Clinical trial NCT04682106
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2021-05-03; Completion date: 2021-11-11
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of LY3493269 in healthy participants. The blood tests will be performed to check how much LY3493269 gets into the bloodstream, how long the body takes to eliminate it and how body handles LY3493269. The study will last up to approximately 71 days for each participant, including screening

Detailed description:

Arms: arm 1: Participants received placebo orally once daily (QD) for three consecutive days. arm 2: Participants received 8 mg LY3493269 and 600 mg SNAC QD administered orally for three consecutive days. arm 3: Participants received 24 mg LY3493269 and 600 mg SNAC QD administered orally for three consecutive days. arm 4: Participants received 12 mg LY3493269 and 300 mg SNAC QD administered orally for three consecutive days. arm 5: Participants received 4 mg LY3493269 and 300 mg SNAC QD administered orally for three consecutive days.
Interventions: intervention 1: LY3493269 intervention 2: Placebo intervention 3: Salcaprozate Sodium
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol J1X-MC-GZHF(a)
A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of an 
LY3493269 Formulation in Healthy Participants
NCT04682106
Approval Date: 05-March-2021


CONFIDENTIAL
Protocol J1X-MC-GZHF(a)
1
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 LY3493269, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of an LY3493269 Oral Formulation in Healthy Participants
Protocol Number: J1X-MC-GZHF
Amendment Number: (a)
Compound: LY3493269
Study Phase: 1
Short Title: A Safety Study of an LY3493269 Formulation Given as Multiple Oral Doses in 
Healthy Participants
Acronym: GZHF
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Approval Date: Protocol Amendment Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 05-Mar-2021 GMT


CONFIDENTIAL
Protocol J1X-MC-GZHF(a)
2
Medical monitor name and contact information will be provided separately.


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Protocol J1X-MC-GZHF(a)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
11-Sep-2020
Amendment (a)
Overall Rationale for the Amendment:
The primary reason for the amendment was to clarify that Cohorts 3 and 4 may be initiated in 
parallel. In addition, additional clinical assessments are described for evaluation of adverse 
events related to skin sensations.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.2. 
Schema
Modified the Schema to represent 
that Dose 3 and Dose 4 may be
done in parallel
The modified schema is aligned with the 
changes described in Section 4.1. 
Section 
2.2.1. 
Summary of 
Clinical 
Experience
Study details of Study J1X-MC-
GZHB and J1X-MC-GZHC have 
been added.
The section was updated based on latest 
available data.
Section 2.3. 
Benefit/Risk 
Assessment
Additional clinical assessment 
details have been added.
These assessments need be done based on 
latest data.
Section 4.1. 
Overall 
Design
Added a statement clarifying
initiation of Cohorts 3 and 4 and 
dose escalation plan.
The exposure from 24 mg LY+300 mg 
SNAC is unlikely to result in exposures 
that will exceed 48 mg LY+600 mg 
SNAC. If safety data from Cohort 2 
(24 mg LY3493269+600 mg SNAC) do 
not preclude dosing of 24 mg LY3493269 
with 300 mg SNAC (Cohort 4), then 
dosing for Cohorts 3 and 4 may be 
initiated in parallel. 
Section 4.3. 
Justification 
for Dose
Additional text for justification of 
dose has been added.
This information was based on latest data.
Section 
6.6.1. Dose 
Escalation
Added a statement clarifying 
initiation of Cohorts 3 and 4.
This statement is aligned with the changes 
described in Section 4.1.  


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Protocol J1X-MC-GZHF(a)
4
Section # and 
Name
Description of Change
Brief Rationale
Section 
6.6.2. Dose-
Escalation 
Stopping 
Criteria
Reference to a safety monitoring 
algorithm has been deleted.
The safety monitoring algorithm has been
deleted from Appendix 7 based on latest 
protocol language.
Section 
8.2.5.2. 
Pancreatic 
Safety 
(Elevated 
Lipase or 
Amylase)
Safety information for
asymptomatic elevation of serum 
amylase and/or lipase have been 
added.
This was updated based on latest available 
data.
Section 
8.2.5.5. 
Additional 
Assessments 
for Adverse 
Events of 
Skin 
Sensations
A new section has been added.
The section was added to include 
additional assessment for skin sensations.
Section 
8.3.7. 
Adverse 
Events of 
Special 
Interest
Skin burning sensation has been 
added as an important identified 
risk for LY3493269.
The section was updated based on latest 
available data.
Section 10.7. 
Appendix 7: 
Pancreatic 
Monitoring
A figure related to the safety 
monitoring algorithm for 
pancreatic enzymes was deleted.
The figure was removed as pancreatic 
enzyme levels have limited clinical value 
for predicting episodes of acute 
pancreatitis.
All sections
Minor corrections and clarifications in the document


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Protocol J1X-MC-GZHF(a)
5
Table of Contents
1.
Protocol Summary......................................................................................................8
1.1.
Synopsis.......................................................................................................................8
1.2.
Schema.......................................................................................................................10
1.3.
Schedule of Activities (SoA) ......................................................................................11
2.
Introduction..............................................................................................................14
2.1.
Study Rationale ..........................................................................................................14
2.2.
Background ................................................................................................................14
2.2.1.
Summary of Clinical Experience ................................................................................15
2.3.
Benefit/Risk Assessment ............................................................................................17
3.
Objectives and Endpoints.........................................................................................19
4.
Study Design .............................................................................................................20
4.1.
Overall Design............................................................................................................20
4.1.1.
Screening Period.........................................................................................................21
4.1.2.
Treatment Period ........................................................................................................21
4.1.3.
Outpatient Visits (Days 6, 8, and 15) ..........................................................................21
4.1.4.
Follow-Up Visits (Days 29 and 43).............................................................................21
4.2.
Scientific Rationale for Study Design .........................................................................21
4.3.
Justification for Dose..................................................................................................22
4.4.
End of Study Definition..............................................................................................25
5.
Study Population ......................................................................................................26
5.1.
Inclusion Criteria........................................................................................................26
5.2.
Exclusion Criteria.......................................................................................................27
5.3.
Lifestyle Considerations .............................................................................................29
5.3.1.
Meals and Dietary Restrictions ...................................................................................29
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................29
5.3.3.
Activity ......................................................................................................................30
5.4.
Screen Failures...........................................................................................................30
6.
Study Intervention....................................................................................................31
6.1.
Study Intervention(s) Administered ............................................................................31
6.1.1.
Administration Details................................................................................................32
6.2.
Preparation/Handling/Storage/Accountability.............................................................32
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................32
6.3.1.
Method of Treatment Assignment...............................................................................32
6.3.2.
Selection and Timing of Doses ...................................................................................33
6.3.3.
Unblinding .................................................................................................................33
6.4.
Study Intervention Compliance...................................................................................33
6.5.
Concomitant Therapy .................................................................................................33
6.6.
Dose Modification......................................................................................................34
6.6.1.
Dose Escalation ..........................................................................................................34
6.6.2.
Dose-Escalation Stopping Criteria ..............................................................................35
6.6.3.
Data Review during the Study ....................................................................................35
6.7.
Intervention after the End of the Study........................................................................35


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Protocol J1X-MC-GZHF(a)
6
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................36
7.1.
Discontinuation of Study Intervention ........................................................................36
7.1.1.
Hepatic Criteria for Discontinuation ...........................................................................36
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................37
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................37
7.3.
Lost to Follow up .......................................................................................................38
8.
Study Assessments and Procedures .........................................................................39
8.1.
Efficacy Assessments .................................................................................................39
8.2.
Safety Assessments ....................................................................................................39
8.2.1.
Physical Examinations................................................................................................39
8.2.2.
Vital Signs..................................................................................................................40
8.2.3.
Electrocardiograms.....................................................................................................40
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................41
8.2.5.
Safety Monitoring.......................................................................................................42
8.2.6.
Glucose Monitoring....................................................................................................45
8.3.
Adverse Events and Serious Adverse Events ..............................................................47
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................47
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................47
8.3.3.
Follow-up of AEs and SAEs.......................................................................................48
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................48
8.3.5.
Pregnancy...................................................................................................................48
8.3.6.
Events or Outcomes....................................................................................................48
8.3.7.
Adverse Events of Special Interest..............................................................................48
8.3.8.
Product Complaints ....................................................................................................49
8.4.
Treatment of Overdose ...............................................................................................50
8.5.
Pharmacokinetics........................................................................................................50
8.5.1.
Bioanalysis .................................................................................................................50
8.6.
Pharmacodynamics.....................................................................................................51
8.6.1.
Body Weight ..............................................................................................................51
8.6.2.
Appetite Analysis .......................................................................................................51
8.6.3.
Pharmacodynamic Markers.........................................................................................51
8.7.
Genetics .....................................................................................................................52
8.8.
Biomarkers.................................................................................................................52
8.9.
Immunogenicity Assessments.....................................................................................52
8.10.
Health Economics.......................................................................................................53
8.11.
Product Acceptability and Palatability Assessments....................................................53
9.
Statistical Considerations.........................................................................................54
9.1.
Statistical Hypotheses.................................................................................................54
9.2.
Sample Size Determination.........................................................................................54
9.3.
Populations for Analyses ............................................................................................54
9.3.1.
Study Participant Disposition......................................................................................54
9.3.2.
Study Participant Characteristics.................................................................................55
9.3.3.
Treatment Compliance................................................................................................55
9.4.
Statistical Analyses.....................................................................................................55


CONFIDENTIAL
Protocol J1X-MC-GZHF(a)
7
9.4.1.
General Considerations...............................................................................................55
9.4.2.
Safety Analyses ..........................................................................................................56
9.4.3.
Product Acceptability and Palatability Analyses .........................................................56
9.4.4.
Pharmacokinetic Analyses ..........................................................................................56
9.4.5.
Pharmacodynamics Analyses......................................................................................57
9.4.6.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................57
9.4.7.
Evaluation of Immunogenicity....................................................................................58
9.5.
Interim Analyses.........................................................................................................58
9.6.
Data Monitoring Committee (DMC)...........................................................................58
10.
Supporting Documentation and Operational Considerations ................................59
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................59
10.1.1.
Regulatory and Ethical Considerations........................................................................59
10.1.2.
Informed Consent Process ..........................................................................................59
10.1.3.
Data Protection...........................................................................................................60
10.1.4.
Dissemination of Clinical Study Data .........................................................................60
10.1.5.
Data Quality Assurance ..............................................................................................61
10.1.6.
Source Documents......................................................................................................62
10.1.7.
Study and Site Start and Closure.................................................................................62
10.1.8.
Publication Policy.......................................................................................................63
10.1.9.
Long-Term Sample Retention.....................................................................................63
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................64
10.2.1.
Blood Sampling Summary..........................................................................................66
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................67
10.3.1.
Definition of AE.........................................................................................................67
10.3.2.
Definition of SAE.......................................................................................................68
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................69
10.3.4.
Reporting of SAEs......................................................................................................70
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................71
10.4.1.
Definitions..................................................................................................................71
10.4.2.
Contraception Guidance..............................................................................................71
10.4.3.
Collection of Pregnancy Information ..........................................................................73
10.5.
Appendix 5: Genetics .................................................................................................75
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................76
10.7.
Appendix 7: Pancreatic Monitoring ............................................................................78
10.8.
Appendix 8: Hypersensitivity Event Tests ..................................................................79
10.9.
Appendix 9: Abbreviations .........................................................................................80
11.
References.................................................................................................................83


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Protocol J1X-MC-GZHF(a)
8
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of an LY3493269 Oral Formulation in Healthy Participants
Short Title: A Safety Study of an LY3493269 Formulation Given as Multiple Oral Doses in 
Healthy Participants 
Rationale: 
LY3493269 is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like
peptide-1 receptor agonist (GLP-1) being developed as a treatment for type 2 diabetes mellitus. 
This study of LY3493269, Study J1X-MC-GZHF (GZHF), will investigate the safety, 
tolerability, and pharmacokinetics of LY3493269 administered as 3 consecutive, once-daily oral 
doses in healthy participants. 
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability of LY3493269 following 
3 once-daily oral doses in healthy participants

TEAEs 
Secondary

To characterize the PK of LY3493269 following 3 once-daily oral doses 
in healthy participants

AUC and Cmax
Abbreviations: AUC = area under the concentration versus time curve; Cmax = maximum observed drug 
concentration; PK = pharmacokinetic(s); TEAE = treatment-emergent adverse event. 
Overall Design
Study GZHF is a Phase 1, single-center, randomized, placebo-controlled, multiple dose, 
dose-escalation study in 4 planned cohorts targeting 10 healthy participants to complete in each 
cohort.
Disclosure Statement: This is a multiple-dose escalation study that is investigator- and 
participant-blind.
Number of Participants:
Up to approximately 56 participants may be randomly assigned to study intervention to ensure 
approximately 10 evaluable participants (8 receiving LY3493269 and 2 receiving placebo) from 
each of the 4 cohorts complete the study. 
Intervention Groups and Duration:
In each cohort, eligible participants will be randomly assigned to receive 3 once-daily doses of 
either LY3493269 or placebo.


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Protocol J1X-MC-GZHF(a)
9
The maximum total duration of study participation for each participant may be up to 71 days, 
across the following study intervals:

Screening, approximately 28 days

Treatment period, approximately 15 days

Follow up, approximately 28 days
Data Monitoring Committee: No


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Protocol J1X-MC-GZHF(a)
10
1.2.
Schema
Abbreviations: LY = LY3493269; PL = placebo; SNAC = salcaprozate sodium.
Note: Cohort 4 may be initiated at the same time as Cohort 3 on review of safety and tolerability data from Cohort 2.


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Protocol J1X-MC-GZHF(a)
11
1.3.
Schedule of Activities (SoA)
Study Activities
Screening
Treatment Period
Follow-up
Comments/ 
Notes
CRU Inpatient Stay
Outpatient
Outpatient
Days
-28 
to 
-2
−1
1
2
3
4
5
6
8
15 
± 
1
29
± 
3
43 
± 
3
ET
Study informed consent
X
Medical history
X
Physical examination
X
Medical assessment
P
P
P
X
X
X
X
X
X
X
Medical review and targeted 
examination, as appropriate.
Height and weight
X
P
X
X
X
X
X
X
Height at screening only.
Admit to CRU
X
Discharge from CRU 
X
At the investigator’s discretion, 
participants may remain inpatient 
after Day 5.
Outpatient visit to CRU
X
X
X
X
X
X
Administer study drug
X
X
X
Refer to Section 6.1.1 for details
Product palatability assessment 
X
X
X
Refer to Section 8.11 for details
AEs/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs: supine BP/PR (h)
X
-0.5, -0.25, P, 
1, 4, 6, 12
P, 1, 4, 
12
-0.5, -0.25, P, 
1, 4, 6, 12
X
X
X
X
X
X
X
X
Body temperature
X
P
P
P
ECG – single
X
X
X
X
ECG – triplicate (h)
-0.5, -0.25, P, 
1, 4, 6, 12
P, 1, 4, 
12
-0.5, -0.25, P, 
1, 4, 6, 12
X
X
X
X
X
Clinical laboratory tests (fasted)
X
P
X
X
X
X
X
X
See Appendix 2 (Section 10.2) for 
details. 
HbA1c
P


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Protocol J1X-MC-GZHF(a)
12
Abbreviations: AE = adverse event; BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination (applicable only to 
study participants who have received study intervention); h = hour; min = minutes; P = predose; PD = pharmacodynamics; PK = pharmacokinetics; PR = pulse 
rate; SNAC = salcaprozate sodium; VAS = visual analog scale. 
Notes: Fasted samples or assessments should be collected or performed after a minimum 8-hour overnight fast. If multiple procedures take place at the same time 
point, ECGs and vital signs must be obtained prior to any blood sample collection. 
For vital signs and triplicate ECGs

time points on Days 1 to 3 are relative to scheduled dosing at “0 h”. Assessments scheduled at “0” are conducted predose (P).

on Day 15, ECG should be measured within approximately 30 min prior to the scheduled PK sample.

on Day 15 and subsequent visits, vital signs should be measured within approximately 30 min prior to the scheduled PK sample.
Pharmacokinetic and immunogenicity samples are not required at ET for participants who discontinue without receiving study intervention.
Study Activities
Screening
Treatment Period
Follow-up
Comments/
Notes
CRU Inpatient Stay
Outpatient
Outpatient
Days
-28 
to 
-2
−1
1
2
3
4
5
6
8
15 
± 
1
29
± 
3
43 
± 
3
ET
Point-of-care safety glucose 
samples (glucose analyzer)
Days 1 – 4: Pre-meals (breakfast, lunch, and 
dinner) and before bedtime
X
X
Days 5-6: Fasted samples collected 
before breakfast.
LY3493269 PK sampling (h)
P, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 5, 
6, 8, 12
P, 0.5, 1, 
2, 3, 4, 
12
P, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 5, 
6, 8, 12
X
X
X
X
X
X
X
X
Days 15, 29, 43, and ET: Samples 
collected anytime during visit.
SNAC PK sampling (h)
P, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 5, 
6, 8, 12
P, 0.5, 1, 
2, 3, 4, 
12
P, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 5, 
6, 8, 12
X
X
PD biomarkers (fasted)
Glucose, Insulin, and C-
peptide 
P
P
X
X
X
X
Triglycerides – (fasted)
P
P
X
X
X
X
Appetite VAS – (fasted)
P
P
P
X
X
X
X
Immunogenicity
P
X
X
X
X
Day 1: Samples are collected within 
30 min of the predose PK samples. 
Pharmacogenetic sample
X
Obtained at any time on Day 1.
Nonpharmacogenetic stored 
samples – (fasted)
P
P
X
X
X
X


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Protocol J1X-MC-GZHF(a)
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The following requirements are not applicable for urinalysis samples. Unless otherwise stated

predose study assessments and procedures should be performed within 3 hours prior to planned dosing,

postdose assessments and procedures up to and including 24 hours should be performed within ±10% of the scheduled time, and

postdose assessments and procedures scheduled after the 24-hour time point should be performed within ±3 hours of the scheduled time.


