Clinical trial NCT04498390
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-09-03; Completion date: 2020-12-28
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study in healthy participants is to learn more about the safety of LY3493269 and any side effects that might be associated with it. Blood tests will be performed to check how much LY3493269 gets into the bloodstream and how long it takes the body to eliminate it. For each participant, the study will last about 10 weeks and may include 12 visits, including five nights in a row in the clinical research center.

Detailed description:

Arms: arm 1: 8, 24 or 48 milligrams (mg) LY3493269 + 250 or 500 mg permeation enhancer sodium caprate(C10) Once daily (QD) administered orally over 3 consecutive study days. arm 2: Placebo administered orally over 3 consecutive study days.
Interventions: intervention 1: LY3493269 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol: J1X-MC-GZHB (a) 
 
A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics 
of LY3493269 in Healthy Participants 
 
NCT04498390 
Approval Date: 22-Jul-2020 


C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H B(a)
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e p r o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of L Y 3 4 9 3 2 6 9 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s. 
N ot e t o R e g ul at or y A ut h oriti e s: T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n 
e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r e l e a s e. 
I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or 
ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
Pr ot oc ol Title: A M ult i ple-Asce n di n g D ose St u d y t o I n vest i gate t he Safety,  T olera bilit y,  a n d 
P har mac o ki net ics of L Y 3 4 9 3 2 6 9 i n Healt h y Part ici pa nts
Pr ot oc ol N u m ber: J 1 X-M C -G Z H B (a)
A me n d me nt N u m ber: (a)
C o m p o u n d : L Y 3 4 9 3 2 6 9
St u d y P h ase: 1
S h ort Title: A Safet y St u d y  of L Y 3 4 9 3 2 6 9 Gi ve n as M ul tiple Oral  D oses i n Healt h y 
P arti cip a nts
Acr o n y m : G Z H B
S p o ns or N a me: El i Lill y  a n d C o mpa n y
Le g al Re gistere d A d dress: I n dia na p olis, I n dia na U S A 4 6 2 8 5
A p pr o v al D ate: Pr ot oc ol J 1 X-M C -G Z H B El ectr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n 1 1 
J u ne 2 0 2 0.
Pr ot oc ol  J 1 X-M C -G Z H B A me n d me nt (a) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n 
a p pr o val date pr o vide d bel o w.
A p pr o v al D at e: 2 2- J ul- 2 0 2 0 G M T


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
11 June 2020
Overall Rationale for Amendment (a):
This amendment addresses feedback from the Health Sciences Authority (HSA) Singapore. Other 
changes were made for clarity and consistency. This table describes the changes made for Amendment 
(a).
Section # and 
Name
Description of Change
Brief Rationale
4.3 Justification 
for Dose, Table 
4.1
The correct version of table 
from the May 2020 Briefing 
Document has been inserted. 
Addressed error with column 
alignments.
6.6.2 Dose-
Escalation 
Stopping Criteria
Clarified that severe 
hypoglycemia will be 
considered a serious adverse 
event and added drug-related 
gastrointestinal effects and 
clinically significant 
cardiovascular adverse events to 
the dose-escalation stopping 
criteria.
In agreement with Health Sciences 
Authority comments.
Throughout the 
protocol
Minor editorial and formatting 
changes
Minor, therefore not described.


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
4
Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ......................................................................................10
2.
Introduction..............................................................................................................13
2.1.
Study Rationale ..........................................................................................................13
2.2.
Background ................................................................................................................13
Summary of Clinical Experience ................................................................................14
2.3.
Benefit/Risk Assessment ............................................................................................15
3.
Objectives and Endpoints.........................................................................................16
4.
Study Design .............................................................................................................17
4.1.
Overall Design............................................................................................................17
Screening Period.........................................................................................................17
Treatment Period ........................................................................................................18
Outpatient Visits (Days 6, 8, and 15) ..........................................................................18
Follow-Up Visits (Days 29 and 43).............................................................................18
4.2.
Scientific Rationale for Study Design .........................................................................18
4.3.
Justification for Dose..................................................................................................19
4.4.
End of Study Definition..............................................................................................23
5.
Study Population ......................................................................................................24
5.1.
Inclusion Criteria........................................................................................................24
5.2.
Exclusion Criteria.......................................................................................................25
5.3.
Lifestyle Considerations .............................................................................................27
Meals and Dietary Restrictions ...................................................................................27
Caffeine, Alcohol, and Tobacco..................................................................................27
Activity ......................................................................................................................28
5.4.
Screen Failures ...........................................................................................................28
6.
Study Intervention....................................................................................................29
6.1.
Study Interventions Administered...............................................................................29
Administration Details................................................................................................30
6.2.
Preparation/Handling/Storage/Accountability .............................................................30
6.3.
Measures to Minimize Bias: Randomization and Blinding ..........................................30
Method of Treatment Assignment...............................................................................30
Selection and Timing of Doses ...................................................................................31
Unblinding .................................................................................................................31
6.4.
Study Intervention Compliance...................................................................................31
6.5.
Concomitant Therapy .................................................................................................32
6.6.
Dose Modification......................................................................................................32
Dose Escalation ..........................................................................................................33
Dose-Escalation Stopping Criteria ..............................................................................33
Data Review during the Study ....................................................................................34
6.7.
Intervention after the End of the Study........................................................................34


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Protocol J1X-MC-GZHB(a)
5
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................35
7.1.
Discontinuation of Study Intervention ........................................................................35
Hepatic Criteria for Discontinuation ...........................................................................35
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................36
Discontinuation of Inadvertently Enrolled Participants ...............................................36
7.3.
Lost to Follow-up .......................................................................................................37
8.
Study Assessments and Procedures .........................................................................38
8.1.
Efficacy Assessments .................................................................................................38
8.2.
Safety Assessments ....................................................................................................38
Physical Examinations................................................................................................38
Vital Signs..................................................................................................................39
Electrocardiograms.....................................................................................................39
Clinical Safety Laboratory Assessments .....................................................................40
Safety Monitoring.......................................................................................................41
Glucose Monitoring....................................................................................................44
8.3.
Adverse Events and Serious Adverse Events ..............................................................45
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................46
Method of Detecting AEs and SAEs ...........................................................................46
Follow-up of AEs and SAEs.......................................................................................46
Regulatory Reporting Requirements for SAEs ............................................................46
Pregnancy...................................................................................................................47
Events or Outcomes....................................................................................................47
Adverse Events of Special Interest..............................................................................47
Product Complaints ....................................................................................................47
8.4.
Treatment of Overdose ...............................................................................................48
8.5.
Pharmacokinetics........................................................................................................48
Bioanalysis .................................................................................................................49
8.6.
Pharmacodynamics.....................................................................................................49
Body Weight ..............................................................................................................49
Appetite Analysis .......................................................................................................49
Pharmacodynamic Markers.........................................................................................50
8.7.
Genetics .....................................................................................................................50
8.8.
Biomarkers.................................................................................................................50
8.9.
Immunogenicity Assessments.....................................................................................51
8.10.
Health Economics.......................................................................................................51
9.
Statistical Considerations.........................................................................................52
9.1.
Statistical Hypotheses.................................................................................................52
9.2.
Sample Size Determination.........................................................................................52
9.3.
Populations for Analyses ............................................................................................52
Study Participant Disposition......................................................................................52
Study Participant Characteristics.................................................................................53
Treatment Compliance................................................................................................53
9.4.
Statistical Analyses.....................................................................................................53
General Considerations...............................................................................................53


