statistical analysis plan (SAP) and clinical study report.  Additional exploratory analyses 
of the data will be conducted as deemed appropriate.
The SAP will be finalized prior to unblinding.  It will include a more technical and detailed 
description of the statistical analyses described in this section.  This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints.
9.4.1. General Considerations
Efficacy analyses will be conducted on the Modified Intent-to-Treat (mITT) Population.  This set 
includes all data from all randomized participants receiving at least 1 dose of the IP according to 
the treatment the participants were assigned.
Safety analyses will be conducted on the Safety Population.  This set includes all data from all 
randomized participants receiving at least 1 dose of the IP according to the treatment the 
participants actually received.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All confidence intervals (CIs) will be given at a 2-sided 95% level. Descriptive 
summaries of continuous data will present the group mean, standard deviation, median, 
minimum, maximum, and sample size. Descriptive summaries of discrete data will report the 
number of participants and incidence as a frequency and as a percentage.
The baseline value for Period 2 is defined as the last nonmissing measurement on or before the
date of first study drug administration (expected at Week 0).  The baseline value for Period 3 is 
the last available value before the initial dose in Period 3 (expected at Week 12).  Other 
definitions of the baseline value may be used to conduct additional supporting analyses.
A number of efficacy outcome measures are in the form of weekly scores derived from patient 
daily diary data. For these measures, the weekly score will be derived from the 7 days 
immediately prior to the study visit. The baseline score will be derived from the 7 days prior to 
Day 1.
9.4.1.1.
Participant Disposition
A detailed description of participant disposition will be provided, including a summary of the 
number and percentage of participants entered into the study, enrolled in the study, and treated, 
as well as number and percentage of participants completing the study (participants who receive 
at least 1 dose of study drug and have at least 1 postbaseline assessment), or discontinuing 
(overall and by reason for discontinuation). A summary of all important protocol deviations will 
be provided.
9.4.1.2.
Participant Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population.  A summary of baseline participants and disease characteristics, 
historical diagnoses, pre-existing conditions, and prior therapies will be reported by cohort using 
descriptive statistics.  Other participant baseline characteristics will be summarized by group as 
deemed appropriate.


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9.4.1.3.
Missing Data Imputation
Missing continuous scores will be imputed using baseline observation carried forward (BOCF) 
analyses.
The UAS7 score is the sum of the daily UAS scores over 7 days each week.  The daily score is 
the average of 2 results when both entries are made, or it is the single result when only 1 entry is 
made in a given day.  When 1 or more of the daily UAS scores are missing, the following 
principles will be applied to handle the missing data:
  If a participant has at least 4 nonmissing daily UAS scores within the 7 days prior to the 
study visit, the UAS7 score is calculated as the sum of the available UAS scores in that 
week, divided by the number of days that have a nonmissing diary UAS score, 
multiplied by 7.
  If there are less than 4 nonmissing daily UAS scores within the prior 7 days, then the 
UAS7 score is missing for the week.
The same principles will be applied to handle the missing data for all of the weekly outcomes.

Nonresponder imputation (NRI):  All participants 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.

Mixed-effects model of repeated measures (MMRM):  Continuous variables will be 
assumed to be missing after discontinuation for which an MMRM analysis will be 
performed.

BOCF, as previously stated.
9.4.2.
Primary Endpoints
The primary efficacy endpoint is the change in UAS7 score from baseline to Week 12 in 
Period 2, defined as the Week 12 UAS7 score minus the baseline UAS7 score.
The analysis of the primary endpoint will consist of treatment comparisons made using analysis 
of covariance (ANCOVA) controlling for baseline UAS7 score. The ANCOVA model will be 
based on the mITT population. Missing Week 12 scores will be imputed by carrying forward the 
participants’ baseline scores (BOCF).
The objective of the primary endpoint is to establish superiority of LY3454738 over placebo.
9.4.3.
Secondary Endpoints
Secondary comparisons of interest are described below. The objective of these secondary 
endpoints is to demonstrate superiority of LY3454738 over placebo.
9.4.3.1.
Change from Baseline in ISS7 at Week 12
Change from baseline in ISS7 at Week 12 is the Week 12 ISS7 score minus the baseline ISS7 
score. An ANCOVA model similar to the one described for the primary endpoint will be used 
for analysis of this secondary endpoint.


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9.4.3.2.
Change from Baseline in HSS7 at Week 12
Change from baseline in HSS7 at Week 12 is the Week 12 HSS7 score minus the baseline HSS7 
score. An ANCOVA model similar to the one described for the primary endpoint will be used 
for analysis of this secondary endpoint.
9.4.3.3.
Proportion of Patients with UAS7 ≤6 at Week 12
The proportions of participants who achieve a UAS7 score ≤6 at Week 12 will be presented for 
each treatment group. Participants will be classified as nonresponders at Week 12 (that is, did 
not achieve UAS7 ≤6 at Week 12) if they have a missing UAS7 score at Week 12.
The Cochran-Mantel-Haenszel test stratified by baseline UAS7 (< median versus ≥median) will 
be performed to compare the proportions of participants with UAS7 ≤6 at Week 12 in the 
LY3454738 group versus placebo.
9.4.3.4.
Pharmacokinetic Analysis
Serum concentrations of LY3454738 will be analyzed using a population approach via nonlinear 
mixed effects modeling (NONMEM) with the NONMEM software.  Model-estimated individual 
clearance values will be used to calculate area under the plasma concentration versus time curve 
(AUC) for individual participants. The PK data from Study FRCF may be combined with data 
from the Phase 1 study FRCC to improve PK parameter estimation.
9.4.4.
Exploratory Endpoints
Exploratory analyses for PD and biomarker data will be described in the SAP that is finalized 
before database lock. Relationships between LY3454738 exposure and the primary efficacy 
endpoint, UAS7 score at Week 12, and other efficacy endpoints and biomarkers may be 
explored.
9.4.4.1.
Evaluation of Immunogenicity
Frequencies and percentages will be tabulated for the following:
  participants with pre-existing ADA, and
  participants who are treatment-emergent ADA positive (TE-ADA+) to LY3454738.
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected 
at baseline (treatment-boosted ADA).  For the TE ADA+ participants, the distribution of 
maximum titers will be described.  The frequency of neutralizing antibodies, when available, will 
also be tabulated for the TE-ADA+ participants.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3454738 may be assessed.  Additional details may be 
provided in the SAP.


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9.4.5.
Safety Analyses
Safety data will be descriptively summarized for the Safety Population by treatment group and 
analyzed using the methods described in Section 9.4.
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 the IP.  A 
treatment-emergent adverse event (TEAE) is defined as an event that first occurred or worsened 
in severity after baseline.  For each event classification term, the number of participants
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 participants from the given gender.
9.5.
Interim Analyses
Analysis for the primary database lock will be conducted when all participants have completed 
the Period 2 (or discontinued Period 2 treatment).  An interim analysis prior to the primary 
database lock may be conducted when approximately 50% of the participants have had the 
opportunity to complete Period 2 (including those who discontinued Period 2 treatment).  Other 
interim analyses may be conducted as needed.  All interim analyses will be used to support 
planning activities associated with the development program.  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 (see Appendix 10.1, Section 10.1.5).  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.  To minimize bias, the SAP and PK/PD analysis plan 
will be finalized and approved before unblinding.  Unblinding details are specified in the SAP
and Unblinding Plan.  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.
9.6.
Data Monitoring Committee (DMC)
Not applicable.  An internal assessment committee will be used to conduct the interim analysis
(see Section 9.5 and Appendix 10.1, Section 10.1.5).


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
Applicable International Council for Harmonisation (ICH) GCP Guidelines, and
Applicable laws and regulations.
The protocol, protocol amendments and addenda, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 United States Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations.
After reading the protocol, each principal investigator will sign the separate protocol signature 
page and send a copy of the signed page to a Lilly representative.
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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10.1.3.
Informed Consent Process
The investigator or his or her representative will explain the nature of the study, including the 
risks and benefits, to the participant or his or her legally authorized representative and answer all
questions regarding the study.
Participants must be informed that their participation is voluntary.
Participants or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.
The medical record must include a statement that written informed consent was obtained before 
the participant participated in any study procedures or received the investigational intervention.  
The statement must include the date on which the written consent was obtained.  The authorized 
person obtaining the informed consent must also sign the ICF(s).
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. A copy of the ICF(s) is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records,
datasets, or tissue samples that are transferred to the sponsor will contain only the identifier; 
participant names or any information that would make the participant identifiable will not be 
transferred.
The participant must be informed that his or her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  The participant will be required to give consent for their data to be 
used as described in the informed consent.
The participant must be informed that his or her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Committee Structure
Internal Assessment Committee (IAC)
In addition to the safety reviews routinely performed by the blinded study team, an IAC will 
review the unblinded efficacy and safety data at the time of any interim analysis.  The IAC will 
include, at a minimum, a Lilly medical physician, a statistician, and a representative from the 
Lilly Global Patient Safety organization, but will not include any Lilly study team members.  
Details about the IAC membership, purpose, responsibilities, and operation will be described in 
an IAC charter.  Investigator sites will receive information about interim analysis results only if 
they need to know for the safety of their study participants.


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10.1.6.
Dissemination of Clinical Study Data
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publically available websites where required by local law or regulation.
Data
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data.  Data are available to request 6 months 
after the indication studied has been approved in the United States and European Union and after 
primary publication acceptance, whichever is later.  No expiration date of data requests is 
currently set once data are made available.
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement.  Data and 
documents, including the study protocol, SAP, clinical study report, and blank or annotated case 
report forms, will be provided in a secure data sharing environment for up to 2 years per 
proposal.
For details on submitting a request, see the instructions provided at 
www.clinicalstudydatarequest.com.
10.1.7.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (for example, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  This might include laboratory tests, medical records, and 
clinical notes.  The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data documents.
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring), are described in the 
monitoring plan, associated sponsor documentation, and required standards and regulations.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (for example, 
contract research organizations).
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents;
the safety and rights of participants are being protected; and 


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the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
In addition, the sponsor or its representatives will periodically check a sample of the participant
data recorded against source documents at the study site.  The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time.  Investigators will be given 
notice before an audit occurs.
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 (EDC) system 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, clinical outcome assessment (COA) data (participant-focused outcome instrument) 
will be collected by the participant, via a paper source document per the SoA, and will be 
transcribed by the investigator site personnel into the EDC system.
Additionally, electronic Clinical Outcome Assessment (eCOA) data (participant-focused 
outcome instrument) will be directly recorded by the participant, into an instrument per the SoA
(for example, hand-held smartphone).  The eCOA data will serve as the source documentation 
and the investigator does not maintain a separate, written or electronic record of these data.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Sponsor data warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.8.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.


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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Current medical records must be available.  What constitutes source data can be found in 
Appendix 10.1, Section 10.1.7.
10.1.9.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the opening of the first site.  The date of that opening will be 
considered the study start date.
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines
inadequate recruitment of participants by the investigator, and
discontinuation of further study drug development.
Premature Termination or Suspension of the Study (“Stopping Rules”)
The internal assessment committee (IAC) will evaluate unblinded safety data if 
●  three or more participants experience TEAEs in the same system organ class, and
●  these TEAEs are assessed as severe by the investigator and/or meet at least 1 serious 
criterion, and 
●  these TEAEs are judged as related to blinded study treatment by the investigator.  
Pending the evaluation by the IAC study, enrollment and/or further dosing may be stopped, or 
the dose and/or other study parameters may be modified (Section 9.5 and Section 10.1.5).  For 
details about the IAC operations (including meeting frequency), see the IAC Charter.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research organizations 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should 
assure appropriate therapy and/or follow-up for the participant.