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Protocol J1X-MC-GZHF(a)
14
2.
Introduction
2.1.
Study Rationale
LY3493269 is a dual GIP and GLP-1 receptor agonist being developed as a treatment for T2DM. 
In addition to SC treatment, an oral formulation of LY3493269 is being developed for once-daily 
administration to improve patient convenience and therapy adherence. The aim of developing an 
oral formulation is to provide an effective oral incretin for patients with T2DM with inadequately 
managed BG goals. This study of LY3493269, Study J1X-MC-GZHF (GZHF), will investigate 
the safety, tolerability, and PK of LY3493269 administered as multiple once-daily oral doses in 
healthy participants. In addition, the PD effects of LY3493269 on fasting glucose, insulin, 
C-peptide, triglycerides, and appetite will be explored following the 3 consecutive oral 
once-daily doses of LY3493269.
2.2.
Background
Type 2 diabetes mellitus is characterized by impaired glycemic control due to insulin resistance 
and inadequate insulin secretion due to the pancreatic beta-cell failure. Type 2 diabetes mellitus 
is frequently associated with comorbidities such as obesity, hypertension, and dyslipidemia 
resulting in increased risk of microvascular and macrovascular complications.
Synthesized and secreted in the proximal intestine, GIP is primarily regulated by nutrients, 
especially fats, and is responsible for the majority of the insulinotropic incretin effect in humans. 
In addition, distinct from GLP-1, GIP promotes glucagon secretion at low BG levels to augment 
endogenous glucose production. It stimulates lipolysis and inhibits insulin-induced lipogenesis in 
human adipocytes.
Glucagon-like peptide-1 is a well-characterized incretin hormone that potentiates insulin 
secretion and reduces glucagon secretion in a glucose-dependent manner after meal ingestion. 
Glucagon-like peptide-1 exerts its insulinotropic action through distinct G protein coupled 
receptors highly expressed on islet β cells and in some non-islet cells. For example, GLP-1Rs are 
expressed throughout the brain, in regions that control

glucose homeostasis

gut motility

food intake

aversive signaling, and

CV function (Campbell and Drucker 2013). 
Currently, there are several approved GLP-1RAs for the treatment of diabetes and obesity. The 
dosing of GLP-1RAs in humans is limited by GI adverse effects, such as nausea and vomiting.
Available preclinical and clinical data indicate that co-stimulation of GIP and GLP-1Rs may 
enhance insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect 
of selective GLP-1R stimulation (Coskun et al. 2018; Frias et al. 2018). 
The LY3493269 oral formulation in Study GZHF will include a permeation enhancer (SNAC), 
to enable oral absorption of the LY3493269 peptide. As peptides are otherwise poorly absorbed 


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Protocol J1X-MC-GZHF(a)
15
orally due to low permeability, an enabling excipient such as SNAC in an oral tablet formulation 
is expected to transiently increase local permeability (Twarog et al. 2019) and result in increased 
oral bioavailability for therapeutic use.  
2.2.1.
Summary of Clinical Experience
Study J1X-MC-GZHA
Study J1X-MC-GZHA (GZHA) was a first-in-human, randomized, placebo-controlled, SAD 
study investigating the safety, tolerability, and PK of LY3493269 administered as single SC 
doses in healthy participants. In addition, a cohort of 6 healthy participants was planned to 
receive a single intravenous dose of LY3493269, to allow estimation of the absolute SC 
bioavailability of LY3493269.
As of 06 April 2020, 3 cohorts of 6 participants received SC doses of LY3493269 at each of the 
0.15-, 0.5-, and 1.5-mg dose levels. There was an increase in the number of AEs (such as nausea, 
vomiting, and abdominal distension) related to the study drug with increasing doses of 
LY3493269 as compared to placebo. The dose of 1.5 mg was considered not well tolerated due 
to increases in the number of GI events, some requiring treatment.  However, the prespecified 
dose escalation stopping criteria were not met. Due to concerns about safety and tolerability with 
the next planned SC dose of 3 mg, the sponsor decided to stop further dosing.
No deaths, serious adverse events (SAEs), or discontinuations due to AEs were noted in this 
study up to the data cut-off, 06 April 2020. 
Of the 30 healthy participants who received either LY3493269 or placebo, 26 (86.7%) reported 
at least 1 TEAE.
Consistent with the incretin class, GI events such as abdominal distension, nausea, vomiting, and 
diarrhea were the most commonly reported AEs in Study GZHA. In addition, decreased appetite 
was also one of the most frequently reported AEs. All TEAEs were considered as mild in 
severity by the investigator, even though some required treatment. In Cohort 2, where subjects 
received 0.5 mg, 1 subject out of 6 presented with nausea, and none presented with vomiting. 
However, 3 subjects out of 6 in Cohort 3 receiving 1.5 mg reported GI AEs of nausea and 
vomiting, requiring anti-emetics. Several other GI AEs were reported in Cohort 3 (for example, 
abdominal pain upper, constipation, eructation, epigastric discomfort, dry mouth, and dyspepsia) 
not previously reported in the other cohorts. 
No clinically significant changes in laboratory data, injection-site reactions, or severe 
hypoglycemia events were noted.
A dose-dependent increase in HR, which is consistent with the incretin class (Lorenz et al. 2017), 
was noted. While no clinically significant changes were noted in ECG results, 3 participants in 
Cohort 3 (1.5 mg) presented mild AEs of tachycardia. No significant changes in the BP 
measurements were noted. The maximum HR (supine) for all 3 participants occurred at 4 hours 
postdose; the HR for these 3 participants returned to below 100 bpm, ranging between 6 hours 
for one participant and Day 3 postdose for another. 
Six participants received the 0.5-mg intravenous dose as planned. Mild events of decreased 
appetite and GI events such as abdominal distension and nausea were noted.


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Protocol J1X-MC-GZHF(a)
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Preliminary PK data from the SC route indicated the median time of tmax was 
 hours, close to 
proportional increase in exposures with increasing dose and a half-life of 
 days, which is 
suitable for a weekly dosing interval. 
Preliminary PD data suggest LY3493269 when administered SC may potentially reduce total 
body weight, appetite, and glucose concentrations during an oral glucose tolerance test.
Study J1X-MC-GZHB
Study J1X-MC-GZHB (GZHB) is a Phase 1, randomized, placebo-controlled, dose-escalation 
study investigating the safety, tolerability, PK, and PD of an LY3493269 formulation 
administered as 3 consecutive once-daily oral doses in healthy participants. In this study, the 
LY3493269 oral formulation contained sodium caprate (C10) as a permeation enhancer.
Four cohorts, each with 8 participants receiving LY3493269 and 2 receiving placebo, received 
the following study treatments: 

Cohort 1 participants received 8 mg LY3493269 or placebo plus 500 mg C10, 
as 2 capsules

Cohort 2 participants received 24 mg LY3493269 or placebo plus 500 mg C10, 
as 2 capsules

Cohort 3 participants received 48 mg LY3493269 or placebo plus 500 mg C10, 
as 2 capsules

Cohort 4 participants received 24 mg LY3493269 or placebo plus 250 mg C10, 
as a single capsule
The last patient visit for this study was achieved on 28 December 2020, and data lock is 
anticipated in March 2021.
Preliminary safety data
No SAEs were reported in the study. Forty male participants received study treatments, of which 
1 participant discontinued from the study due to nausea of moderate severity and which was 
considered related to study treatment. The safety profile for Study GZHB is similar to Study 
GZHA with the most frequent AEs being gastrointestinal AEs:

Decreased appetite

Nausea

Abdominal distension
Study J1X-MC-GZHC (GZHC)
Study GZHC aims to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of 
LY3493269 administered as 4 once-weekly SC doses in patients with T2DM.
Important Safety findings for Study GZHC:
1. GI AEs have been frequently reported.
2. Twenty-one participants out of 56 participants who received study drug reported AEs of 
skin burning sensation (including sensitive skin, paresthesia), with the majority reporting 
onset after the second dose of study drug or later, that resolved approximately 2 weeks 
after the final dose. There are no sequelae identified at this time.
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The AEs of skin burning sensation were variably distributed over the body. Initially reported as 
being of mild severity, further preliminary data indicate that dose escalation in this study was 
associated with an increase in severity of this AE and more extensive anatomical distribution. 
Since these AEs have been considered as clinically significant events, the study drug 
administration has been stopped. A series of in vitro investigations have been initiated to 
determine the mechanism behind this phenomenon.
The AEs of skin burning sensation were not observed in prior studies where LY3493269 was 
administered to healthy participants.
Additional information
Refer to the IB for more information about the nonclinical and clinical data of LY3493269. 
2.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the participants in this trial.
The sponsor has evaluated the preclinical and clinical risks associated with LY3493269. 
Nonclinical safety of SC LY3493269 was evaluated in a CV safety pharmacology study in 
monkeys and 1-month repeat-dose toxicology studies in rats and monkeys. Important 
LY3493269-related findings in the rat and monkey included body weight loss and/or reduced 
body weight gain and decreased food consumption. Additional findings from the monkey studies 
included changes in CV parameters (such as increases in HR and BP). In Study GZHA, similar 
findings were observed, which include 

nausea

vomiting

loss of appetite, and

increased HR.
Salcaprozate sodium has GRAS status and is contained in FDA-approved medical food (Eligen®-
Vitamin B12, Emisphere, Roseland, NJ, USA; Twarog et al. 2019). Rybelsus® tablet, which is 
approved by FDA, European Medicines Agency and Japan Pharmaceuticals and Medical 
Devices Agency, also contains SNAC (daily dose of 300 mg). In addition, in a first-in-human 
trial, up to 600 mg SNAC was evaluated with oral semaglutide with no safety concerns reported 
(Granhall et al. 2019). 
In the completed nonclinical safety pharmacology and toxicology studies, LY3493269 orally 
co-administered with SNAC produced body weight loss and/or decreased body weight gain, and 
decreased food consumption, which are consistent with, or secondary to, incretin pharmacology. 
The effects on body weight were dose limiting and resulted in dosing suspension in monkeys. No 
adverse SNAC-related effects were observed up to 600 mg/kg in any of the toxicology 
studies/assessments. Refer to the IB for more information. 
Based on the nonclinical studies, potential risks for clinical trial participants receiving orally 
administered LY3493269 are similar to those for participants receiving SC administered 
LY3493269 and include CV effects, GI disturbances, inappetence, and weight loss.
All identified risks from the nonclinical and clinical studies are considered monitorable and 
manageable at the planned oral dose range of 8 to 48 mg once daily of LY3493269. To further 


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Protocol J1X-MC-GZHF(a)
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minimize any potential risk, participants will remain at the CRU for at least 5 days for safety and 
tolerability monitoring until discharge. Participants will be closely monitored with scheduled 
medical assessments, vital signs, and triplicate ECG measurements. Additional clinical 
assessments of skin sensation AEs and a detailed neurologic examination are planned if these 
events are reported by study participants (see Section 8.2.1 for additional information). The 
investigator will have the discretion to extend the participant inpatient stay for further safety 
monitoring.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3493269 may be found in the IB.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and 
tolerability of LY3493269 following 
3 consecutive once-daily oral doses in 
healthy participants

TEAEs 
Secondary

To characterize the PK of LY3493269 
following 3 consecutive once-daily 
oral doses in healthy participants 

AUC and Cmax
Exploratory

To investigate the PD effects of 
LY3493269 following 3 consecutive 
once-daily oral doses in healthy 
participants

Changes from baseline levels of 
fasting glucose, insulin, C-peptide, 
triglycerides, and body weight

To assess PK of SNAC following oral 
administration in healthy participants

AUC and Cmax

To explore the effect of LY3493269 
on appetite and food intake following 
3 consecutive once-daily oral doses in 
healthy participants

Change in VAS score for appetite 
assessment in a fasted state

To characterize immunogenicity of 
LY3493269 following 3 once-daily 
oral doses in healthy participants

Incidence of treatment-emergent ADA

To assess the product palatability of 
LY3493269 tablets

Responses to tablet palatability 
questionnaire
Abbreviations: ADA = antidrug antibody; AUC = area under the concentration versus time curve; Cmax = maximum 
observed drug concentration; PD = pharmacodynamic(s); PK = pharmacokinetic(s); TEAE = treatment-emergent 
adverse event; VAS = visual analog scale.


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4.
Study Design
4.1.
Overall Design
Study GZHF is a Phase 1, single-center, randomized, placebo-controlled, multiple dose, 
dose-escalation study in 4 planned cohorts of up to 14 healthy participants randomly assigned in 
each cohort.
This study will evaluate the safety, tolerability, and PK of 3 consecutive once-daily oral doses of 
LY3493269. In addition, the PD effects of LY3493269 on fasting glucose, insulin, triglycerides, 
and appetite will be explored following the 3 consecutive oral once-daily doses of LY3493269.
In each cohort, up to 14 participants may be randomly assigned to achieve 10 completers with 
8 participants receiving LY3493269 and 2 participants assigned to receive placebo. Participants 
who are randomly assigned but not administered treatment prior to discontinuation may be 
replaced to ensure that the target number of participants complete the study.
This is an investigator- and participant-blind study; the sponsor is not blinded.
Study randomization shall occur after confirmation of eligibility.
The planned LY3493269 oral doses for this study range from 8 to 48 mg (Section 1.2), 
administered in the 4 planned “dose cohorts”:

Cohort 1: 8 mg LY3493269 (with 600 mg SNAC)

Cohort 2: 24 mg LY3493269 (with 600 mg SNAC)

Cohort 3: 48 mg LY3493269 (with 600 mg SNAC)

Cohort 4: 24 mg LY3493269 (with 300 mg SNAC)
Cohorts 1 to 3 evaluate doses of LY3493269 from 8 to 48 mg, each dose in combination with 
600 mg SNAC. Cohort 4 evaluates a 24-mg dose of LY3493269 with half the amount (300 mg) 
of SNAC. PK exposures from 24 mg LY3493269 administered with half the amount of SNAC 
(i.e. 300 mg SNAC in Cohort 4) are anticipated to be comparable to exposures from the 24-mg 
dose in Cohort 2, and not exceed exposures from the 48-mg dose in Cohort 3. Hence, Cohort 4
may be initiated at the same time as Cohort 3 if safety and tolerability data from Cohort 2 do not 
preclude dosing of 24 mg LY3493269 or higher doses. 
The LY3493269 dose levels may be adjusted (for example, dose increments may be reduced, a 
dose level may be repeated, or a lower/intermediate dose may be administered) based on ongoing 
review of available safety, tolerability, PK, and PD data (Section 6.6). Any proposal to adjust 
doses from those planned and stated in the protocol, together with supporting data, will be 
reviewed by an independent SRP.
Participants will undergo safety (including but not limited to AEs, medical assessments, clinical 
laboratory tests, body weight, vital signs, and ECGs), PK, and PD assessments according to the 
SoA (Section 1.3).
Safety data including, but not limited to AEs, clinical laboratory tests, vital signs, ECGs, body 
weight, hypoglycemic events, and VAS assessments up to Day 8 from at least 8 participants who 
have received study intervention will be reviewed jointly by the principal investigator and 
sponsor before a joint decision is made to escalate to the next higher planned dose level. 


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Protocol J1X-MC-GZHF(a)
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4.1.1.
Screening Period
The outpatient screening visit may be up to 28 days prior to enrollment. Individuals who are not 
enrolled within 28 days of screening may be subjected to an additional medical assessment 
and/or clinical measurements to confirm their eligibility. Parameters that may be repeated for 
screening include clinical laboratory tests, ECGs, and vital signs.
4.1.2.
Treatment Period
Study participants will be admitted to the CRU on Day -1 and adhere to an overnight fast.
Participants will be randomly assigned to treatment, followed by dosing while inpatient at the 
CRU. Participants will receive 3 consecutive once-daily doses of either LY3493269 or placebo 
on Days 1 through 3. Fasting requirements including food and water restrictions must be adhered 
to for each dose administered (Section 6.1.1). Participants should complete the study assessments 
and procedures planned during this period as specified in Section 1.3. Unless the investigator 
identifies a safety concern, participants may be discharged from the CRU on Day 5.
Pharmacokinetic and PD sampling and safety assessments will be performed according to the 
SoA (Section 1.3). Pharmacokinetic and PD sampling schedules may be modified based on the 
available safety and PK/PD data.
4.1.3.
Outpatient Visits (Days 6, 8, and 15)
Participants will return to the CRU for outpatient visits on Days 6, 8, and 15, for safety 
assessments and PK and/or PD sampling at the times specified in the SoA (Section 1.3). 
Participants may remain as needed at the CRU for safety monitoring based on the investigator’s 
judgment or to facilitate participant compliance.
4.1.4.
Follow-Up Visits (Days 29 and 43)
During the follow-up period, participants should attend the outpatient visits on Days 29 and 43. 
The study assessments and procedures planned during this period should be performed as 
specified in the SoA (Section 1.3).
Participants who received study intervention and who discontinue early will be encouraged to 
return for an early termination visit with procedures performed as shown in the SoA 
(Section 1.3) and a follow-up visit for safety monitoring, including but not limited to 28 days 
after study intervention. Enrolled participants who discontinue without study intervention will 
not be required to attend the early termination visit.
Participants will be discharged from the study after the investigator has completed review of all 
final safety assessments from the last follow-up visit.
4.2.
Scientific Rationale for Study Design
A population of healthy participants is selected to assess the safety and tolerability of 
LY3493269 for initiation of oral administration in humans prior to further investigations in 
participants with T2DM. Using a healthy participant population mitigates possible confounding 
effects of comorbidities and concomitant medications. Therefore, Study GZHF provides an 
unbiased assessment of safety, tolerability, and PK of LY3493269 administered as oral doses.


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The study is intended to estimate a maximum tolerated exposure or establish that exposures 
exceeding the expected therapeutic range are tolerated via the oral route of administration. 
Additionally, the study will inform the target exposure range for subsequent oral dosing of 
LY3493269. Safety, tolerability, PK, and preliminary PD data will assist in identifying an 
appropriate dose range for subsequent clinical studies regardless of administration route.
A study design of once-daily oral dosing for 3 days will be employed to characterize oral PK 
behavior of LY3493269. The dosing duration of 3-days was selected after taking into 
consideration the following factors:

low oral bioavailability expected from oral peptide formulations,

the exceptionally high inter- and intra-individual variabilities in oral bioavailability 
expected of oral peptide formulations,

the sensitivity of the bioanalytical assay, and

once absorbed via the oral route of administration, LY3493269 systemic PK disposition 
should be similar regardless of route of administration, hence safety, tolerability, and PK 
data from the SC SAD study (GZHA) should be applicable to this study.
To predict the oral PK profiles for each cohort, extensive PK simulations were conducted. The 
PK profile following a single oral dose was deemed to be at risk of being highly variable and 
potentially returning lower than quantifiable concentrations at multiple time points. The 
simulation results did suggest that 3 days was adequate for a majority of PK profiles from 
participants in each cohort to remain above the quantification limit of 
 to yield
meaningful PK results. The PK data from Study GZHA estimated the LY3493269 
 
. Therefore, PK exposures from a short dosing duration of 3 days from this 
study are not expected to reach steady state for the respective doses.
Strict oral administration conditions such as controlling the duration of fasting before and after 
dosing and water volume for oral administration of LY3493269 will be imposed. These are 
necessary to reduce any potential variability arising from oral administration conditions that may 
affect oral bioavailability of LY3493269. 
Safety and tolerability assessments will be made across all dose levels, including incidence of 
nausea and/or vomiting, and evaluation of ECGs and vital signs conducted during the study 
(Section 8.2). A preliminary assessment of the PD effects of LY3493269 will be based on the 
concentrations of fasting glucose, insulin, and triglycerides up to Day 29 postdose. The effect of 
LY3493269 on appetite sensations will also be explored. The decision to escalate the dose will 
be based primarily on safety and tolerability data (Sections 6.6.1 and 6.6.2) and all available PK 
data will also be reviewed.
4.3.
Justification for Dose
The proposed LY3493269 oral dose range of 8 to 48 mg once daily is selected to attain 
steady-state exposures anticipated to be within the range equivalent to the Phase 3 dose range 
(SC 5 to 15 mg once weekly) of another GIP-GLP-1 molecule currently in Phase 3 development 
(tirzepatide). These doses have also been tested with no major safety concerns in another study 
(GZHB) where LY3493269 was dosed in combination with another permeation enhancer (C10).
The equivalent LY3493269 oral doses are predicted to be between 4 and 59 mg once daily 
assuming 
This assumed oral bioavailability is more generous than the 
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0.4% to 1.0% reported for another approved oral peptide co-formulated with SNAC (Rybelsus®
[Rybelsus (semaglutide) [package insert], 2020]) to ensure a conservative estimate of exposure 
multiple. Dose equivalents between the 2 molecules
 
. If oral 
bioavailability is doubled to 
 the anticipated average exposures of the first cohort of 8 mg 
once daily × 3 days are expected to be lower than the exposures from the LY3493269 SC 1.5 mg 
dose.
Salcaprozate sodium has generally regarded as safe (GRAS) status and is contained in 
FDA-approved medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA). Rybelsus®
tablet, which is approved by FDA, European Medicines Agency and Japan Pharmaceuticals and 
Medical Devices Agency, contains SNAC at 300 mg. In addition, in a first-in-human trial, up to 
600 mg SNAC was evaluated with oral semaglutide with no safety concerns reported (Granhall
et al. 2019). Cohort 4 is intended to assess if half the amount (300 mg) of SNAC can yield 
comparable oral bioavailability as 600 mg of SNAC at the same 24-mg dose of LY3493269. 
All of the identified risks in Section 2.3 are considered to be reversible, monitorable, and 
manageable and will continue to be monitored closely in clinic. The margin of safety of oral 
administered LY3493269 with SNAC or SNAC alone derived from 1-month repeat-dose toxicity 
studies is listed in Table 4.1 and Table 4.2.
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Table 4.1
Margins of Safety for Oral Administration of LY3493269 with SNAC, Based 
on Body Surface Area and Predicted Exposure
Dose 
(mg/kg)
Dose 
(mg/m2)
Dose multiplea
Cave 
(ng/mL)c
Projected exposure 
multipled
Starting 
dose
Maximum 
dose
Starting 
Dose
Maximum 
dose
Human starting 
dose (8 mg/day)b
0.114
4.218
56.6
Human maximum 
dose (48 mg/day)b
0.686
25.38
341
Multiples Derived from PO GLP Studies (QD)
Rat NOAEL 
(HDT)e
3
18
4.27
0.709
8
0.141
0.0235
Monkey HDTf
3
36
8.53
1.42
1194
21.1
3.5
Monkey LOAEL 
(LDT)f
1
12
2.84
0.472
546
9.65
1.60
Exposure Multiples Derived from SC GLP Studies (Rat: BIW; Monkey: QW)i
Rat NOAELg
0.05
0.3
--
--
83.5
1.48
0.245
Rat HDTg
1
6
--
--
1604
28.3
4.70
Monkey NOAELh
0.05
0.6
--
--
356
6.29
1.04
Monkey HDTh
1
12
--
--
7440
131
21.8
Abbreviations: AUC = area under the plasma concentration versus time curve; BIW= twice weekly dosing; 
Cave = average drug concentration during the dosing interval for a single dose; GLP = glucagon-like-peptide; 
HDT = highest dose tested; LDT = lowest dose tested; LOAEL = lowest-observed-adverse-effect level; 
NOAEL = no-observed-adverse-effect level; QD = once daily dosing; QW = once weekly dosing; 
SC = subcutaneous.
a
Dose multiple (based on body surface area) is calculated as dose in animals (mg/m2)/dose in humans (mg/m2).
b
Typical body weight of 70 kg was assumed for a healthy subject. AUC0-24 following the last dose based on 
assumed 
c
Cave was calculated based on AUC0-t normalized by dosing interval.
Human: Cave was calculated with plasma AUC0-24, based on preliminary PK exposure data from Study GZHA, 
from time 0 to 24 hours after the last (3rd) oral daily dose assuming 
 relative to SC 
administration, divided by 24 hr.
Rat and monkey oral QD: Cave was calculated based on observed plasma AUC0-24 on Day 28, divided by 24 hr.
Rat SC : Cave was calculated based on observed plasma AUC0-96 on Day 29, divided by 96 hr.
Monkey SC: Cave was calculated based on observed plasma AUC0-168 on Day 29, divided by 168 hr.
d
Exposure multiple is the calculated Cave in animals/predicted Cave in humans;
e
Rat NOAEL (HDT) of LY3493269 (with 600 mg/kg SNAC) was determined in a 1-month repeat-dose toxicity 
study via oral gavage (130-843).
f
Monkey HDT and LOAEL (LDT) of LY3493269 (with 600 mg/kg SNAC) was determined in a 1-month repeat-
dose toxicity study via oral gavage (20235767).
g
Rat NOAEL and HDT was determined in a 1-month repeat-dose toxicity study via subcutaneous injection 
(130-735). 
h
Monkey NOAEL and HDT was determined in a 1-month repeat-dose toxicity study via subcutaneous. injection 
(130-739).  
i   Dose multiple was not calculated due to assumed low oral bioavailability of LY3493269.
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Table 4.2
Margins of Safety for oral Administration of SNAC, Based on Body Weight and 
Predicted Exposure 
Dose 
(mg/kg)
Dose 
(mg/m2)
Dose 
multiplea
AUC (0-t)
(ng.hr/mL)
Projected exposure 
multipled
Human dose  
(600 mg/day)b
8.57
317
2258C
Rat NOAELe
600
3600
11.4
36800
16.3
Monkey NOAEL f
600
7200
22.7
319000
141
Abbreviations: AUC = area under the plasma concentration versus time curve; HDT= highest dose tested; 
NOAEL = no-observed-adverse-effect level.
a
Dose multiple (based on body weight, given the effect of SNAC expected to be local) is calculated as dose in 
animals (mg/kg)/dose in humans (mg/kg). 
b
Typical body weight of 70 kg was assumed for a healthy subject. 
c
Human plasma AUC of SNAC was estimated using published SNAC AUC(0-24) at the dose of 300 mg, 
assuming dose proportional increase of AUC from 300 to 600 mg (Bækdal TA, et al. Expert Opinion on Drug 
Metabolism & Toxicology 2018).
d
Exposure multiple is the observed AUC in animals on Day 28/published AUC in humans. 
e
Rat NOAEL of SNAC was determined in a 1-month repeat-dose toxicity study (130-843). It is the mean Male 
+Female from Study 130-843, Day 28 toxicokinetic data.  
f
Monkey NOAEL of SNAC was determined in a 1-month repeat-dose toxicity study (20235767). It is the mean 
Male +Female from Study 20235767, Day 28 toxicokinetic data.
In conclusion, the safety pharmacology and toxicity assessment of oral administered LY3493269
did not reveal any adverse findings in animals. The nonclinical safety data support the proposed 
Phase 1 study for an oral formulation of LY3493269. 
4.4.
End of Study Definition
A participant is considered to have completed the study if they have completed all required 
phases of the study including the last scheduled procedure shown in the SoA (Section 1.3).
Any participant who does not satisfy this definition but who has completed all the key 
assessments may be considered a completer at the discretion of the sponsor.
The end of the study is defined as the date of the last visit of the last participant in the study.


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5.
Study Population
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only, and not continuously throughout the trial.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment. Participants who are not enrolled within 
28 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. Parameters repeated for screening include clinical 
laboratory tests, body weight, ECGs, and vital signs.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Participant Characteristics
1. Are male or female not of childbearing potential from 21 to 65 years of age, inclusive, at 
the time of signing the informed consent.
Note:  For contraception requirements of this protocol, see Appendix 4 (Section 10.4).
2. Body mass index within the range of 19.0 to 40.0 kg/m2 (inclusive).
Type of Participant and Disease Characteristics
3. Participants who are healthy as determined through medical evaluation including 
screening medical history, physical examination, vital signs, clinical laboratory tests, and 
ECG.
4. Have clinical laboratory test results within normal reference range for the population or 
CRU, or results with acceptable deviations that are judged to be not clinically significant 
by the investigator.
5. Have venous access sufficient to allow blood sampling as per the protocol.
6. Are reliable and willing to make themselves available for the duration of the study and 
who will comply with the required study and dosing visits and abide by the clinical 
research site policy and procedure and study restrictions.


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Informed Consent
7. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the 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 a history of atopy (severe or multiple allergic manifestations) or clinically 
significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or 
severe posttreatment hypersensitivity reactions (including, but not limited to, erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
anaphylaxis, angioedema, or exfoliative dermatitis)
2. Have a significant history of or current CV (for example, myocardial infarction, 
congestive heart failure, cerebrovascular accident, venous thromboembolism, etc.), 
respiratory, renal, GI, endocrine, hematological (including history of 
thrombocytopenia), or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; of constituting a risk while taking the 
IP; or of interfering with the interpretation of data
3. Have a supine HR less than 45 bpm or greater than 100 bpm. If a repeat measurement 
shows values within the range, the participant can be included in the trial.
4. Have a mean supine systolic BP higher than 160 mmHg and a mean supine diastolic 
BP higher than 95 mmHg from 2 assessments at screening; therefore, if a repeated
measurement shows values within the range, the participant can be included in the trial.
5. Have undergone any form of bariatric surgery.
6. Have a history of GI bleeding or duodenal ulcers.
7. Have a personal or family history of medullary thyroid carcinoma or have multiple 
endocrine neoplasia syndrome type 2.
8. Have a history of acute or chronic pancreatitis, or elevation in serum lipase and/or 
amylase levels greater than 1.5 times the ULN.
9. Have clinical signs or symptoms of liver disease, acute or chronic hepatitis.
10. Have evidence of significant active neuropsychiatric disease as determined by the 
investigator.
Prior/Concomitant Therapy
11. Have been treated with prescription drugs that promote weight loss within 3 months 
prior to screening. Examples include 

Meridia® (sibutramine), 

Sanorex® (mazindol), 


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
Adipex-P® (phentermine), 

BELVIQ® (lorcaserin), 

Mysimba® (naltrexone/bupropion), 

Saxenda® (liraglutide) or 

similar other body weight loss medications including any over-the-counter 
medications or supplements (for example, alli®).
12. Have received chronic (lasting >14 consecutive days) systemic glucocorticoid therapy 
in the past year, or have received any glucocorticoid therapy within 1 month before 
screening (topical, intra-articular, and inhaled preparations such as steroid nasal spray 
are permitted in the study)
13. Intend to use over-the-counter or prescription medication within 7 or 14 days, 
respectively, prior to planned dosing (apart from vitamin/mineral supplements, 
occasional paracetamol, and thyroid replacement medication) and throughout the study 
period. If this situation arises, inclusion of an otherwise suitable participant may be at 
the discretion of the investigator and sponsor.
Prior/Concurrent Clinical Study Experience
14. Are currently enrolled in a clinical study involving an IP or any other type of medical 
research judged not to be scientifically or medically compatible with this study
15. Have participated within the past 30 days of screening in a clinical study involving an 
IP; at least 5 half-lives or 30 days, whichever is longer, should have passed
Diagnostic assessments
16. Have an abnormality in the 12-lead ECG at screening that, in the opinion of the 
investigator, increases the risks associated with participating in the study or may 
confound ECG (QT) data analysis, such as a QTcF >450 msec for males and 
>470 msec for females, short PR interval (<120 msec), or PR interval >220 msec, 
second and third atrioventricular block, intraventricular conduction delay with QRS 
>120 msec, right bundle branch block, left bundle branch block or Wolff-Parkinson-
White syndrome.
17. Have serum AST or ALT >1.5 × ULN or TBL >1.5 × ULN.
18. Show evidence of HIV infection and/or positive human HIV antibodies.
19. Show evidence of hepatitis C and/or positive hepatitis C antibody.
20. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive 
hepatitis B surface antigen. 
Other Exclusions
21. Are CRU personnel directly affiliated with this study and their immediate families. 
Immediate family is defined as a spouse, biological or legal guardian, child, or sibling
22. Are Lilly employees.
23. Have previously completed or withdrawn from this study. 


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Protocol J1X-MC-GZHF(a)
29
24. Have donated blood of more than 450 mL, or have participated in a clinical study that 
required similar blood volume drawn within the past 3 calendar months.
25. Are women who are lactating.
26. Have known allergies to LY3493269, related compounds, or any components of the 
formulation (including SNAC), or a history of significant atopy.
27. Regularly use known drugs of abuse.
28. Have an average weekly alcohol intake that exceeds 21 units per week (males) and 
14 units per week (females) or are unwilling to stop alcohol consumption as required 
during the study (Section 5.3.2) (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of 
wine; 1.5 oz or 45 mL of distilled spirits).
29. Smoke >10 cigarettes per day or the equivalent, or are unable or unwilling to refrain 
from nicotine during CRU admission.
30. Are unwilling to comply with the dietary restrictions required for this study.
31. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study.
5.3.
Lifestyle Considerations
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
Participants will be required to fast overnight for at least 8 hours before taking each dose of 
LY3493269 (or placebo) on Days 1, 2, and 3 and for each subsequent study day when clinical 
safety laboratory and PD samples are taken. 
Each study intervention dose is taken with 120 mL of water. Any additional water required by
the participant to complete the dose must be recorded in the CRF. After each daily dose, 
participants must continue to fast for 2 hours before receiving a standard meal. Water ad libitum 
is allowed only until 1 hour before dosing and following the 2-hour postdose fast. 
Throughout the inpatient period, standard meals will be administered in the CRU. While not 
resident in the CRU, participants will be encouraged to follow their normal diet.
5.3.2.
Caffeine, Alcohol, and Tobacco
Participants are allowed to maintain their regular caffeine consumption throughout the study. 
No alcohol will be allowed at least 24 hours before each CRU admission and each outpatient 
visit and throughout the duration of each CRU visit. Between CRU visits, daily alcohol should 
not exceed 3 units for males and 2 units for females (a unit is defined in Section 5.2
criterion [28]). 
No nicotine use will be permitted while at the CRU. While not resident in the CRU, participants 
must consume no more than 10 cigarettes or equivalent per day.


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5.3.3.
Activity
Participants will be advised to maintain their regular levels of physical activity/exercise during 
the study, and to abstain from strenuous exercise for at least 24 hours before each blood 
collection for clinical laboratory tests. 
When certain study procedures are in progress at the site, participants may be required to remain 
recumbent or sitting.
5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. However, participants who were eligible for inclusion in previous cohorts, but were 
not randomized for nonmedical reasons, may be reassessed. Additional medical assessments and 
clinical measurements include clinical laboratory tests, vital signs, and ECG to confirm their 
eligibility. 
Repeating of laboratory tests during the screening period or repeating screening tests to comply 
with the protocol-designated screening period does not constitute rescreening.


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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 Intervention(s) Administered
Intervention Name
LY3493269
Placebo
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
Experimental, supplied as 4 dose strengths:

4 mg LY + 300 mg SNAC

12 mg LY + 300 mg SNAC

24 mg LY + 300 mg SNAC

36 mg LY + 300 mg SNAC
Not applicable for placebo
Dose Levels
Each dose described below is administered 
once daily over 3 consecutive study days.
Cohort 1, 8-mg dose:
2 tablets of 4 mg LY+300 mg SNAC
Cohort 2, 24-mg dose:
2 tablets of 12 mg LY+300 mg SNAC
Cohort 3, 48-mg dose:
2 tablets of 24 mg LY+300 mg SNAC
Cohort 4, 24-mg dose:
1 tablet of 24 mg LY+300 mg SNAC
Each dose described below is 
administered once daily over 
3 consecutive study days.

Cohort 1: 2 tablets

Cohort 2: 2 tablets

Cohort 3: 2 tablets

Cohort 4: 1 tablet
Route of 
Administration
Oral, after a minimum fast (no food) of 
8 hours prior to each dose, followed by a 
2-hour fast (no food or water) after each 
dose.
Water intake ad libitum is allowed only after 
the 2-hour fast.
Oral, after a minimum fast 
(no food) of 8 hours prior to 
each dose, followed by a 
2-hour fast (no food or 
water) after each dose.
Water intake ad libitum is 
allowed only after the 2-hour
fast.
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the 
sponsor
Packaging and 
Labeling
Study intervention will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement
Placebo will be provided in 
bottles. Each bottle will be 
labeled as required per 
country requirement
Abbreviations:  IMP = investigational medicinal product; LY = LY3493269; NIMP = noninvestigational medicinal 
product; SNAC = salcaprozate sodium.


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6.1.1.
Administration Details
Tablets of either LY3493269 or placebo will be administered orally with approximately 120 mL 
of room temperature water in the morning of each dosing day in a sitting position. After each 
daily dose, participants must continue to fast for 2 hours before receiving a standard meal. Water 
ad libitum is allowed only until 1 hour before dosing and following the 2-hour postdose fast.
Participants will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated 
or for study procedures.
6.2.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Method of Treatment Assignment
Randomization tables for allocation of either LY3493269 or placebo to participants will be 
prepared by the statistician for the study and provided to the unblinded site pharmacists involved 
in dose preparation. Prior to or on Day 1, eligible participants will be assigned a unique number 
(randomization number). The randomization number encodes the participant’s assignment to 1 of
the 2 arms of the study, according to the randomization schedule. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. Unblinded site pharmacists will be responsible for the dispensing of all study 
interventions. The allocation and dispensing of the study interventions will be fully documented 
and verified by a second person. Detailed records of the amounts of the study intervention 
received, dispensed, and remaining at the end of the study will be maintained by the site 
pharmacist(s). 
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site to verify that randomization/dispensing has been done accurately.


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33
6.3.2.
Selection and Timing of Doses
For each study participant, the doses will be administered at approximately the same times on 
each day. The actual time of all dose administrations will be recorded in the participant’s CRF.
6.3.3.
Unblinding
Emergency codes will be available to the investigator to be retained by the investigator (or 
designee) in a secured area. In case of an emergency, the investigator has the sole responsibility 
for determining if unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. 
If a participant’s intervention assignment is unblinded, the sponsor must be notified immediately 
after breaking the blind. Once the study is complete, all envelopes (sealed and opened) must be 
inventoried and returned to the sponsor.
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
CP for the participant to continue in the study.
6.4.
Study Intervention Compliance
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. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the time 
of dosing by a member of the study site staff other than the person administering the study 
intervention.  Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested.
6.5.
Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or analgesics that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

reason for use

dates of administration including start and end dates, and

dosage information including dose and frequency for concomitant therapy of special 
interest
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (apart from 
vitamin/mineral supplements and thyroid replacement medication) within 7 days (or 14 days if 
the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of 


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34
study intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study.
Paracetamol/acetaminophen, at doses of 3 g/day, is permitted for use any time during the study.
Other concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor.
6.6.
Dose Modification
Dose levels or increments, sampling schedule, and length of stay at the CRU may be adjusted in 
view of emerging safety, tolerability, or PK/PD data during the study.
If considered appropriate,

dose increments for LY3493269 may be reduced, a dose level may be repeated, or a 
lower/intermediate dose may be administered, but dose escalations will not exceed a 
half-log (3.3-fold) increase in dose.

the timing of the sampling may be adjusted and additional samples may be collected, as 
described in Section 8.5, and

the duration of the CRU stay or the duration of safety follow-up may be increased (for 
example, if the half-life of LY3493269 is longer than anticipated) but not decreased.
These changes must be appropriately documented and communicated by the sponsor to the 
investigator. Because these adjustments to timings or dose levels are allowable changes 
permitted by the protocol, they would not require a protocol amendment. However, any changes 
to the planned dose levels, together with the supporting data, will be reviewed by an SRP, 
composed of members independent of the study team and CRU.
6.6.1.
Dose Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis. Interim 
access to study data is scheduled to occur during the study to inform dose-escalation decisions, 
as specified in Section 6.6.3.
Safety data will be the primary criteria for the dose escalation. In addition, if available at the time 
of dose-escalation decision, PK and/or PD results may be used as supporting data for dose 
escalation, but such data are not required. All available PK data and PD results, from Cohort 1 
will be reviewed prior to initiation of Cohort 3. Cohorts 3 and 4 may be initiated in parallel based 
on the review of safety and tolerability data from Cohort 2. No dose decision can occur without 
prior discussion and agreement between the investigator and the Lilly clinical pharmacologist.
Prior to dose escalation, all planned participants in the current cohort should have been dosed 
prior to escalation to next cohort. The investigator and sponsor must review safety and 
tolerability data up to study Day 8 from at least 8 participants receiving study intervention at the 
current dosing level, including but not limited to ECGs, clinical laboratory tests, vital signs, body 
weight, appetite VAS scores, and AEs. After review of these data, an escalation to the next dose 
level will be jointly decided by the investigator and sponsor. The magnitude of dose escalation 
may be reduced following data review, but subsequent escalations cannot be increased by more 
than approximately 3.3-fold (a half-log increment); dose levels may be repeated if warranted 
following data review.


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35
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the study 
intervention unless there is clear evidence that the event is not related.
6.6.2.
Dose-Escalation Stopping Criteria
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1. One treatment-emergent SAE (including severe hypoglycemia) believed to be associated 
with LY3493269 (see Section 8.2.6.1);
2. One or more participants on active drug experience 2 or more clinically significant events 
deemed related to LY3493269, defined as moderate to severe AE, abnormal clinical 
signs, or clinical laboratory findings that may pose a risk to the well-being of the 
participant and would preclude further dosing of a participant who experiences this 
effect. Clinically significant events will be determined by the investigator or suitable 
designee and may include findings that do not fulfill the criteria for SAEs;
3. Forty percent or more of participants in a dose level experience any of the following 
deemed related to LY3493269 administration:

a symptomatic hypoglycemic episode with BG values ≤50 mg/dL (2.8 mmol/L; 
corresponding to PG levels of <54 mg/dL [3.0 mmol/L]), or

drug-related GI effects (for example emesis, diarrhea) causing severe distress 
(prevents daily activities or requires an emergency department visit or 
hospitalization), or 

clinically significant cardiovascular AEs.
4. Two or more participants on active drug develop persistent (>1 week) symptoms 
suggestive of acute pancreatitis. 
6.6.3.
Data Review during the Study
Interim access to safety and tolerability (and any available PK and PD) data is scheduled to occur 
before dosing in the next cohort as described in Section 4. This schedule may be modified as 
applicable, based on emerging safety and/or tolerability data. The purpose of these reviews is to 
guide dose selection for the next dosing cohort.
The investigator and the Lilly sponsor team will jointly make the determination regarding dose 
escalation, based upon their review of the safety and tolerability data, and PK or PD results if 
available. In addition, these data may be used to guide dose selection and inform the need to 
adjust timing of procedures/sampling schedules for the current study.
An SRP will be established and composed of experts in early phase medicine independent of the 
study team and CRU. Any changes to the planned dose levels, together with the supporting data, 
will be reviewed and approved by the SRP.
6.7.
Intervention after the End of the Study
There is no planned/continued intervention after the end of the study.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 1.3 of this protocol.
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for appropriate safety monitoring. See the 
SoA (Section 1.3) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed.
Discontinuation of study intervention should be considered by the investigator if any of the 
following occur in a participant:

an AE that is considered to be intolerable,

an abnormal safety laboratory test result, determined to be clinically significant by the 
investigator, or

QTcF >500 msec and an increase from baseline in QTcF >60 msec, from at least 2 
consecutive readings.
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcF after enrollment), the investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.1.
Hepatic Criteria for Discontinuation
Discontinuation of the study intervention for abnormal liver test results should be considered by 
the investigator when a participant meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST >5 × ULN or

ALT or AST >3 × ULN and TBL >2 × ULN or international normalized ratio (INR) 
>1.5 or

ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP >3 × ULN

ALP >2.5 × ULN and TBL >2 × ULN

ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).


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Participants who discontinue from study intervention due to the abnormal liver test results will 
undergo monitoring as described in Section 10.6.
Discontinuation of the study intervention due to abnormal laboratory results should be 
considered by the investigator when a participant meets 1 of the following conditions after 
consultation with the sponsor-designated medical monitor:

lipase and/or amylase ≥3 × ULN (Appendix 7 [Section 10.7] should be considered by the 
investigator).
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:

at any time at his/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 investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
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, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment.  If the investigator and the sponsor CP agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor CP 
to allow the inadvertently enrolled participant to continue in the study with or without treatment 
with IP. Safety follow up is as outlined in Section 1.3 (SoA), Section 8.2 (Safety Assessments), 
and Section 8.3 (Adverse Events and Serious Adverse Events) of the protocol.


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7.3.
Lost to Follow up
A participant will be considered lost to follow-up if he / she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1
(Section 10.1).


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed.
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.
Assessment collection time
The specifications in this protocol for the timings of safety and sample collection are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon emerging clinical information. The scheduled time points may be subject to minor 
alterations; however, the actual time must be correctly recorded in the CRF. Failure or being late 
(i.e. outside stipulated time allowances) to perform procedures or obtain samples due to 
legitimate clinical issues (e.g. equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note.
If multiple procedures take place at the same time point, ECGs and vital signs must be obtained 
prior to any venipuncture.
Appendix 2 (Section 10.2) lists the laboratory tests that will be performed for this study.
Section 10.2.1 provides a summary of the anticipated number and volume of invasive samples, 
for all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results. Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
8.1.
Efficacy Assessments
Not applicable. 
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
Complete physical examinations and symptom-directed physical examinations will be conducted 
at the visits specified in the SoA (Section 1.3). Symptom-directed physical examinations may 


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also be conducted at other visits, as determined by the investigator, if a participant presents with 
complaints. A complete physical examination will include, at a minimum, assessments of the

cardiovascular

respiratory

gastrointestinal, and

neurological systems.
Height and weight will also be measured and recorded as per SoA (Section 1.3).
8.2.2.
Vital Signs
For each participant, vital sign measurements should be conducted according to the SoA 
(Section 1.3) and as clinically indicated.
Vital sign measurements should be obtained before collection of blood samples (applicable for 
study visits).
Blood pressure and PR should be measured after at least 5 minutes in a supine position.
Note: If white-coat hypertension is suspected at screening, the participant can be included in the 
trial if a repeated measurement (up to 2 additional assessments) shows values within the 
acceptable range.
If orthostatic measurements are required, participants should be supine for at least 5 minutes and
stand for at least 2 minutes. If the participant feels unable to stand, only supine vital signs will be 
recorded.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Additional vital signs may be measured during each study period if 
warranted.
Body temperature will be measured, as specified in the SoA (Section 1.3), and as clinically 
indicated.
8.2.3.
Electrocardiograms
Single and triplicate 12-lead ECGs will be obtained as specified in the SoA (Section 1.3).
Electrocardiograms must be recorded approximately within 30 minutes before collecting any 
blood samples (applicable for study visits). Participants must be supine for approximately 5 to 
10 minutes before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary. 
Collection of additional ECGs at a particular time point is allowed to ensure high-quality 
records.
Electrocardiograms will be interpreted by a qualified physician, the investigator, or qualified 
designee at the site as soon after the time of ECG collection as possible. Ideally, the participant 
should be present

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.


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The machine-read ECG intervals and HR may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).
Single electrocardiograms
Single ECGs will be collected at screening, at early termination, and follow-up on Days 29 and 
43 according to the SoA (Section 1.3). Single ECGs may be obtained at additional times when 
deemed clinically necessary to assess participants’ safety. All single ECGs recorded should be 
stored at the investigational site. Single ECGs will not be transmitted to a central laboratory.
Triplicate electrocardiograms
Triplicate 12-lead ECGs will be obtained as specified in the SoA (Section 1.3).
Collection of more ECG replicates than expected at a certain time point will be permitted to 
ensure high-quality records. At each time point at which triplicate ECGs are required, 3 
individual ECG tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 4 minutes.
Scheduled and unscheduled digital ECGs will be electronically transmitted to a central ECG 
laboratory designated by the sponsor. The central ECG laboratory will perform a basic quality 
control check, for example, demographics and study details, then store the ECGs in a database. 
At a future time, the stored ECG data may be overread at the central ECG laboratory for further 
evaluation of machine-read measurements or to meet regulatory requirements.
8.2.4.
Clinical Safety Laboratory Assessments
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 days after the last dose of study intervention should be repeated until 
the values return to normal or approximately baseline or are no longer considered clinically 
significant by the investigator or medical monitor.

If such values do not return to normal/approximately 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 laboratory manual and the SoA (Section 1.3).

If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF.


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8.2.5.
Safety Monitoring
The Lilly clinical pharmacologist or CRP will monitor safety data throughout the course of the 
study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes

serious and non-SAEs including monitoring of GI events, hypoglycemia, and 
hypersensitivity reactions and reported and adjudicated pancreatitis
When appropriate, the Lilly clinical pharmacologist 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 (see Appendix 6;Section 10.6), including ALT, AST, ALP, TBL, creatine 
kinase, and direct bilirubin, should be repeated, with addition of gamma-glutamyl transferase, 
within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if 1 or more of these conditions occur:
If a participant with baseline 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 participants 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 ≥2 × baseline (except for participants with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver test results should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including symptoms, recent 
illnesses (for example, heart failure, systemic infection, hypotension, or seizures), recent travel, 
history of concomitant medications (including over the counter), herbal and dietary supplements, 
and 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.


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Comprehensive hepatic evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:
If a participant with baseline 
results of...
develops the following elevation:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN with hepatic signs/symptomsa, or ALT or AST 
≥5 × ULN
ALP <1.5 × ULN
ALP ≥3 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for participants with Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline with hepatic signs/symptomsa, or ALT or AST 
≥3 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥1.5 × baseline (except for participants with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
a
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 earlier, as well as tests for prothrombin time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or CT scan).
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for

hepatitis D virus

cytomegalovirus

Epstein-Barr virus

acetaminophen levels

acetaminophen protein adducts

urine toxicology screen

Wilson’s disease

blood alcohol levels

urinary ethyl glucuronide, and

blood phosphatidylethanol.
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.


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Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver test results during the study
Additional hepatic safety data collection in hepatic safety CRFs 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)
a.
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests
2. Elevation of TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome)
a.
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)
a.
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 drug due to a hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days.
8.2.5.2.
Pancreatic Safety (Elevated Lipase or Amylase)
Diagnosis of acute pancreatitis
Acute pancreatitis is an AE of interest in all studies with LY3493269, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 2006; 
Koizumi et al. 2006):

abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to the 
back, often associated with nausea and vomiting)

serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging.
If acute pancreatitis is suspected, the investigator should

obtain appropriate laboratory tests, including pancreatic amylase and lipase

perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal magnetic resonance imaging

evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications.
Discontinuation for acute pancreatitis
If acute pancreatitis is diagnosed, the participant must discontinue use of the study intervention.


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Asymptomatic elevation of serum amylase and/or lipase
Serial measures of pancreatic enzyme levels have limited clinical value for predicting episodes 
of acute pancreatitis in asymptomatic patients (Nauck 2016; Steinberg et al. 2017a, 2017b). 
Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic 
enzymes (lipase and/or p-amylase ≥3X ULN) is not mandated but may be performed based on 
the investigator’s clinical judgment and assessment of the participant’s overall clinical condition.
8.2.5.3.
Nausea, Vomiting, and Diarrhea
Nausea, vomiting, and diarrhea events are considered AEs of interest; each occurrence will be 
recorded as a discrete AE in the CRF. For each event assessment of severity, duration (actual 
date together with onset and end times) and investigator’s opinion of relatedness to IP and 
protocol procedure will be captured.
8.2.5.4.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided 
to the sponsor in the eCRF.
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines.
In case of anaphylaxis or generalized urticaria, additional blood samples should be collected as 
described in Appendix 8 (Section 10.8). The laboratory results are provided to the sponsor via 
the central laboratory.
8.2.5.5.
Additional Assessments for Adverse Events of Skin Sensations
Healthy participants in this short-exposure study are not expected to experience the AEs of skin 
burning sensations (also termed sensitive skin or paresthesia) reported in the longer exposure 
study in patients with diabetes.
Nevertheless, it is possible that this AE of skin sensation might occur. If it does occur, detailed 
information about the skin sensations will be collected by study site staff using a questionnaire
on initial presentation of these AEs, and on subsequent visits until these AEs resolve.
In addition, on first presentation of these events, participants shall undergo a detailed neurologic 
examination by a neurologist. The goal of these activities is to describe the distribution and 
character of the symptoms, as well as their time course.
8.2.6.
Glucose Monitoring
Blood glucose will be monitored for safety according to the SoA (Section 1.3). The study 
participant’s BG concentrations for safety assessment will be monitored during the inpatient part 
of the study and on Day 6, using a validated method (e.g. glucose analyzer) available at the site.


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8.2.6.1.
Hypoglycemia
Participants will be trained by site personnel about signs and symptoms of hypoglycemia and 
how to treat hypoglycemia. 
Once a hypoglycemic event has started, the investigator should perform further bedside testing at 
regular intervals (e.g. every 15 to 30 mins) until normoglycaemia (PG ≥70 mg/dL) is 
documented. If symptoms are present during the hypoglycemic event, then the end time of the 
hypoglycemic event should be either the time of resolution of symptoms or when 
normoglycemia is achieved, whichever is later.
Investigators should use the following classification of hypoglycemia: 
Level 1 hypoglycemia: 
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L):  Level 1 hypoglycemia 
can alert a person to take action such as treatment with fast-acting carbohydrates. Providers 
should continue to counsel participants to treat hypoglycemia at this glucose alert value.
Level 2 hypoglycemia:  
Glucose <54 mg/dL (3.0 mmol/L):  This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence of absence of symptoms of hypoglycemia. 
Level 3 hypoglycemia:  
Severe hypoglycemia (in adults):  A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia.  For example, participants
had altered mental status, and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person was needed to actively administer carbohydrate, glucagon, or other resuscitative
actions. Glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of glucose concentration to normal is considered
sufficient evidence that the event was induced by a low glucose concentration.

The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance.

If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE.
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep.  
To avoid duplicate reporting, all consecutive PG values ≤70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 
2010; Danne et al. 2013)
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 


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evaluated. The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established by the investigator. The participant should 
receive additional education, if deemed appropriate. If applicable, please refer to the protocol 
section regarding management of increased hypoglycemia risks.
8.3.
Adverse Events and Serious Adverse Events
Adverse 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 the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3).
All AEs will be collected from the signing of the ICF until the follow-up visit or participation in 
study has ended.
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the Adverse Event CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to the sponsor begins after the participant has signed the ICF and has received 
study drug. However, if an SAE occurs after signing the ICF, but prior to receiving study 
intervention, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.