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
6
Safety Analyses ..........................................................................................................54
Pharmacokinetic Analyses ..........................................................................................54
Pharmacodynamics Analyses......................................................................................55
Pharmacokinetic/Pharmacodynamic Analyses ............................................................55
Evaluation of Immunogenicity....................................................................................56
9.5.
Interim Analyses.........................................................................................................56
9.6.
Data Monitoring Committee (DMC)...........................................................................56
10.
Supporting Documentation and Operational Considerations ................................57
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................57
Regulatory and Ethical Considerations........................................................................57
Informed Consent Process ..........................................................................................57
Data Protection...........................................................................................................58
Dissemination of Clinical Study Data .........................................................................58
Data Quality Assurance ..............................................................................................59
Source Documents......................................................................................................60
Study and Site Start and Closure.................................................................................60
Publication Policy.......................................................................................................61
Long-Term Sample Retention.....................................................................................61
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................62
Blood Sampling Summary..........................................................................................64
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................65
Definition of AE.........................................................................................................65
Definition of SAE.......................................................................................................66
Recording and Follow-Up of AE and/or SAE .............................................................67
Reporting of SAEs......................................................................................................68
Sponsor Surveillance Process for Dose Escalation or Cohort 
Expansion...................................................................................................................69
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................70
Definitions..................................................................................................................70
Contraception Guidance..............................................................................................70
Collection of Pregnancy Information ..........................................................................72
10.5.
Appendix 5: Genetics .................................................................................................74
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................75
10.7.
Appendix 7: Pancreatic Monitoring ............................................................................77
10.8.
Appendix 8: Hypersensitivity Event Tests ..................................................................79
10.9.
Appendix 9: Abbreviations .........................................................................................80
11.
References.................................................................................................................83


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of LY3493269 in Healthy Participants
Short Title: A Safety Study of LY3493269 Given as multiple oral doses in Healthy Participants
Rationale:
LY3493269 is a dual glucose-dependent insulinotropic polypeptide and glucagon-like-peptide 1
receptor agonist being developed as a treatment for type 2 diabetes mellitus. This study of 
LY3493269, Study J1X-MC-GZHB (GZHB), will investigate the safety, tolerability, and 
pharmacokinetics of LY3493269 administered as 3 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 GZHB 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 (targeting 8 participants receiving LY3493269 and 2 receiving 
placebo).


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
8
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


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
9
1.2.
Schema
Abbreviations: C10 = permeation enhancer sodium caprate; LY = LY3493269; PL = placebo.


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
10
1.3.
Schedule of Activities (SoA)


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
11
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
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 for details. 
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, 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.
C10 PK sampling (h)
P, 0.5, 1, 1.5, 
2, 2.5, 3, 4, 5, 
6, 8, 12
P, 1, 2, 
3, 4, 12
P, 0.5, 1, 1.5,
2, 2.5, 3, 4, 5, 
6, 8, 12
X
X


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
12
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
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
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; HR = heart rate; min = minutes; P = predose; PD = pharmacodynamics; PK = 
pharmacokinetics; PR = pulse rate; 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.
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.


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
13
2.
Introduction
2.1.
Study Rationale
LY3493269 is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-
peptide 1 (GLP-1) receptor agonist being developed as a treatment for type 2 diabetes mellitus
(T2DM). In addition to subcutaneous (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 blood glucose (BG) goals. This study of LY3493269, 
Study J1X-MC-GZHB (GZHB), will investigate the safety, tolerability, and pharmacokinetics 
(PK) of LY3493269 administered as multiple once-daily oral doses in healthy participants.
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-1 
receptors (GLP-1Rs) are expressed throughout the brain, in regions that control

glucose homeostasis

gut motility

food intake

aversive signaling, and

cardiovascular (CV) function (Campbell and Drucker 2013). 
Currently, there are several approved GLP-1 receptor agonists (GLP-1RAs) for the treatment of 
diabetes and obesity. The dosing of GLP-1RAs in humans is limited by gastrointestinal (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 GZHB will include a permeation enhancer (sodium 
caprate, C10), to enable oral absorption of the LY3493269 peptide. As peptides are otherwise
poorly absorbed orally, an enabling excipient such as C10 in an oral enteric-coated capsule 


C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H B(a)
1 4
f or mulat i on is e x pecte d t o tra nsie ntl y i ncrease l ocal per mea bility ( T war o g et al. 2 0 1 9) i n t he 
s mall i ntesti ne a n d res ult i n i ncrease d oral bi oa vaila bilit y f or t hera pe utic use.  
S u m m ar y of Cli nic al E x perie nce
St u d y  J 1 X-M C -G Z H A ( G Z H A ) was a first -i n-h u ma n, ra n d o mize d, place b o -c o nt r olle d, si n gle-
asce n di n g d ose (S A D ) st u d y in vesti gati n g t he safet y, t olera bilit y, a n d P K of L Y 3 4 9 3 2 6 9 
a d mi nistere d as si n gle S C d oses i n healt h y part ici pa nts. I n a d ditio n, a c o h ort of 6 healt h y 
parti ci pa nts was pl a n ne d t o recei ve a si n gle i ntra ve n o us d ose of L Y 3 4 9 3 2 6 9, t o all o w est i mati on 
o f t he a bs o l ute S C bi oa vaila bilit y of L Y 3 4 9 3 2 6 9 .
As of 0 6 A pril 2 0 2 0, 3 c o h orts of 6 partici pa nts recei ve d S C d oses of L Y 3 4 9 3 2 6 9 at eac h of t he 
0. 1 5 -, 0. 5-, a n d 1. 5-m g d ose le vels. T here was a n i ncrease i n t he n u m ber of a d verse e ve nts ( A Es )
(s uc h as na usea, v o mit i n g, a n d a b d o mi nal diste nsi o n) relate d t o t he st u d y dr u g wit h increasi n g 
d oses of L Y 3 4 9 3 2 6 9 as c o m pare d t o place b o. T he t o p d ose of 1. 5 m g was c o nsi dere d n ot well 
t olerate d d ue t o i ncreases i n t he n u m ber of GI e ve nts re q uiri n g treat me nt. T he pres pecifie d 
d ose -escalat i on st o p pi n g criteria were n ot met; h o we ver, d ue t o c o ncer ns a b o ut safety a n d 
t olera bilit y wi t h t he ne xt pla n ne d S C d ose of 3 m g, t he sp o ns or deci de d t o st o p f urt her d osi n g.
N o deat hs, seri o us a d verse e ve nts ( S A Es), or disc o nt i n uati ons d ue t o A Es were n ote d i n t his 
st u d y u p t o t he data c ut-off, 0 6 A pril 2 0 2 0. 
Of  t he 3 0 healt h y partici pa nts w h o recei ve d eit her L Y 3 4 9 3 2 6 9 or place b o, 2 6 ( 8 6. 7 %) re p orte d 
at least 1 treat me nt -e mer ge nt a d verse e ve nt ( T E A E).
C o nsiste nt wi t h t he i ncreti n class, GI e ve nts s uc h as a b d o mi nal diste nsi o n, na usea, v o mit i n g, a n d 
di arr hea were t he m ost c o m m o nl y  re p orte d A Es i n St u d y G Z H A. I n a d ditio n , decrease d a p petite 
was als o 1 of  t he most f re q ue ntl y re p orte d A Es. All T E A Es were c o nsi dere d as mil d i n se verit y
b y t he i n vesti gat or, e ve n t h o u g h s o me re q uire d treat me nt . I n C o h ort 2, w here s u bjects recei ve d 
0. 5 m g, 1 s u bject o ut of 6 prese nte d na usea, a n d n o ne prese nte d v o mit i n g. H o we ver, 3 s u bjects 
o ut of 6 i n C o h ort 3 recei vi n g 1. 5 m g re p orte d GI A Es of na usea a n d v o mit i n g, re q uiri n g a nti-
e met ics. Se veral ot her GI A Es were re p orte d i n C o h ort 3 (f or e xa m ple, a b d o mi nal pai n u p per, 
c o nsti pati o n, er uctati o n, e pi gastric disc o mf ort, dr y m o ut h, a n d d ys pe psia) n ot pre vi o usl y 
re p orte d i n t he ot her c o h orts.
N o cli nicall y  sig nifica nt c ha n ges i n la b orat or y  d at a, n o i njecti o n -site reactio ns, or se vere 
h y p o gl yce mia e ve nts were n ote d.
A d ose -de pe n de nt i ncrea se i n heart rate ( H R), w hic h is c o nsiste nt wit h t he i ncreti n class ( L ore nz 
et al. 2 0 1 7) , was n ote d . W hile n o cli nicall y si g nifica nt c ha n ges were n ote d i n electr ocar dio gra m  
(E C G ) res ults, 3 parti cipa nts i n C o h ort 3 ( 1. 5 m g) prese nte d mil d A Es of tac h ycar dia. N o
sig nifica nt c ha n ges i n t he bl o o d press ure ( B P) me as ure me nts were n ote d . T he ma xi m u m H R
(s u pi ne) f or all 3 partici pa nts occ urre d at 4 h o urs p ost d ose ; the H R f or t hese 3 parti ci pa nts 
ret ur ne d t o bel o w 1 0 0 b p m bet wee n 6 h o urs a n d Da y 3 p ost d ose.
Si x parti ci pa nts recei ve d t he 0. 5 -m g i ntra ve n o us d ose as pla n ne d . M il d e ve nts of decrease d 
a p petite a n d GI e ve nts s uc h as a b d omi nal diste nsi o n a n d na us ea were n ote d.
Preli mi nar y P K data fr o m t he S C r o ute i n dicate d t he me dia n ti me of ma xi m u m o bser ve d dr u g 
c o nce ntrati o n (t ma x ) 
, close t o pr o p orti o nal i ncrease i n e x p os ures wit h i ncreasi n g 
d ose a n d a half -life 
, w hic h is s uita ble f or a wee kl y d osi n g i nter val. 
C CI
C CI