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10.1.10.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal.
10.1.11.
Information about Participating Investigators
Physicians with experience in the diagnosis and treatment of CSU will participate as 
investigators in this clinical trial.
10.1.12.
Long-Term Sample Retention
Sample retention 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
LY3454738 or after LY3454738 becomes commercially available.
The following table lists the maximum retention period for sample types.  The retention period 
begins after the last participant visit for the study. Any samples remaining after the specified 
retention period will be destroyed.
Sample Type
Custodian
Retention Period after Last Participant Visit
Pharmacokinetics
Sponsor or designee
1 year
Long-term storage samples
Sponsor or designee
15 years
    Biomarkers
Sponsor or designee
15 years
    Genetics/DNA
Sponsor or designee
15 years
    Immunogenicity
Sponsor or designee
15 years
Abbreviation:  DNA = deoxyribonucleic acid.


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10.2.
Appendix 2: Clinical Laboratory Tests
Hematology a,b
Clinical Chemistry a,b
Hemoglobin
Sodium
Hematocrit
Chloride
Erythrocyte count (RBCs)
Bicarbonate
Mean cell volume
Potassium
Mean cell hemoglobin
Total bilirubin
Mean cell hemoglobin concentration
Total protein
Leukocytes (WBCs)
Direct bilirubin
Differential
Alkaline phosphatase (ALP)
   Neutrophils, segmented
Alanine aminotransferase (ALT)
   Lymphocytes
Aspartate aminotransferase (AST)
   Monocytes
Gamma-glutamyl transferase (GGT)
   Eosinophils
Blood urea nitrogen (BUN)
   Basophils
Creatinine
Platelets
Creatine kinase (CK)
Cell morphology
Uric acid
Calcium
Urinalysis a,b
Glucose
Specific gravity
Albumin
pH
Cholesterol (total)
Protein
Triglycerides
Glucose
Ketones
Lipid Panel (fasting) a,b,c,k
Bilirubin
High-density lipoprotein
Urobilinogen
Low-density lipoprotein
Blood
Nitrite
Hormones (female)
Urine leukocyte esterase
Pregnancy test (serum a,b,d,h and urine f)
Microscopic examination of sediment
Follicle-stimulating hormone (FSH) a,b,g
Stool evaluation a,b,i
table continues


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Biomarkers a,b
Serology
C-reactive protein, high-sensitivity l
Tuberculosis (TB) testing:
Receptor occupancy assay l
   QuantiFERON-TB Gold test a,b, d or T-SPOT d,j or TST d,j
HIV testing a,b,d
Serum immunoglobulins (IgG, IgM, IgA, IgE) a
HCV testing:
   Hepatitis C antibody a,b,d,e
Pharmacogenomics sample l
HBV testing: 
  Hepatitis B core antibody a,b
Stored Samples l
   Hepatitis B surface antigen a,b
Exploratory storage samples:
   Serum
   Plasma
Pharmacokinetic Samples a,l
   Whole blood (DNA EDTA)
LY3454738 concentration
   RNA
Pharmacokinetics (PK) for immunogenicity (stored)
Immunogenicity Samples a,l
Flow Cytometry a
   Anti-LY3454738 antibodies
TBNK panel
   Anti-LY3454738 antibodies neutralization
Abbreviations:  DNA = deoxyribonucleic acid; EDTA = ethylenediamine tetraacetic acid; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = red blood cell; TBNK = T-cells, 
B-cells, and natural killer (NK) cells; TST = tuberculin skin test; WBC = white blood cell.
a
Assayed by Lilly-designated laboratory.
b Results will be confirmed by the central laboratory/other at the time of initial testing.
c
For the fasting lipid profile, participants should not eat or drink anything except water for 12 hours prior to test.
d Performed at screening only.
e
A positive hepatitis C antibody laboratory assessment will be confirmed with an additional test method.
f
Urine pregnancy test to be performed only on women of childbearing potential and women with history of tubal 
ligation.  Done locally and prior to dosing visits.
g Optional, performed to confirm postmenopausal status.
h
Serum pregnancy test to be performed only on women of childbearing potential and women with history of 
tubal ligation.
i
Only for participants with certain risk factors and eosinophil count >2 times ULN (see Section 5.2 and
Section 8.2.5).
j
Participants who had a TST will return 48 to 72 hours after placement to have their test results read.  
Local laboratory must be qualified by local regulations.
k Fasting is not required for the lipid panel at an early termination visit.
l
Results will not be provided to the investigative sites.


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Selected tests may be obtained in the event of anaphylaxis or systemic allergic/hypersensitivity 
reactions.
Hypersensitivity Tests a
Anti-LY antibodies (immunogenicity)
Tryptase
LY concentration (PK)
N-methylhistamine
Drug Specific IgE b
Basophil Activation Test b
Complements
Cytokine Panel
Abbreviation:  PK = pharmacokinetics.
a
Assayed by Lilly-designated laboratory.
b Will be performed if a validated assay is available.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting
10.3.1.
Definition of AE
AE Definition
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention.
Events Meeting the AE Definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (for example, ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (that is, not related to progression of underlying disease).
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.
New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug–drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE or SAE unless it is 
an intentional overdose taken with possible suicidal or self-harming intent. Such overdoses 
should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE 
or SAE if they fulfil the definition of an AE or SAE.
Events NOT Meeting the AE Definition
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition.
The disease/disorder being studied or expected progression, signs, or symptoms of the 


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disease/disorder being studied, unless more severe than expected for the participant’s condition.
Medical or surgical procedure (for example, endoscopy, appendectomy).  Note: The condition 
that leads to the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing diseases or conditions present or detected at 
the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per the definitions above, the event cannot be an SAE even if serious 
conditions are met (for example, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death, if the event were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted to hospital for 
observation and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt 
as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity
The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(for example, sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect


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f. Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(for example, hospital progress notes, laboratory reports, and diagnostics reports) related to the 
event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
in lieu of completion of the AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on 
the copies of the medical records before submission.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and 
other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, not when it is rated as severe.


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Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-Up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals.
If a participant dies during participation in the study or during a recognized follow-up period,
the investigator will provide a copy of any post-mortem findings including histopathology.
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data within 24 hours of receipt of the 
information.


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10.3.4.
Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool
The primary mechanism for reporting an SAE to the sponsor or the sponsor’s designee will be 
the electronic data collection tool.
If the electronic system is unavailable or if a pregnancy is reported, then the site will use the 
paper SAE or pregnancy data collection tools to report the event within 24 hours.
The site will enter SAE data into the electronic system as soon as it becomes available.
After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then the 
site can report this information directly to the sponsor.
Contacts for SAE reporting can be found in site training documents.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
A female is considered a “woman of childbearing potential (WOCBP)” after menarche and until 
she is a “woman not of childbearing potential.”  A “woman not of childbearing potential” is 
defined in Section 5.1.
Contraception guidance for women of childbearing potential [WOCBP]:
See Section 5.1.
Contraception guidance for men:
See Section 5.1.
Collection of pregnancy information:
Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on a male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive LY3454738.
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed up to determine the outcome of the pregnancy. Information on the status of the mother 
and child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.
Female participants who become pregnant
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant’s 
pregnancy.
The participant will be followed up to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such.
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in Section 8.3.5. While the 


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investigator is not obligated to actively seek this information in former study participants, the 
investigator may learn of an SAE through spontaneous reporting.
See Section 7.1 about the discontinuation of participants who become pregnant.


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10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments
Samples for selected tests may be obtained in the event of a treatment-emergent hepatic 
abnormality and may be required during follow-up with participants in consultation with the 
clinical research physician of the sponsor or designee.
Hepatic Monitoring Tests
Hepatic Hematology a
Haptoglobin a
Hemoglobin
Hematocrit
Hepatic Coagulation a
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologies a,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 Chemistry a
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody a
AST
GGT
Alkaline Phosphatase Isoenzymes a
CPK
Anti-smooth muscle antibody (or anti-actin antibody) a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by sponsor-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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10.6.
Appendix 6: Examples of Infections That May Be Considered 
Opportunistic in the Setting of Biologic Therapy
The following are examples of infections that may be considered opportunistic in the setting of 
biologic therapy (adapted from Winthrop et al. [2015]).  This table is provided to aid the 
investigator in recognizing infections that may be considered opportunistic in the context of 
biologic therapy.  This list is not exhaustive.  Infections will be categorized by Lilly as 
opportunistic according to Opportunistic Infections and Biologic Therapies in Immune-Mediated 
Inflammatory Diseases:  Consensus Recommendations for Infection Reporting during Clinical 
Trials and Postmarketing Surveillance by Winthrop et al. (2015).


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Examples of Infections That May Be Considered Opportunistic in the Setting of Biologic 
Therapy
Bacterial
Bartonellosis (disseminated disease only)
Campylobacteriosis (invasive disease only)
Legionellosis
Listeriosis (invasive disease only)
Nocardiosis
Tuberculosis
Non-tuberculous mycobacterial disease
Salmonellosis (invasive disease only)
Shigellosis (invasive disease only)
Vibriosis (invasive disease due to Vibrio vulnificus)
Viral
BK virus disease including polyomavirus-associated nephropathy
Cytomegalovirus disease
Hepatitis B virus reactivation
Hepatitis C virus progression
Herpes simplex (invasive disease only)
Herpes zoster (any form)
Post-transplant lymphoproliferative disorder (Epstein-Barr virus)
Progressive multifocal leukoencephalopathy (PML), John Cunningham (JC) virus
Fungal
Aspergillosis (invasive disease only)
Blastomycosis
Candidiasis (invasive disease or oropharyngeal, esophageal.  Not isolated lingual)
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Paracoccidioides infections
Penicilliosis
Pneumocystosis
Sporotrichosis
Other invasive molds:  Mucormycosis (zygomycosis) (Rhizopus, Mucor, and Lichtheimia), 
Scedosporium/Pseudallescheria boydii, Fusarium
Parasitic
Leishmaniasis (visceral only)
Strongyloidosis (hyperinfection syndrome or disseminated disease)
Microsporidiosis
Toxoplasmosis
Trypanosoma cruzi infection (Chagas’ disease progression) (disseminated disease only)
Cryptosporidiosis (chronic disease only)
Source:  Adapted from Winthrop et al. (2015).


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10.7.
Appendix 7: Definitions and Selected Abbreviations
Term
Definition
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
anti-HBc
antibody to hepatitis B core antigen
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
blinding
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the 
participants are aware of the treatment received.
CBD
cannabidiol
CFR
United States Code of Federal Regulations
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, Good Clinical Practice (GCP), and applicable regulatory 
requirements
CSU
chronic spontaneous urticaria
CXR
chest x-ray
DLQI
Dermatology Life Quality Index
DNA
deoxyribonucleic acid


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EDC
electronic data capture
ECG
electrocardiogram
eCOA
electronic Clinical Outcome Assessment
eCRF
electronic case report form
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
Ethical Review Board (see IRB)
ETV
early termination visit
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HSS7
Hive Severity Score Over 7 Days
IAC
Internal Assessment Committee
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee (see IRB)
IGRA
interferon gamma release assay
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form.
INR
international normalized ratio


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interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
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.
IRB
Institutional Review Board (IRB), also called Independent Ethics Committee (IEC) or 
Ethical Review Board (ERB)
ISS7
Itch Severity Score Over 7 Days
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IV
intravenous, intravenously
IWRS
interactive web-response system
LTBI
latent tuberculosis infection
MMRM
mixed-effects model of repeated measures
NONMEM
nonlinear mixed effects modeling
NSAID
nonsteroidal anti-inflammatory drug
PA
posterior–anterior
participant
Equivalent to Clinical Data Interchange Standards Consortium (CDISC) term “subject,” 
meaning an individual who participates in a clinical trial, either as recipient of an 
investigational medicinal product or as a control.
In this protocol, the term “participant” is used to indicate an individual who participates 
in a clinical trial, either as a recipient of an investigational medicinal product or as a 
control.  This usage reflects preferences indicated by patient advocates to more 
accurately reflect the role of people who take part in clinical trials.
PD
pharmacodynamic
PK
pharmacokinetic
PPD
purified protein derivative
Q2W
every 2 weeks
RNA
ribonucleic acid
SAE
serious adverse event


