An Open-label, Two-part Study of the Disposition and Absolute Bioavailability of [¹⁴C]-LY3484356 in Healthy Females of Non-Childbearing Potential
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
Protocol J2J-MC-JZLE(b) 
 
 
An Open-label, Two-part Study of the DisposiƟon and Absolute Bioavailability of [¹⁴C]-LY3484356 in 
Healthy Females of Non-Childbearing PotenƟal 
 
 
NCT04991766 
 
 
Approval Date: 05-Aug-2021 

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Protocol number J2J-MC-JZLE(b)
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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 LY3484356, 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 Exemption 4 and may not be reproduced or otherwise 
disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: An Open-label, Two-part Study of the Disposition and Absolute Bioavailability 
of [14C]-LY3484356 in Healthy Females of Non-Childbearing Potential
Protocol Number: J2J-MC-JZLE
Amendment Number: (b)
Compound: LY3484356
Study Phase: 1
Short Title: Two-part Study of the Disposition and Absolute Bioavailability of 
[14C]-LY3484356 
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Number
IND: 145311
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 05-Aug-2021 GMT

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Medical Monitor Name and Contact Information will be provided separately

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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
25-May-2021
Protocol Amendment (a)
25-June-2021
Amendment (b)
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
1.1. Synopsis
Level of detail in study rationale 
reduced
For clarity
1.1. Synopsis; 
3. Objectives and 
Endpoints
Part 1 and Part 2 objectives split out 
into separate tables
For readability
2.2. Background
Level of detail reduced
For readability
2.3. Benefit/Risk 
Assessment
Text structure updated
For readability
5.4. Screen Failures
Interval between re-screenings updated
For clarity
8.6. Pharmacokinetics
Text updated to reflect blood volume 
sampling requirements
For clarity
8.6.1. Bioanalysis
Vendor for plasma profiling and plasma
metabolite identification added
For accuracy
Appendix 2 (Section 
10.2.1.)
Part 2: blood sampling volumes 
amended following feedback from 
analysis vendors
For accuracy

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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................13
2.
Introduction..............................................................................................................18
2.1.
Study Rationale ..........................................................................................................18
2.2.
Background ................................................................................................................18
2.2.1.
Summary of Nonclinical Absorption, Distribution, Metabolism, 
and Excretion Data .....................................................................................................19
2.2.2.
Clinical Pharmacokinetics...........................................................................................20
2.3.
Benefit/Risk Assessment ............................................................................................20
2.3.1.
Genotoxicity...............................................................................................................21
3.
Objectives and Endpoints.........................................................................................23
4.
Study Design .............................................................................................................25
4.1.
Overall Design............................................................................................................25
4.1.1.
Screening (Part 1 and Part 2) ......................................................................................25
4.1.2.
Treatment and Assessment Period...............................................................................25
4.1.3.
Follow-up (Part 1 and Part 2)......................................................................................26
4.2.
Scientific Rationale for Study Design .........................................................................26
4.3.
Justification for Dose..................................................................................................26
4.3.1.
LY3484356 ................................................................................................................26
4.3.2.
Radioactive Dose........................................................................................................26
4.4.
End of Study Definition..............................................................................................27
5.
Study Population ......................................................................................................28
5.1.
Inclusion Criteria........................................................................................................28
5.2.
Exclusion Criteria.......................................................................................................29
5.3.
Lifestyle Considerations .............................................................................................31
5.3.1.
Meals and Dietary Restrictions ...................................................................................31
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................31
5.3.3.
Activity ......................................................................................................................31
5.3.4.
Other ..........................................................................................................................31
5.4.
Screen Failures...........................................................................................................32
5.5.
Criteria for Temporarily Delaying Enrollment/Administration of 
Study Intervention of a Participant..............................................................................32
6.
Study Intervention....................................................................................................33
6.1.
Study Interventions Administered...............................................................................33
6.1.1.
Administration Details................................................................................................33
6.2.
Preparation/Handling/Storage/Accountability.............................................................34
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................34
6.4.
Study Intervention Compliance...................................................................................34
6.5.
Concomitant Therapy .................................................................................................34
6.6.
Dose Modification......................................................................................................35
6.7.
Intervention After the End of the Study ......................................................................35

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7.
Participant Discontinuation/Withdrawal from the Study.......................................36
7.1.
Participant Discontinuation/Withdrawal from the Study .............................................36
7.2.
Lost to Follow-up .......................................................................................................36
8.
Study Assessments and Procedures .........................................................................37
8.1.
Efficacy Assessments .................................................................................................37
8.2.
Safety Assessments ....................................................................................................37
8.2.1.
Physical Examinations................................................................................................37
8.2.2.
Vital Signs..................................................................................................................37
8.2.3.
Electrocardiograms.....................................................................................................37
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................38
8.2.5.
Safety Monitoring.......................................................................................................38
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................41
8.3.1.
Timing and Mechanism for Collecting Events ............................................................41
8.4.
Product Acceptability and Palatability Assessments....................................................43
8.5.
Treatment of Overdose ...............................................................................................43
8.6.
Pharmacokinetics........................................................................................................43
8.6.1.
Bioanalysis .................................................................................................................44
8.6.2.
Expired Air Samples...................................................................................................44
8.7.
Pharmacodynamics.....................................................................................................45
8.8.
Genetics .....................................................................................................................45
8.9.
Biomarkers.................................................................................................................45
8.10.
Immunogenicity Assessments.....................................................................................45
8.11.
Health Economics.......................................................................................................45
9.
Statistical Considerations.........................................................................................46
9.1.
Statistical Hypotheses.................................................................................................46
9.2.
Analyses Sets .............................................................................................................46
9.2.1.
Study Participant Disposition......................................................................................46
9.2.2.
Study Participant Characteristics.................................................................................46
9.2.3.
Treatment Compliance................................................................................................46
9.3.
Statistical Analyses.....................................................................................................46
9.3.1.
Safety Analyses ..........................................................................................................47
9.3.2.
Pharmacokinetic Analyses ..........................................................................................47
9.3.3.
Pharmacokinetic Statistical Inference..........................................................................47
9.3.4.
Pharmacodynamic Analyses .......................................................................................48
9.3.5.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................48
9.4.
Interim Analysis .........................................................................................................48
9.5.
Sample Size Determination.........................................................................................48
10.
Supporting Documentation and Operational Considerations ................................49
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................49
10.1.1.
Regulatory and Ethical Considerations........................................................................49
10.1.2.
Financial Disclosure ...................................................................................................49
10.1.3.
Informed Consent Process ..........................................................................................50
10.1.4.
Data Protection...........................................................................................................50

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10.1.5.
Dissemination of Clinical Study Data .........................................................................51
10.1.6.
Data Quality Assurance ..............................................................................................51
10.1.7.
Source Documents......................................................................................................52
10.1.8.
Study and Site Start and Closure.................................................................................53
10.1.9.
Publication Policy.......................................................................................................53
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................54
10.2.1.
Blood Sampling Summary..........................................................................................56
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................57
10.3.1.
Definition of AE.........................................................................................................57
10.3.2.
Definition of SAE.......................................................................................................58
10.3.3.
Definition of Product Complaints ...............................................................................59
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................59
10.3.5.
Reporting of SAEs......................................................................................................61
10.3.6.
Regulatory Reporting Requirements ...........................................................................61
10.4.
Appendix 4: Contraceptive and Barrier Guidance .......................................................63
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................64
10.6.
Appendix 6: Abbreviations .........................................................................................66
11.
References.................................................................................................................68