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
15
Preliminary pharmacodynamic (PD) data suggest LY3493269 when administered SC may 
potentially reduce total body weight, appetite, and glucose concentrations during an oral glucose 
tolerance test.
Refer to the Investigator’s Brochure (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.
C10 has a long history of use in humans, and has food additive status in the US and EU with no 
daily limits on consumption (Twarog et al. 2019). In the completed nonclinical safety 
pharmacology and toxicology studies, LY3493269 orally co-administered with C10, produced 
increased HR, 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 at the highest dose levels 
tested in monkeys. No adverse C10-related effects were observed in any of the toxicology 
studies/assessments.
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 
minimize any potential risk, participants will remain at the clinical research unit (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. 
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.


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
16
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 C10 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
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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Protocol J1X-MC-GZHB(a)
17
4.
Study Design
4.1.
Overall Design
Study GZHB 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 500 mg C10)

Cohort 2: 24 mg LY3493269 (with 500 mg C10)

Cohort 3: 48 mg LY3493269 (with 500 mg C10)

Cohort 4: 24 mg LY3493269 (with 250 mg C10)
Cohorts 1 to 3 evaluate doses of LY3493269 from 8 to 48 mg, each dose in combination with 
500 mg C10. Cohort 4 evaluates a 24-mg dose of LY3493269 with half the amount (250 mg) of 
C10.
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 Safety Review Panel (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 
Schedule of Activities (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 planned dose level.
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 


CONFIDENTIAL
Protocol J1X-MC-GZHB(a)
18
and/or clinical measurements to confirm their eligibility. Parameters that may be repeated for 
screening include clinical laboratory tests, ECGs, and vital signs.
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 
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 
Schedule of Activities (Section 1.3). Pharmacokinetic and PD sampling schedules may be 
modified based on the available safety and PK/PD data.
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 Schedule of Activities
(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.
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 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 
patients with T2DM. Using a healthy participant population mitigates possible confounding 
effects of comorbidities and concomitant medications. Therefore, Study GZHB provides an 
unbiased assessment of safety, tolerability, and PK of LY3493269 administered as oral doses.
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 


C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H B(a)
1 9
L Y 3 4 9 3 2 6 9. Safet y,  t olera bilit y, P K, an d preli mi nar y  P D data will assist i n i de ntif yi n g a n 
a p pr o priate d ose ra n ge f or s u bse q ue nt cli nical st u dies re gar dless of a d mi nistrati o n r o ute.
A st u d y  desi g n of o nce-dail y  or al d osi n g f or 3 da ys will be e m pl oye d t o c haracterize oral P K 
be ha vi or of L Y 3 4 9 3 2 6 9. T he d osi n g d urati o n of 3 -da ys was selecte d after ta ki n g i nt o 
c o nsi derati o n t he f o ll owi n g fact ors:

l ow oral  bioa vaila bili t y e x pecte d fr o m or al pe ptid e f or m ulat i ons,

t he e xce pt i onall y  hi g h i nter- a n d i ntra-i n di vi d ual varia bilities i n oral bioa vaila bili t y
e x pecte d of oral pe pti de f or m ulat i ons,

t he se nsit i vity of t he bi oa nal yt ical assa y, a n d

o nce a bs or be d via t he oral r o ute of a d mi nistrati o n, L Y 3 4 9 3 2 6 9 s yste mic P K dis p osit i on 
s h o uld be si milar re gar dless of r o ute of a d mi nistrati o n, he nce s afet y,  t olera bilit y, a n d P K 
data fr o m  t he S C S A D st u d y ( G Z H A) s h o uld be a p plica ble t o t his st u d y .
T o pre di ct t he oral P K pr ofiles f or eac h c o h ort, e xte nsi ve P K si m ulati ons were c o n d ucte d. T he 
P K pr ofile f o ll o wi n g a si n gle oral d ose was dee me d t o be at ris k of bei n g hi g hl y varia ble a n d 
p ote nti all y ret ur ni n g lo wer t ha n q ua nt ifia ble c o nce ntrati o ns at m ulti ple ti me p oi nts. T he 
si m ulati on res ults di d s u g gest t hat 3 da y s was a de q uate f or a maj o rit y of P K pr ofiles fr om 
parti ci pa nt s i n eac h c o h ort t o re mai n a b o ve t he q ua ntificati o n li mit of 2 n g/ m L t o yiel d 
mea ni n gf ul P K res ults. T he P K data fr o m St u d y  G Z H A esti mate d t he L Y 3 4 9 3 2 6 9 half-life t o be 
a p pr o xi matel y  
. T heref ore, P K e x p os ures fr o m a s h ort d osi n g d urati o n of 3 da ys fr o m t his 
st u d y are n ot e x pecte d t o reac h stea d y state f or t he res pecti ve d oses.
Stri ct or al a d mi nistratio n c o n di tio ns s uc h as c o ntr olli n g t he d urati o n of fast i n g bef ore a n d after 
d osi n g a n d water v ol u me f or oral a d mi nistrati o n of L Y 3 4 9 3 2 6 9 will be i m p ose d. T hese are 
necessar y  t o re d uce a n y p ote ntial varia bility arisi n g fr o m or al a d mi nistratio n c o n di tio n s t hat ma y 
affect oral bi o a vaila bilit y of L Y 3 4 9 3 2 6 9. 
S af et y a n d t olera bilit y assess me nts will be ma de acr oss all d ose le vels, i ncl u di n g i nci de nce of 
na usea a n d/ or v o mit i n g, a n d e val uati on of E C Gs a n d vital si g ns c o n d ucte d d uri n g t he st u d y  
( Sectio n 8. 2 ). A preli mi nar y assess me nt of t he P D effects of L Y 3 4 9 3 2 6 9 will be base d o n t he 
c o nce ntrati o ns of fast i n g gl uc ose, i ns uli n, a n d tri gl yceri des u p t o Da y 2 9 p ost d ose. T he effect of 
L Y 3 4 9 3 2 6 9 o n a p peti te se nsatio ns will als o be e x pl ore d. T he decisi o n t o escalate t he d ose will 
be base d pri maril y o n safet y  a n d t olera bility d at a ( Secti o ns 6. 6. 1 a nd 6. 6. 2 ) a n d all a vaila ble P K 
data will als o be re vie we d.
4. 3.
J u stific ati o n f or D ose
T he pr o p ose d L Y 3 4 9 3 2 6 9 or al  d ose ra n ge  
 m g o nce dail y  is selecte d t o attai n stea d y-
state e x p os ures a ntici pate d t o be wit hi n t he ra n ge e q ui vale nt t o t he P hase 3 d ose ra n ge  
 
 of a n ot her GI P-G L P m o lec ule c urre ntl y i n P hase 3 de vel o p me nt 
(tirze patide). T he e q ui vale nt L Y 3 4 9 3 2 6 9 oral d oses are pre dicte d t o be bet wee n 
 
o nce dail y ass u mi n g  
 oral bi oa vaila bilit y.  D ose e q ui vale nts bet wee n t he 2 m o lec ules were 
esti mate d usi n g t heir precli nical p ote nc y r atios f or gl yce mic c o ntr ol a n d wei g ht l oss deri ve d 
fr om r o de nt s pecies. If act ual L Y 3 4 9 3 2 6 9 oral bio a vaila bilit y is o nl y half of t he ass u me d, i.e. 
 t he n e x p os ures fr om t hese d oses w o ul d als o be a p pr o xi matel y hal ve d. If oral bioa vaila bili t y 
is 
t he a ntici pate d a vera ge e x p os ures of t he first c o h ort of 8 m g o nc e dail y x 3 
da ys are e x pecte d t o be wit hi n e x p os ures of t he 
 d ose. 
C CI
C CI
C CI
C CI
C C
I
C CI
C CI
C CI