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SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SoA
Schedule of Activities
study drug
See “study intervention”
study intervention
Any investigational intervention, marketed product, placebo, or medical device 
intended to be administered to a study participant according to the study protocol
TB
tuberculosis
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TST
tuberculin skin test
UAS7
Urticaria Activity Score Over 7 Days
ULN
upper limit of normal
UPDD
Urticaria Patient Daily Diary
USA
United States of America; also United States
WBC
white blood cell
WOCBP
women of childbearing potential (see Appendix 10.4)


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10.8.
Appendix 8:  Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment A (23 Aug 2019)
This amendment was considered to be nonsubstantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment
The purpose for the amendment was to provide clarification of the timing of the first post-
treatment follow-up visit (Visit 801) relative to the last dosing visit (Visit 15, Week 22). 
Section # and 
Name
Description of Change
Brief Rationale
Section 4.1, 
Overall Design
Corrected the sentence that 
describes the interval between 
the last dosing visit and the 
first post-treatment follow-up 
visit.  The interval should be 
written as “6 weeks,” not “2 
weeks” in Section 4.1.
For accuracy and consistency 
with information provided in 
Section 4.2 and in the Schedule 
of Activities.
Amendment B (29 Jan 2020)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
The rationale for the amendment is to mainly address regulatory feedback received in 
January 2020.
Section # and Name
Description of Change
Brief Rationale
Table 1, Schedule of activities 
for the screening and treatment 
periods of Study J1B-MC-FRCF
Added ECG assessments for 
visits V9, V16, and ETV for 
the treatment period
Changed per request from the 
regulatory agency
Section 5.2, Exclusion Criteria
Deleted the following text 
from criterion [32]:  “or during 
the study”
Changed per request from the 
regulatory agency


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Section # and Name
Description of Change
Brief Rationale
Section 8.1.3.1, Dermatology 
Life Quality Index
Corrected the scoring
classification for DLQI
Corrected an error
Section 8.3.7.2, Allergic 
Reactions and Hypersensitivity 
Events and
Section 11, References
Added the citation for 
Sampson et al. 2006
Changed per request from the 
regulatory agency
Section 10.1.9, Study and Site 
Start and Closure
Added the “stopping rules” for 
the study
Changed per request from the 
regulatory agency


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11.
References
[2007 Expert Panel] 2007 Expert Panel Report 3: Guidelines for the Diagnosis and Management 
of Asthma Summary Report 2007. Available at: https://www.nhlbi.nih.gov/health-
topics/guidelines-for-diagnosis-management-of-asthma or J Allergy Clin Immunol. 2007;120(5 
suppl):S94-S138.
Balp MM, Khalil S, Tian H, Gabriel S, Vietri J, Zuberbier T. Burden of chronic urticaria relative 
to psoriasis in five European countries. J Eur Acad Dermatol Venereol. 2018;32(2):282-290.
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.
ClinicalTrials.gov. NCT03580369. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03580369?term=ligelizumab&rank=5. Accessed July, 
2019.
ClinicalTrials.gov. NCT03580356. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03580356?term=ligelizumab&rank=6. Accessed June, 
2019.
[EMA] European Medicines Agency. Committee for Medicinal Products for Human Use.  
Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials 
with investigational medicinal products. 2017. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC50
0232186.pdf. Published July 20, 2017. Accessed June 22, 2018.
Flood EM, Zazzali JL, Devlen J. Demonstrating measurement equivalence of the electronic and 
paper formats of the Urticaria Patient Daily Diary in patients with chronic idiopathic urticaria. 
Patient. 2013;6(3):225-231.
Guillén-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, Guillén-Grima F, Ferrer M. 
Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a 
systematic review and meta-analysis. Br J Dermatol. 2016;175(6):1153-1165.
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.
Mathias SD, Crosby RD, Rosén KE, Zazzali JL. The minimal important difference for measures 
of urticaria disease activity: Updated findings. Allergy Asthma Proc. 2015;36(5):394-398.
Maurer M, Abuzakouk M, Bérard F, Canonica W, Oude Elberink H, Giménez-Arnau A, 
Grattan C, Hollis K, Knulst A, Lacour JP, Lynde C, Marsland A, McBride D, Nakonechna A, 
Ortiz de Frutos J, Proctor C, Sussman G, Sweeney C, Tian H, Weller K, Wolin D, Balp MM. 
The burden of chronic spontaneous urticaria is substantial: real-world evidence from 
ASSURE-CSU. Allergy. 2017;72(12):2005-2016.
Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, Agarwal S, Doyle R, 
Canvin J, Kaplan A, Casale T. Omalizumab for the treatment of chronic idiopathic or 


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spontaneous urticaria [published correction appears in N Engl J Med. 2013;368(24):2340-
2341]. N Engl J Med. 2013;368(10):924-935.
Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J, 
Canonica GW, Church MK, Godse KV, Grattan CEH, Greaves MW, Hide M, 
Kalogeromitros D, Kaplan AP, Saini SS, Zhu XJ, Zuberbier T. Unmet clinical needs in chronic 
spontaneous urticaria. A GA2LEN task force report. Allergy. 2011;66(3):317-330.
Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchock JD.
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies [published 
correction appears in Ann Oncol. 2016;27(7):1362]. Ann Oncol. 2015;26(12):2375-2391.
O’Donnell B, Lawlor F, Simpson J, Morgan M, Greaves M. The impact of chronic urticaria on 
the quality of life. Br J Dermatol. 1997;136(2):197-201.
Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis of immune
activating products and first-in-human dose selection. Reg Toxicol Pharmacol. 
2016;81:448-456.
Saini SS, Kaplan AP. Chronic spontaneous urticaria: the devil’s itch. J Allergy Clin Immunol 
Pract. 2018;6(4):1097-1106.
Saini S, Bindslev-Jensen C, Maurer M, Grob JJ, Bülbül Baskan E, Bradley M, Canvin J, 
Rahmaoui A, Georgiou P, Alpan O, Spector S, Rosén K. Efficacy and safety of omalizumab in 
patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 
antihistamines: a randomized, placebo-controlled study. J Invest Dermatol. 
2015;135(1):67-75.
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown 
SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, 
Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, 
Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol. 2006;117(2):391-397.
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 
recommendations for infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis. 2015;74(12):2107-2116.
Xolair [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, Bernstein JA, 
Bindslev-Jensen C, Brzoza Z, Buense Bedrikow R, Canonica GW, Church MK, Craig T, 
Danilycheva IV, Dressler C, Ensina LF, Giménez-Arnau A, Godse K, Gonçalo M, Grattan C, 
Hebert J, Hide M, Kaplan A, Kapp A, Katelaris CH, Kocatürk E, Kulthanan K, 
Larenas-Linnemann D, Leslie TA, Magerl M, Mathelier-Fusade P, Meshkova RY, Metz M, 
Nast A, Nettis E, Oude-Elberink H, Rosumeck S, Saini SS, Sánchez-Borges M, 
Schmid-Grendelmeier P, Staubach P, Sussman G, Toubi E, Vena GA, Vestergaard C, Wedi B, 
Werner RN, Zhao Z, Maurer M. The EAACI/ GA2LEN/EDF/WAO guideline for the 


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definition, classification, diagnosis and management of urticaria. Allergy. 
2018;73(7):1393-1414.


Leo Document ID = d84f48a2-ea55-48ea-ba85-6d019973e54c
Approver:
Approval Date & Time: 10-Jun-2020 20:53:34 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 10-Jun-2020 21:26:05 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan (c): J1B-MC-FRCF 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Crossover Study to 
Evaluate the Efficacy and Safety of LY3454738 in Adults with Chronic Spontaneous Urticaria 
Inadequately Controlled with H1-Antihistamines 
 
NCT04159701 
Approval Date: 04-Jun-2021 


J1B-MC-FRCF (c) Statistical Analysis Plan Version 2 
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Statistical Analysis Plan:  
J1B-MC-FRCF (c): A Multicenter, Randomized, Double-
Blind, Placebo-Controlled, Phase 2 Crossover Study to 
Evaluate the Efficacy and Safety of LY3454738 in Adults 
with Chronic Spontaneous Urticaria Inadequately 
Controlled with H1-Antihistamines 
 
Confidential Information 
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.. 
LY3454738 
Study J1B-MC-FRCF (c) is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 2 crossover study to evaluate the efficacy and safety of LY3454738 500 mg given 
intravenously (IV) every 2 weeks (Q2W) versus placebo IV Q2W in adults with CSU 
inadequately controlled with H1-antihistamines. 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol J1B-MC-FRCF(c) 
Phase 2 
 Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below. 
 


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1. Table of Contents 
Section 
Page 
Statistical Analysis Plan:  J1B-MC-FRCF (c): A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 2 Crossover 
Study to Evaluate the Efficacy and Safety of LY3454738 in Adults 
with Chronic Spontaneous Urticaria Inadequately Controlled with 
H1-Antihistamines ...................................................................................................................1 
1. 
Table of Contents ....................................................................................................................2 
2. 
Revision History ......................................................................................................................7 
SAP Amendment Summary of Changes Table .............................................................................7 
3. 
Study Objectives ......................................................................................................................9 
3.1. 
Primary Objective ...............................................................................................................9 
3.2. 
Secondary Objectives .........................................................................................................9 
3.3. 
Exploratory Objectives .......................................................................................................9 
4. 
Study Design .........................................................................................................................10 
4.1. 
Summary of Study Design................................................................................................10 
4.2. 
Method of Assignment to Treatment ................................................................................11 
5. 
A Priori Statistical Methods ..................................................................................................12 
5.1. 
Statistical Hypotheses .......................................................................................................12 
5.2. 
Sample Size Determination ..............................................................................................12 
5.3. 
General Considerations ....................................................................................................12 
5.3.1. 
Analysis Populations ................................................................................................13 
5.3.2. 
Definition of Baseline and Postbaseline Measures ..................................................13 
5.3.3. 
Patient Disposition ...................................................................................................13 
5.3.4. 
Patient Characteristics ..............................................................................................14 
5.3.4.1. 
Demographics .....................................................................................................14 
5.3.4.2. 
Baseline Disease Characteristics ........................................................................14 
5.4. 
Handling of Dropouts or Missing Data ............................................................................14 
5.5. 
Efficacy and Health Outcome Analyses ...........................................................................15 
5.5.1. 
Primary Outcome and Methodology ........................................................................25 
5.5.2. 
Secondary and Exploratory Efficacy and Health Outcomes 
Analyses ...................................................................................................................25 
5.6. 
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods ....................................25 
5.7. 
Safety Analyses ................................................................................................................25 
5.7.1. 
Extent of Exposure ...................................................................................................26 
5.7.2. 
Adverse Events ........................................................................................................26 
5.7.2.1. 
Serious Adverse Event Analyses ........................................................................27 


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5.7.2.2. 
Other Significant Adverse Events ......................................................................27 
5.7.3. 
Clinical Laboratory Evaluation ................................................................................27 
5.7.4. 
Vital Signs and Other Physical Findings .................................................................28 
5.7.5. 
Immunogenicity .......................................................................................................29 
5.7.6. 
Special Safety Topics, including Adverse Events of Special 
Interest ......................................................................................................................29 
5.7.6.1. 
Abnormal Hepatic Tests .....................................................................................30 
5.7.6.2. 
Renal Function Effects .......................................................................................30 
5.7.6.3. 
Infections ............................................................................................................31 
5.7.6.4. 
Allergic Reactions/Hypersensitivities ................................................................32 
5.8. 
Protocol Deviations ..........................................................................................................32 
5.9. 
Interim Analyses and Data Monitoring ............................................................................33 
5.10. Annual Report Analyses ...................................................................................................33 
5.11. Clinical Trial Registry Analyses ......................................................................................34 
6. 
References .............................................................................................................................35 
7. 
Appendices ............................................................................................................................38 
 


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Table of Contents 
Table 
Page 
Table FRCF.5.1. 
Description and Derivation of Primary, Secondary and Exploratory Efficacy 
Outcomes 
16 
Table FRCF.5.2. 
Description of Primary, Secondary and Exploratory Efficacy Analyses in 
Period 2 
21 
Table FRCF.5.3. 
Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure and 
Pulse Measurement, and Categorical Criteria for Weight Changes for Adults .....................29 
Table FRCF.5.4 
Common Terminology Criteria for Adverse Events (CTCAE) Related to 
Renal Effects 31 
 


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Table of Contents 
Figure 
Page 
Figure FRCF.4.1. 
Illustration of study design for Clinical Protocol J1B-MC-FRCF. ..............11 


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Table of Contents 
Appendix 
Page 
Appendix 1. 
Lilly-Defined MedDRA Preferred Terms for Herpes Zoster .............................39 
Appendix 2. 
Lilly-Defined MedDRA Preferred Terms for Tuberculosis ...............................40 
Appendix 3. 
Lilly-Defined MedDRA Preferred Terms for Potential Opportunistic Infections
 
43 
 


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2. Revision History 
Statistical Analysis Plan (SAP) Version 2 is based on Protocol J1B-MC-FRCF (c) and was 
approved prior to unblinding.   
 