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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.7),
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
provided in Appendix 3 (Section 10.3).
8.3.4.
Regulatory Reporting Requirements for SAEs
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, IRB/IEC, and investigators.
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.
8.3.5.
Pregnancy
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until at least 5 terminal half-lives after the last 
dose.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4 (Section 10.4).
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Events or Outcomes
Not applicable.
8.3.7. Adverse Events of Special Interest 
Adverse events of special interest for this program include

CV events

GI events

Pancreatic events (elevated amylase/lipase)

hypersensitivity reactions 

skin burning sensations, and

hypoglycemic events.


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Each occurrence will be recorded as a separate AE in the CRF. For each event assessment of 
severity, duration (actual date, time of onset, and end times), and investigator’s opinion of 
relatedness to study intervention and protocol procedure will be captured.
Skin burning sensation is an important identified risk for LY3493269. If these events are 
reported, participants shall undergo additional assessments as described in Section 8.2.5.5.
8.3.8. Product Complaints
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 
trial intervention.
The sponsor collects product complaints on IPs and drug delivery systems used in clinical studies 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Sections 8.3.3 and Appendix 3 (Section 10.3) of the protocol.
8.3.8.1.
Time Period for Detecting Product Complaints
Product complaints that result in an AE will be detected, documented, and reported to the 
sponsor during all periods of the study in which the drug/device is used.
If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a drug/device 
provided for the study, the investigator will promptly notify the sponsor.
8.3.8.2. Prompt Reporting of Product Complaints to the Sponsor
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint.
The Product Complaint Form will be sent to the sponsor by the method provided in the form. If 
the primary method is unavailable, then an alternative method provided in the form should be 
utilized.
8.3.8.3.
Follow-up of Product Complaints
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product complaint.
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator and submitted to the sponsor.


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8.4.
Treatment of Overdose
For this study, any dose of LY3493269 greater than the daily dose assigned through 
randomization will be considered an overdose. Treatment for overdose is supportive care.
In the event of an overdose, the investigator should
1. contact the medical monitor immediately.
2. closely monitor the participant for any AE/SAE and laboratory abnormalities until 
LY3493269 can no longer be detected systemically, and
3. document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
Refer to the LY3493269 IB for more information about treatment of overdose.
8.5.
Pharmacokinetics
Plasma samples will be collected for measurement of plasma concentrations of study 
intervention as specified in the SoA (Section 1.3).
A maximum of 2 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring.
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.
Samples will be used to evaluate the PK of study intervention. Samples collected for analyses of 
study intervention plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study.
Genetic analyses will not be performed on these plasma samples. Participant confidentiality will 
be maintained.
Drug concentration information that would unblind the study will not be reported to CRUs or 
blinded personnel until the study has been unblinded.
8.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3493269 and SNAC will be assayed using validated liquid chromatography 
with tandem mass spectrometry methods. Analyses of samples collected from placebo-treated 
participants are not planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last participant visit for the study. During this time, samples remaining after the 


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bioanalyses may be used for exploratory metabolism studies or exploratory analyses such as 
bioanalytical assay validation or cross-validation exercises.
8.6.
Pharmacodynamics
8.6.1.
Body Weight
Weight will be measured as indicated in the SoA (Section 1.3). Wherever possible, the same 
scale will be used for all weight measurements throughout the study and the scale will not be 
moved or recalibrated.
Participants will be weighed in light clothing at approximately the same time in the morning 
before dosing (on Day 1 only) and after an overnight fast and evacuation of bowel and the 
bladder, if possible. Weight will be measured twice on each scheduled occasion, with the 
participant stepping off the scale between measurements. The mean of the 2 weight 
measurements will be recorded in the source document and the CRF.
8.6.2.
Appetite Analysis
To explore the effects of LY3493269 on meal intake and appetite sensation, participants will be 
asked to rate their appetite sensations using a 100-mm VAS for parameters of hunger, fullness, 
satiety, and prospective food consumption prior to dosing on Day 1, and in the fasted state while 
inpatient as well as on scheduled outpatient visits. These measurements shall be performed 
according to the SoA (Section 1.3).
The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000). The VAS 
is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “extremely” and 
“not at all”. Participants are required to rate their subjective sensations on four 100-mm scales 
combined with questions similar to the following:
1. “How hungry do you feel?”
2. “How satisfied do you feel?”
3. “How full do you feel?”
4. “How much do you think you could eat?”
A staff member will use a caliper to measure the distance from 0 to the mark that the participant 
placed on the VAS and record the measurement in the source document. Overall appetite score is 
calculated as the average of the 4 individual scores: satiety + fullness + (100-prospective food 
consumption) + (100-hunger) / 4 (van Can et al. 2014). The higher overall appetite score 
indicates less appetite, and the lower score indicates more appetite.
8.6.3.
Pharmacodynamic Markers
Samples for PD markers will be collected at the times specified in the SoA (Section 1.3).
Fasting serum samples for glucose, insulin, and C-peptide will be evaluated as PD markers.
Fasting lipids (triglycerides only) will be evaluated as exploratory mechanistic markers.
Plasma and serum concentrations of these markers will be assayed using validated analytical 
methods. Instructions for the collection and handling of blood samples for these analyses will be 
provided by the sponsor.


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The samples will be stored for up to a maximum of 1 year after the last participant visit for the 
study at a facility selected by the sponsor.
8.7.
Genetics
A blood sample for DNA isolation will be collected from participants.
See Appendix 5 (Section 10.5) for information regarding genetic research and Appendix 1 
(Section 10.1.9) for details about sample retention and custody.
8.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements. Exploratory biomarker measures may include potential markers of 
GIP and GLP-1R target engagement.
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3493269, pathways associated with T2DM, obesity, or diabetes complications including 
NASH, mechanism of action of LY3493269, and/or research method, or for validating diagnostic 
tools or assay(s) related to T2DM, obesity, or diabetes complications including NASH.
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the CRU personnel.
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and/or ERBs impose shorter time limits, at a facility selected 
by Lilly or its designee. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3493269 or after LY3493269 or is commercially available.
8.9.
Immunogenicity Assessments
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
for analysis to determine antibody production against LY3493269. Antibodies may be further 
characterized for cross-reactive binding to native GIP and GLP-1. To interpret the results of 
immunogenicity, a venous blood sample will be collected at the same time points to determine 
the plasma concentrations of LY3493269.
Treatment-emergent-antidrug antibodies are defined in Section 9.4.7. In the case that ADA
samples are tested before end of study and if the immunogenicity sample at the last scheduled 
assessment or discontinuation visit is TE-ADA positive and if available, the ADA 
cross-reactively binds to native GIP and GLP-1, additional samples may be taken every 3 months 
until the ADA signal returns to baseline (i.e. no longer TE-ADA positive) or for up to 1 year 
after last dose.


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A PK sample will continue to be collected at each time point at the investigator’s discretion. 
Participants followed for at least 1 year since last dose, whose titer has not returned to within 
2-fold of the baseline, will be assessed for safety concerns. If no clinical sequelae are recognized 
by the clinical team, then no further follow-up will be required.
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor. The 
duration allows the sponsor to respond to future regulatory requests related to the IP. Any 
samples remaining after 15 years will be destroyed.
8.10.
Health Economics
Not applicable.
8.11.
Product Acceptability and Palatability Assessments
The participant will be asked to provide responses to questions designed to assess the 
acceptability and palatability of the tablet. The questionnaire will assess the participant’s 
experience relating to the taste, mouthfeel, and aftertaste of the tablet in the oral cavity.
The questionnaire will be completed by the participant immediately after administration of the 
tablet(s). 


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
This study will compare LY3493269 with placebo in healthy adults. The primary study objective 
is to determine the safety and tolerability of multiple oral doses of LY3493269. 
9.2.
Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety and PK and is not powered on 
the basis of statistical hypothesis testing. 
Up to approximately 56 participants may be randomly assigned to study intervention to ensure 
approximately 10 evaluable participants (8 receiving LY3493269 and 2 receiving placebo) from 
each of the 4 cohorts complete the study. Participants who are randomized but not administered 
treatment prior to discontinuation may be replaced to ensure that the target number of 
participants complete the study. 
Participants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF
Enrolled
All participants assigned to treatment, regardless of whether they take 
any doses of study treatment, or if they took the correct treatment. 
Participants will be analyzed according to the treatment group to 
which they were assigned.
Safety
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received.
Pharmacokinetic 
Analysis
All participants who received at least 1 full dose of LY3493269 and 
have evaluable PK sample.
Pharmacodynamic 
Analysis
All participants who received at least 1 dose of LY3493269 and have 
evaluable PD data.
9.3.1.
Study Participant Disposition
All participants who discontinue from the study will be identified and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. A detailed description of participant disposition will be provided at the end of the study.


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9.3.2.
Study Participant Characteristics
The participant’s age, sex, weight, height, or other demographic characteristics will be recorded 
and may be used in the PK, PD, and safety analyses as quantitative or classification variables.
9.3.3.
Treatment Compliance
At the inpatient visit, the study intervention will be administered and documented at the clinical 
site.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate. Study results may be pooled with the results of other studies 
for population PK analysis purposes.
The SAP will be finalized prior to first participant first visit and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
Pharmacokinetic and PD analyses will be conducted on data from all participants who receive at 
least 1 dose of study intervention and have evaluable PK and PD, respectively.
Safety analyses will be conducted for all randomized participants who received study 
intervention, whether or not they completed all protocol requirements.
9.4.1.
General Considerations
Data listings will be provided for all data that are databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in the SAP. For continuous data (e.g., the 
demography data, clinical laboratory data, vital signs data, ECG data, appetite analysis data, and 
PD data), summary statistics will include the arithmetic mean, arithmetic standard deviation, 
median, minimum, maximum, and the number of observations; for log-normal data (e.g., the PK 
parameters: AUC during 1 dosing interval [AUC{0-τ}] and Cmax), the geometric mean and 
geometric coefficient of variation (%) will also be presented. For categorical data (e.g., the AE 
data and hypoglycemic classification data), frequency count and percentages will be presented. 
Data listings will be provided for all participants up to the point of withdrawal, with any 
participants excluded from the relevant population highlighted. Summary statistics and statistical 
analyses will generally be performed only for participants included in the relevant analysis 
population. For the calculation of summary statistics and statistical analysis, unrounded data will 
be used.
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 


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participant’s baseline value from the value at the time point. Baseline is defined to be Day 1 
pre-dose measurements unless otherwise stated.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.4.2.
Safety Analyses 
All safety analyses will be made on the Safety Population.
All AEs will be listed, and if the frequency of events allows, safety data will be summarized 
using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with the study drug as perceived by the investigator. Symptoms reported to occur prior to the 
first study drug dosing will be distinguished from those reported as new or increased in severity 
during the study. Each symptom will be classified by the most suitable term from the Medical 
Dictionary for Regulatory Activities.
All SAEs will be reported.
In addition to AEs, safety parameters that will be assessed include laboratory tests, vital signs, 
immunogenicity, hypoglycemic events, injection-site reactions, and ECG parameters. The 
parameters will be listed and summarized using standard descriptive statistics. Additional 
analyses may be performed if warranted based upon review of the data.
Laboratory measurements will be summarized regarding observed values and change from 
baseline by treatment group, at each time point, using descriptive statistics. In addition, all 
clinical chemistry, hematology, and urinalysis data outside the reference ranges will be tabulated 
by parameter and treatment group.
Vital signs will be summarized regarding observed values and change from baseline values by 
treatment at each time point using descriptive statistics. For change from baseline values, a 
mixed-model repeated-measure model with treatment, day (of measurement), and treatment-by-
day interaction as fixed effects, participant as random effect, and baseline as covariate will be
used to determine the effects of LY3493269. Least squares means as well as 90% CIs will be 
reported.
Electrocardiogram parameters will be summarized, including the PR, QT, RR, and QTcF 
intervals, QRS duration, and HR. A concentration-response analysis will also be performed to 
assess the effect of LY3493269 on QTcF. Additional analyses may be performed to determine 
the effects of PK and PD parameters on QTcF and other intervals.
9.4.3.
Product Acceptability and Palatability Analyses
Responses from the product palatability questionnaires will be summarized categorically 
(frequency and percentage).
9.4.4.
Pharmacokinetic Analyses 
Pharmacokinetic parameter estimates for LY3493269 and SNAC will be calculated using 
standard noncompartmental methods of analysis. The primary parameters for analysis will be 
Cmax, AUC, and tmax. Pharmacokinetic parameters for Cmax and AUC will be computed after the 
first, second, and third doses. Other parameters, such as half-life, apparent clearance, and 


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apparent volume of distribution, may be reported. If deemed necessary, additional model-based 
analysis may be performed for LY3493269 or data may be combined with Study GZHA for 
further analysis.
Pharmacokinetic dose proportionality for Days 1 and 3 will be explored separately. Log-
transformed Cmax and AUC of LY3493269 from Cohorts 1 to 3 will be evaluated separately for 
Days 1 and 3 using a power model (where log-dose acts as an explanatory variable) to estimate 
ratios of dose-normalized geometric means and corresponding 90% CIs. The estimated ratio of 
dose-normalized geometric means of PK parameters between the highest and lowest doses will 
be used to assess dose proportionality. A subinterval within the highest and lowest doses may 
also be considered for assessment of dose proportionality using the same approach. Additional 
details will be provided in the SAP.
The parameter tmax of LY3493269 and SNAC will be analyzed using a nonparametric method. 
All PK parameters will be summarized using descriptive statistics.
9.4.5.
Pharmacodynamics Analyses
Inferences will be sought regarding the effect of LY3493269 on the PD endpoints. Such effects 
will be explored over different doses of LY3493269 and at applicable time points as per the SoA 
(Section 1.3).
Pharmacodynamic parameters may be transformed before statistical analyses, if deemed 
necessary. Absolute values, as well as change from baseline, in each parameter will be analyzed 
using mixed-effects models to evaluate treatment effects, as well as treatment comparisons. The 
model will include treatment, visit, and treatment-by-visit interaction as fixed effects and 
participant as a random effect. Baseline values, as well as other influencing variables, may be 
used as covariates. Differences between each LY3493269-treated group and placebo group will 
be estimated. Participants who received placebo will be pooled across all cohorts. Least squares 
means and 90% CIs will be reported.
All PD parameters, including the baseline-corrected parameters, will be summarized and 
tabulated by treatment group and visit. Summary statistics will be provided. The individual 
observed and mean time profile of the postdose PD parameters will be plotted by treatment 
group.
9.4.6.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/PD analyses or graphical explorations may be used to assess the relationship 
between LY3493269 doses and/or concentrations and key

safety parameters, such as 
o
QTcF interval
o
BP
o
HR, and
o
PR interval,

tolerability parameters, such as 
o
nausea, and
o
vomiting, and


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
PD parameters, such as 
o
fasting glucose, and
o
weight.
Endpoints may include but are not necessarily limited to those listed earlier.
The impact of ADA and its titers on LY3493269 clearance and drug effect, if applicable, will be 
evaluated.
9.4.7.
Evaluation of Immunogenicity
Upon full assay validation, TE-ADAs may be assessed. The frequency and percentage of 
participants with preexisting ADA and with TE-ADA+ to LY3493269 may be tabulated. 
Treatment-emergent ADAs are defined as those with a signal increase, greater than assay 
variability, compared to baseline. Treatment-emergent ADAs are defined as those with a

titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were 
detected at baseline (treatment-induced ADA), or

4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA).
The frequency of cross-reactive binding to native GIP, GLP-1, or neutralizing antibodies may 
also be tabulated in TE ADA+ participants, when available.
The relationship between the presence of antibodies and PK exposures and PD response 
including safety and efficacy to LY3493269 may be assessed.
9.5.
Interim Analyses 
Interim access to safety and tolerability (and any available PK or PD) data is scheduled to occur 
after every dosing session as described in Section 6.6.1. The investigator will remain blinded,
and the Lilly sponsor team will be unblinded during these reviews.
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the
appropriate medical director or designee to determine if it is necessary to amend the protocol.
Unblinding details are specified in the unblinding plan section of the SAP or in a separate 
unblinding plan document.
9.6.
Data Monitoring Committee (DMC)
A Data Monitoring Committee will not be used in this study.


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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 
International Ethical Guidelines

Applicable ICH GCP Guidelines, and

Applicable laws and regulations
The protocol, protocol amendments, ICF, IB, 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.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Investigator sites are compensated for participation in the study as detailed in the CTA.
10.1.2.
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, 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.


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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.
A participant who undergoes repeat screening tests to confirm eligibility is not required to sign 
another ICF.
10.1.3.
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 that would make the participant identifiable will not be transferred.
The participant must be informed that his/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 their data to be used as 
described in the informed consent. 
The participant must be informed that his/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.
10.1.4.
Dissemination of Clinical Study Data
Communication of suspended for 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 the investigator (for example, through phone and/or 
email) as soon as possible. It will be a requirement that the investigator responds upon receipt to 
confirm that he understands the communication and has taken the appropriate action prior to 
further dosing any participants with study intervention. A failure by the investigator to respond 
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 the 
investigator 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.


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10.1.5.
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 
CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Source data may include laboratory tests, medical records, and 
clinical notes.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
Monitoring details describing strategy (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).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; 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, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site. The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.


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Data collected via the sponsor-provided data capture system(s) will be stored by third parties. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s). Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.6.
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 10.1.5.
10.1.7.
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, and

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.


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10.1.8.
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.
10.1.9.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3493269 or after LY3493269 becomes commercially available.
The following table lists the maximum retention period for sample types. The retention period 
begins after the last participant visit for the study.
The maximum retention times may be shorter, if specified in local regulations and/or if 
ERBs/IRBs impose shorter time limits.
Any samples remaining after the specified retention period will be destroyed.
The sample retention facility will be selected by the sponsor or its designee.
Sample Type
Custodian
Retention Period after Last Participant Visita
Biomarkers
Sponsor or designee
15 years
PK
Sponsor or designee
1 years
PD
Sponsor or designee
1 year
Genetics
Sponsor or designee
15 years
Immunogenicity
Sponsor or designee
15 years
Abbreviations: PD = pharmacodynamics; PK = pharmacokinetics.
a
Retention periods may differ locally.
The sponsor has a right to retain a portion of submitted biopsy tissue. Archival blocks will be 
returned to the study site. Slides and tissue samples collected on study will not be returned.