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Protocol J1X-MC-GZHB(a)
20
While C10 has food additive status with no daily limits on consumption, up to 550 mg per day 
has been evaluated in an 8-week Phase 2 trial with oral insulin in patients with T2DM with no 
safety concerns reported (Halberg et al. 2019), Cohort 4 is intended to assess if half the amount 
(250 mg) of C10 can yield comparable oral bioavailability as 500 mg of C10 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 C10 or C10 alone derived from 1-month repeat-dose toxicity 
studies is listed in Table 4.1 and Table 4.2.
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.


C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H B(a)
2 1
C CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H B(a)
2 2
C CI
C CI


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Protocol J1X-MC-GZHB(a)
23
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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Protocol J1X-MC-GZHB(a)
24
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 must 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:  Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. For 
contraception requirements of this protocol, see 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 glycated hemoglobin level of <6.5%.
6. Have venous access sufficient to allow blood sampling as per the protocol.
7. 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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Protocol J1X-MC-GZHB(a)
25
Informed Consent
8. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have 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 
investigational product (IP); or of interfering with the interpretation of data
3. Have a supine HR less than 50 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 (excluding white-coat 
hypertension); therefore, if a repeated measurement shows values within the range, the 
patient 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 upper limit of normal (ULN).
9. Have obvious 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], 


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Protocol J1X-MC-GZHB(a)
26

Sanorex® [mazindol], 

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 QT interval corrected using Fridericia’s 
formula (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 aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
>1.5X ULN or total bilirubin level (TBL) >1.5X ULN.
18. Show evidence of human immunodeficiency virus (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


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Protocol J1X-MC-GZHB(a)
27
22. Are Lilly employees.
23. Have previously completed or withdrawn from this study.
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 C10), 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.
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 case report form (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.
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]). 


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Protocol J1X-MC-GZHB(a)
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.
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
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. 
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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Protocol J1X-MC-GZHB(a)
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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Interventions Administered
Intervention 
Name
LY3493269
Placebo
Type
Drug
Drug
Dose Formulation
Capsule
Capsule
Unit Dose 
Strength(s)
Experimental, supplied as 4 dose 
strengths:

4 mg LY + 250 mg C10

12 mg LY + 250 mg C10

24 mg LY + 250 mg C10

36 mg LY + 250 mg C10
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 capsules of 4 mg 
LY+250 mg C10

Cohort 2, 24-mg dose:
2 capsules of 12 mg 
LY+250 mg C10

Cohort 3, 48-mg dose:
2 capsules of 24 mg 
LY+250 mg C10

Cohort 4, 24-mg dose:
1 capsule of 24 mg 
LY+250 mg C10
Each dose described below is 
administered once daily over 3 
consecutive study days.

Cohort 1: 2 capsules

Cohort 2: 2 capsules

Cohort 3: 2 capsules

Cohort 4: 1 capsule
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/water) after each dose.
Oral, after a minimum fast (no 
food) of 8 hours prior to each 
dose, followed by a 2-hour fast 
(no food/water) after each dose.
Use
Experimental
Placebo


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Protocol J1X-MC-GZHB(a)
30
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.
Administration Details
Enteric-coated capsules 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 interventions received and any discrepancies are reported 
and resolved before use of the study intervention.
Only participants enrolled in the study may receive study interventions and only authorized site 
staff may supply or administer study interventions. All study interventions 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
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 


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Protocol J1X-MC-GZHB(a)
31
(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.
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.
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 
clinical research physician (CRP) 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.


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Protocol J1X-MC-GZHB(a)
32
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.
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 (including vitamins 
and dietary or herbal supplements) 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 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.
Nausea and/or vomiting during this study may be treated with antiemetics but these medications 
should not be used prophylactically.
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
Considerations for discontinuation of study intervention in an individual participant are 
described in Section 7.1.
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.


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Dose Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
maximum tolerated dose is determined or when stopping criteria are met. The highest dose level 
that is tolerated will be designated as the maximum tolerated dose for 3 consecutive oral doses in 
healthy participants. 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 if available, 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. 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.
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.
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 ≤2.8 mmol/L (50 mg/dL; 
corresponding to plasma glucose (PG) levels of ≤3.1 mmol/L [56 mg/dL]), or

drug-related GI effects (for example emesis, diarrhea) causing severe distress 
(prevents daily activities or requires an emergency department visit or 
hospitalization), or


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Protocol J1X-MC-GZHB(a)
34

clinically significant cardiovascular AEs
4. Two or more participants on active drug develop persistent (>1 week) symptoms 
suggestive of acute pancreatitis. Refer to algorithm for the monitoring of asymptomatic 
hyperenzymemia in Section 10.7.
Data Review during the Study
Interim access to safety and tolerability (and any available PK and PD) data is scheduled to occur 
after every dosing session 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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35
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 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.
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 >5X ULN or

ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio (INR) >1.5 
or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X 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 patient meets 1 of the following conditions after 
consultation with the sponsor-designated medical monitor:

lipase and/or amylase ≥3X ULN (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 request of his/her designee (for example, parents or legal guardian)
●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons
●
if the participant becomes pregnant during the study 
●
if enrollment in any other clinical study involving an IP or enrollment in any other 
type of medical research judged not to be scientifically or medically compatible 
with this study, and
●
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 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.
The replacement strategy for discontinued participants is described in Section 9.2. If deemed 
appropriate by the investigator, early discontinuation procedures will be performed as shown in 
the SoA (Section 1.3).
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from using the 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 CRP agree it is 


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37
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP 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 (Schedule of Activities), 
Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events)
of the protocol.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.


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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
related to eligibility criteria 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.
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).
Physical Examinations
Complete physical examinations and symptom-directed physical examinations will be conducted 
at the visits specified in Section 1.3. Symptom-directed physical examinations may also be 


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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.
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.
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.
Electrocardiograms
Single and triplicate 12-lead ECGs will be obtained as specified in Section 1.3. 
Electrocardiograms must be recorded approximately within 30 minutes before collecting any 
blood samples. 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 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 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.
Clinical Safety Laboratory Assessments
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA 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 that 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 baseline or are no longer considered clinically significant by the 
investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol-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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Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly 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, injection-site 
reactions, 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 (Section 10.6), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm 
the abnormality and to determine if it is increasing or decreasing, if 1 or more of these conditions 
occur:
If a participant with baseline results of...
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥2x baseline (except for patients 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, 
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 <1.5x ULN
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or ALT or AST 
≥5x ULN
ALP <1.5x ULN
ALP ≥3x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or ALT or AST 
≥3x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥1.5x baseline (except for patients 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 computed tomography [CT] scan).
Based on the patient’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

serum 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 ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN)
a.
In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests
2. Elevation of TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)
a.
In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN)
a.
In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x 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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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 electronic case report form (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 Section 10.8. The laboratory results are provided to the sponsor via the central 
laboratory.
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.
8.2.6.1.
Hypoglycemia
Site personnel will collect information on episodes of hypoglycemia at each study visit according 
to the SoA. Participants will be trained by site personnel about signs and symptoms of 
hypoglycemia, how to treat hypoglycemia, and how to collect appropriate information for each 
episode of hypoglycemia. Site personnel will enter this information into the eCRF at each visit.
Investigators should use the following definitions and criteria while diagnosing and categorizing 
an episode considered to be related to hypoglycemia.
Note: The PG values in this section refer to values determined by a laboratory or International 
Federation of Clinical Chemistry and Laboratory Medicine plasma equivalent glucose meters 
and strips (ADA 2019)
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
PG level of ≤70 mg/dL (≤3.9 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia, but with a measured PG ≤70 mg/dL (≤3.9 mmol/L).