SAP Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment A 
07-Jul-2020 
Original SAP 
05-Mar-2020 
Amendment A 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2, Sample Size 
Determination 
Updated the effect size 
assumption for LY3454738 and 
updated the power.  
Clarified per ethics committee 
feedback.  
Section 5.3.1, Analysis 
Populations 
Added definition for Per-
Protocol (PPS) population. 
Added one more type of analysis 
populations. 
Section 5.3.4.1, Demographics 
Added this new subsection to 
clarify the patient’s 
demographics we want to 
collect. 
Added more details. 
Section 5.3.4.2, Baseline 
Disease Characeteristics 
Added this new subsection to 
clarify the patient’s baseline 
disease activities information 
we want to collect. 
Added more details. 
Table FRCF.5.2, Description of 
Primary, Secondary and 
Exploratory Efficacy Analyses 
in Period 2 
Added analyses of percent 
change from baseline for 
UAS7/ISS7/HSS7 at Week 12. 
Added analyses on PPS 
population for some key 
endpoints. Added the factors in 
the logistic regression model 
for DLQI(0,1). 
Added more exploratory analyses. 
Added some analyses on PPS 
population. 
Table FRCF.5.3, Description of 
Exploratory Efficacy Analyses 
in Period 3 
Changed the analysis method 
for HSS7 change from baseline 
from “MMRM” to “Summary 
Statistics”.  
Typo correction. 
Section 5.7.2, Adverse Events 
Clarified the definition for 
TEAEs.  
Minor clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.7.6.5, Columbia 
Suicide Severity Rating Scale 
Deleted this whole section 
because this information is not 
available for this study. 
Deleted unnecessary sections.  
Section 5.8, Protocol 
Deviations 
Changed the mITT population 
to PPS population.  
Minor clarification. 
 


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3. Study Objectives 
3.1. Primary Objective 
The primary objective of this study is to test the hypothesis that treatment with LY3454738 is 
superior to placebo in adult participants with CSU, as assessed by the mean change from baseline 
at Week 12 in weekly Urticaria Activity Score (UAS7), which is the sum of weekly Itch Severity 
Score (ISS7) and weekly Hives Severity Score (HSS7).  
3.2. Secondary Objectives 
The secondary objectives of the study are the following: 
Objectives 
Endpoints 
●  To compare the efficacy of LY3454738 to 
placebo as measured by improvement in 
signs and symptoms of CSU 
●  Mean change from baseline to 
Week 12 in  
○ 
ISS7 
○ 
HSS7 
●  Proportion of patients achieving 
UAS7 ≤6 at Week 12 
●  To characterize the pharmacokinetics (PK) 
of LY3454738 
●  Cmax and AUC 
3.3. Exploratory Objectives 
Exploratory objectives and endpoints may include the following: 
Objectives/Endpoints 
• To evaluate signs and symptoms and measures of quality of life at various time points 
in Period 2 (first 12 week treatment period) and in Period 3 (second 12-week treatment 
period, after crossover) using the DLQI and the UPDD items. 
• To assess the potential development of anti-LY3454738 antibodies and their impact on 
the safety profile and PK of LY3454738. 
• To explore relationships between LY3454738 exposure and select biomarkers and 
clinical efficacy endpoints. 


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4. Study Design 
4.1. Summary of Study Design 
Study J1B-MC-FRCF (FRCF) is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 2 crossover study to evaluate the efficacy and safety of LY3454738 500 mg given 
intravenously (IV) every 2 weeks (Q2W) versus placebo IV Q2W in adults with CSU 
inadequately controlled with H1-antihistamines. 
The study duration will be up to approximately 39 weeks over 4 study periods, as shown below: 
Period 1:  Screening, lasting up to 35 days before Week 0 (Visit 2, baseline) 
Period 2:  First 12-week treatment, from Week 0 (Day 1) through Week 12: 
• Participants will be randomized in a 3:1 ratio to receive  
either LY3454738 500 mg IV or placebo IV Q2W 
Period 3:  Second 12-week treatment (crossover), from Week 12 through Week 24: 
• Participants who received LY3454738 500 mg IV in Period 2 will receive 
placebo IV Q2W in Period 3. 
• Participants who received placebo IV in Period 2 will receive  
LY3454738 500 mg IV Q2W in Period 3. 
Period 4:  Post-treatment follow-up for approximately 10 weeks. 
• Participants will not receive study drug in Period 4. 
• The last dose of study drug is given at Week 22, which is 6 weeks before the 
first post-treatment follow-up visit (Visit 801).  Thus, participants will have 
been withdrawn from study drug for a total of 12 weeks at the last 
post-treatment follow-up visit (Visit 802). 
Approximately 85 patients will be screened to achieve approximately 60 randomized 
participants.  A total of approximately 52 evaluable participants are expected. 
Throughout the study, participants will take a second-generation H1-antihistamine at a dose 
specified in approved product labeling.  Certain participants may receive rescue therapy as 
described in Section 6.5.2 in the protocol. 
Participants who permanently discontinue the study drug early will undergo early termination 
procedures, including an early termination visit (ETV) and the post-treatment follow-up visits 
specified in the Schedule of Activities (SoA) (Section 1.3 in the protocol). 
Figure FRCF.4.1 illustrates the study design.  The blinding procedure is described in the 
Protocol. 
 
 


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Figure FRCF.4.1. 
Illustration of study design for Clinical Protocol J1B-MC-FRCF. 
Abbreviations:  C = crossover visit; D = day; Q2W = every 2 weeks; R = randomization visit; W = study week 
relative to randomization visit; V = visit. 
4.2. Method of Assignment to Treatment 
Subjects who meet all criteria for enrollment will be randomized in a 3:1 ratio 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).  
 


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5. A Priori Statistical Methods 
5.1. Statistical Hypotheses 
The study will compare LY3454738 with placebo in adults with CSU. The primary study 
objective is to demonstrate superior efficacy of LY3454738 over placebo. 
The primary comparison of interest is the mean change of the UAS7 from baseline to Week 12. 
Secondary comparisons include the mean change of the ISS7 and the HSS7 from baseline to 
Week 12 as well as the proportion of participants achieving a UAS7 ≤6 at Week 12. 
Efficacy comparisons will be made regardless of treatment discontinuation and without regard to 
changes to any background therapies. No adjustments for multiplicity will be made across the 
efficacy assessments. 
5.2. Sample Size Determination 
Assuming a 30% screen fail rate, approximately 85 participants will be screened to achieve 60 
participants randomly assigned to study intervention for an estimated total of 52 evaluable 
participants. 
The sample of 52 evaluable participants provides more than 87% power to the primary endpoint. 
This calculation is based on a 2-sample t-test, assuming a mean change from baseline to Week 
12 in the UAS7 for LY3454738 and for placebo of 17 points and 10 points, respectively, a 
standard deviation of 7 points for the change from baseline, and a 0.05 two-sided significance 
level. 
5.3. General Considerations 
This plan describes a priori statistical analyses for efficacy, health outcomes, and safety that will 
be performed.   
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly).  The 
statistical analyses will be performed using SAS® Version 9.4 or higher.  
Not all displays described in this SAP will necessarily be included in the clinical study report 
(CSR).  Not all displays will necessarily be created as a “static” display.  Some may be 
incorporated into interactive display tools instead of or in addition to a static display.  Any 
display described in this SAP and not included in the CSR would be available upon request. 
For continuous measures, summary statistics will include sample size, mean, standard deviation 
(SD), minimum, median, and maximum.  The 1st quartile and 3rd quartile may also be presented.   
For categorical measures, summary statistics will include the sample size, frequency count, and 
percentage.  Percentages will be presented to 1 decimal place unless otherwise stated.  
Percentages will not be presented for zero counts.  Incidence rates and 95% confidence interval 
(CI) will be displayed for select safety endpoints. 
Statistical tests of treatment effects and CIs will be performed at a 2-sided significance level of 
0.05, unless otherwise stated. 


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All p-values will be rounded up to 3 decimal places.  For example, any p-value strictly greater 
than 0.049 and less than or equal to 0.05 will be displayed as 0.050.  This guarantees that on any 
printed statistical output, the unrounded p-value will always be less than or equal to the displayed 
p-value.  A displayed p-value of 0.001 will always be understood to mean ≤0.001.  Likewise, any 
p-value displayed as 1.000 will be understood to mean >0.999 and ≤1. 
5.3.1. Analysis Populations 
Entered: All participants who sign the informed consent form. 
Modified Intent-to-Treat (mITT): All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will be analyzed according to the 
intervention to which they were assigned. 
Per-Protocol (PPS) population: The PPS populations is defined as all randomized patients who 
do not commit an Important Protocol Deviation (IPD) that could potentially compromise efficacy 
results. For more details, patients who missed more than one dose in Period 2 or were enrolled 
inadvertently will be excluded from Per-Protocol-Set. 
Safety: All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention they actually 
received within each study period. 
Pharmacokinetic (PK) Analysis: All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and have PK data available. 
Efficacy analyses will be conducted on the Modified Intent-to-Treat (mITT) Population. This set 
includes all data from all randomized participants receiving at least 1 dose of the IP according to 
the treatment the participants were assigned. 
Safety analyses will be conducted on the Safety Population. This set includes all data from all 
randomized participants receiving at least 1 dose of the IP according to the treatment the 
participants actually received. 
5.3.2. Definition of Baseline and Postbaseline Measures 
The baseline value for Period 2 is defined as the last nonmissing measurement on or before the 
date of first study drug administration (expected at Week 0). The baseline value for Period 3 is 
the last available value before the initial dose in Period 3 (expected at Week 12). Other 
definitions of the baseline value may be used to conduct additional supporting analyses.  
A number of efficacy outcome measures are in the form of weekly scores derived from patient 
daily diary data. For these measures, the weekly score will be derived from the 7 days 
immediately prior to the study visit. The baseline score will be derived from the 7 days prior to 
Day 1 (Visit 2) for Period 2, and 7 days prior to Day 85 (Visit 9) for Period 3. 
5.3.3. Patient Disposition 
A detailed description of participant disposition will be provided, including a summary of the 
number and percentage of participants entered into the study, enrolled in the study, and treated, 