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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: An Open-label, Two-part Study of the Disposition and Absolute Bioavailability 
of [14C]-LY3484356 in Healthy Females of Non-Childbearing Potential
Short Title: Two-part Study of the Disposition and Absolute Bioavailability of 
[14C]-LY3484356
Rationale: Study J2J-MC-JZLE (JZLE) is a Phase 1 open-label, 2-part study of LY3484356 
containing [14C]-LY3484356 administered to healthy females of non-childbearing potential.
Part 1 of this study determines the disposition of [14C]-LY3484356 and identifies the metabolites 
present in plasma, urine, and feces following a single oral administration of LY3484356 
containing [14C]-LY3484356 as a solution. This study will provide understanding of the 
clearance pathways of LY3484356 in humans, which is important to assess the likelihood of 
effects of renal or hepatic impairment on the disposition of LY3484356 and the likelihood for 
drug-drug interactions (DDIs) with LY3484356. Furthermore, knowledge of the metabolism and 
elimination of parent drug and its metabolites and major circulating metabolites is useful for 
evaluating needs of metabolite(s)-mediated DDI studies and metabolite(s) in safety testing 
requirements elucidated in the Food and Drug Administration Guidance and International 
Conference on Harmonisation M3. 
Part 2 of this study determines the absolute bioavailability of LY3484356 of a tablet formulation 
in humans using an intravenous (IV) microtracer of [14C]-LY3484356 (containing 
 
radioactivity). Absolute bioavailability information aids quantitative evaluation of drug 
disposition of LY3484356.
Objectives and Endpoints:
Part 1
Objectives
Endpoints
Primary

To determine the disposition of 
radioactivity in healthy 
nonchildbearing women following 
oral administration of a single dose of 
 [14C]-LY3484356

Urinary and fecal excretion of total 
radioactivity over time expressed as a 
percentage of the total radioactive 
dose
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Secondary

To determine the pharmacokinetics 
(PK) of total radioactivity and 
LY3484356 in plasma following a 
single oral dose of 
 
[14C]-LY3484356

To assess the mass balance by 
quantifying radioactivity excretion in
urine, feces, and expired air (if 
applicable) 

To identify metabolites of LY3484356 
in plasma, urine, and feces

To assess the safety and tolerability of 
a single dose of 
 
[14C]-LY3484356 (containing 
100 µCi) in healthy nonchildbearing 
women
AUC(0-∞) and Cmax for radioactivity  
and LY3484356 in plasma

Total radioactivity recovered in urine, 
feces, and expired air (if applicable)

Total number of metabolites and 
identification of metabolites

A summary of TEAEs
Part 2
Objectives
Endpoints
Primary

To determine the absolute 
bioavailability of LY3484356 
following a single oral dose of 
 
of LY3484356 along with an IV dose 
of 
 of [14C]-LY3484356 
 

absolute bioavailability (F) of 
LY3484356
Secondary

To evaluate the PK of LY3484356, 
[14C]-LY3484356 and total 
radioactivity following oral dosing of 
LY3484356 and IV dosing of 
[14C]-LY3484356

To assess the safety and tolerability of 
LY3484356 following a single oral 
dose of 
 LY3484356 along 
with an IV dose of 
of 
[14C]-LY3484356 
 
in healthy nonchildbearing women

AUC(0-∞) and Cmax for total 
radioactivity, [14C]-LY3484356 and 
LY3484356 in plasma

A summary of TEAEs
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Overall Design:
Screening (Part 1 and Part 2)
All participants will be screened within 28 days prior to enrollment.
Treatment and Assessment Period
Part 1:
Participants will be admitted to the Clinical Research Unit (CRU) on Day -1. On the morning of 
Day 1, following an overnight fast of at least 10 hours, participants will receive a single oral dose 
of 
 of [14C]-LY3484356 
 administered as an oral solution. 
Participants will be discharged from the CRU as early as Day 12 and up to Day 22, provided 
recovery of radioactivity has reached the following threshold values: 

≥90% of the radioactive dose is recovered, and 

≤1% of the radioactive dose per day is recovered in excreta (urine and feces combined) 
for 2 consecutive days on which a fecal sample is collected. 
Sample collection and CRU confinement will continue until discharge criteria are met or the 
maximum stay is reached, unless otherwise agreed upon by the sponsor and investigator (or 
designee). 
For participants experiencing emesis within 4 hours following 14C dosing, vomitus will be 
collected. Attempts will be made to collect vomitus from participants experiencing emesis after 
4 hours post dose. All vomitus will be collected and stored for possible analysis as deemed 
appropriate.
Part 2: 
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, following an 
overnight fast of at least 10 hours, participants will receive a single oral dose of 
 of 
LY3484356 as 
 tablets and followed 
 by a single dose of 
 of 
[14C]-LY3484356 (containing 
 of radioactivity [microtracer]) administered as 
approximately a 
 IV infusion. Participants will remain resident in the CRU until Day 9.
During the infusion and for at least 2 hours post-infusion, the blood samples will be taken from 
the arm contra-lateral to the infusion site.
Follow-up (Part 1 and Part 2)
Participants will receive a follow-up call approximately 7 days after clinic discharge.
Disclosure Statement: This study is an open-label, 2-part, disposition and absolute 
bioavailability study of [14C]-LY3484356 in healthy females with non-childbearing potential at a 
single Phase 1 Clinical Research Unit (CRU).
Number of Participants: In Part 1, it is planned that up to 6 participants may be enrolled to 
ensure that at least 4 participants complete the study or have evaluable PK data; in Part 2, it is 
planned that up to 8 participants may be enrolled to ensure that at least 6 participants complete 
the study or have evaluable PK data for both treatments (oral and IV). Participants in Part 1 will 
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not participate in Part 2, nor will participants in Part 2 participate in Part 1. Part 1 and Part 2 are 
independent of each other and do not need to be conducted in sequential order.
Intervention Groups and Duration: Participants in Part 1 participate in 1 treatment period. 
Participants in Part 1 will be screened within 28 days prior to enrollment and will receive a 
single oral dose of 
 of [14C]-LY3484356 (containing 
).
Participants in Part 2 will participate in 1 treatment period. Participants in Part 2 will be screened 
within 28 days prior to enrollment and will receive a single oral dose of 
 of LY3484356 
followed 4 hours later by a single dose of 
 of [14C]-LY3484356 (containing 
 of 
radioactivity [microtracer]). 
Participants in both study parts will receive a follow-up phone call approximately 7 days after 
discharge from the study site.
The study duration for participants in each cohort is expected to be as follows:

Part 1: up to 59 days

Part 2: up to 46 days
Data Monitoring Committee: No
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2.
Introduction
LY3484356 is an orally bioavailable, non-covalent, selective estrogen receptor degrader (SERD)
in development for the treatment of breast cancer and endometrial cancer (EC). It is a potent 
degrader and selective antagonist of wild-type and mutant estrogen receptor α (ERα or ESR1). 
Full details of the preclinical safety, efficacy, and pharmacokinetics (PK), and clinical PK may 
be found in the Investigator’s Brochure (IB).
2.1.
Study Rationale
Study J2J-MC-JZLE (JZLE) is a Phase 1 open-label, 2-part study of LY3484356 containing 
[14C]-LY3484356 administered to healthy females of nonchildbearing potential.
Part 1 of this study determines the disposition of [14C]LY3484356 and identifies the metabolites 
present in plasma, urine, and feces following a single oral administration of LY3484356 
containing [14C]-LY3484356. This provides understanding of the clearance pathways of 
LY3484356, which is important to assess the likelihood of effects of renal or hepatic impairment 
on the disposition of LY3484356 and the likelihood for drug-drug interactions (DDIs) with 
LY3484356. Furthermore, knowledge of the metabolism and elimination of parent drug and its 
metabolites and major circulating metabolites is useful for evaluating needs of
metabolite(s)-mediated DDI studies and metabolite(s) in safety testing requirements elucidated in 
the Food and Drug Administration Guidance and International Conference on Harmonisation 
M3. 
Part 2 of this study determines the absolute bioavailability of LY3484356 of a tablet formulation 
in humans using an intravenous (IV) microtracer of [14C]-LY3484356 (containing 
 
radioactivity). Absolute bioavailability information aids quantitative evaluation of drug 
disposition of LY3484356 and subsequent planning and designing of additional clinical 
pharmacology studies. 
2.2.
Background
Breast cancer is the most frequent cancer among women and is a major cause of cancer-related 
deaths worldwide. It is estimated that more than 2 million new cases of breast cancer occurred 
worldwide in women in 2018 (Brayet al. 2018). Treatment options for women with breast cancer 
are largely determined by tumor HR and HER2 status (NCCN 2018; Waks and Winer 2019), and 
over 2 thirds of breast cancers express estrogen receptor (ER) - a key driver of breast cancer 
initiation and progression. For patients with advanced HR+/HER2-status, treatment includes 
endocrine therapy (ET) (e.g., tamoxifen, anastrozole, letrozole, fulvestrant) alone or in 
combination with cyclin-dependent kinase (CDK)4 and 6 inhibitors as indicated (e.g., 
abemaciclib, palbociclib, or ribociclib), as well as standard chemotherapy (e.g., capecitabine, 
docetaxel, paclitaxel, nab-paclitaxel [NCCN 2018; Waks and Winer 2019]). For patients with 
advanced HR+/HER2+status, treatment includes HER2-directed therapies e.g., trastuzumab, 
pertuzumab, or trastuzumab emtansine administered alone and in combination with other 
HER2-directed therapies, chemotherapy, or ET.
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I n most E R + breast ca ncers, E R is a n i m p orta nt t hera pe utic tar get e ve n after de vel o p me nt of 
resista nce t o e n d ocri ne t hera pies ( Weat her ma n et al. 1 9 9 9; Basel gaet al. 2 0 1 2; T ur ner et al. 
2 0 1 5; Fi n n et al . 2 0 1 6; A n dré et al. 2 0 1 9). SE R Ds are o ne of t he treat me nt o pti o ns f or estr o ge n 
rece pt or-p osi tive ( E R +)/ h u ma n e pi der mal gr o wt h fact or rece pt or 2-ne gati ve ( H E R 2-) breast 
ca ncer patie nts. F ul vestra nt is c urre nt l y t he o nl y re g ulat or y a ge nc y-a p pr o ve d S E R D f or t he 
treat me nt of E R + metastatic breast ca ncer ( m B C) (Nar d o ne et al. 2 0 1 9). Its efficac y is hi g hl y 
d ose -de pe n de nt, w here i ncreasi n g t he a d mi nistere d d ose le d t o i m pr o ve d s ur vi val ( Di Le o et al. 
2 0 1 4). H o we ver, t he i ntra m usc ular (I M) r o ute of f ul vestra nt a d m i nistrati o n li mits t he a mo u nt of 
f ul vestra nt t hat ca n be gi ve n t o patie nts. S e veral st u dies ha ve s h o w n t hat wit h t he c urre nt 
ma xi m u m feasi ble d ose, f ul vestra nt treat me nt is n ot a ble t o c o m pletel y de gra de E R i n pat ient s 
a n d ca n be ass ociate d wit h earl y pr o g ressi o n ( va n Kr uc hte n et al. 2 0 1 5). T h us, t here is u n met 
me dical nee d t o de vel o p oral S E R Ds wit h hi g her bi oa vaila bilit y,  greater E R tar geti n g, a n d 
de gra dati o n efficie nc y ( Nar d o ne et al. 2 0 1 9).
E n d o metrial ca ncer, w hile less fre q ue ntl y dia g n ose d t ha n breast ca ncer, is i ncreasi n g w orl d wi de. 
I n t he U nite d States, t he i nci de nce of E C has i ncrease d b y a p pr o xi matel y 1 2, 0 0 0 cases bet wee n 
2 0 1 3 a n d 2 0 1 9 ( H o wla der et al. 2 0 2 0). E n d o metri oi d E C re prese nts a b o ut 8 0 % of E C cases, a n d 
o vere x pressi o n of estr o ge n ma y c o ntri b ute t o t u m or pr oliferat i on ( Elle ns o n et al. 2 0 1 1). 
P ati e nts wit h E R + breast ca ncer ha ve se veral treat me nt o pti o ns. H o we ver, at t he ti me of
pr o gressi o n o n E T, t he disease bec o me s less res p o nsi ve, a n d o ptio ns are ofte n li mite d t o
c he m ot hera p y. M utati o ns i n E S R 1 ca n lea d t o a n estr o ge n i n de pe n de nt acti vat i on of E R 
pat h wa y , dri vi n g t u mor gr o wt h a n d resista nce t o c o m m o nl y  use d estr o ge n de pri vat i on strate gies 
(e g, ar o matase i n hi bit ors). M uta nt E R α
m ut a nt E R +, H E R 2- breast ca ncers are p ote ntiall y 
a me na ble t o t hera p y wit h L Y 3 4 8 4 3 5 6 base d o n precli nical data. A d dit i onall y , for E R +, H E R 2 + 
breast ca ncers, after pr o gressi o n o n pri or H E R 2 directe d t hera pies, c he mot h era p y, a n d t ype 1 
di a betes me llit us, cli nical e vi de nce s u p p orts t he a d mi nistrati o n of f ul vestra nt, a S E R D, i n 
c o m bi nat i on wi t h trast uz u ma b ( R o berts o n et al. 2 0 1 0). T he cli nical be nefit i n t his pat ient  
p o p ul at i on c o ul d p ote ntiall y  be f urt her i m pr o ve d wit h t he use of L Y 3 4 8 4 3 5 6 as S E R D.
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2.2.2.
Clinical Pharmacokinetics
Pharmacokinetic data from cancer patient studies showed that maximal plasma concentrations 
were reached approximately 4 hours post dose with an elimination half-life of approximately 25 
to 30 hours. Increases in exposures were also observed from 200 to 1200 mg QD in patient 
studies and were approximately dose proportional. Additional content is described in 
Section 5.1.1 in the IB.
2.3.
Benefit/Risk Assessment
LY3484356 is a potent antagonist and degrader of ERα and has demonstrated significant activity 
in preclinical models against ER wild-type and mutant tumors. There is no anticipated benefit for 
the healthy participants in this study. 
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3.
Objectives and Endpoints
Part 1
Objectives
Endpoints
Primary

To determine the disposition of 
radioactivity in healthy 
nonchildbearing women following 
oral administration of a single dose of 
 [14C]-LY3484356

Urinary and fecal excretion of total 
radioactivity over time expressed as a 
percentage of the total radioactive 
dose
Secondary

To determine the pharmacokinetics 
(PK) of total radioactivity and 
LY3484356 in plasma following a 
single oral dose of 
 
[14C]-LY3484356

To assess the mass balance by 
quantifying radioactivity excretion in 
urine, feces, and expired air (if 
applicable) 

To identify metabolites of LY3484356 
in plasma, urine, and feces

To assess the safety and tolerability of 
a single dose of 
 
[14C]-LY3484356 
 
 in healthy nonchildbearing
women

AUC(0-∞) and Cmax for radioactivity  
and LY3484356 in plasma

Total radioactivity recovered in urine, 
feces, and expired air (if applicable)

Total number of metabolites and 
identification of metabolite

A summary of TEAEs
Part 2
Objectives
Endpoints
Primary

To determine the absolute 
bioavailability of LY3484356 
following a single oral dose of 
 
of LY3484356 along with an IV dose 
of 
 of [14C]-LY3484356 
 

absolute bioavailability (F) of 
LY3484356
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Secondary

To evaluate the PK of LY3484356, 
[14C]-LY3484356, and total 
radioactivity following oral dosing of 
LY3484356 and IV dosing of 
[14C]-LY3484356

To assess the safety and tolerability of 
LY3484356 following a single oral 
dose of 
 LY3484356 along 
with an IV dose of
 of 
[14C]-LY3484356 
 
in healthy nonchildbearing women

AUC(0-∞) and Cmax for total 
radioactivity, [14C] LY3484356, and  
LY3484356 in plasma

A summary of TEAEs
Abbreviations: AUC0-∞= area under the concentration-time curve from time 0 extrapolated to 
infinity; Cmax = maximum observed concentration; F = absolute bioavailability (LY3484356 
only); TEAE = treatment-emergent adverse event.
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4.
Study Design
4.1.
Overall Design
Study JZLE is an open-label, 2-part, disposition and absolute bioavailability study of 
[14C]-LY3484356 in healthy females with nonchildbearing potential at a single Phase 1 CRU. In 
Part 1, it is planned that up to 6 participants may be enrolled to ensure that at least 4 participants
complete the study or have evaluable PK data. In Part 2, it is planned that up to 8 participants
may be enrolled to ensure that at least 6 participants complete the study or have evaluable PK 
data for both treatments (oral and IV). Participants in Part 1 will not participate in Part 2, nor will 
participants in Part 2 participate in Part 1. Part 1 and Part 2 are independent of each other and do 
not need to be conducted in sequential order.
The schemata in Section 1.2 illustrate the study design.
Safety assessments, including AEs, clinical laboratory tests, vital signs, and ECGs, and blood 
sampling for PK, will be performed according to the SoA (Section 1.3).
4.1.1.
Screening (Part 1 and Part 2)
All participants will be screened within 28 days prior to enrollment.
4.1.2.
Treatment and Assessment Period
Part 1: 
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, following an 
overnight fast of at least 10 hours, participants will receive a single oral dose of 
 of 
[14C]-LY3484356 
 administered as an oral solution. 
Participants will be discharged from the CRU as early as Day 12 and up to Day 22, provided 
recovery of radioactivity has reached the following threshold values: 

≥90% of the radioactive dose is recovered, and 

≤1% of the radioactive dose per day is recovered in excreta (urine and feces combined) 
for 2 consecutive days on which a fecal sample is collected. 
Sample collection and CRU confinement will continue until discharge criteria are met or the 
maximum stay is reached, unless otherwise agreed upon by the sponsor and investigator (or 
designee). 
For participants experiencing emesis within 4 hours following 14C dosing, vomitus will be 
collected. Attempts will be made to collect vomitus from participants experiencing emesis after 
4 hours post dose. All vomitus will be collected and stored for possible analysis as deemed 
appropriate.
Part 2: 
Participants will be admitted to the CRU on Day -1. On the morning of Day 1, following an 
overnight fast of at least 10 hours, participants will receive a single oral dose of 
 of 
LY3484356 as 
 tablets and followed 
 later by a single dose of 
of 
[14C]-LY3484356 (containing 
 of radioactivity [microtracer]) administered as 
approximately a 
 IV infusion. Participants will remain resident in the CRU until Day 9. 
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During the infusion and for at least 2 hours post-infusion, the blood samples will be taken from 
the arm contra-lateral to the infusion site.
4.1.3.
Follow-up (Part 1 and Part 2)
Participants will receive a follow-up call approximately 7 days after clinic discharge.
4.2.
Scientific Rationale for Study Design
This study has an open-label design because the study endpoints are not considered subjective.
This study also has no control treatment which is standard and widely used in radiolabeled 
studies. 
In Parts 1 and 2, oral administration has been chosen since this is the intended clinical route of 
LY3484356 administration. 
The IV microtracer method to be used in Part 2 allows for simultaneous oral and IV dosing in the 
same participants, which is expected to result in less variability in absolute bioavailability 
estimates as the systemic clearance is equivalent for the IV and oral doses. 
Analysis of urine and fecal concentrations of [14C]-LY3484356 and total radioactivity will allow 
for determination of the amount and percentage of LY3484356 excreted unchanged in urine and 
feces. 
Conducting the study in healthy participants will allow the evaluation of LY3484356 disposition
and bioavailability in the absence of concomitant medications and comorbidities. Healthy 
females of nonchildbearing potential have been selected as the study population since the 
pharmacologic mechanism of LY3484356 is to degrade the ER, and effects on the female 
reproductive organs are expected (see Section 2.3).
The doses, participant population, study duration, and sample collection timing are considered 
adequate to achieve the study objectives.
4.3.
Justification for Dose
4.3.1.
LY3484356
4.3.2.
Radioactive Dose
For Part 1, the planned radioactive dose of 
 of [14C]-LY3484356 
 is 
expected to provide a sufficient radioactive signal to achieve the study objectives with minimal 
radiation risk to participants. 
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4.4.
End of Study Definition
A participant is considered to have completed the study if she has completed all scheduled 
procedures shown in the SoA (Section 1.3). 
The end of the study is defined as the date of the last follow-up phone call for the last participant 
in the study.
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5.
Study Population
Eligibility of participants for enrollment in the study will be based on the results of medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG.
The nature of any conditions present at the time of the physical examination and any pre-existing 
conditions will be documented.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent.
Type of Participant 
2. Participants who are overtly healthy as determined by medical assessment including 
medical history, physical examination, laboratory tests, 12-lead ECG, and vital signs. 
3. Participants who have clinical laboratory test results within the normal reference range 
for the population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
4. Participants who have venous access sufficient to allow for blood sampling as per the 
protocol.
5. Participants who have a history of a minimum of 1 bowel movement per day (Part 1 
only).
Weight
6. Body mass index within the range 18.0 to 35.0 kg/m2 (inclusive).
Sex
7. Female participants of nonchildbearing potential. This includes females who are not 
pregnant, non-lactating and either:

Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy, bilateral tubal ligation, or bilateral tubal occlusion), or 
alternate medical cause/congenital anomaly (e.g., Müllerian agenesis). For individuals 
with permanent infertility due to an alternate medical cause/congenital anomaly, 
investigator discretion should be applied to determining study entry.
or

Postmenopausal (see Appendix 4 [Section 10.4] for details)

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Informed Consent
8. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have known allergies to LY3484356, related compounds or any components of the 
formulation as appropriate, or history of significant atopy
2. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, 
respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or 
designee)
3. Current or chronic history of liver disease or known hepatic or biliary abnormalities (such 
as symptomatic gallstones)
4. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the investigator (or designee)
5. Have a clinically significant abnormality of blood pressure and/or pulse rate as 
determined by the investigator
6. Have a history or presence of cardiovascular (e.g., symptomatic bradycardia with resting 
heart rate of <60 bpm [asymptomatic bradycardia is acceptable]), respiratory, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; of constituting 
a risk when taking the investigational product; or of interfering with the interpretation of 
data. Appendectomy, and hernia repair are considered as acceptable. Gilbert’s syndrome 
with a total bilirubin ≤3.0 × ULN and direct bilirubin within normal limits is acceptable.
Cholecystectomy is not acceptable.
7. History of alcoholism or drug/chemical abuse within 2 years prior to check-in
8. Alcohol consumption of > 14 units for females. One unit of alcohol equals ½ pint 
(285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits
9. Positive ethanol urine test result or positive urine drug screen at screening or check-in
10. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive hepatitis 
B surface antigen
11. Show evidence of hepatitis C and/or positive hepatitis C antibody. Participants with a 
positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.
12. Have evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies
13. Have donated blood of more than 500 mL within the previous 3 months of study 
screening, have donated plasma from 2 weeks prior to screening, or have donated 
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Prior/Concomitant Therapy
14. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to 
dosing, unless deemed acceptable by the investigator (or designee)
15. Use or intend to use any prescription medications/products within 14 days prior to dosing 
until completion of the follow-up phone call, unless deemed acceptable by the 
investigator (or designee) and/or sponsor
16. Use or intend to use slow-release medications/products considered to still be active 
within 14 days or 5 half-lives prior to dosing (whichever is longer), unless deemed 
acceptable by the investigator (or designee) and/or sponsor
17. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
dosing until completion of the follow-up phone call, unless deemed acceptable by the 
investigator (or designee) and/or sponsor
Prior/Concurrent Clinical Study Experience
18. Participation in a clinical study involving administration of an investigational drug (new 
chemical entity) in the past 30 days prior to dosing, or 5 half-lives; whichever is longer
19. Have previously completed or withdrawn from this study or any other study investigating 
LY3484356, and have previously received LY3484356
20. Have previously received a SERD in the past 30 days prior to dosing, or 5 half-lives; 
whichever is longer
Other Exclusions
21. Smoke more than 10 cigarettes or use the equivalent tobacco, smoking-cessation 
products, nicotine-containing products, or e-cigarettes (nicotine and non-nicotine) per 
day. Participants must be willing to abstain from smoking while resident at the CRU
22. Received or intend to receive a vaccination within 30 days of dosing or while on study
23. Receipt of blood products within 2 months prior to check-in
24. History of a major surgical procedure within 30 days prior to screening
25. have had exposure to significant diagnostic, therapeutic, or employment-related radiation 
within 12 months prior to dosing (e.g. serial x-ray or computed tomography scans, 
barium meal, current employment in a job requiring radiation exposure monitoring)
26. Intend to donate ova from check-in (Day -1) and at any time postdose
27. Part 1 only: Participation in a radiolabeled drug study where exposures are known to the 
Investigator (or designee) within the previous 4 months prior to check-in, or participation 
in a radiolabeled drug study where exposures are not known to the Investigator (or 
designee) within the previous 6 months prior to check-in. The total 12-month exposure 
from this study and a maximum of 2 other previous radiolabeled studies within 4 to 
12 months prior to this study will be within the Code of Federal Regulations (CFR) 
recommended levels considered safe, per United States Title 21 CFR 361.1: less than 
5000 mrem whole body annual exposure with consideration given to the half-lives of the 
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28. Part 2 only: Participation in any other radiolabeled investigational study intervention 
trial within 12 months prior to check-in. Any previous radiolabeled study intervention 
must have been received more than 12 months prior to check-in.
29. Participants who, in the opinion of the investigator (or designee), should not participate 
in this study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
While confined at the CRU, participants will receive a standardized high fiber diet at scheduled 
times that do not conflict with other study-related activities. Pitted prunes or prune juice may be 
given on an as-needed basis to aid in normal bowel function and will not be considered a 
concomitant medication.
Participants will refrain from the consumption of red wine, Seville oranges, Seville 
orange-containing foods or beverages, poppy seeds, grapefruit or grapefruit juice, from 7 days 
before check-in until through discharge from the CRU.
In both Parts 1 and 2, oral dosing will be preceded by an overnight fast of at least 10 hours; 
participants will continue to be fasted for at least 4 hours post-oral dose. 
5.3.2.
Caffeine, Alcohol, and Tobacco
1. Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g.,
coffee, tea, cola drinks, and chocolate) for 72 hours prior to check-in through discharge 
from the CRU.
2. During each dosing session, participants will abstain from alcohol for 72 hours prior to 
check-in through discharge from the CRU.
3. Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the CRU.
5.3.3.
Activity
1. Participants will abstain from strenuous exercise from 5 days prior to check-in through 
discharge from the CRU. Participants may participate in light recreational activities 
during the study (e.g., watching television, reading).
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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Individuals may be rescreened up to 1 time. The interval between re-screenings 
should be at the discretion of the investigator. Each time rescreening is performed, the individual 
must sign a new ICF and will be assigned a new identification number. 
If participants have minor deviations in screening assessments (e.g., laboratory safety tests, vital 
signs) these may be repeated at the investigator’s discretion to confirm eligibility.
5.5.
Criteria for Temporarily Delaying Enrollment/Administration of 
Study Intervention of a Participant
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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Interventions Administered
Part 1:
Study Intervention
[14C]-LY3484356
Dose Formulation
solution
Unit Dose Strength
TBC
Route of 
Administration
Oral
Sourcing
provided centrally by the sponsor
Part 2:
Study Intervention
[14C]-LY3484356
LY3484356
Dose Formulation
solution 
tablet
Unit Dose Strength
TBC
LY3484356)
Route of 
Administration
IV microtracer
oral
Sourcing
provided centrally by the sponsor
provided centrally by the sponsor
6.1.1.
Administration Details
In Part 1, participants will receive a single oral dose of 
 of [14C]-LY3484356
 
 as an oral solution with a total volume of
mL (dose volume + container rinses + 
water chaser).
In Part 2, participants will receive a single oral dose of 
 LY3484356 as 
-mg 
tablets with 240 mL of room temperature water followed 4 hours later by a single dose of 
 [14C]-LY3484356
 radioactivity [microtracer]) as an IV infusion over 
minutes (±1 minute). 
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In both parts, an additional 100 mL of water may be administered if needed.
Each unit dose will be prepared by qualified CRU staff. Each unit dose container will be 
appropriately labeled.
LY3484356 tablets should be swallowed whole. Participants should not break, crush, or chew the 
study intervention. 
All oral doses will be administered while the participants are seated, and participants will not be 
permitted to lie supine for 4 hours post-oral dose unless clinically indicated or for study 
procedures. Participants may be asked to be semi-supine/supine for the IV dosing.
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate storage conditions have been
maintained during transit for all study intervention received and any discrepancies are
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention. Only authorized
study personnel may supply, prepare, 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 the investigator and authorized study personnel.
3. The investigator or authorized study personnel are responsible for study intervention
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and
final disposition records).
4. Further guidance and information for the final disposition of unused study interventions
are provided in the study materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label, nonrandomized study.
6.4.
Study Intervention Compliance
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and in the electronic case report form (eCRF).
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff. 
6.5.
Concomitant Therapy
Participants will refrain from use of any prescription or nonprescription medications/products 
during the study until the follow-up phone call, unless the investigator (or designee) and/or 
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A mild laxative (i.e. Milk of Magnesia or Colace) may be used to help with bowel movements, if 
necessary. 
The Clinical Pharmacologist (CP)/CRP should be contacted if there are any questions regarding 
concomitant or prior therapy. If acetaminophen (or paracetamol) treatment is needed for pain 
management, the maximal allowed dose will be 3 g/day from all acetaminophen-containing 
medicinal products. Other concomitant medication may be considered on a case-by-case basis by 
the investigator in consultation with the Lilly CP/CRP, or designee.
6.6.
Dose Modification
Dose modification will not be permitted in this study.
6.7.
Intervention After the End of the Study
LY3484356 will not be made available to participants after completion of the study.

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7.
Participant Discontinuation/Withdrawal from the Study
Participants discontinuing from study intervention prematurely for any reason should complete 
AE and other follow-up/early discontinuation procedures as per the SoA (Section 1.3). 
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up/early discontinuation procedures as per the SoA (Section 1.3). 
Discontinuation of the study as a whole is described in Appendix 1 (Section 10.1).
7.1.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:
●
at any time at her own request 
●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons
●
if 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.
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued both from the study intervention and from the 
study at that time.
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, she may request destruction of any samples taken and not tested, and 
the investigator must document this in the site study records.
7.2.
Lost to Follow-up
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3).
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
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.
8.1.
Efficacy Assessments
Not applicable to this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in the 
SoA (Section 1.3) and as clinically indicated.
8.2.2.
Vital Signs
For each participant, supine blood pressure, supine pulse rate, and oral body temperature should 
be assessed at the times indicated in the SoA (Section 1.3). 
Blood pressure and pulse rate should be measured singly after at least 5 minutes supine. For each 
individual participant, the same cuff size should be used throughout the study for the 
measurements of blood pressure. The cuff should be attached to the participant’s dominant arm, 
when possible. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Where orthostatic measurements are required, participants should be 
supine for at least 5minutes and then participants will stand, and standing blood pressure will be 
measured after 2 minutes, but no longer than 3 minutes. If the participant feels unable to stand, 
supine vital signs only will be collected. Additional vital signs may be measured if warranted.
8.2.3.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.
Electrocardiograms must be recorded before collecting any blood samples. Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 

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during ECG collection. Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site. 
Electrocardiograms will be interpreted by the investigator or qualified designee at the site as 
soon after the time of ECG collection as possible, and, ideally, while the participant is still 
present. This interpretation is to determine whether the participant meets entry criteria at the 
relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the participant can 
continue in the study. The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE.
8.2.4.
Clinical Safety Laboratory Assessments
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency.
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the investigator, CP, or CRP.

If such 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.

All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the SoA and standard collection requirements.
If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then report the information as an AE.
8.2.5.
Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review the following data: 

trends in safety data 

laboratory analytes including hematology and clinical chemistry 

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When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
8.2.5.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 2; Section 10.2), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if one or more of these 
conditions occur:
If a participant with baseline 
(Day -1) results of... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients with 
Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥1.5 × baseline (except for patients with 
Gilbert’s syndrome)
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 CP/CRP. At a minimum, this evaluation should include physical examination and a thorough 
medical history, including symptoms, recent illnesses (e.g., heart failure, systemic infection, 
hypotension, or seizures), recent travel, history of concomitant medications (including 
nonprescription), herbal and dietary supplements, history of alcohol drinking and other substance 
abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:

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If a participant with baseline 
results of... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN with hepatic signs/symptoms*, or
ALT or AST ≥5 × ULN
ALP <1.5 × ULN
ALP ≥3 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline with hepatic signs/symptoms*, or
ALT or AST ≥3 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥2 × baseline (except for patients with Gilbert’s 
syndrome) 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time/international normalized ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (e.g., ultrasound or computed tomography scan). 
Based on the participant’s history, initial results, and at investigator’s discretion, further testing 
should be considered in consultation with the CP/CRP, including tests for cytomegalovirus, 
Epstein-Barr virus, acetaminophen levels, urine toxicology screen, Wilson’s disease, blood 
alcohol levels, and urinary ethyl glucuronide. Based on the circumstances and the investigator’s 
assessment of the participant’s clinical condition, the investigator should consider referring the 
participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety eCRF) in study participants who have 
abnormal liver tests during the study:
Additional hepatic safety data collection in hepatic safety eCRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5 × ULN)
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests
2. Elevated TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome)
In participants with baseline TBL ≥1.5 × ULN, the threshold should be TBL 
≥2 × baseline
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN)
In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study intervention due to a hepatic event 

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Protocol number J2J-MC-JZLE(b)
41
NOTE: the interval between the 2 consecutive blood tests should be at least 2 days.
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
The definitions of the following events can be found in Appendix 3 (Section 10.3):

AEs

SAEs

Product complaints (PCs)
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (see Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.2). 
For PCs, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Appendix 3 (Section 10.3).
8.3.1.
Timing and Mechanism for Collecting Events
This table describes the timing, deadlines, and mechanism for collecting events.
Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Adverse Event
AE
signing of 
the informed 
consent form 
(ICF)
participation 
in study has 
ended
as soon as possible 
upon site awareness
AE eCRF
N/A

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Protocol number J2J-MC-JZLE(b)
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
signing of 
the informed 
consent form 
(ICF)
start of 
intervention
within 24 hours of 
awareness
SAE Report
SAE paper 
form
SAE and SAE 
updates – after 
start of study 
intervention
start of 
intervention
resolution of 
the SAE
within 24 hours of 
awareness
SAE Report
SAE paper 
form
SAE – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware
after 
participant’s 
study 
participation 
has ended
N/A
Promptly
SAE Report
N/A
Product Complaints
PC associated 
with an SAE or 
might have led 
to an SAE
start of study 
intervention
end of study 
intervention
within 24 hours of 
awareness
Product Complaint 
form
N/A
PC not 
associated with 
an SAE
start of study 
intervention
end of study 
intervention
within 1 business day 
of awareness
Product Complaint 
form
N/A
Updated PC 
information
—
—
as soon as possible 
upon site awareness
originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator
N/A

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Protocol number J2J-MC-JZLE(b)
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
PC (if 
investigator 
becomes aware)
participation 
in study has 
ended
N/A
Promptly
Product Complaint 
form
8.4.
Product Acceptability and Palatability Assessments
Participants in Part 1 will be asked to provide responses to questions designed to assess the 
acceptability and palatability of the solution after treatment administration. The questionnaire 
will assess the participant’s experience relating to the taste, mouthfeel, and aftertaste of the 
solution in the oral cavity. The questionnaire will be completed by the participant immediately 
after administration of the solution i.e. within 5 minutes of dosing.
8.5.
Treatment of Overdose
For this study, any dose of LY3484356 greater than 
 within a 24-hour time period will be 
considered an overdose. In the event of an overdose, the investigator or treating physician 
should: 
1. Contact the Lilly CP immediately 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities
In case of overdose, supportive therapy should be used. There is no known antidote to 
LY3484356 overdose.
8.6.
Pharmacokinetics
At the visits and times specified in the SoA (Section 1.3), in Part 1, venous blood samples of up 
to 
 each will be collected to determine the plasma concentrations of LY3484356; venous 
blood samples of up to 
 will be collected to determine the plasma concentrations of total 
radioactivity; venous blood samples of up to 
 will be collected to determine metabolite 
profiling of LY3484356 in plasma (as outlined in Appendix 2 [Section 10.2.1]). Plasma from the 
1 ×
 blood samples may be used to determine metabolite profiling of LY3484356. In Part 2,
at the visits and times specified in the SoA (Section 1.3), venous blood samples of up to 
 
each will be collected to determine the plasma concentrations of LY3484356; venous blood 
samples of up to 
 will be collected to determine the plasma concentrations of 
[14C]-LY3484356 and to determine the plasma concentrations of total radioactivity. Up to 3 
samples may be collected at additional time points during the study if warranted and agreed upon 
between both the investigator and sponsor.
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded, as well 
as the date and time of each LY3484356 dose.
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Protocol number J2J-MC-JZLE(b)
44
In Part 1, urine samples will be collected for the determination of total radioactivity and 
metabolite profiling (total number and identity). In Part 1, feces samples will be collected for the 
determination of total radioactivity and metabolite profiling (total number and identity). Urine 
and feces will be collected before IP administration (control samples); however, the inability to 
produce a urine or fecal sample will not be considered a protocol deviation. After dosing with IP, 
cumulative feces and urine samples will be collected in specified containers according to the 
SoA (Section 1.3) until the specified release criteria have been met.
Urine will be collected at the specified intervals into 1 or more containers (depending on volume 
excreted) according to the SoA (Section 1.3) until the specified release criteria have been met. 
An aliquot of each sample will be analyzed to determine concentrations of LY3484356, yield the 
percentage radioactivity recovered within that interval, and to determine its metabolic profile.
Feces from each bowel movement will be collected and the time of collection will be noted. 
Fecal samples will be pooled over each 24-hour collection period according to the SoA
(Section 1.3) and analyzed to yield the percentage radioactivity recovered over that period as 
well as to determine its metabolic profile.
8.6.1.
Bioanalysis
In Parts 1 and 2, plasma concentrations of LY3484356 will be determined using a validated
liquid chromatography with tandem mass spectrometry bioanalytical method
 
In Part 1, total radioactivity will be determined in plasma by 
 
 and in urine and feces by
 
. Plasma concentration of [14C]-LY3484356 will be 
quantified by high performance 
 Profiling and identification of metabolites in plasma
 
, urine, and, where possible, feces will be conducted using standard laboratory 
procedures
 As needed, plasma profiling and plasma metabolite identification 
may be done by 
In Part 2, concentrations of [14C]-LY3484356 in plasma will be determined using 
 
 
Concentrations of total radioactivity in plasma will be determined using 
 
Specifics of the analytical methods will be provided in separate documents.
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Samples collected for the analysis of plasma concentrations of LY3484356 may be stored and 
analyzed for future exploratory analysis, such as quantification of metabolites of LY3484356.
8.6.2.
Expired Air Samples
A sample of expired breath will be collected for analysis of 14CO2 at the times indicated in the
SoA (Section 1.3). If a significant amount of the radioactivity is present in breath samples, the 
raw data will be extrapolated to provide an estimate of the percentage dose eliminated via 14CO2. 
Additional breath samples may be collected at some or all of the times that blood samples are 
drawn and only analyzed if needed.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Protocol number J2J-MC-JZLE(b)
45
8.7.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3), where local regulations allow.
8.9.
Biomarkers
Biomarkers are not evaluated in this study.
8.10. Immunogenicity Assessments
Not applicable for this study.
8.11. Health Economics
This section is not applicable for this study.

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Protocol number J2J-MC-JZLE(b)
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9.
Statistical Considerations
9.1.
Statistical Hypotheses
Not applicable for this study.
9.2.
Analyses Sets
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF.
Enrolled/Intent-to-Treat
All participants assigned to treatment, regardless of whether they take any 
doses of IP, or if they take the correct treatment.
Safety
All enrolled participants who take at least 1 dose of LY3484356 or 
[14C]-LY3484356, whether or not they completed all protocol requirements.
Pharmacokinetic Analysis
All participants who received at least 1 dose of LY3484356 or 
[14C]-LY3484356, and have evaluable PK data.
9.2.1.
Study Participant Disposition
A detailed description of participant disposition will be provided at the end of the study.
9.2.2.
Study Participant Characteristics
The participant’s age, sex, and other demographic characteristics will be recorded and 
summarized.
9.2.3.
Treatment Compliance
The date and time of dosing will be recorded and listed.
9.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Pharmacokinetic analyses will be conducted on data from all participants who received at least 1 
dose of LY3484356 or [14C]-LY3484356 and have evaluable PK data. 
Safety analyses will be conducted for all enrolled participants who received at least 1 dose of 
LY3484356 or [14C]-LY3484356, whether or not they completed all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.

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Protocol number J2J-MC-JZLE(b)
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9.3.1. Safety Analyses
9.3.1.1.
Clinical Evaluation of Safety
All study intervention and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarized using descriptive methodology. 
The incidence of AEs for each treatment will be presented by severity and by association with 
study intervention as perceived by the investigator. Adverse events reported to occur prior to 
enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each AE will be classified by the most suitable term from the medical regulatory 
dictionary. 
The number of investigational SAEs will be reported.
9.3.1.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 
ECG parameters. Additional analysis will be performed if warranted upon review of the data.
9.3.2.
Pharmacokinetic Analyses
9.3.2.1.
Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for plasma total radioactivity, plasma LY3484356, and 
plasma [14C]-LY3484356 will be calculated by standard noncompartmental methods. The 
primary PK parameters for analysis will be: AUC(0-∞) and Cmax. 
Other noncompartmental parameters, such as tmax, t1/2, apparent total body clearance of drug 
calculated after extravascular administration (CL/F), apparent volume of distribution during the 
terminal phase after extravascular administration (Vz/F), and volume of distribution at steady 
state (Vdss), may be reported as appropriate. In Part 2, the absolute bioavailability (F) of 
LY3484356 will also be calculated.
The plasma:total radioactivity ratio of LY3484356 will be calculated for each time point. The 
percent of radiolabeled dose recovered in feces, urine, and expired air will be calculated in 
Part 1.
The following PK parameters will be determined from urinary concentrations of total 
radioactivity: amount of drug excreted in urine (Ae), cumulative Ae, percentage of dose excreted 
in urine (fe), cumulative fe. Renal clearance (CLR) will also be determined for [14C]-LY3484356 
only.
The following PK parameters will be determined from fecal concentrations of total radioactivity: 
amount of drug excreted in feces (Aef), cumulative Aef, percentage of dose excreted in feces
(fef), and cumulative fef.
9.3.3.
Pharmacokinetic Statistical Inference
No formal statistical analyses are planned.

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9.3.4.
Pharmacodynamic Analyses
Not applicable for this study.
9.3.5.
Pharmacokinetic/Pharmacodynamic Analyses
Not applicable for this study.
9.4.
Interim Analysis 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
9.5.
Sample Size Determination
No formal statistical assessment of sample size has been conducted as this study does not have a 
hypothesis. The sample size chosen for this study is common in human radiolabeled studies and 
is considered sufficient to achieve the objectives of the study. In Part 1, up to 6 participants may 
be enrolled to ensure that at least 4 participants complete the study or have evaluable PK data; in 
Part 2, up to 8 participants may be enrolled to ensure that at least 6 participants complete the 
study or have evaluable PK data for both treatments (oral and IV). Each participant will 
participate in either Part 1 or Part 2. In the event of early withdrawal of any participants and/or to 
ensure the appropriate number of participants complete each part of the study, replacement 
participants may be enrolled at the discretion of the sponsor.

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Protocol number J2J-MC-JZLE(b)
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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 ICH Good Clinical Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, investigator Brochure, and other 
relevant documents (e.g., 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.
●
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation 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 study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
●
Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement.
10.1.2.
Financial Disclosure
Investigators and sub-investigators 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 

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Protocol number J2J-MC-JZLE(b)
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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3.
Informed Consent Process
●
The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions 
regarding the study.
●
Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, Health Insurance Portability and Accountability Act 
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 was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
●
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 and 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 the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred.
The participant must be informed that 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 who will be required to give consent for her data to be used 
as described in the informed consent.
The participant must be informed that 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.
The sponsor has processes in place to ensure data protection, information security and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach.

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Protocol number J2J-MC-JZLE(b)
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10.1.5.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (e.g., by phone and/or email) as soon 
as possible. It will be a requirement that investigators respond upon receipt to confirm that they 
understand the communication and have taken the appropriate action prior to further dosing any 
participants with study intervention. Any investigator not responding will be followed up by 
Lilly personnel prior to any further planned dosing. If a dose is planned imminently, Lilly 
personnel will immediately, and continually, use all efforts to reach investigators until contact is 
made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
10.1.6.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These predefined parameters 
will be monitored during the study and important excursions from the QTLs and remedial 
actions taken will be summarized in the clinical study report.
Monitoring details describing strategy (e.g., 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 are provided in the Monitoring Plan.
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 (e.g., 
contract research organizations).

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Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
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 the time period outlined in the clinical trial 
agreement 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, 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 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.
Data collected via the sponsor-provided data capture system will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. 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 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 sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
Source Documents
●
Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected. Source documents are filed at the
investigator’s site.
●
Data reported on the 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. Also, current medical records must be
available.
●
Definition of what constitutes source data can be found in Section 10.1.6.

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10.1.8.
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 sponsor 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 

Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
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 assures 
appropriate participant therapy and/or follow-up. 
10.1.9.
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 if the results are deemed to be of significant medical 
importance.

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10.2. Appendix 2: Clinical Laboratory Tests
The tests detailed below will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Investigators must document their review of the laboratory safety results.

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Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Platelets
Glucose (random)
Creatine kinase
Gamma-glutamyl transferase (GGT)
Differential WBC (% and absolute counts) of
Blood urea nitrogen (BUN)
Neutrophils
Uric acid 
Lymphocytes
Direct bilirubin
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Coagulationc  
Aspartate aminotransferase (AST)
   Prothrombin time (PT)
Alanine aminotransferase (ALT)
Activated partial thromboplastin time (aPTT)
Creatinine
International normalized ratio (INR)
Urinalysisa
Specific gravity
pH
Ethanol testingb
Protein
Urine drug screenb
Glucose
Hepatitis B surface antigenc
Ketones
Hepatitis B core antibodyc
Bilirubin
Hepatitis C antibodyc, d
Urobilinogen
HIV antibodyc
Blood
FSH c, e
Nitrite
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell. 
a
Performed by dipstick. A microscopic examination will be run if blood, protein, nitrites or leukocyte esterase is 
positive.
b
Urine drug screen and ethanol (urine) level performed at screening and check-in.
c
Performed at screening only.
d
Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test.
e
Postmenopausal women only.

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10.2.1.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
CCI

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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 participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., 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 conditions detected or diagnosed after study intervention administration even 
though they 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/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): 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 disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

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10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
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, which 
hypothetically might have caused death, if it 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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
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 

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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.
Definition of Product Complaints
Product Complaint

A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints:
o
Deficiencies in labeling information, and
o
Use errors for device or drug-device combination products due to ergonomic 
design elements of the product.

Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate eCRF page and 
product complaint information is reported on the Product Complaint Form.
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the eCRF page for AE/SAE and 
the Product Complaint Form for product complaints.

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
There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. 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 to sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or 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: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.

Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with a 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.
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 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.

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
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. 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 to sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a 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 by sponsor or 
designee 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.
10.3.5.
Reporting of SAEs
SAE Reporting via SAE Report

Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the sponsor or designee.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE report.
10.3.6.
Regulatory Reporting Requirements
SAE Regulatory Reporting

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met.
●
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

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●
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., 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.

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10.4. Appendix 4: Contraceptive and Barrier Guidance
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
1. Women in the following categories are not considered WOCBP:
a.
Premenopausal female with 1 of the following:

hysterectomy

bilateral salpingectomy

bilateral oophorectomy

bilateral tubal ligation

bilateral tubal occlusion
For individuals with permanent infertility due to an alternate medical cause/congenital 
anomaly other than the above, (e.g., Müllerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
b. Postmenopausal female, defined as women with:

12 months of amenorrhea for women >55, with no need for FSH

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL 
and no other medical condition such as anorexia nervosa and not taking 
medications during the amenorrhea (e.g. oral contraceptives, hormones, 
gonadotropin releasing hormone, anti-estrogens, selective ER modulators, or 
chemotherapy that induced amenorrhea).
Contraception Guidance:
Contraception is not required during this study.

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments
See Section 8.2.5.1 for guidance on appropriate test selection. 
The liver safety tests will be performed by the local laboratory. A Lilly-designated central 
laboratory may be used if the local laboratory is unable to perform the tests.
Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - red blood cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - white blood cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
  Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
  Lymphocytes
Creatine kinase (CK)
  Monocytes
Other Chemistrye
  Basophils
Acetaminophen
  Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl alcohol (EtOH)
Prothrombin time, international normalized ratio (INR) 
(PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (quantitative)
Hepatitis A virus (HAV) testing:
Immunoglobulin IgG (quantitative)
  HAV total antibody
Immunoglobulin IgM (quantitative)
  HAV IgM antibody
Phosphatidylethanol (PEth)
Hepatitis B virus (HBV) testing:
Urine Chemistry
  Hepatitis B surface antigen (HBsAg)
Drug screen
  Hepatitis B surface antibody (anti-HBs)
Ethyl glucuronide (EtG)
  Hepatitis B core total antibody (anti-HBc)
Other Serology
  Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)
  Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA) a
  HBV DNA d
Anti-actin antibody b
Hepatitis C virus (HCV) testing:
Epstein-Barr virus (EBV) testing:

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  HCV antibody
  EBV antibody
  HCV RNA d
  EBV DNA d
Hepatitis D virus (HDV) testing:
Cytomegalovirus (CMV) testing:
  HDV antibody
  CMV antibody
Hepatitis E virus (HEV) testing:
  CMV DNA d
  HEV IgG antibody
Herpes simplex virus (HSV) testing:
  HEV IgM antibody
  HSV (Type 1 and 2) antibody 
  HEV RNA d
  HSV (Type 1 and 2) DNA d
Microbiology c
Liver kidney microsomal type 1 (LKM-1) antibody
Culture:
  Blood
  Urine
a
Not required if anti-actin antibody is tested.
b
Not required if anti-smooth muscle antibody (ASMA) is tested.
c
Assayed ONLY by investigator-designated local laboratory; no central testing available.
d
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
e 
To be performed only in the event of increase AST/ALT.

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10.6. Appendix 6: Abbreviations
Term
Definition
ALT
alanine aminotransferase
AMS
accelerator mass spectrometry
AST
aspartate aminotransferase
CIOMS
Council for International Organizations of Medical Sciences
Companion diagnostic 
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
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.
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
DMC
data monitoring committee
Device Deficiencies
Equivalent to product complaint
ECG
electrocardiogram
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.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
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.

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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a 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.
IWRS
interactive web-response system
NIMP
Non-investigational Medicinal Product
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PC
product complaint
PK/PD
pharmacokinetics/pharmacodynamics
PPS
per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QTc
corrected QT interval
SAE
serious adverse event
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. 
SUSARs
suspected unexpected serious adverse reactions
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.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2J-M C -J Z L E( b)
6 8
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Leo Document ID = 8ed1b742-a202-41ec-bc95-282b378e7dd1
Approver: 
Approval Date & Time: 04-Aug-2021 21:19:15 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Aug-2021 13:32:26 GMT
Signature meaning: Approved
PPD
PPD