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
Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured PG ≤70 mg/dL (≤3.9 
mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
PG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia, but with a measured PG <54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured PG <54 mg/dL (<3.0 
mmol/L).
Severe hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, glucagon, 
or other resuscitative actions. These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Blood glucose measurements may not be 
available during such an event, but neurological recovery attributable to the restoration of 
BG to normal is considered sufficient evidence that the event was induced by a low BG 
concentration.
Other hypoglycemia categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking.
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE CRF and report it to Lilly as an SAE.
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 
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.
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 


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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 (Section 7).
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. 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.
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 Section 10.3. 
Care will be taken not to introduce bias while detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
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 up 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 Section 10.3.
Regulatory Reporting Requirements for SAEs
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met.


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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, institutional review boards (IRBs)/independent ethics committees 
(IECs), and investigators.
An investigator who receives an investigator safety report describing an 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.
Pregnancy
Details of all pregnancies in female participants and, if indicated, 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 Section 10.4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
Events or Outcomes
Not applicable.
Adverse Events of Special Interest 
Adverse events of special interest for this program include

CV events

GI events

hypersensitivity reactions, and

hypoglycemic events.
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.
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.


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NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Sections 8.3.3 and 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.
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.


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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.
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 C10 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 
bioanalyses may be used for exploratory metabolism studies or exploratory analyses such as 
bioanalytical assay validation or cross-validation exercises.
8.6.
Pharmacodynamics
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.
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 


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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.
Pharmacodynamic Markers
Samples for PD markers will be collected at the times specified in 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.
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 Section 10.5 for information regarding genetic research and 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.


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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 
nonalcoholic steatohepatitis (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 (TE-ADAs) are defined in Section 9.4.6. In the case that 
antidrug antibody (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.
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.


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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. 
Patients 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.
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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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.
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 statistical analysis plan (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 patient 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 enrolled participants who received study intervention, 
whether or not they completed all protocol requirements.
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: area under the concentration versus time curve [AUC] during 1 dosing interval 
[AUC{0-τ}] and maximum observed drug concentration [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.
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% confidence 
intervals (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.
Pharmacokinetic Analyses 
Pharmacokinetic parameter estimates for LY3493269 and C10 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 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.


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Pharmacokinetic dose proportionality will be explored. Log-transformed Day 3 Cmax and AUC of 
LY3493269 from Cohorts 1 to 3 will be evaluated 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 C10 will be analyzed using a nonparametric method. All 
PK parameters will be summarized using descriptive statistics.
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.
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

PD parameters, such as 
o
fasting glucose, and
o
weight.
Endpoints may include but are not necessarily limited to those listed earlier.


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The impact of ADA and its titers on LY3493269 clearance and drug effect, if applicable, will be 
evaluated.
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
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 International Council for Harmonisation (ICH) good clinical 
practice (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 clinical trial
agreement (CTA).
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.


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The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative and is kept on file.
A participant who undergoes repeat screening tests to confirm eligibility is not required to sign 
another ICF.
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.
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.


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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.
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 CTA 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.


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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.
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.
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.
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.


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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.
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.
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 Patient 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 visit (if applicable).
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
Uric acid
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysis
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Lipase
Protein
Amylase
Glucose
Triglyceride
Ketones
Total cholesterol
Bilirubin
HbA1ca
Urobilinogen
Nitrite
Blood
Serology
Leukocytes
Hepatitis B surface antigenb
Microscopyc
Hepatitis B core antibody, totalb
Hepatitis C virus serology (anti-HCV)b
Follicle-stimulating hormone (FSH)d
Human immunodeficiency virus (HIV)b
Serum pregnancy teste
Urine pregnancy testf
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell.
a
Performed at screening only 
b
Tests may be waived if they have been performed within 6 months before screening with reports available for 
review.
c
If clinically indicated, per investigator’s discretion.
d
Performed for females at screening, if needed to confirm postmenopausal status.
e
For females, at screening only. 
f
For females, at Day 43 and if applicable at early termination. 


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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-GZHB Blood Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Approximate 
Number of Blood 
Samples
Approximate 
Total Volume 
(mL)
Screening testsa (local laboratory)
23
1
23
Clinical laboratory testsa (local laboratory)

Study visits
10
4
40

Follow-up visit
10
2
20
LY3493269 and C10 pharmacokinetics
(1 blood sample for both analytes)
3
37
111
Potential additional LY3493269 and C10 
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
5
50
Total
376.1
Total for clinical purposes (rounded up to the nearest 10 mL)
380
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
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 sign 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 that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
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.
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) that 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 1 of the other 


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outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
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 the 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 the 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 the 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 an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
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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
The investigator will consider any AEs, SAEs, and clinically important laboratory 
abnormalities as related to the study intervention unless there is clear evidence that the 
event is not related.

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 the 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 the sponsor 
or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used while 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 the 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 the sponsor or designee with a copy of any 
postmortem findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information.
Reporting of SAEs
SAE Reporting via SAE Report

Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the sponsor or designee.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames.

Contacts for SAE reporting can be found in SAE Report.


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Sponsor Surveillance Process for Dose Escalation or Cohort Expansion
The sponsor has systematic and robust internal processes in place that ensure safety surveillance 
of development compounds in line with the Food and Drug Administration’s expectations for 
safety assessment committee (SAC) (FDA Draft Guidance: “Safety Assessment for IND Safety 
Reporting”; FDA Guidance: “Safety Reporting Requirements for INDs and BA/BE Studies”). 
This includes processes with clearly described roles and responsibilities that are owned by the 
sponsor’s Global Patient Safety organization. These processes are designed to monitor the 
evolving safety profile (that is, review of cumulative SAEs, other important safety information) 
by designated cross-functional teams in a timely manner at predefined intervals or on an ad hoc 
basis. In addition, a dedicated process may be used to perform unblinded comparisons of event 
rates for SAEs as necessary.
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program are reviewed on a regular basis and that important new safety 
information such as the need for protocol modification or other relevant safety related material is 
identified and communicated to regulators and investigators appropriately and in a timely 
manner. An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate. Any serious adverse reaction are reported within the required timeline 
for expedited reporting.
In addition to annual periodic safety updates and to further inform investigators, a line listing 
report of suspected unexpected serious adverse reactions is created and distributed to 
investigators on a biannual (twice yearly) basis. Any significant potential risk/safety concerns 
that are being monitored as well as any results being reported in other periodic reports for the 
compound; SAC decisions; and other significant safety data (for example, nonclinical, clinical 
findings, removal of serious adverse reactions) are included in the report.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
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 WOCBP
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., Müllerian 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
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-GZHB(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
Effective methods of contraception (use 2 forms combined except where noted)
Male condom with spermicidea
Diaphragm with spermicide
Female condom with spermicidea
Cervical sponge
Cervical cap with spermicide
a
Male and female condoms should not be used in combination.


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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.
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-GZHB(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-GZHB(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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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 anti-smooth muscle antibody (ASMA) is tested.
d
Assayed ONLY by investigator-designated local laboratory; no central testing available.


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Protocol J1X-MC-GZHB(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, even in asymptomatic participants (see the following figure). 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 >3X 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. However, experience with GLP-1 agonists has 
demonstrated that some participants asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase levels. For participants considered by 
investigators to be asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase 
are ≥3X ULN, an algorithm is in place to follow these participants safely and to quickly reach (or 
not reach) a diagnosis of pancreatitis.
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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Protocol J1X-MC-GZHB(a)
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Figure 1
Abbreviations: CT = computed tomography; MRI = magnetic resonance imaging; ULN = upper limit of normal.