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LY3454738 
as well as number and percentage of participants completing the study (participants who receive 
at least 1 dose of study drug and have at least 1 postbaseline assessment), or discontinuing 
(overall and by reason for discontinuation). A summary of all important protocol deviations will 
be provided. 
5.3.4. Patient Characteristics 
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population. A summary of baseline participants and disease characteristics, 
historical diagnoses, pre-existing conditions, and prior therapies will be reported by cohort using 
descriptive statistics. Other participant baseline characteristics will be summarized by group as 
deemed appropriate. 
5.3.4.1. Demographics 
Patient demographics will be summarized as described above.  The following demographic 
information will be included: 
• Age 
• Gender (male, female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple) 
• Region (US, Germany and Poland) 
• Country  
• Weight (kg) 
• Height (cm) 
• Body mass index (kg/m2)  
A listing of patient demographics will also be provided for the ITT population.  
5.3.4.2. Baseline Disease Characteristics 
The following baseline disease information (but not limited to only these) will be presented for 
baseline urticaria clinical characteristics, baseline health outcome measures, and other baseline 
demographic and disease characteristics as described above:  
• Weekly Urticaria Activity Score (UAS7) 
• Weekly Itch Severity Score (ISS7) 
• Weekly Hives Severity Score (HSS7) 
• Dermatology Life Quality Index (DLQI) 
5.4. Handling of Dropouts or Missing Data 
Missing continuous scores will be imputed using baseline observation carried forward (BOCF) 
analyses. 
The UAS7 score is the sum of the daily UAS scores over 7 days each week. The daily score is 
the average of 2 results when both entries are made, or it is the single result when only 1 entry is 
made in a given day. When 1 or more of the daily UAS scores are missing, the following 
principles will be applied to handle the missing data: 


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LY3454738 
• If a participant has at least 4 nonmissing daily UAS scores within the 7 days prior to the 
study visit, the UAS7 score is calculated as the sum of the available UAS scores in that 
week, divided by the number of days that have a nonmissing diary UAS score, multiplied 
by 7. 
• If there are less than 4 nonmissing daily UAS scores within the prior 7 days, then the 
UAS7 score is missing for the week. 
The same principles will be applied to handle the missing data for all of the weekly outcomes. 
• Nonresponder imputation (NRI): All participants 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. 
• Mixed-effects model of repeated measures (MMRM): Continuous variables will be 
assumed to be missing after discontinuation for which an MMRM analysis will be 
performed. The model will include treatment, visit, and treatment-by-visit-interaction as 
fixed categorical effects and baseline and baseline-by-visit-interaction as fixed 
continuous effects.  An unstructured (co)variance structure will be used to model the 
between- and within-patient errors.  If this analysis fails to converge, the heterogeneous 
autoregressive [ARH(1)], followed by the heterogeneous compound symmetry (CSH), 
followed by the heterogeneous Toeplitz (TOEPH) will be used.  The Kenward-Roger 
method will be used to estimate the degrees of freedom.  Type III tests for the least-
squares means (LSM) will be used for the statistical comparison.  The LSM difference, 
standard error, p‑value and 100(1-alpha)% CI will also be reported.  
• BOCF, as previously stated. 
5.5. Efficacy and Health Outcome Analyses 
The general methods used to summarize efficacy data, including the definition of baseline value 
for assessments are described in Section 5.3. 
Table FRCF.5.1 Error! Reference source not found.includes the descriptions and derivations 
of the primary, secondary, and exploratory efficacy and health outcomes. 
Table FRCF.5.2 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and comparisons for efficacy and health outcome analyses. 


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Table FRCF.5.1. 
Description and Derivation of Primary, Secondary and Exploratory Efficacy Outcomes 


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Measure 
Description 
Variable 
Derivation / Comment 
Imputation Approach if 
with Missing Components 
Weekly 
Urticaria 
Activity 
Score 
(UAS7) 
 
The UAS7 score is a composite 
measure of itch (0−3 point scale) and 
hives (0−3 point scale) recorded twice 
daily (morning and evening) that is 
averaged daily and summed over the 
course of 1 week (range 0 to 42). 
Scoring itch: 0 = None, 1 = Mild, 2 = 
Moderate, 3 = Severe. Scoring hives: 0 
= None, 1 = Mild (1-6 hives/12 hour), 2 
= Moderate (7-12 hives/12 hour), 3 = 
Intense (> 12 hives/12 hour). 
 
The UAS7 scores are categorized into 
five disease states: urticaria-free (UAS7 
= 0), well-controlled urticaria (UAS7 = 
1-6), mild-activity urticaria (UAS7 = 7-
15), moderate-activity urticaria (UAS7 
= 16-27) and severe-activity urticaria 
(UAS7 = 28-42). 
▪ UAS7 score 
The UAS7 score is the sum of the 
average daily UAS scores over 7 days 
each week (range 0 to 42). For each of 
the morning and evening entries, the 
UAS score is calculated as the sum of 
the itch and hives scores. The daily 
UAS score is then calculated as the 
average of the morning and evening 
UAS scores.  
 
The baseline UAS7 score is the sum of 
the daily UAS scores over the 7 days 
prior to randomization, and the UAS7 
score at postbaseline visits is the sum of 
daily UAS scores over the 7 days prior 
to the visit. The same principles of 
calculating baseline and postbaseline 
weekly scores will be applied to the 
following weekly outcomes unless 
otherwise stated.   
When either the morning or 
evening score is missing, 
the non-missing UAS score 
for that day (morning or 
evening) will be used as the 
daily score. When one or 
more of the daily UAS 
scores are missing, the 
following principles will be 
applied to handle the 
missing data: 
If a patient has at least 4 
non-missing daily UAS 
scores within the 7 days 
prior to the study visit, the 
UAS7 score is calculated as 
the sum of the available 
UAS scores in that week, 
divided by the number of 
days that have a non-
missing diary UAS score, 
multiplied by 7. 
If there are less than 4 non 
missing daily UAS scores 
within the prior 7 days, then 
the UAS7 score is missing 
for the week. 
▪ Change from 
baseline in UAS7 
score 
Change from baseline: observed UAS7 
score – baseline UAS7 score 
Missing if baseline or 
observed value is missing. 
▪ UAS7 ≤ 6 
Observed UAS7 score ≤ 6 
Single item, missing if 
missing. 


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LY3454738 
Measure 
Description 
Variable 
Derivation / Comment 
Imputation Approach if 
with Missing Components 
▪ UAS7 = 0 
Observed UAS7 score = 0. UAS7 = 0 
means symptom remission. 
Single item, missing if 
missing. 
▪ Time to relapse 
Relapse occurs at the first instance in 
Period 3 when a patient’s UAS7 score 
is greater than 6 among the UAS7 ≤ 6 
responders at Week 12. 
Single item, missing if 
missing. 
Weekly Itch 
Severity 
Score (ISS7) 
 
The ISS7 score is the sum of daily itch 
score (ISS, 0−3 point scale) over 7 days 
(range 0 to 21), with daily itch score: 0 
= None, 1 = Mild, 2 = Moderate, 3 = 
Severe. The daily itch score is the 
average of the morning and evening 
scores. 
▪ ISS7 score 
The ISS7 score is the sum of the 
average daily ISS scores over 7 days 
each week (range 0 to 21). The daily 
ISS score is calculated as the average of 
the morning and evening ISS scores.  
 
When either the morning or 
evening score is missing, 
the non-missing ISS score 
for that day (morning or 
evening) will be used as the 
daily score. When one or 
more of the daily ISS scores 
are missing, the following 
principles will be applied to 
handle the missing data: 
If a patient has at least 4 
non-missing daily ISS 
scores within the 7 days 
prior to the study visit, the 
ISS7 score is calculated as 
the sum of the available ISS 
scores in that week, divided 
by the number of days that 
have a non-missing diary 
ISS score, multiplied by 7. 
If there are less than 4 non 
missing daily ISS scores 
within the prior 7 days, then 
the ISS7 score is missing 
for the week. 
Change from baseline in 
ISS7 score 
Change from baseline: observed ISS7 
score – baseline ISS7 score 
Missing if baseline or 
observed value is missing. 


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LY3454738 
Measure 
Description 
Variable 
Derivation / Comment 
Imputation Approach if 
with Missing Components 
ISS7 = 0 
Observed ISS7 score = 0. ISS7 = 0 
means complete itch response. 
Single item, missing if 
missing. 
Weekly 
Hives 
Severity 
Score (HSS7) 
 
The HSS7 score is the sum of daily 
number of hives score (HSS, 0−3 point 
scale) over 7 days (range 0 to 21), with 
daily number of hives score: 0 = None, 
1 = Mild (1-6 hives/12 hour), 2 = 
Moderate (7-12 hives/12 hour), 3 = 
Intense (> 12 hives/12 hour). The daily 
number of hives score is the average of 
the morning and evening scores. 
▪ HSS7 score 
The HSS7 score is the sum of the 
average daily HSS scores over 7 days 
each week (range 0 to 21). The daily 
HSS score is calculated as the average 
of the morning and evening HSS scores.  
When either the morning or 
evening score is missing, 
the non-missing HSS score 
for that day (morning or 
evening) will be used as the 
daily score. When one or 
more of the daily HSS 
scores are missing, the 
following principles will be 
applied to handle the 
missing data: 
If a patient has at least 4 
non-missing daily HSS 
scores within the 7 days 
prior to the study visit, the 
HSS7 score is calculated as 
the sum of the available 
HSS scores in that week, 
divided by the number of 
days that have a non-
missing diary HSS score, 
multiplied by 7. 
If there are less than 4 non 
missing daily HSS scores 
within the prior 7 days, then 
the HSS7 score is missing 
for the week.   
▪ Change from 
baseline in HSS7 
score 
Change from baseline: observed HSS7 
score – baseline HSS7 score 
Missing if baseline or 
observed value is missing. 


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Measure 
Description 
Variable 
Derivation / Comment 
Imputation Approach if 
with Missing Components 
▪ HSS7 = 0 
Observed HSS7 score = 0. HSS7 = 0 
means complete hives response. 
Single item, missing if 
missing. 
Dermatology 
Life Quality 
Index (DLQI) 
 
The Dermatology Life Quality Index 
(DLQI) is a simple, 
patient-administered, 10-item, 
validated, quality-of-life 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  “a 
little,” “a lot,” and “very much,” with 
corresponding scores of 1, 2, and 3, 
respectively, and “not at all,” or 
unanswered (“not relevant”) responses 
scored as 0.  Scores range from 0-30 
with higher scores indicating greater 
impairment of quality of life.  A DLQI 
total score of 0 to 1 is considered as 
having no effect on a patient’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). 
▪ Symptoms and 
feelings domain 
Sum of questions 1 and 2, range 0 to 6. 
N/A – partial assessments 
cannot be saved.    
▪ Daily activities 
domain 
Sum of questions 3 and 4, range 0 to 6. 
N/A – partial assessments 
cannot be saved.    
▪ Leisure domain 
Sum of questions 5 and 6, range 0 to 6. 
N/A – partial assessments 
cannot be saved.    
▪ Work and school 
domain 
Sum of questions 7 and 7B (if it is 
answered), range 0 to 3.  
Responses of “yes” and “no” on 
Question 7 are given scores of 3 and 0 
respectively.  If Question 7 is answered 
“no” then Question 7b is answered with 
“a lot”, “a little”, “not at all” getting 
scores of 2, 1, 0 respectively.   
N/A – partial assessments 
cannot be saved.    
▪ Personal 
relationships domain 
Sum of questions 8 and 9, range 0 to 6. 
N/A – partial assessments 
cannot be saved.    
▪ Treatment domain  
Question 10, range 0 to 3. 
N/A – partial assessments 
cannot be saved.    
▪ DLQI total score 
DLQI total score: sum of all six DLQI 
domain scores, range 0 to 30. 
N/A – partial assessments 
cannot be saved.    
▪ Change from 
baseline in DLQI 
Change from baseline: observed DLQI 
score – baseline DLQI score 
Missing if baseline or 
observed value is missing. 
▪ DLQI 0/1 
Observed DLQI score equals 0 or 1 
N/A – partial assessments 
cannot be saved.  
 