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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.
Pregnancy Testing: a serum pregnancy test will be performed at screening and urine pregnancy 
test at the Day 43 (follow-up) or early termination, see table below.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to CRUs or other 
blinded personnel.


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Safety Laboratory Tests
Hematology
Clinical Chemistry (fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphate
Leukocytes (WBC)
Magnesium
Absolute counts of
Creatinine
Neutrophils
Glucose (fasting)
Lymphocytes
Urea
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Urinalysis
Alanine aminotransferase (ALT)
Specific gravity
Lipase
pH
Amylase
Protein
Triglyceride
Total cholesterol
Glucose
High-density lipoprotein
Ketones
Low-density lipoprotein
Bilirubin
HbA1cf
Urobilinogen
Creatine kinase
Nitrite
Blood
Leukocytes
Microscopyb
Serology (at Screening only)
Hepatitis B surface antigena
Follicle-stimulating hormone (FSH)c
Hepatitis B core antibody, totala
Serum pregnancy testd
Hepatitis C virus serology (anti-HCV)a
Urine pregnancy teste
Human immunodeficiency virus (HIV)a
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell.
a
Tests may be waived if they have been performed within 6 months before screening with reports available for 
review.
b
If clinically indicated, per investigator’s discretion.
c
Performed for females at screening, if needed to confirm postmenopausal status.
d
For females, at screening only. 
e
For females, at Day 43 and if applicable at early termination. 
f
Predose at Day 1 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.
Protocol J1X-MC-GZHF Blood Sampling Summary
Purpose
Blood Volume 
per Sample 
(mL)
Approximate 
Number of 
Blood Samples
Approximate Total 
Volume (mL)
Screening testsa (local laboratory)
20
1
20
Clinical laboratory testsa (local laboratory)

Study visit: Day 1
13
1
13

Study visits: Days 5, 8, and 15
10
3
30

Follow-up visit
10
2
20
LY3493269 and SNAC pharmacokinetics
(1 blood sample for both analytes)
3
38
114
Potential additional LY3493269 and SNAC
pharmacokinetic samples
3
2
6
Blood discard for cannula patency
0.3
49
14.7
Point-of-care safety glucose (on-site)
0.3
18
5.4
Pharmacodynamics (central laboratory)

Glucose
2
6
12

Insulin
2
6
12

C-peptide
2
6
12
Mechanistic biomarker (central laboratory)

Triglycerides
3.5
6
21
Pharmacogenetic sample (stored)
10
1
10
Nonpharmacogenetic sample (stored)

Plasma
2
6
12

Serum
2.5
6
15

P800
2
6
12
Immunogenicity
10
4
40
Total
369.1
Total for clinical purposes (rounded up to the nearest 10 mL)
370
Abbreviations: SNAC = salcaprozate sodium.
a
Additional samples may be drawn if needed for safety purposes.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (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 (i.e., 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 it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/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.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless 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).


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
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.
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).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 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
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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Protocol J1X-MC-GZHF(a)
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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.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the AE/SAE CRF page.

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: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with 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.


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Protocol J1X-MC-GZHF(a)
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
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 and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report 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.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any 
post-mortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to Sponsor or designee within 
24 hours of receipt of the information.
10.3.4.
Reporting of SAEs
SAE Reporting via SAE Report

Facsimile transmission of the SAE paper CRF 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 CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE report.


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Protocol J1X-MC-GZHF(a)
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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
10.4.1.
Definitions
Females of Childbearing Potential
A female 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 the first dose of study intervention, additional evaluation should be considered.
Females NOT of Childbearing Potential
Females in the following categories are not considered women of childbearing potential:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with

12 months of amenorrhea for women >55 years, with no need for follicle-stimulating 
hormone

12 months of amenorrhea for women >40 years with follicle-stimulating hormone of 
≥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 estrogen receptor 
modulators, or chemotherapy that induced amenorrhea), and

hormone levels consistent with a postmenopausal state per the local laboratory 
reference range
10.4.2.
Contraception Guidance
10.4.2.1.
Female participants
Female participants of childbearing potential are excluded from this study.
Female participants who are not of childbearing potential may participate in this study.


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Protocol J1X-MC-GZHF(a)
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10.4.2.2.
Male participants
Male participants, regardless of their fertility status, with partners who are nonpregnant women 
of childbearing potential, must agree to either
1. remain abstinent (if this is their preferred and usual lifestyle), or
2. use condoms plus 1 additional highly effective contraception method.
Male participants with pregnant partners must agree to use condoms during intercourse.
Male participants must agree to continue abstinence or contraception methods for the duration of 
the study plus 105 days, which corresponds to approximately 5 months following the last dose of 
study intervention.
Male participants should refrain from sperm donation for the duration of the study plus 105 days, 
which corresponds to approximately 5 months and until their plasma concentrations are below 
the level that could result in a relevant potential exposure to a possible fetus.
10.4.2.3.
Contraception methods
Abstinence
Participants who are abstinent (if this is complete abstinence, as their preferred and usual 
lifestyle) must agree to either remain abstinent without sexual relationships with the opposite 
sex.
Same-sex relationships
Participants who are in a same-sex relationship (as part of their preferred and usual lifestyle) 
must agree to stay in a same-sex relationship without sexual relationships with the opposite sex. 
Participants who are in exclusively same-sex relationships as their preferred and usual lifestyle 
are not required to use contraception.
Highly effective and effective contraception methods
Highly effective methods of contraception (less than 1% failure rate)
Combined oral contraceptive pill and 
mini-pill
Intrauterine device (such as Mirena® and ParaGard®)
NuvaRing®
Contraceptive patch – ONLY women less than 198 pounds (90 
kg)
Implantable contraceptives
Vasectomy – for men in clinical trials
Injectable contraceptives (such as 
Depo-Provera®)
Fallopian tube implants (Essure®) if confirmed by 
hysterosalpingogram
Total abstinence
a
Male and female condoms should not be used in combination.


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Protocol J1X-MC-GZHF(a)
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Unacceptable contraception methods
Unacceptable methods of contraception include

periodic abstinence, such as
o
calendar
o
ovulation
o
symptothermal, or
o
post-ovulation methods

declaration of abstinence just for the duration of the trial, and

withdrawal.
10.4.3.
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive LY3493269.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed up to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported including fetal status 
(presence or absence of anomalies) and indication for the procedure. 
Female participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 

The participant will be followed up to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, including fetal status (presence or absence of anomalies) or 
indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 

A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at >20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 


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Protocol J1X-MC-GZHF(a)
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
Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. The discontinued participant should follow the standard 
discontinuation process and continue directly to the follow-up phase.


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Protocol J1X-MC-GZHF(a)
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10.5.
Appendix 5: Genetics
Use/Analysis of DNA
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease being 
treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected 
for DNA analysis from consenting participants.
DNA samples will be used for research related to the drug target and mechanism of action of 
LY3493269 or diabetes, obesity, and diabetic complications including NASH and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
LY3493269 and interventions of this drug class and diabetes, obesity, and diabetic complications 
including NASH. Genetic research may consist of the analysis of 1 or more candidate genes or 
the analysis of genetic markers throughout the genome (as appropriate).
Additional analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved in 
the response to LY3493269 or study interventions of this class to understand study disease or 
related conditions.
The results of genetic analyses may be reported in the clinical study report or in a separate study 
summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on LY3493269, similar study interventions of this 
class, or diabetes, obesity, and diabetic complications including NASH continues but no longer 
than 15 years or other period as per local requirements.


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Protocol J1X-MC-GZHF(a)
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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See Section 8.2.5.1 for guidance on appropriate test selection.
The sponsor-designated central laboratory must complete the analysis of all selected testing 
except for microbiology testing.
Local testing may be performed in addition to central testing when necessary for immediate 
participant management.
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 Chemistry
  Basophils
Acetaminophen
  Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Prothrombin time, INR (PT-INR)
Ethyl alcohol (EtOH)
Serology
Haptoglobin
Hepatitis A virus (HAV) testing:
Immunoglobulin IgA (quantitative)
  HAV total antibody
Immunoglobulin IgG (quantitative)
  HAV IgM antibody
Immunoglobulin IgM (quantitative)
Hepatis B virus (HBV) testing:
Phosphatidylethanol (PEth)
  Hepatitis B surface antigen (HBsAg)
Urine Chemistry
  Hepatitis B surface antibody (anti-HBs)
Drug screen
  Hepatitis B core total antibody (anti-HBc)
Ethyl glucuronide (EtG)
  Hepatitis B core IgM antibody
Other Serology
  Hepatitis B core IgG antibody
Anti-nuclear antibody (ANA)
  HBV DNAb
Anti-smooth muscle antibody (ASMA)a
Hepatis C virus (HCV) testing:
Anti-actin antibodyc
  HCV antibody
Epstein-Barr virus (EBV) testing:
  HCV RNAb
  EBV antibody
Hepatitis D virus (HDV) testing:
  EBV DNAb
  HDV antibody
Cytomegalovirus (CMV) testing:
Hepatitis E virus (HEV) testing:
  CMV antibody
  HEV IgG antibody
  CMV DNAb
  HEV IgM antibody
Herpes simplex virus (HSV) testing:
  HEV RNAb
  HSV (Type 1 and 2) antibody
Microbiologyd
  HSV (Type 1 and 2) DNAb
Culture:
Liver kidney microsomal type 1 (LKM-1) antibody
  Blood
  Urine


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Abbreviations: Ig = immunoglobulin; INR = international normalized ratio.
a
Not required if anti-actin antibody is tested.
b
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
c
Not required if ASMA is tested.
d
Assayed ONLY by investigator-designated local laboratory; no central testing available.


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Protocol J1X-MC-GZHF(a)
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10.7.
Appendix 7: Pancreatic Monitoring
Glucagon-like peptide 1 agonists have been associated with a possible risk of acute pancreatitis. 
In 2006, the United States prescribing information for exenatide was revised to include the event 
of pancreatitis. In 2007, the US prescribing information for this medication was amended to 
include pancreatitis under “Precautions”. Epidemiologic studies have indicated that there is an 
increased incidence and prevalence of pancreatitis in persons with T2DM.
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, to assess for any potential effects of LY3493269 on the exocrine pancreas, 
amylase and lipase values will be monitored in all current and future clinical trials with 
LY3493269.
Additional monitoring will be requested for amylase or lipase values ≥3X the ULN at any visit 
after randomization. Lipase and amylase may also be obtained at any time during the clinical 
trials for any participant suspected of having symptoms suggestive of pancreatitis (such as severe 
GI signs and/or symptoms), at the investigator’s discretion.
Acute pancreatitis is an AE defined as an acute inflammatory process of the pancreas that may 
also involve peripancreatic tissues and/or remote organ systems. The diagnosis of acute 
pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase >3 × ULN, and

characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging
Most participants with acute pancreatitis experience abdominal pain that is located generally in 
the epigastrium and radiates to the back in approximately one-half of the cases. The pain is often 
associated with nausea and vomiting. 
Participants diagnosed with pancreatitis will be discontinued from the study. Investigators will 
be responsible for following, through an appropriate health care option, these pancreatitis AEs 
until the events resolve or are explained. Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs. For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to IP.


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10.8.Appendix 8: Hypersensitivity Event Tests
This table lists the recommended tests that should be obtained in case of a clinically significant 
hypersensitivity/allergy event. Selected tests may be obtained in the event of anaphylaxis or 
generalized urticaria.
Anti-LY antibodies (immunogenicity)
Tryptase
LY concentration (PK)
N-methylhistamine
Drug-specific IgEa
Basophil activation testa
Complements
Cytokine Panel
Abbreviations: Ig = immunoglobulin; LY = LY3493269; PK = pharmacokinetics.
a
Basophil activation test will be performed if a drug-specific IgE assay is unavailable.


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Protocol J1X-MC-GZHF(a)
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10.9.
Appendix 9: Abbreviations
Term
Definition
ADA
antidrug antibody
AE
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
BG
blood glucose
BP
blood pressure
CI
confidence interval
Cmax
maximum observed drug concentration
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.
CP
clinical pharmacologist
CRF
case report form
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.
CRU
clinical research unit
CT
computed tomography
CV
cardiovascular
ECG
electrocardiogram
eCRF
electronic case report form


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Protocol J1X-MC-GZHF(a)
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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
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
GLP-1R
GLP-1 receptor
GLP-1RA
GLP-1 receptor agonist
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed, and dated informed consent form.
INR
International normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigator
A person responsible for the conduct of the clinical study at a study site. If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IP
investigational product
IRB
institutional review board
NASH
nonalcoholic steatohepatitis
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
PG
plasma glucose


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PK/PD
pharmacokinetics/pharmacodynamics
PR
pulse rate
randomize
The process of assigning participants to an experimental group on a random basis.
QTcF
QT interval corrected using Fridericia’s formula
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SNAC
salcaprozate sodium
SoA
Schedule of Activities
SRP
Safety Review Panel
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TE-ADA
treatment-emergent-antidrug antibody
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.
tmax
time of maximum observed drug concentration 
ULN 
upper limit of normal
VAS
visual analog scale


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11.
References
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101:2379-2400.
Bækdal TA, Breitschaft A, Navarria A, Hansen CW. A randomized study investigating the 
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Metab Toxicol. 2018;14(8):869-877.
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin 
hormone action. Cell Metab. 2013;17(6):819-837. 
Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor 
agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of 
concept. Mol Metab. 2018;18:3-14. 
Danne T, Philotheou A, Goldman D, et al. A randomized trial comparing the rate of 
hypoglycemia—assessed using continuous glucose monitoring—in 125 preschool 
children with type 1 diabetes treated with insulin glargine or NPH insulin (the 
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. 
Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual 
analogue scales in assessment of appetite sensations in single test meal studies. Int J 
Obes. 2000;24(1):38-48. 
Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP 
and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, 
placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 
2018;392(10160):2180-2193. 
Granhall C, Donsmark M, Blicher TM et al. Safety and pharmacokinetics of single and 
multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in 
healthy subjects and subjects with type 2 diabetes. Clinical Pharmacokinetics. 2019; 
58:781–791.
Koizumi M, Takada T, Kawarada Y, et al. JPN guidelines for the management of acute 
pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
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Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon‑like peptide‑1 
receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16(1):6.
Nauck M. Incretin therapies: highlighting common features and differences in the modes 
of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 
inhibitors. Diabetes Obes Metab. 2016;18(3):203-216.
Rybelsus (semaglutide) [package insert]. Novo Nordisk Inc. US Food and Drug 
Administration website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213182s000,213051s001lbl
.pdf Revised January 2020. Accessed on 2 September 2020.
Steinberg WM, Buse JB, Ghorbani MLM, et al. LEADER Steering Committee; LEADER 
Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 


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diabetes treated with liraglutide: results from the LEADER randomized trial. Diabetes 
Care. 2017a;40(7):966-972. [Erratum in: Diabetes Care. 2018;41(7):1538.]
Steinberg WM, Rosenstock J, Wadden TA, et al. Impact of liraglutide on amylase, lipase, 
and acute pancreatitis in participants with overweight/obesity and normoglycemia, 
prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE 
clinical development program. Diabetes Care. 2017b;40(7):830-848.
Twarog C, Fattah S, Heade J, et al. Intestinal permeation enhancers for oral delivery of 
macromolecules: a comparison between salcaprozate sodium (SNAC) and sodium 
caprate (C10). Pharmaceutics. 2019;11(2):78.
van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on 
gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-
diabetic adults. Int J Obes. 2014;38(6):784-793. 
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
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Diabetes Sci Technol. 2010;4(3):577-582. 


Leo Document ID = d80168d7-85f8-45bb-94ed-5afe97b7a417
Approver: 
Approval Date & Time: 05-Mar-2021 15:21:11 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Mar-2021 19:10:44 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan JlX-MC-GZHF (Final Version 3) 
A Multiple-Ascending Dose Study to fuvestigate the Safety, Tolerability, and Phaim acokinetics of an 
L Y3493269 Fo1mulation in Healthy Pa1ticipants 
NCT04682106 
Approval Date: 27-Sep-2021 


STATISTICAL ANALYSIS PLAN 
A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of an LY3493269 Oral Formulation in Healthy Participants 
Statistical Analysis Plan Status: Final Version 3 
Statistical Analysis Plan Date: 24-September-2021 
Study Drng: L Y3493269 
Sponsor Reference: JlX-MC-GZHF 
Covance CRU Study: 1001215-8451031 
Clinical Phase I 
Approval Date: 27-Sep-2021 GMT 
Final V3, 24 Sep 2021 
Page 1 of22 


Statistical Analysis Plan 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Covance Clinical StudyNo. 1001215-8451031 
1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................... 2 
2. 
ABBREVIATIONS ........................................................................................................ 4 
3. 
INTRODUCTION ......................................................................................................... 6 
4. 
STUDY OBJECTIVES .................................................................................................. 6 
4.1 
Primaiy Objective .................................................................................................... 6 
4.2 
Secondary Objective ................................................................................................ 6 
4.3 Exploratory Objectives ............................................................................................ 7 
5. 
STUDY DESIGN ........................................................................................................... 7 
6. 
TREATMENTS ............................................................................................................. 9 
7. 
SAMPLE SIZE m s TIFICATION ................................................................................. 9 
8. 
DEFINITION OF ANALYSIS POPULATIONS .......................................................... 10 
9. 
STATISTICAL METHODOLOGY ............................................................................. 10 
9.1 
General. ................................................................................................................. 10 
9.2 
Demographics and Participant Disposition ............................................................. 11 
9. 3 Phaim acokinetic Assessment ................................................................................. 11 
9. 3 .1 
Pharm acokinetic Analysis ............................................................................. 11 
9 .3 .2 
Pharmacokinetic Statistical Methodology ..................................................... 11 
9.4 Pha1macodynamic Assessment .............................................................................. 12 
9.4.1 
Pharm acodynamic Analysis .......................................................................... 12 
9.4.2 
Pha1macodynamic Statistical Methodology .................................................. 12 
9.5 Phaimacokinetic/Pharm acodynamic Analyses ....................................................... 13 
9.6 
Safety and Tolerability Assessments ...................................................................... 14 
9.6.1 
Adverse events ............................................................................................. 14 
9.6.2 
Glucose Monitoring and Hypoglycemia ........................................................ 14 
9.6.3 
Concomitant medication ............................................................................... 15 
9.6.4 
9.6.5 
9.6.6 
9.6.7 
9.6.8 
9.6.9 
9.6.10 
9.6.11 
9.6.12 
Clinical laboratmy parameters ...................................................................... 15 
Vital signs .................................................................................................... 16 
Electrocardiogram ........................................................................................ 16 
Hepatic Monitoring ...................................................................................... 18 
Immunogenicity Assessments ....................................................................... 20 
Appetite Analysis ......................................................................................... 20 
Hypersensitivity reactions ............................................................................. 20 
Product Acceptability and Palatability Analyses ........................................... 20 
Body Weight ................................................................................................ 21 
9.6.13 Other assessments ......................................................................................... 21 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
10. INTERIM ANALYSES ............................................................................................... 21 
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 21 
12. REFERENCES ............................................................................................................ 21 
13. DATA PRESENTATION ............................................................................................ 21 
13 .1 Derived Parameters ............................................................................................... 21 
13.2 Missing Data ......................................................................................................... 21 
13 .3 Insufficient Data for Presentation .......................................................................... 22 
14. APPENDICES ............................................................................................................. 22 
Appendix 1 : Document History ...................................................................................... 22 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
2. ABBREVIATIONS 
Abbreviations pe1tain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs ]). 
ADA 
AE 
ALP 
ALT 
AUC 
AST 
BW 
CI 
Cmax 
CRF 
CRU 
CSR 
ECG 
HR 
ICH 
LS 
MedDRA 
PD 
PG 
PK 
QD 
QTcF 
SAE 
SAP 
SNAC 
TBL 
TEADA 
TEAE 
TFLs 
Final V3, 24 Sep 2021 
Anti-mug antibody 
Adverse event 
Alkaline phosphatase 
Alanine aminotransferase 
Area under the concentration versus time curve 
Aspaitate aminotransferase 
Bodyweight 
Confidence interval 
Maximum observed mug concentration 
Case Repo1t F orn1 
Clinical Research Unit 
Clinical Study Repmt 
Electrocardiogram 
Hea1trate 
International Conference on Ha1m onisation 
Least squai·es 
Medical Dictiona1y for Regulato1y Activities 
Phaimacodynarnic 
Plasma glucose 
Pharmacokinetic 
Once daily 
QT interval conected using Fridericia' s fo1mula 
Serious adverse event 
Statistical Analysis Plan 
Salcaprozate sodium 
Total bilirnbin 
Treatment-emergent anti-mug antibody 
Treatment-emergent adverse event 
Tables, Figures, and Listings 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
tmax 
Time of maximum observed drng concentration 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WHO 
World Health Organization 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
3. INTRODUCTION 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
11 September 2020), Protocol Amendment (a) (final version dated 05 March 2021) SAP 
Version 1 (final version dated 04 November 2020), and SAP Version 2 (final version dated 
08 March 2021). 
This SAP describes the planned analysis of the safety, tolerability, phannacokinetic (PK) and 
phaim acodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study repmi (CSR) is provided in the accompanying TFL shell 
document. 
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on info1mation from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of infmm ation concerning this 
study (e.g., objectives, study design) is given to help the reader's interpretation. When the SAP 
and TFL shells are agreed upon and finalized, they will se1ve as the template for this study' s 
CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be perfo1m ed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Ha1monisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Repo1is2. 
4. STUDY OBJECTIVES 
4.1 
Primary Objective 
The prima1y objective of the study is to investigate the safety and tolerability of LY3493269 
following 3 consecutive once daily (QD) oral doses in healthy participants. 
The primary endpoint of the study is treatment-emergent adverse events (TEAEs). 
4.2 
Secondary Objective 
The seconda1y objective of the study is to characterize the PK of LY3493269 following 3 
consecutive QD oral doses in healthy participants. 
The seconda1y endpoints of the study are: 
• 
Area under the concentr·ation versus time cmve (AUC) 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
• 
Maximum observed chug concentration (Cnax)-
4.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• 
To investigate the PD effects ofLY3493269 following 3 consecutive QD oral doses in 
healthy pa1iicipants 
o Endpoint: Changes from baseline levels of fasting glucose, insulin, C-peptide, 
triglycerides, and body weight (BW) 
• 
To assess PK of salcaprozate sodium (SNAC) following oral administration in healthy 
pa1iicipants 
o Endpoint: AUC and Cmax 
• 
To explore the effect of L Y3493269 on appetite and food intake following 3 consecutive 
QD oral doses in healthy participants 
o Endpoint: Change in visual analog scale (VAS) score for appetite assessment in a 
fasted state 
• 
To characterize immunogenicity of L Y3493269 following 3 QD oral doses in healthy 
pa1iicipants 
o Endpoint: Incidence of treatment-emergent anti-dmg antibody (TE ADA) 
• 
To assess the product palatability of L Y3493269 tablets. 
o Endpoint: Responses to tablet palatability questionnaire. 
5. STUDY DESIGN 
Study GZHF is a Phase 1, single-center, randomized, placebo-controlled, multiple dose, dose 
escalation study in 4 planned coho1is of up to 14 healthy pa1iicipants randomly assigned in each 
coho1t. 
This study will evaluate the safety, tolerability, and PK of 3 consecutive QD oral doses of 
LY3493269. In addition, the PD effects of L Y3493269 on fasting glucose, insulin, triglycerides, 
and appetite will be explored following the 3 consecutive oral QD doses ofLY3493269. 
In each coho1t, up to 14 pa1iicipants may be randomly assigned to achieve 10 completers with 
8 pa1ticipants receiving L Y3493269 and 2 pa1iicipants assigned to receive placebo. Pa1ticipants 
who are randomly assigned but not administered treatment prior to discontinuation may be 
replaced to ensure that the target number of participants complete the study. 
This is an investigator- and paiiicipant-blind study; the sponsor is not blinded. 
Study randomization shall occur after confamation of eligibility. 
The planned L Y3493269 oral doses for this study range from 8 to 48 mg, administered in the 4 
planned "dose coho1ts": 
• 
Cohort 1: 8 mg L Y3493269 (with 600 mg SNAC) 
• 
Cohort 2: 24 mg L Y3493269 (with 600 mg SNAC) 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
• 
Cohort 3: 48 mg LY3493269 (with 600 mg SNAC) 
• 
Cohort 4: 24 mg L Y3493269 (with 300 mg SNAC) 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Cohorts 1 to 3 evaluate doses of LY3493269 from 8 to 48 mg, each dose in combination with 
600 mg SNAC. Cohort 4 evaluates a 24-mg dose ofLY3493269 with half the amount (300 mg) 
ofSNAC. 
The LY3493269 dose levels may be adjusted (for example, dose increments may be reduced, a 
dose level may be repeated, or a lower/inte1mediate dose may be administered) based on ongoing 
review of available safety, tolerability, PK, and PD data. Any proposal to adjust doses from those 
planned and stated in the protocol, together with supporting data, will be reviewed by an 
independent safety review panel. 
Pa1t icipants will undergo safety (including but not limited to adverse events [AEs], medical 
assessments, clinical laborato1ytests, BW, vital signs, and electrocardiograms [ECGs]), PK, and 
PD assessments. 
Safety data including, but not limited to AEs, clinical laborat01y tests, vital signs, ECGs, BW, 
hypoglycemic events, and VAS assessments up to Day 8 from at least 8 pa1ticipants who have 
received study inte1vention will be reviewed jointly by the principal investigator and sponsor 
before a joint decision is made to escalate to the next planned dose level. 
A general schema for GZHF can be seen in Figure 1. 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
, 
,-, 
, 
, 
I , , I 
• 
!). 
DoHl 
(&-ng LY/Pl~ 600mgSNAC) 
I 
I 
Single oral dose of 
LY3493269 or Placebo 
/j. Dose escalation 
safety rev1ew 
-1 
l 
2 
3 
4 
5 
6 
7 
8 
15 
29 
43 (Follow-up) 
Inpatient Stay 
ff 
1l 
11 
rr 
Outpatient Visits 
Abbmi3tio:is: SNAC = salc:aprozate sodlum; LY = L Y34!lJ269; PL = pl:!cebo. 
Figure 1 - General schema for GZHF 
6. TREATMENTS 
u 
The following is a list of the study treatment abbreviations that will be used in the TFLs. 
Cohort 
Study Treahnent Name 
All 
Placebo QD 
8 mg LY3493269 QD + 600 mg SNAC QD 
2 
24 mg LY3493269 QD + 600 mg SNAC QD 
3 
12 mg LY3493269 QD + 300 mg SNAC QD 
4 
4 mg L Y3493269 QD + 300 mg SNAC QD 
7. SAMPLE SIZE JUSTIFICATION 
Treahnent order in 
TFL 
l 
2 
3 
4 
5 
The sample size is customa1y for Phase 1 studies evaluating safety and PK and is not powered on 
the basis of statistical hypothesis testing. 
Up to approximately 56 participants may be randomly assigned to study intervention to ensure 
approximately 10 evaluable pa1ticipants (8 receiving LY3493269 and 2 receiving placebo) from 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
each of the 4 cohorts complete the study. Paiiicipants who are randomized but not administered 
treatment prior to discontinuation may be replaced to ensure that the target number of 
pa1iicipants complete the study. 
Pa1iicipants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement pa1iicipant will be assigned to the same treatment as the discontinued 
participant. 
8. DEFINITION OF ANALYSIS POPULATIONS 
The "Entered" population will consist of all pa1iicipants who sign the infonned consent fom1. 
The "Emolled" population will consist of all pa1ticipants assigned to treatment, regai·dless of 
whether they take any doses of study treatment, or if they took the conect treatment. Pa1iicipants 
will be analyzed according to the treatment group to which they were assigned. 
The "Safety" population will consist of all pa1iicipants randomly assigned to study intervention 
and who take at least 1 dose of study inte1vention. Participants will be analyzed according to the 
inte1vention they actually received. 
The "Pha1macokinetic" population will consist of all pa1ticipants who received at least 1 full 
dose ofLY3493269 and have evaluable PK data. Pa1ticipants may be excluded from the PK 
summa1y statistics and statistical analysis if a pa1iicipant has an AE of vomiting that occurs at or 
before 2 times median time of maximum obse1ved drng concentration (tmax)-
The "Pha1macodynainic" population will consist of all pa1ticipants who received at least 1 dose 
ofL Y3493269 and have evaluable PD data. Pa1iicipants may be excluded from the PD summary 
statistics and statistical analysis if a participant has an AE of vomiting that occurs at or before 2 
times median tmax-
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when pa1iicipants ai·e assigned to analysis populations. 
9. STATISTICAL METHODOLOGY 
9.1 
General 
Data listings will be provided for all data that is databased. Summa1y statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summaiy statistics will include the arithmetic mean, arithmetic standard deviation, median, min, 
max and N; for log-n01mal data (e.g. the PK paraineters: AUCs and Cmax) the geometric mean 
and geometric coefficient of variation will also be presented. For categorical data, frequency 
count and percentages will be presented. Data listings will be provided for all pai·ticipants up to 
the point of withdrawal, with any pa1ticipants excluded from the relevant population highlighted. 
Summa1y statistics and statistical analyses will generally only be perfo1med for pa1ticipants 
included in the relevant analysis population. For the calculation of summa1y statistics and 
statistical analysis, umounded data will be used. 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Mean change from baseline is the mean of all individual pa1ticipants' change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
paiticipant's baseline value from the value at the timepoint. The individual pa1ticipant's change 
from baseline values will be used to calculate the mean change from baseline using a SAS 
procedure such as Proc Univariate. 
Data analysis will be perfo1med using SAS® Version 9 .4 or greater. 
9.2 
Demographics and Participant Disposition 
Pa1t icipant disposition will be listed. The demographic variables age, sex, race, ethnicity, BW, 
height, HbAlc and body mass index will be summarized and listed. 
9.3 
Pharmacokinetic Assessment 
9.3.1 
Pharmacokinetic Analysis 
The PK parameter estimates will be performed by Lilly for LY3493269 and SNAC will be 
calculated using standard noncompa1tmental methods of analysis. The software and version used 
for the final analyses will be specified in the clinical study rep01t. 
The prima1y parameters for analysis will be Cmax, AUC and tmax. The PK parameters for Cmax and 
AUC(0-24) will be computed after the first, second, and third doses, with AUC(0-t1ast) and 
AUC(0-oo) also calculated after the third dose. Other parameters, such as half-life, apparent 
clearance, and apparent volume of distribution, may be reported. 
The PK data will be provided by Eli Lilly and Company for the analysis. 
9.3.2 
Pharmacokinetic Statistical Methodology 
For all cohorts, log-transfo1med Cmax, AUC(0-24), AUC(0-tias1) (Day 3 only), and AUC(0-oo) 
(Day 3 only) parameters ofLY3493269 on Days 1 (first dose) and 3 (third dose) independently 
will be evaluated using a power model (where log-dose acts as an explanat01y variable, and 
SNAC fitted as a dichotomous variable in which the variable equals 0 for those doses with 300 
mg SNAC, and 1 for those with 600 mg SNAC) to estimate ratios of dose-norn1alized geometric 
means and co1Tesponding 90% confidence intervals (Cls). The estimated ratio of dose-
n01malized geometric means of PK parameters between the highest and lowest doses will be 
used to assess dose propo1tionality. The 90% CI will also be reported for the parameter of the 
SNAC variable. A subinte1val within the highest and lowest doses may also be considered for 
assessment of dose propo1tionality using the same approach. 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Example of the SAS code (for Cmax and AUC[0-24]) for the analysis: 
proc mi xed data=xxx; 
c l ass usubj i d SNAC ; 
model l og_pk = log_ dose SNAC / a l pha=O. l c l s ol ution outpred=resi ds ddf m=kr; 
estimate ' xx mg ' intercept 1 log_ do se yy / a l pha=0 . 1 cl; /*Log value of xx*/ 
estimate ' zz mg -
xx mg ' l og_ dose pp/ a l pha=0 . 1 cl; /*Di f f erence i n log 
val ues of zz and xx*/ 
ods output soluti onf=est; 
ods output esti mates=esti ms ; 
run; 
The L Y3493269 parameter tmax will be analyzed non-parametrically using the Krnskal-Wallis 
test to investigate its independence, and, hence, dose propo1tionality, with the respective p-value 
repo1t ed. For each dose, 90% Cls for the median will also be repo1ted. 
Example SAS code is as follows: 
proc nparlway data=xxx 
class dose; 
var pk; 
ods output KruskalWal l i sTest=krusk; 
run; 
For Coh01ts 1 and 2, and 3 and 4 independently, log-transf01med dose n01malized Cmax, 
AUC(0-24), AUC(0-t1ast) (Day 3 only), and AUC(0-oo) (Day 3 only) parameters ofLY3493269 
on Days 1 (first dose) and 3 (third dose) will be analyzed independently an analysis of variance 
model to assess dose prop01tionality. The model will include treatment as a fixed effect. The 
difference in least-square (LS) treatment means and respective LS means will be back 
transf01med to produce the ratio of geometric means, and the 90% Cls of the LS means and 
difference between the means will be rep01t ed. 
Example of the SAS code for the dose n01malized analysis: 
proc mi xed dat a =xxx; 
c l ass usubjid; 
model log_ DNpk = treatment/ alpha=0 . 1 cl soluti on outpred=resids ddfm=kr; 
ods output l smeans=l sm dif fs=estims ; 
run; 
9.4 
Pharmacodynamic Assessment 
9.4.1 
Pharmacodynamic Analysis 
Pharmacodynamic data will be provided by Eli Lilly and Company for the analysis. 
9.4.2 
Pharmacodynamic Statistical Methodology 
The PD parameters from the placebo-treated participants across all coh01ts will be pooled for the 
final analysis. 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
All explorat01y PD parameters, including the change from baseline parameters, will be 
summarized and listed by treatment group and visit. Individual obse1ved and mean time profiles 
of the postdose PD parameters will be plotted by treatment groups. 
The PD parameters that will be statistically analyzed, which have a baseline defined as Day 1 
predose, are as follows: 
• 
Fasting glucose 
• 
Fasting insulin 
• 
Fasting C-peptide 
• 
Fasting 1:J.iglycerides 
• 
Body weight 
• 
Appetite VAS 
The PD parameters, as well as the change from baseline parameters, will be analyzed using a 
mixed effect model. In the model, 1:J.·eatment, visit, and treatment-by-visit interaction will be 
modelled as fixed effects; pa1ticipants will be modelled as a random effect. Baseline will also be 
included as a covariate when the response involves change from baseline. An uns1:J.11ctured 
covariance st:J.ucture will be used to model the covariance between a pa1ticipant's multiple 
obse1vations, with an alternative strncture to be used if the model fails to converge, using a 
measure such as Akaike's info1mation criterion to decide which st:J.ucture will be used. If 
necessary, the response may be transformed before the analysis, with back-1:J.·ansfo1ming to the 
original scale implemented for the results. For each PD parameter, the difference in LS treatment 
means, comparing LY3493269 (test) and placebo (reference), along with the 90% CI, will be 
rep01ted. 
Example of the SAS code to be used for the mixed effect model analysis: 
proc mi xed data=xxx; 
class treat visit subject; 
model PD = treat visit treat*visit /residual ddfm=kr; 
repeated visit/ subject=subject type=un; 
lsmeans treat*visit / c l pdiff alpha=O. l ; 
ods output lsmeans=lsm diffs=estims ; 
run; 
9.5 
Pharmacokinetic/Phat'macodynamic Analyses 
PK/PD analyses or graphical explorations may be used to assess the relationship between 
L Y3493269 doses and/or concentrations and 
• 
Safety parameters, such as 
o QT inte1val conected using Fridericia's fo1mula (QTcF) inte1val 
o Blood pressure 
o Heart rate (HR) 
o PR inte1val, 
• 
Tolerability parameters, such as 
o nausea 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
o 
vomiting 
o diaIThea, 
• 
PD parameters, such as 
o fasting glucose 
o fasting insulin 
o fasting C-peptide 
o fasting triglycerides 
o weight. 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Endpoints may include but are not necessarily limited to those listed earlier. 
The impact of anti-drug antibody (ADA) and its titers on L Y3493269 clearance and drug effect, 
if applicable, may be evaluated. 
9.6 
Safety and Tolerability Assessments 
9.6.1 
Adverse events 
Where changes in severity are recorded in the Case Repo1t Fo1m (CRF), each separate severity 
of the AE will be repo1ted in the listings, only the most severe will be used in the summa1y 
tables. A pre-existing condition is defined as an AE that sta1t s before the pa1ticipant has provided 
written info1med consent and is ongoing at consent. A non-TEAE is defined as an AE which 
sta1ts after informed consent but prior to dosing. A TEAE is defined as an AE which occurs 
postdose or which is present prior to dosing and becomes more severe postdose. 
All AEs will be listed. TEAEs will be summarized by treatment, severity and relationship to the 
study drug. The frequency (the number of AEs, the number of participants experiencing an AE 
and the percentage of participants experiencing an AE) of TEAEs will be summa1ized by 
treatment, Medical Dictiona1y for Regulat01y Activities (MedDRA) version 23.0 system organ 
class and prefened te1m. The summa1y and frequency AE tables will be presented for all 
causalities and those considered related to the study drug by the investigator. Any serious AEs 
(SAEs) will be listed. 
Any AEs of special interest will be summarized and listed, these include cardiovascular events, 
gastrointestinal events (eg. , nausea, vomiting, dianhea), hypersensitivity reactions, acute 
pancreatitis, and hypoglycemic events. 
Discontinuations due to AEs will be listed. 
9.6.2 
Glucose Monitoring and Hypoglycemia 
During the study, blood glucose concentrations will be monitored for safety assessments. 
Glucose data will be listed and summarized by treatment together with changes from baseline, 
where baseline is defined as Day 1 predose. 
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows: 
• 
Level 1 Hypoglycemia, Plasma glucose (PG) <70 mg/dL (3.9 mmol/L) and 
54 mg/dL (3.0 mmol/L): 
Level 1 hypoglycemia can ale1t a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel pa1iicipants to treat hypoglycemia at 
this glucose alert value. 
• 
Level 2 Hypoglycemia, PG <54 mg/dL (3.0 mmol/L): 
This is also refen ed to as documented or blood glucose confnmed hypoglycemia with 
glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is clinically relevant regardless 
of the presence of absence of symptoms of hypoglycemia. 
• 
Level 3 Hypoglycemia: Severe hypoglycemia (in adults): 
A severe event characterized by altered mental and/or physical status requiring assistance 
for treatment of hypoglycemia. For example, pa1iicipants had altered mental status, and 
could not assist in their own care, or were semiconscious or unconscious, or expelienced 
coma with or without seizures, and the assistance of another person was needed to 
actively administer carbohydrate, glucagon, or other resuscitative actions. Glucose 
measurements may not be available during such an event, but neurological recove1y 
attributable to the restoration of glucose concentration to nmm al is considered sufficient 
evidence that the event was induced by a low glucose concentration. 
• 
Nocturnal Hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep. 
Investigator review of glucose results clinically indicative of hypoglycemia will be required. 
To avoid duplicate repo1ting, all consecutive PG values <70 mg/dL (3.9 mmol/L) occuning 
within a I-hour period may be considered to be a single hypoglycemic event 
9.6.3 
Concomitant medication 
Concomitant medication will be coded using the World Health Organization (WHO) drng 
dictiona1y (Version WHODD MAR20B3). Concomitant medication will be listed. 
9.6.4 
Clinical laboratory parameters 
All clinical chemistly and hematology data will be summarized by parameter and treatment 
together with changes from baseline, where baseline is defined as the Day 1 predose assessment. 
Clinical chemistry, hematology and urinalysis data will be listed. Additionally, clinical 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
chemistry, hematology and urinalysis data outside the reference ranges will be listed and flagged 
on individual participant data listings. 
9 .6.5 
Vital signs 
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual participants will be listed. 
Changes from baseline values will be analyzed using a repeated measurement mixed effect 
model. The model will include treatment, timepoint, and treatment-by-timepoint interaction as 
fixed effects; pa1ticipant will be included as a random effect. Baseline will also be included as a 
covariate in the model. An unstrnctured covariance strncture will be used to model the 
covariance between a pa1ticipant's multiple observations, with an alternative strncture to be used 
if the model fails to converge, using a measure such as Akaike 's infonnation criterion to decide 
which structure will be used. The difference in least-square tr·eatment means, comparing 
LY3493269 (test) and placebo (reference), along with the 90% CI, will be repo1ted. Example 
SAS code for the analysis: 
proc mixed da t a =xxx; 
c las s t i me t reat subject ; 
model change
= t reat t ime treat*ti me bas e /re s i dual ddfm=kr; 
repe ate d day / sub j e ct=subject type =un; 
l smea n s treat*da y / c l pdiff a l p ha=O. l ; 
ods out put l smeans=lsm d iffs=e stims ; 
run; 
9 .6.6 
Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR, 
QT, QRS duration, RR and HR. In addition, QTcF will be calculated as follows: 
QTcF ~ 
3 60/ 
/ HR 
The ECG data will be summarized by tI·eatment together with changes from baseline, where 
baseline is defined as the mean of the triplicate Day 1 -0.5 h, -0.25, and predose assessments. 
Figures of mean ECG data and mean changes from baseline will be presented by tr·eatment. The 
frequency of participants with a maximum increase from baseline in QTcF interval will be 
summarized for each treatment according to the following categories: >30 ms and >60 ms. In 
addition, the frequency of pa1ticipants with QTcF postdose values, according to the following 
categories: >450 ms, >480 ms and >500 ms, will be summarized by tr·eatment. 
Plasma PK Concentration versus delta and double delta ECG parameter analysis 
A plasma LY3493269 concentI·ation-ECG parameter analysis will be perf01med to assess the 
relationship between changes from baseline (mean of Day 1 -0.5 h, -0.25 h, and predose 
Final V3, 24 Sep 2021 
Page 16 of22 


Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
triplicate assessments) in ECG parameters (QTc, PR inte1val, QRS duration, and HR) and plasma 
L Y3493269 concentrations across all treatments. The change from baseline adjustment will be 
based on individual paiticipant's Day 1 -0.5 h, -0.25 h, and predose values. Further details on 
how these will be calculated: 
• 
Calculate the baseline ECG value for each participant, which is the mean of ECG 
parameter values of each individual pa1ticipant over 3 predose time points at Day 1. 
• 
Calculate the change from baseline at each timepoint for each individual participant. 
• 
Calculate the mean ECG pai·ameter value across all pa1ticipants at baseline. 
• 
For each pa1ticipant subtract the mean ECG parameter value from their own individual 
obse1ved ECG parameter value. This will be each paiticipant' s centered ECG pai·ameter 
value. 
• 
BLQ L Y3493269 concentration data will be imputed to the lower limit of 
quantification/square root(2) for the purposes of the analysis. 
The relationship between LY3493269 concentrations and ECG parameters will be explored 
graphically by plotting delta ECG parameter values against L Y3493269 concentrations, 
including all post dosing timepoints. 
A mixed effects analysis model will be employed with change from baseline in ECG parameter 
as the dependent variable, LY3493269 concentration and centered ECG parameter value as 
continuous covariates, treatment and time as categorical factors, and a random intercept and 
slope per paiticipant. Treatment will be fitted as a binary variable (Placebo, or L Y3493269). The 
model will have the form: 
/::,.ECGijkl = (00 + T/o,i) + 01 TR½ + (02 + T/z,i)Cijkl + 03kTIMEk + 041Day1 + 05TIMEk X DAYi 
+ 06(ECGi,j,k=O,l=O - ECGk=O,l=o) + Eijkl 
where !::.ECGijkl is the change from baseline in ECG parameter for pa1ticipant i in treatment j at 
time k after dosing on day l. 00 is the population mean intercept in the absence of treatment 
effect, TJo i is the random effect associated with the intercept te1m 0o, 01 is the fixed effect 
categorical vai·iable associated with treatment TRTi, 02 is the population mean slope of the 
assumed linear association between concentration and ~ECGijkt, 7]2.; is the random effect 
associated with the slope 02, C ijkt is the concentration for pa1ticipant i in treatment j , time k , and 
day l, 03k is the fixed effect associated with time after dose k on the same day, 0 41 is the fixed 
effect associated to day l, 05 is the fixed effect associated with the interaction between time and 
day, 06 is the fixed effect associated with baseline ECG;J,k==OJ=O, ECGk=O,l=o is the overall mean 
of ECG;J,k=OJ=o (the mean of all the baseline ECG parameter values, at day 0, time 0), and Eijkl is 
the residual enor. It will be assumed the random effects are multivariate Gaussian distributed 
with mean vector O and an unstructured covariance matr"ix G, whereas the residuals, Eijkz, are 
Gaussian distributed with mean O and variance r. 
If the model fails to converge, the interaction te1m will be omitted from the model, with day also 
omitted and time redefined to be time after the first dose if the model still fails to converge. The 
random effects may reduce to fixed effects and a different covariance structure may be used if 
there ai·e fiuther convergence issues. 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
The predicted mean change from baseline and placebo-conected change from baseline in ECG 
parameter (~ECG and ~~ECG respectively) at the observed geometric mean Cmax of each 
treatment (slope estimate * Cmax + treatment effect) and two-sided 90% CI at different dose 
levels will be calculated. Residual plots will be produced to assess the adequacy of the model. 
The hysteresis loop plot between QTcF change from baseline concentration may be generated 
within 24 hours. 
Example of SAS code as follows: 
pro c mixed data=xxx; 
by param; 
c l ass treat time subject ; 
mode l ~ECG = t reat t i me basel ine ECG PKconc / s o l ution c l alpha=0 . 1 d df m=kr; 
random intercept PKconc / type=u~ subject=subj e c t; 
estimat e ' Placebo ' intercept 1 treat 1 0 PKconc 0/ CL a lpha=0 . 1 ; 
estimate ' XX mg LY34 93269 ' i ntercept 1 treat 0 1 PKconc [cmax XXmg] / CL 
a l pha=0 .1; 
estimate ' XX mg LY3493269 -
Placebo' treat -1 1 PKconc [cmax XXmg] / CL 
a l pha=0 .1; 
ods output c ovparms =c ovp (where= (covparm=" Residual")) ; 
ods output soluti o nF=s o l ; 
ods output esti mates=estim; 
run; 
9.6.7 Hepatic Monitoring 
Close hepatic monitoring 
If a pa1ticipant who had nonnal or near normal baseline alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirnbin (TBL) (i.e., <1.5x 
upper limit ofno1mal [ULN]), experiences elevated ALT2::3x ULN, AS'[23x ULN, ALP22x 
ULN, or TBL22x ULN, laborato1y tests should be repeated within 48 to 72 hours, including 
ALT, AST, ALP, TBL, direct bilirnbin, gamma-glutamyltransferase, and creatinine kinase to 
confitm the abn01mality and to dete1mine if it is increasing or decreasing. 
In pa1ticipants emolled with elevated baseline ALT, AST, ALP or TBL (21.5x ULN), the 
thresholds for close monitoring are AL'f22x baseline, AS'f22x baseline, ALP22x baseline, or 
TBL22x baseline. 
At a minimum, this evaluation should include physical examination and a thorough medical 
hist01y, including symptoms, recent illnesses, (for example, hea1t failure, systemic infection, 
hypotension, or seizures), recent travel, hist01y of concomitant medications (including over-the-
counter), herbal and dieta1y supplements, hist01y of alcohol drinking and other substance abuse. 
If the abno1mality persists or worsens, clinical and laborato1y monitoring, and evaluation for 
possible causes of abno1mal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. 
Comprehensive hepatic evaluation 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
If a study participant, who had baseline ALT, AST, ALP, TBL<l .5x ULN, experiences elevated 
ALT2:5x ULN, AST2:5x ULN, ALP 2:3x ULN, TBL 2:2x ULN, or elevated ALT, AST 2:3x ULN 
with hepatic signs/symptoms (severe fatigue, nausea, vomiting, right upper quadrant abdominal 
pain, fever, rash, and/or eosinophilia>5%), a comprehensive evaluation should be perf01med to 
search for possible causes of liver injmy. 
fu pruticipants who had elevated baseline ALT, AST, ALP, or TBL (2:l .5x ULN), the thresholds 
for performing this evaluation ru·e ALT2:3x baseline, AST2:3x baseline, ALP2:2x baseline, 
TBL2:1.5x baseline, or ALT, AST 2:2x baseline with hepatic signs/symptoms. 
At a minimum, this evaluation should include physical examination and a thorough medical 
histo1y, as outlined above, as well as tests for prothrombin time-international nom1alized ratio, 
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for 
example, ultrasound or computed tomography scan). 
Additional hepatic data collection in participants who have abnormal liver tests during the 
study 
Additional hepatic safety data collection should be perfo1med in pa1t icipants who meet 1 or more 
of the following 5 conditions: 
1. Elevation of sennn ALT to 2:5 x ULN on 2 or more consecutive blood tests (if baseline 
ALT<l.5x ULN) 
fu pa1ticipants with baseline AL T2:1.5x ULN, the threshold is ALT2:3x baseline 
on 2 or more consecutive tests 
2. Elevatation of TBL to 2:2x ULN (if baseline TBL <1.5x ULN) 
fu pruticipants with baseline TBL 2:l.5x ULN, the threshold should be TBL 2:2x 
baseline 
3. Elevation of serum ALP to 2:2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
fu pa1ticipants with baseline ALP2:l.5x ULN, the tlu-eshold is ALP 2:2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of the investigational product due to a hepatic event 
Where applicable, the following will be presented. The part icipants' liver disease hist01y and 
associated person liver disease hist01y data will be listed. Any concomitant medications that have 
potential for hepatotoxicity, including acetaminophen will be listed. Results from any hepatic 
monitoring procedures, such as a magnetic resonance elastography scan, and biopsy assessments 
will be listed, if performed. 
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drng use data will also be listed. 
Final V3, 24 Sep 2021 
Page 19 of22 


Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings. 
9.6.8 
Immunogenicity Assessments 
The frequency and percentage of pa1iicipants with pre-existing ADA and with TE ADA to 
LY3493269 will be tabulated and listed. 
For paiiicipants who are ADA negative at baseline, TE ADAs ai·e defined as those with a titer 
2-fold (1 dilution) greater than the minimum required dilution of the assay (1:10). For 
participants who ai·e ADA positive at baseline, TE ADAs are defined as those with a 4-fold (2 
dilution) increase in titer compared to baseline. The frequency and percentage of participants 
with cross-reactive and neutralizing antibodies, if measured, may also be tabulated for 
participants with TE ADA. 
The relationship between the presence of antibodies and PK exposmes and PD response 
including safety and efficacy to L Y3493269 may be assessed. 
9 .6.9 
Appetite Analysis 
To explore the effects of LY3493269 on meal intake and appetite sensation, participants will be 
asked to rate their appetite sensations using a 100-mm validated VAS for parameters of hunger, 
fullness, satiety, and prospective food consumption. Overall appetite will be derived using the 
four pai·ameters. Overall appetite score is calculated as the average of the 4 individual scores: 
Overall = (satiety + fullness + (100 - prospective food consumption) 
+ (100 - hunger))/ 4 
A higher overall appetite score indicates less appetite, and a lower score indicates more 
appetite. 
The data will be listed and summarized, along with change from baseline ( defined as Day 1 
predose), by treatment and timepoint. 
9.6.10 Hypersensitivity reactions 
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to 
assess the paiiicipant's medical histo1y, alternative causes, and symptoms. 
These data will be listed. 
9.6.11 Product Acceptability and Palatability Analyses 
Responses from the product palatability questionnaires will be summarized categorically 
(frequency and percentage) and listed. 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
9.6.12 Body Weight 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
Body weight data, along with change from baseline, which is defined as Day 1 predose, will be 
summarized and listed. Figures of mean body weight data by treatment over time, as well as 
change from baseline, will be plotted. 
9.6.13 Other assessments 
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
10. 
INTERIM ANALYSES 
Interim access to safety and tolerability (and any available PK or PD) data is scheduled to occur 
after eve1y dosing session. The investigator will remain blinded, and the Lilly sponsor team will 
be unblinded during these reviews. 
No interim statistical analyses are planned. 
11. 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol specified statistical analyses. 
12. 
REFERENCES 
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pha1maceuticals for Human Use, ICH Ha1monized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 Febrna1y 1998. 
2. International Conference on Ha1m onization of Technical Requirements for Registration of 
Pha1maceuticals for Human Use, ICH Haimonized Tripa1t ite Guideline, Stru cture and 
Content of Clinical Study Repo1ts (E3), 30 November 1995. 
13. 
DATA PRESENTATION 
13.1 
Derived Parameters 
Individual derived parameters (e.g. PK parameters) and appropriate summa1y statistics will be 
repo1ted to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be rep01ted as received. N and percentage 
values should be rep01ted as whole numbers. Median values should be u-eated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values. 
13.2 
Missing Data 
Missing data will not be displayed in listings. 
Final V3, 24 Sep 2021 
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Statistical Analysis Plan 
Covance Clinical StudyNo. 1001215-8451031 
CONFIDENTIAL 
Sponsor Reference JlX-MC-GZHF 
13.3 
Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of part icipants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, "No serious adverse events occuned for this study." 
14. 
APPENDICES 
Appendix 1: Document History 
Status and Version 
Final Version 1.0 
Final Version 2.0 
Final Version 3.0 
NA = not applicable 
Final V3, 24 Sep 2021 
Date of Change 
Summary/Reason for Changes 
NA 
NA; the first version. 
08 Mar 2021 
Included Day 1 in dose propmtionality PK statistical 
analysis. 
24 SEP 2021 
Removed SNAC statistical analysis, amended dose 
propmtionality PK stats analysis to include all doses, 
and added independent dose nmmalized analysis. 
Page 22 of22 


Leo Document ID= 6ad72824-0d35-409c-96e7-b9de43a5cf39 
Approver: PP 
-----------------------
Approval Date & Time: 24-Sep- 2021 14:42:22 GMT 
Signature meaning: Approved 
Approver: PPD 
--------------
Approval Date & Time: 24-Sep- 2021 18:12:37 GMT 
Signature meaning: Approved 
Approver: PP ______________ ... 
Approval Date & Ti me: 27-Sep- 2021 06:18 : 36 GMT 
Signature meaning: Approved