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Protocol J1X-MC-GZHB(a)
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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-GZHB(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
CFR
Code of Federal Regulations
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.
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
CTA
clinical trial agreement
CV
cardiovascular
ECG
electrocardiogram
eCRF
electronic case report form


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Protocol J1X-MC-GZHB(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
IP
investigational product
IRB
institutional review board
NASH
nonalcoholic steatohepatitis
NOAEL
no-observed-adverse-effect level
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
PK/PD
pharmacokinetics/pharmacodynamics


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Protocol J1X-MC-GZHB(a)
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PG
plasma glucose
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
SAC
safety assessment committee
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. 
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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Protocol J1X-MC-GZHB(a)
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11.
References
[ADA] American Diabetes Association. 6. Glycemic targets: standards of medical care in 
diabetes—2019. Diabetes Care. 2019;42(suppl 1):S61-S70. 
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101:2379-2400.
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. 
Halberg IB, Lyby K, Wassermann K, et al. the effect of food intake on the 
pharmacokinetics of oral basal insulin: a randomised crossover trial in healthy male 
subjects. Clin Pharmacokinet. 2019;58:1497-1504.
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.
2006;13(1):25-32.
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.
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 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J 
Diabetes Sci Technol. 2010;4(3):577-582. 


L e o  D o c u m e n t  I D  =  6 b f 8 8 5 1 9 - 8 f 8 f - 4 4 b 3 - a a 3 d - f c 3 8 c 6 9 6 8 1 b c
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 1 - J u l - 2 0 2 0  1 8 : 5 1 : 3 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 2 - J u l - 2 0 2 0  0 2 : 2 9 : 3 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan: J1X-MC-GZHB (V2) 
 
A Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics 
of LY3493269 in Healthy Participants 
 
NCT04498390 
Approval Date: 15-Feb-2021 


Final Version 2.0, 11 February 2021
             Page 1 of 19
STATISTICAL ANALYSIS PLAN
A Multiple-Ascending Dose Study to Investigate the Safety, 
Tolerability, and Pharmacokinetics of LY3493269 in Healthy
Participants
Statistical Analysis Plan Status: Final Version 2.0
Statistical Analysis Plan Date: 11-February-2021
Study Drug: LY3493269
Sponsor Reference: J1X-MC-GZHB
Covance CRU Study: 1001215-8439717
Clinical Phase I
Approval Date: 15-Feb-2021 GMT


Final Version 2.0, 11 February 2021
             Page 2 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objective......................................................................................................6
4.3
Exploratory Objectives ..................................................................................................7
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................9
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
9.
STATISTICAL METHODOLOGY .....................................................................................9
9.1
General..........................................................................................................................9
9.2
Demographics and Subject Disposition........................................................................10
9.3
Pharmacokinetic Assessment.......................................................................................10
9.3.1
Pharmacokinetic analysis....................................................................................10
9.3.2
Pharmacokinetic statistical methodology ............................................................11
9.4
Pharmacodynamic Assessment ....................................................................................12
9.4.1
Pharmacodynamic analysis.................................................................................12
9.4.2
Pharmacodynamic statistical methodology .........................................................12
9.5
Pharmacokinetic/Pharmacodynamic Analysis..............................................................13
9.6
Safety and Tolerability Assessments............................................................................13
9.6.1
Adverse events ...................................................................................................13
9.6.2
Glucose Monitoring and Hypoglycemia..............................................................14
9.6.3
Concomitant medication.....................................................................................15
9.6.4
Clinical laboratory parameters............................................................................15
9.6.5
Vital signs ..........................................................................................................15
9.6.6
Electrocardiogram (ECG)...................................................................................15
9.6.7
Hepatic Monitoring ............................................................................................17
9.6.8
Hypersensitivity reactions...................................................................................18
9.6.9
Immunogenicity assessments..............................................................................18
9.6.10
Other assessments...............................................................................................18


Final Version 2.0, 11 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
10. INTERIM ANALYSES .....................................................................................................18
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............18
12. REFERENCES ..................................................................................................................18
13. DATA PRESENTATION ..................................................................................................19
13.1 Derived Parameters .....................................................................................................19
13.2 Missing Data ...............................................................................................................19
13.3 Insufficient Data for Presentation ................................................................................19


Final Version 2.0, 11 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ADA
Anti-drug antibody
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
BQL
Below the quantifiable lower limit of the assay
C10
Permeation enhancer sodium caprate
CI
Confidence interval
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PD
Pharmacodynamic
PG
Plasma Glucose
PK
Pharmacokinetic
QD
Once daily
SAP
Statistical Analysis Plan
SD
Standard deviation 
SOP
Standard Operating Procedure
TBL
Total bilirubin
TE
Treatment emergent


Final Version 2.0, 11 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
TE ADA
Treatment-emergent anti-drug antibodies
TEAE
Treatment emergent adverse event
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
WHO
World Health Organization


Final Version 2.0, 11 February 2021
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
11 June 2020 and final amendment a dated 22 July 2020).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (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 information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information 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 serve 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 performed 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 Harmonisation (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 Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective
The primary objective of this study is:

To investigate the safety and tolerability of LY3493269 following 3 consecutive 
once-daily oral doses in healthy participants.
The primary endpoint for this study is:

Treatment emergent adverse events (TEAEs).
4.2
Secondary Objective
The secondary objective of this study is:

To characterize the PK of LY3493269 following 3 consecutive once-daily oral doses in 
healthy participants.


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The secondary endpoints of this study are:

Area under the concentration versus time curve (AUC) and maximum observed drug 
concentration (Cmax).
4.3
Exploratory Objectives
The exploratory objectives of the study are:

To investigate the PD effects of LY3493269 following 3 consecutive once-daily oral
doses in healthy participants.

To assess PK of permeation enhancer sodium caprate (C10) following oral administration 
in healthy participants.

To explore the effect of LY3493269 on appetite and food intake following 3 consecutive 
once-daily oral doses in healthy participants.

To characterize immunogenicity of LY3493269 following 3 once-daily oral doses in 
healthy participants.
The exploratory endpoints of the study are:

Changes from baseline levels of fasting glucose, insulin, C-peptide, triglycerides, and 
body weight.

AUC and Cmax.

Change in visual analogue scale (VAS) score for appetite assessment in a fasted state.

Incidence of treatment-emergent antidrug antibody (ADA).
5. STUDY DESIGN
Study GZHB 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.
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.
A general schema for the study can be seen in Figure 1.
The planned LY3493269 oral doses for this study range from 8 to 48 mg, administered in the 4 
planned “dose cohorts”:


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
Cohort 1: 8 mg LY3493269 (with 500 mg C10)

Cohort 2: 24 mg LY3493269 (with 500 mg C10)

Cohort 3: 48 mg LY3493269 (with 500 mg C10) 

Cohort 4: 24 mg LY3493269 (with 250 mg C10)
Figure 1 - A general schema of GZHB
6. TREATMENTS
The following is a list of the study treatment labels that will be used in the TFLs.
Cohort
Study Treatment Name
Study Treatment 
Abbreviation
Treatment order in 
TFL
All
Placebo
Placebo
1
1
8 mg LY3493269 with 500 mg C10 QD
8 mg LY + 500 mg C10 QD
2
2
24 mg LY3493269 with 500 mg C10 QD
24 mg LY + 500 mg C10 QD
3
3
48 mg LY3493269 with 500 mg C10 QD
48 mg LY + 500 mg C10 QD
4
4
24 mg LY3493269 with 250 mg C10 QD
24 mg LY + 250 mg C10 QD
5


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7. SAMPLE SIZE JUSTIFICATION
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.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of 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.
The “Pharmacokinetic” population will consist of all participants who received at least 1 full 
dose of LY3493269 and have evaluable PK sample. Subjects may be excluded from the PK 
summary statistics and statistical analysis if a subject has an adverse event of vomiting that 
occurs at or before 2 times median tmax.
The “Pharmacodynamic” population will consist of all participants who received at least 1 dose 
of LY3493269 and have evaluable PD data Subjects may be excluded from the PD summary 
statistics and statistical analysis if a subject has an adverse event of vomiting that occurs at or 
before 2 times median tmax. 
All protocol deviations that occur during the study including those related to COVID-19, will be 
considered for their severity/impact and will be taken into consideration when subjects are 
assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 