 
 
 


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Table FRCF.5.2. 
Description of Primary, Secondary and Exploratory Efficacy Analyses in Period 2 
Measure 
Variable 
Analysis Method 
Population 
(Section 
5.3.1) 
Comparison/Time 
Point 
Analysis 
Type 
Weekly Urticaria 
Activity Score 
(UAS7) 
 
• Change from baseline in UAS7 
score at Week 12 
ANCOVA using BOCF 
 
mITT; PPS 
LY3454738 500-mg vs 
PBO; Week 12 
Primary 
analysis 
• Percent change from baseline 
in UAS7 score at Week 12 
ANCOVA using BOCF 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Change from baseline in UAS7 
score by visit (Week 0 through 
Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Percent change from baseline 
in UAS7 score by visit (Week 
0 through Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
UAS7 score ≤ 6 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline UAS7 (< 
median versus ≥ median) using NRI 
mITT; PPS 
LY3454738 500-mg vs 
PBO; Week 12 
Secondary 
analysis 
• Proportion of patients with 
UAS7 score ≤ 6 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline UAS7 (< 28 
versus ≥ 28) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
UAS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline UAS7 (< 
median versus ≥ median) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
UAS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline UAS7 (< 28 
versus ≥ 28) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 


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LY3454738 
Measure 
Variable 
Analysis Method 
Population 
(Section 
5.3.1) 
Comparison/Time 
Point 
Analysis 
Type 
Weekly Itch Severity 
Score (ISS7) 
 
• Change from baseline in ISS7 
score at Week 12 
ANCOVA using BOCF 
 
mITT; PPS 
LY3454738 500-mg vs 
PBO; Week 12 
Secondary 
analysis 
• Percent change from baseline 
in ISS7 score at Week 12 
ANCOVA using BOCF 
 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Change from baseline in ISS7 
score by visit (Week 0 through 
Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Percent change from baseline 
in ISS7 score by visit (Week 0 
through Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
ISS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline ISS7 (< median 
versus ≥ median) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
ISS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline ISS7 (< 14 
versus ≥ 14) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
Weekly Hives 
Severity Score 
(HSS7) 
 
• Change from baseline in HSS7 
score at Week 12 
ANCOVA using BOCF 
 
mITT; PPS 
LY3454738 500-mg vs 
PBO; Week 12 
Secondary 
analysis 
• Percent change from baseline 
in HSS7 score at Week 12 
ANCOVA using BOCF 
 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Change from baseline in HSS7 
score by visit (Week 0 through 
Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Percent change from baseline 
in HSS7 score by visit (Week 0 
through Week 12) 
MMRM 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
HSS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline HSS7 (< 
median versus ≥ median) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 
• Proportion of patients with 
HSS7 = 0 at Week 12 
Cochran-Mantel-Haenszel test 
stratified by baseline HSS7 (< 14 
versus ≥ 14) using NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
analysis 


J1B-MC-FRCF (c) Statistical Analysis Plan Version 2 
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LY3454738 
Measure 
Variable 
Analysis Method 
Population 
(Section 
5.3.1) 
Comparison/Time 
Point 
Analysis 
Type 
Dermatology Life 
Quality Index 
(DLQI) 
 
• DLQI total score at Week 12 
• Change from baseline in DLQI 
at Week 12 
MMRM 
mITT; PPS 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
Analysis 
• Proportion of patients with 
DLQI 0/1 at Week 12 
Logistic regression (Treatment as the 
only factor) with NRI 
mITT 
LY3454738 500-mg vs 
PBO; Week 12 
Exploratory 
Analysis 
Abbreviations: ANCOVA = Analysis of Covariance; BOCF = baseline observation carried forward; mITT = modified intent-to-treat; MMRM = mixed model 
repeated measures; NRI = nonresponder imputation; PBO = placebo; PPS = per protocol set. 
 
 
 
 
 
 
 
 
 
 
 


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Table FRCF.5.3. 
Description of Exploratory Efficacy Analyses in Period 3 
Measure 
Variable 
Analysis 
Method 
Population 
(Section 
5.3.1) 
Analysis Type 
Weekly Urticaria Activity 
Score (UAS7) 
 
• Change from baseline in UAS7 score by visit (Week 12 through 
Week 24) 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Proportion of patients with UAS7 score ≤ 6 at Week 24 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Proportion of patients with UAS7 = 0 at Week 24 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Proportion of patients who maintain UAS7 score ≤ 6 at Week 24 
among the responders at Week 12 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Median time to relapse 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
Weekly Itch Severity Score 
(ISS7) 
 
• Change from baseline in ISS7 score by visit (Week 12 through 
Week 24) 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Proportion of patients with ISS7 = 0 at Week 24 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
Weekly Hives Severity Score 
(HSS7) 
 
• Change from baseline in HSS7 score by visit (Week 12 through 
Week 24) 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
• Proportion of patients with HSS7 = 0 at Week 24 
Summary 
Statistics 
mITT 
Exploratory 
analysis 
Abbreviations: mITT = modified intent-to-treat


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LY3454738 
5.5.1. Primary Outcome and Methodology 
The primary efficacy endpoint is the change in UAS7 score from baseline to Week 12 in Period 
2, defined as the Week 12 UAS7 score minus the baseline UAS7 score. The analysis of the 
primary endpoint will consist of treatment comparisons made using analysis of covariance 
(ANCOVA) controlling for baseline UAS7 score. The ANCOVA model will be based on the 
mITT population. Missing Week 12 scores will be imputed by carrying forward the participants’ 
baseline scores (BOCF) as described in Section 5.4. 
The objective of the primary endpoint is to establish superiority of LY3454738 over placebo. 
5.5.2. Secondary and Exploratory Efficacy and Health Outcomes 
Analyses 
The secondary and exploratory efficacy analyses are detailed in Table FRCF.5.1Error! 
Reference source not found. and Table FRCF.5.2. There will be no adjustment for multiple 
comparisons forother analyses. 
5.6. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods  
Pharmacokinetic, Pharmacodynamic and Biomarker analyses to address secondary and 
exploratory objectives of this study will be described by Lilly in separate PK/PD and Biomarker 
analysis plans. 
5.7. Safety Analyses 
The general methods used to summarize safety data, including the definition of baseline value 
are described in Section 5.3.2. 
Safety analyses will include data after rescue, unless otherwise stated, and patients will be 
analyzed according to the investigational product to which they were randomized at Week 0 
(Visit 2).  Additional analyses may be conducted using data after rescue to systemic therapy for 
some safety topics such as systemic treatment-emergent adverse events (TEAEs), and serious 
adverse events (SAEs).  Safety analyses will take place using the safety population defined in 
Section 5.3.1. 
Safety topics that will be addressed include the following:  AEs, clinical laboratory evaluations, 
vital signs and physical characteristics, Columbia Suicide Severity Rating Scale (C-SSRS), the 
Self-Harm Supplement Form, safety in special groups and circumstances, including adverse 
events of special interest (AESI) (see Section 5.7.5), and investigational product interruptions. 
Unless otherwise specified, by-visit summaries will include planned on-treatment visits.  For 
tables that summarize events (such as AEs, categorical lab abnormalities, shift to maximum 
value), post-last dose follow-up data will be included.  Follow-up data is defined as all data 
occurring up to 30 days (planned maximum follow-up time) after last dose of treatment including 
rescue, regardless of study period except for deaths and malignancies.  For deaths and 
malignancies, all available follow-up data up to the end of the study will be included.  Listings 
will include all safety data. 


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LY3454738 
For selected safety assessments, descriptive statistics may be presented for the last measure 
observed during post-treatment follow-up (up to 30 days after the last dose of treatment 
including rescue, regardless of study period).    
5.7.1. Extent of Exposure 
Duration of exposure (in days) to study drug will be summarized for the safety population in 
both Period 2 and 3 by treatment group using descriptive statistics (n, mean, SD, minimum, 1st 
quartile, median, 3rd quartile, maximum).   
For subjects without drug interruption, the duration of exposure for each patient is the date of last 
dose – date of first dose +1.  If subjects have drug interruption, the duration of exposure for each 
patient is the (Treatment end date before drug interruption – date of first dose +1) + (date of last 
dose – treatment re-start date +1). 
5.7.2. Adverse Events 
Adverse events are recorded in the eCRFs.  Each AE will be coded to system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) 
version that is current at the time of database lock.  Severity of AEs is recorded as mild, 
moderate, or severe. 
A TEAE is defined as an event that either first occurred or worsened in severity after the first 
dose of study treatment and on or prior to the last visit date during the analysis period. For each 
event classification term, the number of participants experiencing a TEAE with that 
classification term will be tabulated. For this study, the TEAEs should be counted by periods: 
TEAEs for Period 2 for V2-V9; TEAEs for Period 3 for V10-V16; TEAEs for Period 4 after 
V16.  
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 participants from the given gender. 
Adverse events are classified based upon the MedDRA PT.  The MedDRA Lowest Level Term 
(LLT) will be used in defining which events are treatment-emergent.  The maximum severity for 
each LLT during the baseline period up to first dose of the study medication will be used as 
baseline.  If an event with missing severity is preexisting during the baseline period, and persists 
during the treatment period, then the baseline severity will be considered mild for determining 
TEAE (that is, the event is treatment-emergent if the severity is coded moderate or severe 
postbaseline and not treatment-emergent if the severity is coded mild postbaseline).  If an event 
occurring postbaseline has a missing severity rating, then the event is considered treatment-
emergent.  The day and time for events where onset is on the day of the first dose of study 
treatment will both be used to distinguish between pretreatment and posttreatment in order to 
derive treatment-emergence.  Should there be insufficient data for AE start date to make this 
comparison (for example, the AE start year is the same as the treatment start year, but the AE 
start month and day are missing), the AE will be considered treatment-emergent. 


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In an overview table, the number and percentage of subjects who experienced a TEAE or serious 
adverse event (SAE), died due to an AE, or discontinued from study due to an AE will be 
summarized by treatment.   
The frequency and percentages of patients with TEAEs will be summarized by treatment using 
MedDRA PT nested within SOC.  Events will be ordered by decreasing frequency within SOC.  
The frequency and percentages of patients with TEAEs by maximum severity will also be 
summarized by treatment using MedDRA PT nested within SOC.   
Fisher’s exact test will be performed to compare percentages for each LY3454738 dose group 
and Placebo at both the SOC and PT levels. 
Listings will be presented for all AEs, all SAEs, all AEs leading to death, all AEs leading to 
study drug temporary interruption, and all AEs leading to discontinuation from the study. 
In this study, the following events are being captured as study endpoints and will not be reported 
as AEs: 
• Pruritus (itching) 
• Angioedema 
• Hives (wheals) 
Information on these events will be captured via the UPDD (patient electronic diary). 
However, if any of these events is an SAE, the event should be reported as an SAE. 
5.7.2.1. Serious Adverse Event Analyses 
The number and percentage of patients who experienced an SAE (including the SAEs that led to 
death) during the study drug period will be summarized by treatment using MedDRA PT nested 
within SOC.  Events will be ordered by decreasing frequency within SOC. 
5.7.2.2. Other Significant Adverse Events  
The number and percentage of patients who permanently discontinued from study treatment due 
to an AE (including AEs that led to death) during the study drug period will be summarized by 
treatment using MedDRA PT nested within SOC.  Events will be ordered by decreasing 
frequency within SOC. 
Fisher’s exact test will be performed to compare percentages for each LY3454738 dose group 
and Placebo at both the SOC and PT levels. 
5.7.3. Clinical Laboratory Evaluation 
Laboratory analyses will include planned analytes only.  Planned analytes are those specified in 
the protocol.  Summaries will be provided in both Système International (SI) and United States 
(US) conventional (CN) units (when different).  Limits from the performing lab will be used to 
define low and high. Analyses of laboratory values will be produced using the measurements 
collected at scheduled time points. All unscheduled assessments will appear only in data listings. 


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• Box plots for observed values:  Values at each visit (starting at randomization) will be 
displayed in box plots for patients who have both a baseline and a result for the specified 
visit.  Unplanned measurements will be excluded.  Original-scale data will be used for the 
display.  These box plots will be used to evaluate trends over time and to assess a 
potential impact of outliers on central tendency summaries.  The box plot will be a 
notched box for each treatment with outliers displayed, individual measurements outside 
of reference limits will also be displayed using distinct symbols overlaying the box plot, 
and descriptive summary statistics will be included in a table below the box plot.   
• Box plots for change values:  Change from baseline to each visit will be displayed in 
box plots for patients who have both a baseline and a result for the specified visit.  
Change from baseline to last observation will also be summarized and analyzed for 
patients who have both baseline and at least 1 postbaseline result.  Baseline will be the 
last non-missing observation in the baseline period.  The last non-missing observation in 
the Dosing Period will be used as the last observation.  Unplanned measurements will be 
excluded.  The box plot will be a notched box for each treatment with outliers displayed, 
change from baseline to last observation will be summarized within the box plot of 
changes (rightmost column), and descriptive summary statistics will be included in a 
table below the box plot, along with a p-value using the ANCOVA model containing 
terms for treatment and the continuous covariate of baseline measurement.  Type III sums 
of squares will be used.  The significance of within-treatment group changes from 
baseline will be evaluated by testing whether the treatment group LSMean changes from 
baseline are different from zero using a t-statistic.  In addition to the LSMeans and tests, 
the SD, minimum, Q1, median, Q3, and maximum will be displayed.   
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin will not 
be included in this analysis as different ranges will be used as described in Section 5.7.5. 
5.7.4. Vital Signs and Other Physical Findings 
Vital signs and physical characteristics include systolic blood pressure (SBP), diastolic blood 
pressure (DBP), pulse, weight, and BMI.  Original-scale data will be analyzed.  When these 
parameters are analyzed as continuous numerical variables, unplanned measurements will be 
excluded.  When these parameters are analyzed as categorical outcomes and/or treatment-
emergent abnormalities, planned and unplanned measurements will be included.   
The planned analyses described for the laboratory analytes in Section 5.7.3 will be used to 
analyze the vital signs and physical characteristics, except for the inclusion of a threshold for 
change in addition to a limit for the definition of treatment-emergent.Table FRCF.5.3 defines the 
low and high baseline values as well as the criteria used to define treatment-emergence based on 
post-baseline values.   


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Table FRCF.5.3. 
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for 
Weight Changes for Adults 
Parameter 
Low 
mmHg 
High 
mmHg 
Systolic BP (mm Hg)  
(Supine or sitting – 
forearm at heart level) 
≤90 and decrease from baseline ≥20 
≥140 and increase from baseline ≥20 
Diastolic BP (mm Hg)  
(Supine or sitting – 
forearm at heart level) 
≤50 and decrease from baseline ≥10 
≥90 and increase from baseline ≥10 
Pulse (bpm)  
(Supine or sitting) 
<50 and decrease from baseline ≥15 
>100 and increase from baseline ≥15 
Weight (kg) 
(Consistent clothing and 
timing in relationship to 
meals and voiding)  
(Loss) decrease ≥7% 
(Gain) increase ≥7% 
 
5.7.5. Immunogenicity 
Frequencies and percentages will be tabulated for the following: 
• participants with pre-existing ADA, and 
• participants who are treatment-emergent ADA positive (TE-ADA+) to LY3454738. 
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected 
at baseline (treatment-boosted ADA). For the TE ADA+ participants, the distribution of 
maximum titers will be described. The frequency of neutralizing antibodies, when available, will 
also be tabulated for the TE-ADA+ participants. 
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3454738 may be assessed. 
5.7.6. Special Safety Topics, including Adverse Events of Special 
Interest 
In addition to general safety parameters, safety information on specific topics of special interest 
will also be presented.  Additional special safety topics may be added as warranted.  The topics 
outlined in this section include the protocol-specified AESI. 
In general, for topics regarding safety in special groups and circumstances, patient profiles 
and/or patient listings, where applicable, will be provided when needed to allow medical review 
of the time course of cases/events, related parameters, patient demographics, study drug 
treatment and meaningful concomitant medication use.  In addition to the safety topics for which 


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provision or review of patient data is specified, these will be provided when summary data are 
insufficient to permit adequate understanding of the safety topic. 
5.7.6.1. Abnormal Hepatic Tests 
Analyses for abnormal hepatic tests will involve 4 laboratory analytes:  ALT, AST, total 
bilirubin, and ALP.  In addition to the analyses described in Section 5.7.3, this section describes 
specific analyses for this topic.   
The central laboratory reference ranges (CLRM reference ranges) will be used for these 
laboratory assessments (ALT, AST, total bilirubin, and ALP). 
Analyses for change from baseline to last observation, change from the baseline value to the 
minimum value during Period 2 and 3, change from the baseline value to the maximum value 
during Period 2 and 3, and treatment-emergent high or low laboratory results at any time are 
described in Section 5.7.3. 
The patients with the following abnormal elevations in hepatic laboratory tests at any time will 
be listed for both Period 2 and 3: 
• ALT measurement ≥3 times, ≥5 times and ≥10 times the central laboratory ULN.   
• AST measurement ≥3 times, ≥5 times and ≥10 times the central laboratory ULN.   
• Total bilirubin measurement ≥2 times the central laboratory ULN. 
• ALP measurement ≥1.5 times the central laboratory ULN. 
5.7.6.2. Renal Function Effects 
Effects on renal function will be assessed through analysis of elevated creatinine. 
The CTCAE will be applied for laboratory tests related to renal effects (Table FRCF.5.4).  This 
CTCAE grading scheme is consistent with both Version 3.0 and Version 4.03 of the CTCAE 
guidelines.   
Shift tables will show the number and percentage of subjects from baseline to maximum during 
Period 2 and 3, with baseline depicted by highest grade during the baseline period.  A shift table 
summary displaying the number and percentage of subjects with maximum postbaseline results 
will be presented by treatment group within the following categories:   
• Decreased; postbaseline category < baseline category 
• Increased; postbaseline category > baseline category 
• Same; postbaseline category = baseline category. 
Treatment-emergent lab abnormalities related to elevated creatinine occurring at any time during 
the Dosing Period will be tabulated using the CTCAE grades shown in Table FRCF.5.4.  Planned 
and unplanned measurements will be included. 
Treatment-emergence will be characterized using 5 criteria:   


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• any increase in postbaseline CTCAE grade from worst baseline grade 
• increase to Grade 1 or above at worst postbaseline 
• increase to Grade 2 or above at worst postbaseline 
• increase to Grade 3 or above at worst postbaseline 
• increase to Grade 4 at worst postbaseline. 
 
Table FRCF.5.4 
Common Terminology Criteria for Adverse Events (CTCAE) Related 
to Renal Effects 
Lab Test 
CTCAE Version 
Grade 
Criteria in SI or CN Units 
Elevated creatinine 
3.0 
0 (normal) 
1 
2 
3 
4 
≤ ULN 
> ULN and ≤1.5× ULN 
>1.5× ULN and ≤3× ULN 
>3× ULN and ≤6× ULN 
>6× ULN 
Abbreviations:  CN = conventional (US); CTCAE = Common Terminology Criteria for Adverse Events; 
SI = Système International; ULN = upper limit of normal. 
5.7.6.3. Infections 
Infections will be defined using the PTs from the MedDRA Infections and Infestations SOC, 
with additional terms from the Investigations SOC being used in selected instances, as described 
below. 
Treatment-emergent infections will be analyzed according to various groups of infectious events 
including: 
• all infections 
o all PTs in the Infections and Infestations SOC, 
• serious infections 
o all PTs in the Infections and Infestations SOC that are SAEs, 
• infections that require therapeutic intervention (antibiotics, antivirals, antifungals, and so 
on) 
o all PTs in the Infections and Infestations SOC for which there is an antimicrobial 
concomitant medication associated with that event for that subject, 
• herpes zoster 
o specific Lilly-defined PTs from the Herpes Viral Infections high-level term (HLT) 
in the Infections and Infestations SOC, shown in Appendix 1, 
• tuberculosis 
o specific Lilly-defined PTs from the Tuberculous Infections HLT and the 
Investigations SOC, shown in Appendix 2 
• viral hepatitis 
o all PTs from the Hepatitis Viral Infections HLT (HLT code 10057212) in the 
Infections and Infestations SOC. 


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For each infection event, the frequency for each PT will be provided, ordered by decreasing 
frequency in the LY3454738 highest dose group by infection group:  all infections, serious 
infections (overall and on each approach to identifying SAEs), infections that require therapeutic 
intervention, herpes zoster infections, tuberculosis, and viral hepatitis. 
In addition to the incidence of infectious AEs by MedDRA PT as described above, the number 
and percentage of subjects with treatment-emergent infectious AEs by treatment group will be 
summarized and listed.   
Potential Opportunistic Infections: 
Potential opportunistic infections (POIs) will be identified according to 2 different approaches. 
POIs are identified from TEAEs based on a Lilly-defined list of MedDRA PTs, shown in the 
Appendix 3.  These PTs are a subset of terms from the Infections and Infestations SOC.   
For the POIs identified from MedDRA PTs, the number and percentage of subjects overall and 
for each specific PT will be summarized by treatment group, with specific event terms ordered 
by decreasing frequency in the LY3454738 highest dose. 
Association of Infections with Lymphopenia or Neutropenia: 
The relationship between the occurrence of lymphopenia and neutropenia with the occurrence of 
infections will be evaluated based on case reviews.  Inferential analyses and/or graphical displays 
may be conducted if warranted.  Infection outcomes considered for this analysis are any 
infection, any serious infection, infections that require therapeutic intervention (antibiotics, 
antivirals, antifungals, and so on), tuberculosis, herpes zoster, and viral hepatitis.   
5.7.6.4.  Allergic Reactions/Hypersensitivities 
A search will be performed using the current MedDRA version 20.0 SMQs to search for relevant 
events, using the following queries: 
• Anaphylactic reaction SMQ (20000021) 
• Hypersensitivity SMQ (20000214) 
• Angioedema SMQ (20000024) 
Events that satisfy the queries will be listed, by temporal order within patient ID, and will 
include SOC, PT, SMQ event categorization including detail on the scope (narrow or broad), 
reported AE term, AE onset and end dates, severity, seriousness, outcome, etc. 
5.8. Protocol Deviations 
Protocol deviations will be tracked by the clinical team, and their importance will be assessed by 
key team members during protocol deviation review meetings.  Out of all important protocol 
deviations (IPDs) identified, a subset occurring during Period 2 prior to the primary endpoint 
(Week 12) with the potential to affect efficacy analyses will result in exclusion from the PP 
population. 


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Potential examples of deviations include patients who receive excluded concomitant therapy, 
significant non-compliance with study medication (<80% of assigned doses taken, failure to take 
study medication and taking incorrect study medication), patients incorrectly enrolled in the 
study, and patients whose data are questionable due to significant site quality or compliance 
issues.  Refer to a separate document for the important protocol deviations. 
The number and percentage of patients having IPD(s) will be summarized within category and 
subcategory of deviation by treatment group for Period 2 using the mITT population. Individual 
patient listings of IPDs will be provided. A summary of reasons patients were excluded from the 
PPS will be provided by treatment group. 
5.9. Interim Analyses and Data Monitoring  
The assessment committee is authorized to evaluate unblinded interim efficacy and safety 
analyses.  Study sites will receive information about interim results ONLY if they need to know 
for the safety of their patients. 
Unblinding details are given in a separated unblinding plan. 
Analysis for the primary database lock will be conducted when all participants have completed 
the Period 2 (or discontinued Period 2 treatment). An interim analysis prior to the primary 
database lock may be conducted when approximately 50% of the participants have had the 
opportunity to complete Period 2 (including those who discontinued Period 2 treatment). Other 
interim analyses may be conducted as needed. All interim analyses will be used to support 
planning activities associated with the development program. 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. 
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 of the planned interim data analyses and the assessment committee data review process 
are included in an assessment committee charter. 
5.10. Annual Report Analyses 
Annual report analyses, such as the Development Update Safety Report (DSUR), will be 
documented in a separate document.  


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5.11. Clinical Trial Registry Analyses 
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.   
Analyses provided for the CTR requirements include a summary of AEs, provided as a dataset 
which will be converted to an XML file.  Both SAEs and ‘Other’ AE are summarized: by 
treatment group, by MedDRA PT. 
• An AE is considered ‘Serious’ whether or not it is a TEAE. 
• An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided: 
o the number of participants at risk of an event 
o the number of participants who experienced each event term 
o the number of events experienced. 
• Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/patients in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold). 
• AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.  
Similar methods will be used to satisfy the European Clinical Trials Database (EudraCT) 
requirements.  
 
 
 
 


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6. References 
[2007 Expert Panel] 2007 Expert Panel Report 3: Guidelines for the Diagnosis and Management 
of Asthma Summary Report 2007. Available at: https://www.nhlbi.nih.gov/health-
topics/guidelines-for-diagnosis-management-of-asthma or J Allergy Clin Immunol. 2007;120(5 
suppl):S94-S138. 
Balp MM, Khalil S, Tian H, Gabriel S, Vietri J, Zuberbier T. Burden of chronic urticaria relative 
to psoriasis in five European countries. J Eur Acad Dermatol Venereol. 2018;32(2):282-290. 
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. 
ClinicalTrials.gov. NCT03580369. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03580369?term=ligelizumab&rank=5. Accessed July, 
2019. 
ClinicalTrials.gov. NCT03580356. Available at: 
https://clinicaltrials.gov/ct2/show/NCT03580356?term=ligelizumab&rank=6. Accessed June, 
2019. 
[EMA] European Medicines Agency. Committee for Medicinal Products for Human Use.  
Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials 
with investigational medicinal products. 2017. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC50
0232186.pdf. Published July 20, 2017. Accessed June 22, 2018. 
Flood EM, Zazzali JL, Devlen J. Demonstrating measurement equivalence of the electronic and 
paper formats of the Urticaria Patient Daily Diary in patients with chronic idiopathic urticaria. 
Patient. 2013;6(3):225-231. 
Guillén‐Aguinaga S, Jáuregui Presa I, Aguinaga‐Ontoso E, Guillén‐Grima F, Ferrer M. 
Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a 
systematic review and meta‐analysis. Br J Dermatol. 2016;175(6):1153-1165. 
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. 
Mathias SD, Crosby RD, Rosén KE, Zazzali JL. The minimal important difference for measures 
of urticaria disease activity: Updated findings. Allergy Asthma Proc. 2015;36(5):394-398. 
Maurer M, Abuzakouk M, Bérard F, Canonica W, Oude Elberink H, Giménez-Arnau A, 
Grattan C, Hollis K, Knulst A, Lacour JP, Lynde C, Marsland A, McBride D, Nakonechna A, 
Ortiz de Frutos J, Proctor C, Sussman G, Sweeney C, Tian H, Weller K, Wolin D, Balp MM. 
The burden of chronic spontaneous urticaria is substantial: real-world evidence from 
ASSURE-CSU. Allergy. 2017;72(12):2005-2016. 
Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, Agarwal S, Doyle R, 
Canvin J, Kaplan A, Casale T. Omalizumab for the treatment of chronic idiopathic or 


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spontaneous urticaria [published correction appears in N Engl J Med. 2013;368(24):2340-
2341]. N Engl J Med. 2013;368(10):924-935. 
Maurer M, Weller K, Bindslev‐Jensen C, Giménez‐Arnau A, Bousquet PJ, Bousquet J, 
Canonica GW, Church MK, Godse KV, Grattan CEH, Greaves MW, Hide M, 
Kalogeromitros D, Kaplan AP, Saini SS, Zhu XJ, Zuberbier T. Unmet clinical needs in chronic 
spontaneous urticaria. A GA2LEN task force report. Allergy. 2011;66(3):317-330. 
Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchock JD. 
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies [published 
correction appears in Ann Oncol. 2016;27(7):1362]. Ann Oncol. 2015;26(12):2375-2391. 
O’Donnell B, Lawlor F, Simpson J, Morgan M, Greaves M. The impact of chronic urticaria on 
the quality of life. Br J Dermatol. 1997;136(2):197-201. 
Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis of immune 
activating products and first-in-human dose selection. Reg Toxicol Pharmacol. 
2016;81:448-456. 
Saini SS, Kaplan AP. Chronic spontaneous urticaria: the devil’s itch. J Allergy Clin Immunol 
Pract. 2018;6(4):1097-1106. 
Saini S, Bindslev-Jensen C, Maurer M, Grob JJ, Bülbül Baskan E, Bradley M, Canvin J, 
Rahmaoui A, Georgiou P, Alpan O, Spector S, Rosén K. Efficacy and safety of omalizumab in 
patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 
antihistamines: a randomized, placebo-controlled study. J Invest Dermatol. 
2015;135(1):67-75. 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown 
SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, 
Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, 
Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol. 2006; 117:391-397. 
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 
recommendations for infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis. 2015;74(12):2107-2116. 
Xolair [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. 
Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, Bernstein JA, 
Bindslev-Jensen C, Brzoza Z, Buense Bedrikow R, Canonica GW, Church MK, Craig T, 
Danilycheva IV, Dressler C, Ensina LF, Giménez-Arnau A, Godse K, Gonçalo M, Grattan C, 
Hebert J, Hide M, Kaplan A, Kapp A, Katelaris CH, Kocatürk E, Kulthanan K, 
Larenas-Linnemann D, Leslie TA, Magerl M, Mathelier-Fusade P, Meshkova RY, Metz M, 
Nast A, Nettis E, Oude-Elberink H, Rosumeck S, Saini SS, Sánchez-Borges M, 
Schmid-Grendelmeier P, Staubach P, Sussman G, Toubi E, Vena GA, Vestergaard C, Wedi B, 
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definition, classification, diagnosis and management of urticaria. Allergy. 
2018;73(7):1393-1414. 


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7. Appendices 


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Appendix 1. 
Lilly-Defined MedDRA Preferred Terms for 
Herpes Zoster 
Preferred Term (MedDRA Version 18.0) 
Preferred Term Code 
Herpes zoster 
10019974 
Ophthalmic herpes zoster 
10030865 
Herpes zoster infection neurological 
10061208 
Herpes zoster oticus 
10063491 
Herpes zoster disseminated 
10065038 
Genital herpes zoster 
10072210 
Herpes zoster pharyngitis 
10074245 
Herpes zoster meningoencephalitis 
10074248 
Herpes zoster meningomyelitis 
10074251 
Herpes zoster meningitis 
10074259 
Herpes zoster cutaneous disseminated 
10074297 
Varicella zoster virus infection 
10075611 
 
 


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Appendix 2. 
Lilly-Defined MedDRA Preferred Terms for 
Tuberculosis 


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Preferred Term (MedDRA Version 18.0) 
Preferred Term Code 
Adrenal gland tuberculosis 
10001358 
Bone tuberculosis 
10056377 
Bovine tuberculosis 
10006049 
Choroid tubercles 
10008779 
Congenital tuberculosis 
10010657 
Conjunctivitis tuberculous 
10010754 
Cutaneous tuberculosis 
10011684 
Disseminated tuberculosis 
10013453 
Ear tuberculosis 
10014027 
Epididymitis tuberculous 
10015004 
Erythema induratum 
10015213 
Extrapulmonary tuberculosis 
10064445 
Female genital tract tuberculosis 
10061150 
Immune reconstitution inflammatory syndrome associated tuberculosis 
10072797 
Interferon gamma release assay positive 
10072866 
Intestinal tuberculosis 
10075268 
Joint tuberculosis 
10056367 
Latent tuberculosis 
10065048 
Lupus vulgaris 
10025143 
Lymph node tuberculosis 
10025183 
Male genital tract tuberculosis 
10061234 
Meningitis tuberculosis 
10027259 
Mycobacterium tuberculosis complex test positive 
10070325 
Oesophogeal tuberculosis 
10030200 
Pericarditis tuberculous 
10055069 
Peritoneal tuberculosis 
10053583 
Prostatitis tuberculous 
10064743 
Pulmonary tuberculoma 
10066927 
Pulmonary tuberculosis 
10037440 
Renal tuberculosis 
10038534 
Salpingitis tuberculous 
10039463 
Silicotuberculosis 
10068876 
Spleen tuberculosis 
10041640 
Thyroid tuberculosis 
10043774 
Tuberculin test positive 
10044728 
Tuberculoma of central nervous system 
10052883 
Tuberculosis 
10044755 
Tuberculous abscess central nervous system 
10052884 
Tuberculosis bladder 
10044758 
Tuberculosis gastrointestinal 
10061390 


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LY3454738 
Preferred Term (MedDRA Version 18.0) 
Preferred Term Code 
Tuberculosis liver 
10058120 
Tuberculosis of central nervous system 
10061391 
Tuberculosis of eye 
10044819 
Tuberculosis of genitourinary system 
10044828 
Tuberculosis of intrathoracic lymph nodes 
10044846 
Tuberculosis of peripheral lymph nodes 
10044965 
Tuberculosis ureter 
10045026 
Tuberculous endometritis 
10071559 
Tuberculous laryngitis 
10045072 
Tuberculous pleurisy 
10045104 
Tuberculous tenosynovitis 
10059161 
 
 


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Appendix 3. 
Lilly-Defined MedDRA Preferred Terms for 
Potential Opportunistic Infections 
Preferred Term (MedDRA Version 18.0) 
Preferred Term Code 
Candida pneumonia 
10053158 
Respiratory moniliasis 
10038705 
Gastrointestinal candidiasis 
10017938 
Oesophageal candidiasis 
10030154 
Coccidioides encephalitis 
10054214 
Coccidioidomycosis 
10009825 
Cutaneous coccidioidomycosis 
10068747 
Meningitis coccidioides 
10027207 
Cryptococcal cutaneous infection 
10054216 
Cryptococcal fungaemia 
10067112 
Disseminated cryptococcosis 
10013439 
Gastroenteritis cryptococcal 
10011485 
Meningitis cryptococcal 
10027209 
Neurocryptococcosis 
10068368 
Biliary tract infection cryptosporidial 
10067319 
Gastroenteritis cryptosporidial 
10017899 
Cytomegalovirus colitis 
10048983 
Cytomegalovirus duodenitis 
10049014 
Cytomegalovirus enteritis 
10049074 
Cytomegalovirus enterocolitis 
10049015 
Cytomegalovirus gastritis 
10049016 
Cytomegalovirus gastroenteritis 
10051349 
Cytomegalovirus gastrointestinal infection 
10052817 
Cytomegalovirus gastrointestinal ulcer 
10075619 
Cytomegalovirus hepatitis 
10011830 
Cytomegalovirus mucocutaneous ulcer 
10065036 
Cytomegalovirus myelomeningoradiculitis 
10065621 
Cytomegalovirus myocarditis 
10056261 
Cytomegalovirus oesophagitis 
10049018 
Cytomegalovirus pancreatitis 
10049566 
Cytomegalovirus pericarditis 
10056721 
Cytomegalovirus proctocolitis 
10049019 
Cytomegalovirus urinary tract infection 
10051350 
Disseminated cytomegaloviral infection 
10049075 
Encephalitis cytomegalovirus 
10014586 
 


Leo Document ID = a3a05199-e06c-46c6-bd82-7aa2a5b9326b
Approver: 
Approval Date & Time: 04-Jun-2021 20:41:21 GMT
Signature meaning: Approved
PPD