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subjects 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 subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
All protocol deviations and data issues (eg, missing data or data outside of the protocol windows) 
that occur during the study, including those related to COVID-19, will be considered prior to 
database lock for their severity/impact on how the data will be displayed and analyzed 
statistically.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed. All other demographic 
variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic analysis
PK parameter estimates will be determined by Lilly using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 8.1 or later) using standard
noncompartmental methods of analysis. The software and version used for the final analyses will 
be specified in the clinical study report.
Any exceptions or special handling of data will be clearly documented within the final study
report.
Concentrations of LY3493269 and C10 will be used to determine the following PK parameters,
when possible: Cmax, AUC, and tmax. Pharmacokinetic parameters for Cmax and AUC from time 
zero to 24 hour, AUC(0-24) will be computed after the first, second, and third doses, AUC(0-inf) 
will be calculated after the third dose. AUC(0-tlast) will also be calculated. Other parameters, 
such as half-life, apparent clearance, and 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.
Individual concentration versus time profiles will be plotted utilizing actual sampling times. The 
terminal point selections will be indicated on a semi-logarithmic plot. Average concentration 
versus time profiles will be plotted using nominal sampling times and will use arithmetic mean 
concentrations


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9.3.2
Pharmacokinetic statistical methodology
All PK parameters will be summarized using descriptive statistics. Mean PK concentration-time 
profiles will be presented graphically, these outputs will be the responsibility of Lilly. The 
inferential PK statistical analyses detailed below will be the responsibility of Covance.
Dose proportionality assessment
PK dose proportionality will be assessed for LY3493269 on Day 1 and Day 3 separately. Log-
transformed Cmax, AUC(0-24), AUC(0-infinity) and AUC(0-tlast) of LY3493269 from Cohorts 
1 to 3 will be evaluated using a power model (where log-dose acts as an explanatory variable) to 
estimate ratios of dose-normalized geometric means and corresponding 90% confidence intervals 
(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. 
Example SAS code is as follows:
proc mixed data=xxx;
model log_pk = log_dose / alpha=0.1 cl solution outpred=resids ddfm=kr2;
estimate 'xx mg' intercept 1 log_dose yy / alpha=0.1 cl; /*Log value of xx*/
estimate 'zz mg - xx mg' log_dose pp / alpha=0.1 cl; /*Difference in log 
values of zz and xx*/
ods output solutionf=est;
ods output estimates=estims;
run;
The parameter tmax of LY3493269 from Cohorts 1 to 3 will be analyzed non parametrically using 
the Kruskal-Wallis test to investigate its independence, with the respective p-value reported. 
Example SAS code is as follows:
proc npar1way data=xxx
  class dose;
  var pk;
  ods output KruskalWallisTest =krusk;
run;
C10 dose comparison
Log-transformed Day 1 and Day 3 Cmax, AUC(0-24), AUC(0-infinity) and AUC(0-tlast) of 
LY3493269 from Cohorts 2 and 4 will be analyzed separately to compare the PK parameters 
following differing doses of C10. Each parameter will be analyzed using a linear model with 
treatment as a fixed effect. The lsmeans along with the difference between Cohort 2 (500mg 
C10) and Cohort 4 (250mg C10) will be estimated from the model along with the associated 90% 
CI. These will be back transformed to obtain the geometric lsmeans, the ratio of Cohort 2 
(500mg C10) versus Cohort 4 (250mg C10) and the associated 90% CI.
Example SAS code is as follows:


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proc mixed data=xxx;
model log_pk = treatment /residual ddfm=kr2;
lsmeans treatment / pdiff alpha=0.1 cl;
ods output diffs=diffs;
ods output lsmeans=lsmeans;
run;
The Day 1 and Day 3 parameter tmax of LY3493269 from Cohorts 2 and 4 will be analyzed non 
parametrically separately for each day. Estimates of the median difference between Cohort 2 
(500mg C10) versus Cohort 4 (250mg C10), 90% CIs, and p-values from the Wilcoxon rank sum 
test will be calculated.
9.4
Pharmacodynamic Assessment
9.4.1
Pharmacodynamic analysis
All PD parameters, including the baseline-corrected parameters, will be summarized and
tabulated by treatment and visit. This includes absolute and change from baseline values, where 
baseline is defined as Day 1 predose, in:

Fasting glucose.

Fasting insulin.

Fasting C-peptide.

Fasting triglycerides.

Body weight.

Appetite visual analog scale (VAS) for parameters of hunger, fullness, satiety, and 
prospective food consumption. Overall appetite score is calculated as the average of the 4 
individual scores: satiety + fullness + (100-prospective food consumption) + (100-
hunger) / 4). The higher overall appetite score indicates less appetite, and the lower score 
indicates more appetite.
9.4.2
Pharmacodynamic statistical methodology
To determine the effect of LY3493269 on the PD endpoints (raw values, as well as change from 
baseline), each parameter will be analyzed using repeated measure mixed effect models. The 
model will include treatment, visit, and treatment-by-visit as fixed effects and subject as a 
random effect. Baseline values, as well as other influencing variables, may be used as covariates. 
An unstructured covariance structure will be used to model the correlation between a 
participant’s multiple observations; an alternative appropriate structure will instead be used if the 
model fails to converge. For each PD endpoint, the difference in least-square treatment means, 
comparing each LY3493269 treated group and the pooled placebo group, along with the 90% CI
will be reported. A comparison will also be reported for 24 mg LY3493269 + 500 mg C10 versus 
24 mg LY3493269 + 250 mg C10.
Pharmacodynamic parameters may be transformed before statistical analyses if deemed
necessary. Back-transforming to the original scale will be implemented if transformations of the 
parameters are done. 


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Example SAS code is as follows:
proc mixed data=xxx;
class subject treatment visit;
model PD = treatment visit treatment*visit /residual ddfm=kr2;
repeated visit/ subject=subject type=un;
lsmeans treatment*visit / cl pdiff alpha=0.1;
ods output lsmeans=lsm diffs=estims;
run;
Summary statistics will be provided for all the PD parameters stated in Section 9.4.1. The 
individual observed and mean time profile of the postdose PD parameters will be plotted by 
treatment for raw values and changes from baseline.
9.5
Pharmacokinetic/Pharmacodynamic Analysis
Pharmacokinetic/PD analyses or graphical explorations may be used to assess the relationship
between LY3493269 doses and/or concentrations. These will only be performed if there is a 
clear trend for dose-related effect that informs dose-selection for future protocols.
9.6
Safety and Tolerability Assessments
9.6.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE 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. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug by the investigator. 
Any serious AEs will be listed. Any AEs of special interest will be listed, these include 
cardiovascular events, gastrointestinal (GI) events (nausea, vomiting and diarrhea), 
hypersensitivity reactions and hypoglycemic events.
Barcharts of the frequency of gastrointestinal events of nausea, vomiting and diarrhea, by 
severity will be presented for each day by treatment.
Discontinuations due to AEs will be listed.


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9.6.2
Glucose Monitoring and Hypoglycemia
During the study, blood glucose concentrations will be monitored for safety assessments. 
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 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment.
Participants will be trained by site personnel about signs and symptoms of hypoglycemia and 
how to treat hypoglycemia.
The investigator 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 eCRF and report it to Lilly as an SAE.


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9.6.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version WHODD 
MAR20B3/C3). Concomitant medication will be listed.
9.6.4
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized, along with change from 
baseline, where baseline is defined as Day 1 predose, by parameter and treatment, and listed. 
Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed and flagged on individual subject 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 mean of the Day 1 predose assessments (-30, -15 and 0 minutes).
Figures of mean vital signs and mean changes from baseline profiles will be presented by 
treatment. 
Values for individual subjects will be listed.
For the change from baseline values, a repeated measure mixed effect model will be used to 
determine the effects of LY3493269. The model will include treatment, timepoint, and 
treatment-by-timepoint interaction as fixed effects and subject as a random effect. Baseline will 
also be included as a covariate. An unstructured covariance structure will be used to model the 
correlation between a participant’s multiple observations; an alternative appropriate structure 
will instead be used if the model fails to converge. Least-square treatment means, the difference 
in least-square treatment means, comparing each LY3493269 treated group and the placebo 
group, along with the 90% CI will be reported. 
9.6.6
Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR
interval, QT, QRS duration, RR and heart rate. In addition, QT interval corrected using 
Fridericia’s formula (QTcF) will be calculated as follows:


3 60HR
QT
QTcF 
The ECG data will be summarized by treatment together with changes from baseline, where
baseline is defined as the mean of the triplicate Day 1 predose assessments (-30, -15 and 
0 minutes). Figures of mean ECG data and mean changes from baseline will be presented by 
treatment. The frequency of subjects 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 subjects with QTcF postdose values, according to the 
following categories: >450 ms, >480 ms and >500 ms, will be summarized by treatment. 


Fi nal Versi o n 2 . 0, 1 1 Fe br uar y 2 0 2 1
             Pa ge 1 6 of 1 9
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 12 1 5- 8 4 3 9 7 1 7 
S p o ns or Refere nce J 1 X -M C -G Z H B
Pl as m a P K C o nce ntr ati o n vers us delt a a n d d o u ble delt a E C G p ar a meter a n al ysis
A ti me-matc he d plas ma L Y 3 4 9 3 2 6 9 c o nce ntrati o n- E C G para meter a nal ysis will be perf or me d t o 
assess t he relat i ons hi p bet wee n c ha n ges fr o m baseli ne ( me a n of D a y 1 pre d ose triplicate 
assess me nts) i n E C G para meters ( Q Tc, P R, a n d R R i nter vals, Q R S d urati o n, a n d heart rate) a n d 
pl as ma L Y 3 4 9 3 2 6 9 c o nce ntrati o ns acr oss all treat me nts. T he c ha n ge fr o m baseli ne a dj ust me nt  
will be base d o n i n di vi d ual part ici pa nt’s Da y  1 pre d ose value. F urt her details o n h o w t hese will 
be cal c ulate d:

Calc ulate t he baseli ne E C G val ue f or eac h parti ci pa nt , w hic h is t he me a n of E C G 
para m eter valu es of  eac h i n di vi d ual partici pa nt o ver 3 pre d ose ti me p oi nts at da y 1.

Calc ulate t he c ha n ge fr o m baseli ne at eac h ti me p o i nt for eac h i n di vi d ual p arti ci pa nt .

Calc ulate t he mea n E C G para meter val ue acr oss all partici pa nts at baseli ne.

F or eac h partici pa nt s u btract t he mea n E C G para meter val ue fr o m t heir o w n i n di vi d ual 
o bser ve d E C G para meter val ue. T his will be eac h partici pa nt’s ce ntere d E C G para meter 
val ue.

B L Q L Y 3 4 9 3 2 6 9 c o nce ntrati o n data will be i m p ute d t o L L O Q/ s q uare r o ot( 2) f or t he 
p ur p oses of t he a nal ysis.
T he rel at i ons hi p bet wee n L Y 3 4 9 3 2 6 9 c o nce ntrati o ns a n d E C G para meters will be e x pl ore d 
gra p hicall y  b y pl otti n g delta E C G para meter val ues a gai nst L Y 3 4 9 3 2 6 9 c o nce ntrati o ns, 
i ncl u di n g all p ost d osi n g ti me p o i nts.
A mi xe d effects a nal ysis m o del will be e m pl o ye d wit h c ha n ge fr o m baseli ne i n E C G para meter 
as t he de pe n de nt varia ble, L Y 3 4 9 3 2 6 9 c o nce ntrati o n a n d ce ntere d E C G para meter val ue as 
c o nti n u o us c o variates, treat me nt a n d ti me as cate g orical fact ors, a n d a ra n d o m i nterce pt a n d 
slo pe per partici pa nt . Treat me nt will be fitte d as a bi nar y varia ble ( P lace b o, or L Y 3 4 9 3 2 6 9 ). T he 
m o d el  will ha ve t he f or m
∆      =    +  ,  +       +    +  ,     +  ,      +   (   ,    −   )
+    ,
w here ∆      is t he c ha n ge fr om baseli ne i n E C G para meter f or partici pa nt  i n treat me nt  at 
ti me ,     is t he p o p ulati on mea n i nterce pt i n t he a bse nce o f treat me nt effect,  , is t he ra n d om 
effect ass ociate d wit h t he i nterce pt ter m  0,  1 is t he fi xe d effect cate g orical varia ble ass ociate d 
wi t h treat me nt     ,  2 is t he p o p ulati on mea n sl o pe of t he ass u me d li near ass ociati o n bet wee n 
c o nce ntr atio n a n d Δ E C G  ,  2,  is t he ra n d om effect ass ociate d wit h t he slo pe  2,    is t he 
c o nce ntrati o n f or partici pa nt  i n treat me nt  a n d ti me  ,  3 is t he fixe d effect ass ociate d wit h 
ti me,  4 is t he fi xe d effect ass ociate d wit h baseli ne E C G,= 0 ,     is t he o verall mea n of E C G ,0
(t he me a n of all t he baseli ne E C G para meter val ues, at ti me 0), a n d     is t he resi d ual err or. It 
will be ass u me d t he ra n d o m effects are m ult i variate Gaussia n distri b ute d wi t h mea n vect or 0 a n d 
a n u nstr uct ure d c o varia nce matri x G, w hereas t he resi d uals ,    , are Ga ussia n distri b ute d wi t h 
mea n 0 a n d varia nce  .
T he pre di ct e d mea n c ha n ge fr o m baseli ne a n d place b o -c orrecte d c ha n ge fr o m baseli ne i n E C G 
para m eter ( Δ E C G a n d Δ Δ E C G res pecti vel y) at t he o bser ve d ge o metric mea n C ma x of  eac h 


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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.
Example of SAS code as follows:
proc mixed data=xxx;
by param;
class treat time subject;
model ΔECG = treat time baseline_ECG PKconc / solution cl alpha=0.1 ddfm=kr2;
random intercept PKconc / type=un subject=subject;  
estimate ‘Placebo ' intercept 1 treat 1 0 PKconc 0/ CL alpha=0.1;
estimate ‘YY mg LY3493269 ' intercept 1 treat 0 1 PKconc [cmax YYmg] / CL 
alpha=0.1;
estimate ‘YY mg LY3493269 - Placebo' treat -1 1 PKconc [cmax YYmg] / CL 
alpha=0.1;
ods output covparms=covp(where=(covparm=”Residual”));
ods output solutionF=sol;
ods output estimates=estim;
run;
9.6.7
Hepatic Monitoring
If a subject experiences 1 or more of the elevations in the table below then the liver tests will be 
performed to confirm the abnormality. 
Additional safety data may be collected if required, as defined in the protocol. Where applicable, 
the following will be presented.
The subjects’ liver disease history and associated person liver disease history 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 (MRE) 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 drug use data will also be listed.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.6.8
Hypersensitivity reactions
Hypersensitivity reactions will be listed.
9.6.9
Immunogenicity assessments
The frequency and percentage of patients with pre-existing ADA and with treatment-emergent 
ADAs (TE ADA) to LY3493269 will be tabulated and listed when data becomes available. 
For patients who are ADA negative at baseline, TE ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution of the assay. For patients who are ADA 
positive at baseline, where baseline is defined as Day 1 predose, TE ADAs are defined as those 
with a 4-fold (2 dilution) increase in titer compared to baseline. The frequency and percentage of 
patients with cross-reactive and neutralizing antibodies, if measured, may also be tabulated for 
patients with TE ADA. 
The relationship between the presence of antibodies and PK exposures and PD response 
including safety and efficacy to LY3493269 may be assessed. 
9.6.10
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
10.
INTERIM ANALYSES
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 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8439717 
Sponsor Reference J1X-MC-GZHB
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated 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.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects 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 occurred for this study.”


Leo Document ID = 86d4ae5c-ce09-4a7c-986b-938357831980
Approver: 
Approval Date & Time: 11-Feb-2021 14:24:23 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Feb-2021 05:58:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Feb-2021 02:56:06 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Feb-2021 12:44:07 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD