Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple-Ascending Subcutaneous Doses of LY3493269 in Patients With Type 2 Diabetes Mellitus
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company

Protocol J1X-MC-GZHC (c) 
 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple- 
Ascending Subcutaneous Doses of LY3493269 in Patients with Type 2 Diabetes 
Mellitus 
NCT04515576 
Approval Date: 16-Jul-2021 

C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H C (c)
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 pr 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: S af et y,  T olera bility,  P har mac o ki netics, a n d P har mac o d y na mics of M ult i ple-
Asce n di n g S u bc uta ne o us D oses of L Y 3 4 9 3 2 6 9 i n Patie nts wit h T y pe 2 Di a betes 
Mellit us
Pr ot oc ol N u m ber: J 1 X-M C -G Z H C
A me n d me nt N u m ber: c
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: M ul tiple -Asce n di n g D ose St u d y  of L Y 3 4 9 3 2 6 9 A d mi nistere d S u bc uta ne o usl y
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
Re g ul at or y A ge nc y I de ntifier N u m ber: I N D 1 4 8 2 7 8
A p pr o v al D ate :
Pr ot oc ol  A me n d me nt ( c) El e ctr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n date pr o vide d bel o w.
A p pr o v al D at e: 1 6- J ul- 2 0 2 1 G M T

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

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Protocol J1X-MC-GZHC(c)
3
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (b)
13-October-2020
Amendment (a)
11-July-2020
Original Protocol
27-May-2020
Amendment [c] 
This amendment is considered to be nonsubstantial.
Overall Rationale for the Amendment:
This amendment serves to clarify that all samples collected for determination of acetaminophen 
concentrations (as a pharmacodynamic marker for gastric emptying) must be analyzed, 
regardless of the treatment assigned to the trial participant.
Section # and 
Name
Description of Change
Brief Rationale
8.5.1.2. 
Bioanalysis of 
Acetaminophen
Removed the sentence 
“Analysis of samples collected 
from placebo treated 
participants are not planned”
The statement was removed as all 
samples collected for PD markers must 
be analyzed.
9.4.4. 
Pharmacodynamic 
Analysis
Added placebo in the sentence 
“Baseline-adjusted Cmax of 
acetaminophen (ratio to Day -1 
value) will be calculated and 
log transformed to compare the 
gastric-emptying effect of 
LY3493269 to that of 
dulaglutide and placebo”
To clarify that data from placebo-
treated participants will also be 
analyzed.

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Protocol J1X-MC-GZHC(c)
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..............................................................................................................17
2.1.
Study Rationale ..........................................................................................................17
2.2.
Background ................................................................................................................17
2.2.1.
Summary of Clinical Experience ................................................................................18
2.3.
Benefit/Risk Assessment ............................................................................................19
3.
Objectives and Endpoints.........................................................................................20
4.
Study Design .............................................................................................................22
4.1.
Overall Design............................................................................................................22
4.1.1.
Screening Period.........................................................................................................23
4.1.2.
Baseline Period...........................................................................................................23
4.1.3.
Treatment Period ........................................................................................................23
4.1.4.
Follow-up Period........................................................................................................24
4.2.
Scientific Rationale for Study Design .........................................................................24
4.2.1.
Participant Input into Design ......................................................................................25
4.3.
Justification for Dose..................................................................................................25
4.4.
End of Study Definition..............................................................................................28
5.
Study Population ......................................................................................................29
5.1.
Inclusion Criteria........................................................................................................29
5.2.
Exclusion Criteria.......................................................................................................30
5.3.
Lifestyle Considerations .............................................................................................33
5.3.1.
Meals and Dietary Restrictions ...................................................................................33
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................33
5.3.3.
Activity ......................................................................................................................34
5.4.
Screen Failures ...........................................................................................................34
6.
Study Intervention....................................................................................................35
6.1.
Study Interventions Administered...............................................................................35
6.1.1.
Administration Details................................................................................................35
6.2.
Preparation/Handling/Storage/Accountability.............................................................35
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................36
6.4.
Study Intervention Compliance...................................................................................37
6.5.
Concomitant Therapy .................................................................................................37
6.6.
Dose Modification......................................................................................................38
6.6.1.
Dose Escalation ..........................................................................................................39
6.6.2.
Dose-Escalation Stopping Criteria ..............................................................................39
6.6.3.
Data Review during the Study ....................................................................................40
6.7.
Intervention after the End of the Study........................................................................40
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................41

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Protocol J1X-MC-GZHC(c)
5
7.1.
Discontinuation of Study Intervention ........................................................................41
7.1.1.
Liver Enzymes and Other Laboratory .........................................................................41
7.1.2.
Persistent Hyperglycemia/Hypoglycemia....................................................................42
7.1.3.
Hypersensitivity Reactions .........................................................................................42
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................42
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................43
7.3.
Lost to Follow-up .......................................................................................................43
8.
Study Assessments and Procedures .........................................................................44
8.1.
Efficacy Assessments .................................................................................................44
8.2.
Safety Assessments ....................................................................................................44
8.2.1.
Physical Examinations................................................................................................44
8.2.2.
Vital Signs..................................................................................................................45
8.2.3.
Electrocardiograms.....................................................................................................45
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................46
8.2.5.
Safety Monitoring.......................................................................................................46
8.2.6.
Glucose Monitoring....................................................................................................50
8.3.
Adverse Events and Serious Adverse Events ..............................................................52
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................52
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................52
8.3.3.
Follow-up of AEs and SAEs.......................................................................................53
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................53
8.3.5.
Pregnancy...................................................................................................................53
8.3.6.
Adverse Events of Special Interests ............................................................................53
8.3.7.
Product Complaints ....................................................................................................54
8.4.
Treatment of Overdose ...............................................................................................54
8.5.
Pharmacokinetics........................................................................................................55
8.5.1.
Bioanalysis .................................................................................................................55
8.6.
Pharmacodynamics.....................................................................................................56
8.6.1.
Oral Glucose Tolerance Test.......................................................................................56
8.6.2.
Gastric-Emptying Test................................................................................................56
8.6.3.
Six-Point Plasma Glucose Profiles..............................................................................56
8.6.4.
Pharmacodynamic Markers.........................................................................................56
8.6.5.
Appetite Analysis with a Visual Analog Scale ............................................................57
8.6.6.
Body Weight ..............................................................................................................57
8.6.7.
Waist Circumference ..................................................................................................57
8.7.
Genetics .....................................................................................................................58
8.8.
Biomarkers.................................................................................................................58
8.9.
Immunogenicity Assessments.....................................................................................58
8.10.
Health Economics.......................................................................................................59
9.
Statistical Considerations.........................................................................................60
9.1.
Statistical Hypotheses.................................................................................................60
9.2.
Sample Size Determination.........................................................................................60
9.3.
Populations for Analyses ............................................................................................61
9.4.
Statistical Analyses.....................................................................................................61
9.4.1.
General Considerations...............................................................................................61

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Protocol J1X-MC-GZHC(c)
6
9.4.2.
Safety Analyses ..........................................................................................................62
9.4.3.
Pharmacokinetic Analyses ..........................................................................................63
9.4.4.
Pharmacodynamic Analyses .......................................................................................63
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................64
9.4.6.
Evaluation of Immunogenicity....................................................................................64
9.5.
Interim Analyses.........................................................................................................65
9.6.
Data Monitoring Committee (DMC)...........................................................................65
10.
Supporting Documentation and Operational Considerations ................................66
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................66
10.1.1.
Regulatory and Ethical Considerations........................................................................66
10.1.2.
Informed Consent Process ..........................................................................................66
10.1.3.
Data Protection...........................................................................................................67
10.1.4.
Dissemination of Clinical Study Data .........................................................................67
10.1.5.
Data Quality Assurance ..............................................................................................68
10.1.6.
Source Documents......................................................................................................69
10.1.7.
Study and Site Start and Closure.................................................................................69
10.1.8.
Publication Policy.......................................................................................................70
10.1.9.
Long-Term Sample Retention.....................................................................................70
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................71
10.2.1.
Blood Sampling Summary..........................................................................................74
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................76
10.3.1.
Definition of AE.........................................................................................................76
10.3.2.
Definition of SAE.......................................................................................................77
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................78
10.3.4.
Reporting of SAEs......................................................................................................80
10.3.5.
Sponsor Surveillance Process for Dose Escalation or Cohort 
Expansion...................................................................................................................80
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................81
10.4.1.
Definitions..................................................................................................................81
10.4.2.
Contraception Guidance..............................................................................................81
10.4.3.
Collection of Pregnancy Information ..........................................................................83
10.5.
Appendix 5: Genetics .................................................................................................85
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................86
10.7.
Appendix 7: Pancreatic Monitoring ............................................................................88
10.8.
Appendix 8: Hypersensitivity Event Tests ..................................................................90
10.9.
Appendix 9: Abbreviations .........................................................................................91
10.10.
Appendix 10: Protocol Amendment History ...............................................................95
11.
References.................................................................................................................98

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple-
Ascending Subcutaneous Doses of LY3493269 in Patients with Type 2 Diabetes Mellitus
Short Title: Multiple-Ascending Dose Study of LY3493269 Administered Subcutaneously
Rationale:
LY3493269 is a dual glucose-dependent insulinotropic polypeptide and glucagon-like-peptide 1 
(GLP-1) receptor agonist being developed as a treatment for type 2 diabetes mellitus (T2DM).
This is the first study in participants with T2DM to test multiple subcutaneous (SC) doses of 
LY3493269 to establish early exposure-responses for key efficacy, safety, and tolerability 
relationships (for example, blood glucose, glycated hemoglobin). Using a stepwise escalation, it 
is planned that this study will test dose levels higher than those tested in the single-ascending 
dose study.
Study J1X-MC-GZHC (GZHC) will investigate the safety, tolerability, pharmacokinetics, and 
pharmacodynamics (PD) of LY3493269 administered as 4 once-weekly SC doses in patients 
with T2DM. Trulicity® (dulaglutide) will be used as a positive control for PD of GLP-1 
pharmacology.
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
LY3493269 following 4 once-weekly SC doses

TEAEs and SAEs
Secondary

To characterize the PK of LY3493269 following 
4 once-weekly SC doses

Cmax and AUC

To evaluate the change in FG following 4 once-
weekly SC doses of LY3493269 and dulaglutide

Change from baseline in FG
Abbreviations: AUC = area under the concentration versus time curve; Cmax = maximum observed drug 
concentration; FG = fasting glucose; PD = pharmacodynamics; PK = pharmacokinetics; SC = subcutaneous; 
TEAE = treatment-emergent adverse event; SAE = serious adverse event.
Overall Design
Study GZHC is a Phase 1, multicenter, randomized, investigator- and participant-blind, placebo-
controlled, comparator-controlled, 4-week multiple-dose escalation study in patients with T2DM.
Disclosure Statement: This is a multiple-dose escalation study that is investigator- and 
participant-blind.
Number of Participants:
Approximately 64 participants may be randomly assigned to study intervention such that 
approximately 12 evaluable participants from each of the 4 cohorts complete the study. If 
participants are discontinued during the study, additional participants may be enrolled to 
complete the target number of evaluable participants.

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Protocol J1X-MC-GZHC(c)
8
Intervention Groups and Duration:
Eligible participants will be randomly assigned to study intervention:

8 to LY3493269

2 to dulaglutide, and

2 to placebo.
Each participant’s involvement in the study is expected to last up to 16 weeks, including a

6-week screening period

1-week baseline period

4-week treatment period, and 

a minimum 4-week follow-up period after the last dose.
Data Monitoring Committee: No

C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H C (c)
9
1. 2.
Sc he m a
A b bre viati o n: F U = f oll o w - u p.
N ote: T he i nitiati o n of eac h co h ort will be sc he d ule d s uc h t hat a pla n ne d escalate d d ose ( i n b ol d gr a y circles) is 
s u p p orte d b y a re vie w of 2-wee k safet y a n d t olera bilit y data fr o m t he prece di n g l o wer d ose ( i n dicate d b y b ol d 
vertical gr a y li nes). Partici pa nts i n C o h orts 3 a n d 4 will recei ve t he wee kl y d oses i n ste p wise i n cre me nts. T he d ose-
escalati o n sc he me a n d d ose ma y be altere d base d o n e mer gi n g safet y a n d t olera bilit y data .
Fi g ure 1.
Sc he m a of St u d y J 1 X -M C -G Z H C .
C CI
C CI
C CI
C CI

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Protocol J1X-MC-GZHC(c)
10
1.3.
Schedule of Activities (SoA)
Study Schedule for Cohorts 1 and 2
Procedure
Screening
Baseline
Treatment (Cohorts 1 and 2)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9
10
E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
12 ±1
14 ±1
15 ±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
Informed consent
X
Drug/alcohol screen
(local laboratory
throughout)
X
X
X
X
Per site policy or 
investigator’s 
discretion during 
the study.
Admission to site
X*
X
X
*May occur on
Day -3 or -2.
Discharge from site
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
Days 25 and 26 
procedures may be 
conducted while 
inpatient. 
Overnight fast
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer study 
drug
X
X
X
X
Medical history
X
Physical
examination
X
Medical assessment
P
X
X
P
P
P
X
X
X
X
X
X
X
Medical review 
and targeted 
examination, as 
appropriate.
Height
X
Weight and waist 
circumference
X
X
P
P
P
X
X
X
X
Body temperature
X
X
X
P
X

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
11
Procedure
Screening
Baseline
Treatment (Cohorts 1 and 2)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9
10
E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
12 ±1
14 ±1
15 ±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
Vital signs – BP/HR
(h)
X
X
X
P, 1, 4, 
6, 12
24
48
72
X
P
P
P, 
6, 12
24
48
X
X
X
X
X
ECG – single (h)
X
X
X
X
X
ECG – triplicate (h)
-0.5, 
-0.25, 
P, 1, 4, 
6, 12
24
48
72
X
P
P
P, 
6, 12
24
48
X
X
PK sampling (h)
P, 
6, 12
24
48
72
96
P
P
P, 
6, 12
24
48
X
X
X
X
X
X
Clinical laboratory 
tests - fasting
X
P
X
X
P
P
P
X
X
X
X
Hemoglobin A1c
X
P
X
X
X
AEs/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone calls for 
safety monitoring
X
X
X
X
SMBG supply 
distribution, training
on self-monitoring 
and patient diaries
X
X
X
X
X
Complete prior to 
discharge from 
Visit 1.
Fasting plasma 
glucose
X
P
P
P
P
X
X
X
6-point glucose
X
X
X
X
X
OGTT
Glucose
Insulin
C-peptide
Glucagon
X
X
X
X
See Table 1 for 
sampling schedule.
Acetaminophen PK
for GE test
X
X
X
See Table 1 for 
sampling schedule.

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
12
Procedure
Screening
Baseline
Treatment (Cohorts 1 and 2)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9
10
E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
12 ±1
14 ±1
15 ±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
Lipid panel, fasting
TG 
Total cholesterol
LDL-cholesterol
VLDL-cholesterol
HDL-cholesterol
P
X
X
Satiety VAS fasting
X
P
P
P
P
X
PGx sample
P
Non-PGx sample
fasting (storage)
P
P
P
P
X
X
Immunogenicity
P
P
X
X
X
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; GE = gastric emptying; h = 
hour; HDL = high-density lipoprotein; HR = heart rate; LDL = low-density lipoprotein; min = minutes; OGTT = oral glucose tolerance test; 
P = predose; PD = pharmacodynamics; PGx = pharmacogenetics; PK = pharmacokinetics; SMBG = self-monitored blood glucose; TG = triglyceride; VAS = 
visual analog scale; VLDL = very low-density lipoprotein; X = at any time during visit (for OGTT and GE test – refer to Table 1).
Table Color Code
Outpatient Visit
Inpatient visit
Off-site activity
Notes:

Clinical laboratory tests at screening shall be analyzed at a local laboratory. All other clinical laboratory tests, PK, PD, and biomarker samples obtained 
during the study will be analyzed at a Central Laboratory.

Where “fasting” is required, participants must have fasted for a minimum of 8 hours prior to the scheduled assessment(s).

If multiple procedures take place at the same time point, the following order of the procedure should be used: vital signs, ECG, and blood collection at 
the scheduled time point. 

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. 

Postdose assessments and procedures scheduled after the 24-hour time point should be performed within ±3 hours of the scheduled time.

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Protocol J1X-MC-GZHC(c)
13
Study Schedule for Cohorts 3 and 4
Procedure
Screening
Baseline
Treatment (Cohorts 3 and 4)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9 10 E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
9±1
12 ±1
14 ±1
15 ±1
16±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
Informed consent
X
Drug/alcohol screen
(local laboratory 
throughout)
X
X
X
X
X
X
Per site policy or 
investigator’s 
discretion during 
the study.
Admission to site
X*
X
X
X
X
*May occur on
Day -3 or -2.
Discharge from site
X
X
X
X
X
Outpatient visit
X
X
X X
X X X
Days 25 and 26 
procedures may 
be conducted 
while inpatient.
Overnight fast
X X X
X
X X
X
X
X
X
X
X X
Administer study 
drug
X
X
X
X
Medical history
X
Physical examination
X
Medical assessment
P
X
X
P
P
P
X X
X X X X X
Medical review 
and targeted 
examination, as 
appropriate.
Height
X
Weight and waist 
circumference
X
X
P
P
P
X
X X X
Body temperature
X
X X
P
X
ECG – single (h)
X
X
X X X

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
14
Procedure
Screening
Baseline
Treatment (Cohorts 3 and 4)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9 10 E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
9±1
12 ±1
14 ±1
15 ±1
16±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
ECG – triplicate (h)
-0.5, -0.25, 
P, 1, 4, 6, 
12
24 48 72
X
P, 1, 
4, 6, 
12
24
P, 1, 
4, 6, 
12
24
P, 1, 
4, 6, 
12
24 48
X X
Vital signs – BP/HR
(h)
X
X X
P, 1, 4, 6, 
12
24 48 72
X
P, 1, 
4, 6, 
12
24
P, 1, 
4, 6, 
12
24
P, 1, 
4, 6, 
12
24 48
X X X X X
PK sampling (h)
P, 6, 12
24 48 72
96
P, 4
P, 4
P, 6, 
12
24 48 X X
X
X X X
Clinical laboratory 
tests - fasting
X
P
X
X
P
P
P
X
X X X
Hemoglobin A1c
X
P
X
X
X
AEs/concomitant 
medications
X
X X X
X
X X X
X
X
X
X X
X
X X
X
X X X X X X X X X X
Phone calls for safety 
monitoring
X
X X
X
SMBG supply 
distribution, training
on self-monitoring 
and patient diaries
X
X
X
X
X
Complete prior to 
discharge from 
Visit 1.
Fasting plasma 
glucose
X
P
P
P
P
X
X
X
6-point glucose
X
X
X
X
X
OGTT
Glucose
Insulin
C-peptide
Glucagon
X
X
X
X
See Table 1 for 
sampling 
schedule.
Acetaminophen PK
for GE test
X
X
X
See Table 1 for 
sampling 
schedule.

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
15
Procedure
Screening
Baseline
Treatment (Cohorts 3 and 4)
FU
Comments
Visit #
1
2
3
4
5
6
7
8
9 10 E
D
Days
-42 to -4
−3
−2
−1
1
2
3
4
5
7 ±1
8 ±1
9±1
12 ±1
14 ±1
15 ±1
16±1
18 ±1
21
22
23
24
25
26
28 ±1
29
30
36 ±2
57 ±7
Lipid panel, fasting
TG
Total cholesterol
LDL-cholesterol
VLDL-cholesterol
HDL-cholesterol
P
X
X
Satiety VAS fasting
X
P
P
P
P
X
PGx sample
P
Non-PGx sample 
fasting (storage)
P
P
P
P
X
X
Immunogenicity
P
P
X
X X
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; GE = gastric emptying; h = 
hour; HDL = high-density lipoprotein; HR = heart rate; LDL = low-density lipoprotein; min = minutes; OGTT = oral glucose tolerance test; 
P = predose; PD = pharmacodynamics; PGx = pharmacogenetics; PK = pharmacokinetics; SMBG = self-monitored blood glucose; TG = triglyceride; VAS = 
visual analog scale; VLDL = very low-density lipoprotein; X = at any time during visit (for OGTT and GE test – refer to Table 1).
Table Color Code
Outpatient Visit
Inpatient visit
Off-site activity
Notes:

Clinical laboratory tests at screening shall be analyzed at a local laboratory. All other clinical laboratory tests, PK, PD, and biomarker samples obtained 
during the study will be analyzed at a Central Laboratory.

Where “fasting” is required, participants must have fasted for a minimum of 8 hours prior to the scheduled assessment(s).

If multiple procedures take place at the same time point, the following order of the procedure should be used: vital signs, ECG, and blood collection at 
the scheduled time point. 

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. 

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-GZHC(c)
16
Table 1.
Assessment Schedule for Oral Glucose Tolerance Test and Gastric Emptying 
Test
Oral Glucose Tolerance Test (OGTT)
Gastric Emptying (GE) Test
Timing 
(h)a
Activity
OGTT samplesb
Timing 
(h)c
Activity
Acetaminophen 
PK samples
0d
Oral glucose 
solution intake
Xe
-0.5
0.5
X
0
Acetaminophen 
solution intake
Xf
1
X
0.5
X
1.25
-
0.75 
X
1.5
X
1
X
2
End of OGTT
X
1.5
-
2
X
3
X
4
X
6
X
9
X
12
X
24
End of GE test
X
Abbreviations: GE = gastric emptying; OGTT = oral glucose tolerance test; PK = pharmacokinetics.
a
OGTT sample collections are scheduled with reference to the oral glucose solution intake at time “0 h” in this 
column. Sample collections should occur within ±10% of the scheduled time.
b
At each OGTT timepoint, samples are collected for glucose, insulin, C-peptide and glucagon.
c
Acetaminophen PK sample collections are scheduled with reference to the acetaminophen solution intake at time 
“0 h” in this column. Sample collections should occur within ±10% of the scheduled time.
d
Time “0 h” for OGTT on Day -1 should be scheduled at least 25 hours before the intended study intervention 
dosing on Day 1.
e
Sample collection occurs before intake of glucose solution, after a minimum 8-hour fast.
f
Acetaminophen pre-dose sample collection. Acetaminophen PK samples and oral dose are scheduled with 
reference to acetaminophen dosing at time = 0h and approximately 30 minutes after the glucose solution intake 
for OGTT.

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
17
2.
Introduction
LY3493269 is a dual-agonist peptide that combines actions of 2 incretin hormones, glucose-
dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 1 (GLP-1). LY3493269 is 
being developed as a once-weekly (QW) subcutaneous (SC) treatment for type 2 diabetes 
mellitus (T2DM). In addition, a once-daily oral formulation of LY3493269 is also in 
development. 
2.1.
Study Rationale
Study J1X-MC-GZHC (GZHC) will investigate the safety, tolerability, pharmacokinetics (PK), 
and pharmacodynamics (PD) of LY3493269 administered as 4 QW SC doses in patients with 
T2DM compared with placebo. The primary objective is to assess safety and tolerability, and the 
secondary objectives are to evaluate the PK and change in fasting glucose from baseline.
This is the first study to test multiple weekly SC doses of LY3493269 to establish early 
exposure-responses for key efficacy, safety, and tolerability relationships (for example, blood 
glucose, glycated hemoglobin [HbA1c]). Using a stepwise dose-escalation approach, this study 
will test dose levels higher than those investigated in Study J1X-MC-GZHA (GZHA), the first-
in-human single-ascending dose (SAD) study of LY3493269.
Trulicity® (dulaglutide) will be used as a positive control for PD of GLP-1 pharmacology.
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 blood glucose (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). 

C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H C (c)
1 8
C urre nt l y, t here are se veral a p pr o ve d G L P -1 rece pt or a g o nists ( G L P -1 R As ) f or t he treat me nt of 
di a betes a n d o besit y.  T he d osi n g of G L P-1 R As i n h u ma ns is li mite d b y  gastr oi nt esti nal ( GI )
a d verse effects, s uc h as na usea a n d v o mit i n g.
A vaila ble precli nical a n d cli nical data i n dicate t hat c o- sti m ulati on of GI P a n d G L P - 1 Rs ma y 
e n ha nce i ns uli n secreti o n, i m pr o ve i ns uli n se nsit i vity,  a n d re d uce b o d y wei g ht be yo n d t he effect 
of  selective G L P -1 R st i m ulati o n ( C os k u n et al. 2 0 1 8; Frias et al. 2 0 1 8). 
2. 2. 1.
S u m m ar y of Cli nic al E x perie nce
St u d y  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, S A D st u d y in vest i gati n g t he 
safety,  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 
parti ci pa nts. I n a d diti on, a c o h ort of 6 healt h y partici 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 o n of t he a bs ol 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 
 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 -escalati o n 
st o p pi n g criteria were n ot m et ; h o we ver , d ue t o c o ncer ns a b o ut safety a n d t olera bilit y wit h t he 
ne xt pla n ne d 
 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 d verse e ve nts ( 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 
 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 wit 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 diti on, decrease d a p petit e 
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 ome re q uire d treat me nt . A n i ncrease i n t he n u m ber of A Es 
relate d t o st u d y dr u g was n ote d wit h i ncreasi n g d oses of L Y 3 4 9 3 2 6 9 as c om pare d t o place b o. I n 
C o h ort 2, w here s u bjects recei ve d 
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  
 re p orte d GI A Es 
of  na usea a n d v omit i n g, re q uirin g a nt i-e met ics. Se veral ot h er GI A Es were re p orte d i n C o h ort 3 
(f or e xa m ple, a b d omi nal pai n u p per, c o nsti pat i on, er uctati o n, e pi gastric disc o mf o rt, dr y  mo ut h, 
a n d d ys pe ps ia.) 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  data, 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 ncrease i n heart rate ( H R) was n ote d, w hic h is c o nsiste nt wit h t he i ncret i n 
class ( L ore nz et al. 2 0 1 7). W hile n o cli nicall y  si g nifica nt c ha n ges were n ote d i n 
electr ocar dio gr a m  (E C G ) res ults, 3 parti ci pa nts i n 
 prese nte d mil d A Es of 
tac h yc ar dia. N o si gnifica nt c ha n ges i n t he bl o o d press ure meas 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 
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 usea we re n ote d.
C CI
C CI
C CI
C CI
C CI
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 C (c)
1 9
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 (tma x ) was
 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 of  
, w hic h is s uit a bl e for a wee kl y  d osi n g i nter val.
Preli mi nar y P D data s u g gest L Y 3 4 9 3 2 6 9 w he n a d mi nistere d S C ma y p ote ntiall y re d uce t otal 
b o d y  wei g ht, a p petite, a n d gluc ose c o nce ntrati o ns d uri n g a n oral gl uc ose t olera nce test ( O G T T) .
F urt her details are a vaila ble i n t he I n vest i gat or’s Br oc h ure (I B) f or L Y 3 4 9 3 2 6 9. 
2. 3.
Be nefit/ Ris k Assess me nt
T here i s n o a nticipate d t hera pe uti c be nefit for t he parti ci pa nts i n t his trial.
T he s p o ns or has e val uate d t he precli nical a n d cli nical ris ks ass ociat ed wi t h L Y 3 4 9 3 2 6 9. 
N o ncli nical safet y of  L Y 3 4 9 3 2 6 9 was e val uate d i n a C V safet y p har mac olo g y  st u d y in m o n ke ys 
a n d 1-m o nt h re peat -d ose t o xic o l og y  st u dies i n rats a n d m o n ke ys. I m p orta nt L Y 3 4 9 3 2 6 9- relate d 
fi n di n gs i n t he rat a n d m o n ke y i ncl u de d b o d y wei g ht los s a n d/ or re d uce d b o d y w eig ht gai n a n d 
decrease d f o o d c o ns u m pt i on. A d dit i onal fi n di n gs fr o m t he m o n ke y st u dies, i ncl u di n g c ha n ges i n 
C V para m eters (s uc h as i ncreases i n H R a n d bl o o d press ure). I n St u d y G Z H A, si milar fi n di n gs 
were o bser ve d, w hic h i ncl u de 

na usea

v o mit i n g

l oss of a p pet ite, a n d

i ncrease d H R.
Refer t o t he I B f or m ore i nf or mat i on a b o ut t he n o ncli nical a n d cli nical data of L Y 3 4 9 3 2 6 9. 
All i de ntifie d ris ks fr om precli nical a n d cli nical st u dies are c o nsi dere d m o nit ora ble a n d 
ma na gea ble at t he pla n ne d d ose ra n ge of 
 of L Y 3 4 9 3 2 6 9. Ris ks are si milar t o t h ose 
n ote d d uri n g de vel o p me nt of GI P a n d G L P -1 a g o nists. T o f urt her mi ni mize a n y p ote ntial ris k, 
parti ci pa nts will re mai n at t he i n vest i gati ve site f or at least 4 da ys after t he first d ose for s af et y 
a n d t olera bilit y m o nit ori n g u nt il disc har ge. Partici pa nts will be cl osel y m o nit ore d wi t h sc he d ule d 
me dical assess me nts, vital si g ns, a n d tri plicate E C G meas ure me nts. T he i n vest i gat or will ha ve 
t he discret i on t o e xte n d t he partici pa nt i n pat ient  sta y f or furt her safet y m o nit ori n g.
Refer t o t he I B f or m ore i nf or mat i on a b o ut t he n o ncli nical a n d cli nical data of L Y 3 4 9 3 2 6 9. M ore 
detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefit s a n d ris ks a n d reas o na bl y e x pecte d 
A E s of L Y 3 4 9 3 2 6 9 ma y b e fo u n d i n t he I B.
Refer t o t he Prescri bi n g I nf or mati o n f or Tr ulicit y ( Tr ulicit y U nite d States Pac ka ge I nsert, 2 0 1 9)
f or mor e i nf or mati on a b o ut t he k n o w n a n d e x pecte d be nefit s a n d ris ks of d ul a gl ut i de .
C CI
C CI

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
20
3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To investigate the safety and 
tolerability of LY3493269 
following 4 once-weekly SC doses

TEAEs and SAEs
Secondary

To characterize the PK of 
LY3493269 following 4 once-
weekly SC doses

Cmax and AUC

To evaluate the change in FG 
following 4 once-weekly SC doses 
of LY3493269 and dulaglutide

Change from baseline in FG
Exploratory

To explore PD effects of 
LY3493269 and dulaglutide 
following 4 once-weekly SC doses

Change from baseline in mean daily PG (6-point PG profile)

Change from baseline in HbA1c

Change from premeal fasting during OGTT for
o
PG concentrations
o
insulin concentrations
o
C-peptide concentrations
o
glucagon concentrations

Change from baseline in indices of beta-cell function

HOMA2-B

disposition index from OGTT

ΔI30/ΔG30 from OGTT

Insulin AUC0-120min from OGTT

Change from baseline in
o
fasting insulin sensitivity indices

HOMA2-IR

fasting insulin
o
postprandial insulin sensitivity indices

Matsuda

OGIS

Stumvoll

Change from baseline in fasting lipid parameters

triglycerides

total cholesterol, and

LDL-, HDL-, and VLDL-cholesterol, and

Change from baseline in body weight

Change from baseline in waist circumference

Change from baseline in gastric emptying

Change in appetite visual analog scale at fasting

To characterize the 
immunogenicity of LY3493269 
following 4 once-weekly SC doses

Incidence of treatment-emergent ADA

CONFIDENTIAL
Protocol J1X-MC-GZHC(c)
21
Abbreviations: ADA = antidrug antibody; AUC = area under the concentration versus time curve; AUC0-120min = 
AUC from 0 to 120 minutes; Cmax = maximum observed drug concentration; ΔG30 = 30-minute glucose in 
OGTT- baseline (0 minute) fasting glucose in OGTT; ΔI30 = 30-minute insulin in OGTT- baseline (0 minute) 
fasting insulin in OGTT; FG = fasting glucose; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; 
HOMA2-IR = homeostatic model assessment for insulin resistance; HOMA2-B = updated homeostatic model 
assessment for beta-cell function; LDL = low-density lipoprotein; OGIS = oral glucose insulin sensitivity; OGTT 
= oral glucose tolerance test; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = 
serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse event; VLDL = very low-density 
lipoprotein.

C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H C (c)
2 2
4.
St u d y Desi g n
St u d y  G Z H C is a P hase 1, ra n d o mize d, i n vesti gat or- a n d partici pa nt -bli n d, pl ace b o -c o ntr olle d, 
c o mp ar at or -c o nt r olle d, 4-wee k m ult i ple-d ose escalati o n st u d y  in pat ient s wit h T 2 D M.
Tr ulicit y ( d ula gl uti de) will be use d as a p ositi ve c o ntr ol f or P D of G L P-1 p har mac o l og y .
4. 1.
O ver all Desi g n
U p t o 4 c o h orts are pla n ne d t o r ecei ve a wee kl y d ose of st u d y int er ve nt i on f or 4 wee ks
(Fi g ure 1 ). T he i n vesti gat or or desi g nee will a d mi nister t he st u d y i nter ve nti on at t he i n vesti gate 
sit e.
P arti cipa nts f o u n d t o be eli gi ble acc or di n g t o t he st u d y  e ntr y crit eria will be ra n d o ml y assi g ne d
t o recei ve L Y 3 4 9 3 2 6 9, place b o, or d ula gl uti de. Parti ci pa nts n ot ra n d o ml y assig n e d t o 
L Y 3 4 9 3 2 6 9 will recei ve a 
 of d ula gl uti de or a place b o Q W f or 4 wee ks. De pe n di n g 
o n t heir c o h ort, partici pa nts ra n d o m l y assi g ne d t o L Y 3 4 9 3 2 6 9 will recei ve
 
Q W f or 4 wee ks (Ta ble 2 ). C o h orts 1 a n d 2 will recei ve 4 fi xe d d oses. C o h orts 3 a n d 4 will 
recei ve t he wee kl y d oses i n ste p wise i ncre me nts, as g uide d b y  e mer gi n g t olera bilit y, P K, a n d/ or 
P D data i n t he prece di n g d ose c o h orts.
T he nee d t o a dj ust t he starti n g d ose of a c o h ort ( C o h orts 2, 3, a n d 4) a n d dose -escalat i on 
decisi o ns wi t hi n C o h orts 3 a n d 4 will be base d o n t he e val uat i on of preli mi nar y  s af et y a n d 
t olera bilit y data. A n y a vaila ble P K a n d P D data ma y be i ncl u de d i n t he d ose -escalat i on decisi o n, 
t o be ma de joi nt l y b y t he i n vest i gat or a n d s p o ns or after re vie w of all a vaila ble data ( Secti o n 6. 6 ).
Eac h partici pa nt’s i n v o l ve me nt i n t he st u d y is e x pecte d t o last u p t o 1 6 wee ks, i ncl u di n g a

6- wee k scree ni n g peri o d

1 -wee k baseli ne peri o d

4 -wee k treat me nt peri o d, a n d

A mi ni m u m 4 -wee k f o ll ow- u p peri o d after t he l ast d ose.
T here w ill be a mi ni m u m of 3 i n pat ient  visits a n d u p t o 8 o ut pati e nt visits, d uri n g w hic h 
parti ci pa nts will recei ve st u d y int er ve nt i on a n d u n der g o safet y,  P K, a n d P D assess me nts 
acc or di n g t o Secti o n 1. 3 . F or a d dit i onal safety m o nit ori n g d uri n g i n pat ient  visits, partici pa nts 
ma y re mai n at t he i n vesti gati ve site f or a d dit i onal da ys after recei vi n g wee kl y d ose at a n y  of t he 
sc he d ule d d osi n g visits. Disc har ge fr o m t he i n vesti gati ve site will be base d o n t he i n vesti gat or’s 
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medical judgment. If required, the inpatient period may be extended to facilitate adherence to site 
policy, local guidelines, and/or regulations. 
4.1.1.
Screening Period
The outpatient screening visit may be up to 42 days prior to enrollment. Individuals who are not 
enrolled within 42 days of screening shall undergo an additional medical assessment and/or 
clinical measurements (including but not limited to clinical laboratory tests, ECG, vital signs, 
weight, and waist circumference measurements) to confirm their eligibility. Parameters that may 
be repeated for screening include clinical laboratory tests, ECGs, and vital signs.
4.1.2.
Baseline Period
During this baseline period, participants may be admitted to the investigative site on Day -3 and 
observe an overnight fast of at least 8 hours on that evening. Otherwise, participants may be 
admitted on Day -2 but should be fasting for at least 8 hours upon arrival to the investigative site. 
Participants should complete the study assessments and procedures planned during this period as 
specified in Section 1.3.
Eligible participants will be randomly assigned to study intervention on the morning of Day 1:

8 to LY3493269

2 to placebo, and

2 to dulaglutide.
If eligible per screening window and inclusion/exclusion criteria, participants who complete the 
baseline assessments but are not assigned to study intervention on the following day may repeat 
the baseline assessments once, on a later occasion, if it falls within the screening window of 42 
days prior to their next planned enrollment.
4.1.3.
Treatment Period
While inpatient at the investigative site, participants will receive their first SC dose of study 
intervention on Day 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 investigative site on Day 4.
Participants can be inpatient or outpatient for the study assessments and procedures planned on 
Day 5. Participants who are discharged on Day 4 must return to the investigative site on Day 5 
for an outpatient visit. Participants who are not discharged on Day 4 will complete their inpatient 
visit on Day 5. If the investigator determines that additional safety monitoring is needed, a 
sample for clinical laboratory tests may be collected along with the other assessments and 
procedures planned on Day 5 in Section 1.3.
At the 2 outpatient visits planned on Days 8 and 15, participants will receive their second and 
third doses of study intervention, respectively. Participants should be fasting for at least 8 hours 
upon arrival to the investigative site. The study assessments and procedures planned during this 
period should be performed as specified in Section 1.3, after which the participants shall be 
discharged from the investigative site. When not at the investigative site, participants should
record their fasting BG daily in their patient diary. The investigator or designee must review the 
diaries at each return visit to the site.

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T w o a d dit i onal i n patie nt visit s are pla n ne d f or t his st u d y. P artici pa nts will be a d mitte d t o t he 
i n vesti gati ve sites o n Da ys 2 1 a n d 2 8. Partici pa nts will recei ve t he fi nal d ose of st u d y 
i nter ve nt i on o n Da y  2 2. T he st u d y assess me nts a n d pr oce d ures plan ne d d uri n g t his peri o d s h o ul d 
be perf or m e d as s pecifie d i n Sect i on 1. 3 . U nless t he i n vest i gat or i de ntifies a safety c o ncer n, 
parti ci pa nts will be disc har ge d fr o m t he i n vest i gati ve site o n Da ys 2 4 a n d 3 0. P artici pa nts ma y 
r e mai n reside nt at t he si te o n Da ys 2 5 a n d 2 6 per i n vesti gat or’s discret i on, t o facilitate site 
l ogist ics a n d/ or c o mplia nce t o t he sc he d ule d assess me nts o n t hese da ys .
T hree o ut pati e nt visits are pl a n ne d o n Da ys 2 5, 2 6, a n d 3 6 of  t he st u d y. T he st u d y assess me nts 
a n d pr oce d ures pla n ne d d uri n g t his visit s h o ul d be perf or me d as s pecifie d i n Sect i on 1. 3 .
T he i n vest i gat or s hall i ncl u de tele p h o ne calls f or safety m o nit ori n g w he n partici pa nts are n ot at 
t he i n vest i gat or site, as s pecifie d i n Secti on 1. 3 .
4. 1. 4. 
F o ll o w-u p Peri o d
D uri n g t he f o ll ow -u p peri o d, parti ci pa nts s h o ul d atte n d t he o ut patie nt visit o n D a y 5 7. T he 
f oll ow- u p visit s h o ul d occ ur at least 2 8 da ys after t he last d ose of st u d y i nter ve nti o n. T he st u d y 
assess me nts a n d pr oce d ures pla n ne d d uri n g t his peri o d s h o ul d be perf or me d as s pecifie d i n 
Secti o n 1. 3 . If a partici p a nt is fo u n d t o be treat me nt -e mer ge nt -a nti dr u g a nt i b o d y (T E -A D A )
p osi tive at t he fi nal visit, he or s he s h o ul d u n der g o a d dit i onal m o nit ori n g as descri be d i n Sect i on
9. 4. 6 .
All p arti ci pa nts w h o are disc o nt i n ue d earl y fr om t he st u d y will be as ke d t o c o m plete a f oll ow- u p 
visit wit h Da y 5 7 pr oce d ures after a was h o ut peri o d of at least 2 8 da y s fr o m t h e last d ose of 
st u d y dr u g ( Sectio n 7. 2 ).
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
Se q ue nti al st u d y desi g n
T his st u d y  will be t he first assess me nt of t he safet y a n d t olera bilit y of mul tiple d oses of 
L Y 3 4 9 3 2 6 9 a d mi nistere d Q W i n pat ient s wit h T 2 D M. T he se q ue ntial desi g n e ns ures t hat eac h 
pati e nt is na ive t o st u d y  int er ve nt i on at t he ti me o f a d mi nistrati o n a n d a v o i ds a n y p ote ntial 
carr yo ver effects or effect of a nt i dr u g a nti b o dies (A D As ) o n i nter pretati o n of cli nical data.
Ste p wise d ose esc al ati o n wit hi n c o h ort
T he S A D St u d y  G Z H A de mo nstrate d t hat d ose l e vels of 
 were ass ociate d wit h GI 
A Es. G astr oi ntest i nal e ve nts (i ncl u di n g na usea a n d v o miti n g) were ge nerall y  d ose de pe n de nt. 
Ste p wi s e d ose i ncreases ma y pr o ve usef ul as a p ote nt ial mit i gati on f or t hese GI effects. T his 
a p pr oac h f or escalati n g d oses f or a dr u g wit h G L P -1 R a g o ni st acti vit y is e x pecte d t o all o w 
parti ci pa nts t o reac h hi g her mai nte na nce d ose le vels wit h acce pta ble GI -r elate d AE s.
C o m p ar at or a n d pl ace b o c o ntr ols
I n eac h c o h ort, u p t o 2 partici pa nts will be ra n d o m l y assi g ne d t o recei ve 
, i n a 
bli n de d ma n ner f or i n vest i gat or, site staff, a n d partici pa nts, as a p ositi ve c o ntr ol t o esta blis h a 
q ua nt itati ve ra n ge f or t he a ntici pate d G L P- 1 p har mac o l og y . U p t o 2 partici pa nt s will be 
ra n d om l y assi g ne d t o place b o, w hic h is i ncl u de d as a c o ntr ol, i n a bli n de d ma n ner f or 
i n vesti gat or, site staff, a n d parti ci pa nts, t o all o w a n u n biase d assess me nt of t he data ge nerate d, 
w hic h will all o w a m ore r o b ust c o m paris o n of safet y , t olera bilit y, a n d P D data.
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O n g oi n g d at a re vie ws
S afet y,  t olera bilit y , a n d a n y a vaila ble P K a n d P D data o btai ne d fr o m t he c urre nt st u d y i n 
parti ci pa nts wi t h T 2 D M will assist i n i de ntif yi n g a n a p pr o priate d ose ra n ge f or

t he ne xt c o h ort i n t his st u d y, a n d

s u bse q ue nt cli nical st u dies.
S af et y a n d t olera bilit y assess me nts will be ma de o ver all d ose le vels, i ncl u di n g i nci de nce o f 
na usea a n d/ or v o mit i n g, a n d e val uati on of vital si g ns a n d E C Gs. See Secti o n 6. 6 f or decisi o ns o n 
d oses.
4. 2. 1.
P artici p a nt I n p ut i nt o Desi g n
T hr o u g h o ut t his pr ot oc ol, t he ter m “partici pa nt ” is use d t o i n dicate a n i n di vi d ual w h o partici pates 
i n a cli nical trial, as a reci pie nt of a st u d y int er ve nti o n. T his usa ge reflects prefere nces i n dicate d 
b y patie nt a d v ocates t o m ore acc uratel y  reflect t he r ole of pe o ple w h o ta ke part i n cli nical trials.
4. 3.
J u stific ati o n f or D ose
St u d y  G Z H C pla ns t o e val uate a d ose ra n ge of  
 of L Y 3 4 9 3 26 9 i n pat ient s wit h 
T 2 D M. T he pla n ne d d ose le vels i n t his st u d y  are selecte d t o pr o vide a f ull  e v alu ati o n of  t he 
safety a n d t olera bilit y of  L Y 3 4 9 3 2 6 9 f oll owi n g m ul tiple d oses a d mi nistere d t hr o u g h S C 
i njecti on usi n g a Q W d ose re gi me n w hile pr o vi di n g earl y i nf or mat i on o n p ote ntial gl yce mic 
efficac y. 
 
 T his d ose ra n ge was selecte d f o ll owi n g 
e val uat i on of n o ncli nical data a n d res ults (t olera bilit y,  safety,  P K, a n d P D) fr om t he S A D st u d y, 
G Z H A. St u d y  G Z H A e val uate d L Y 3 4 9 3 2 6 9 at 
 i n health y 
parti ci pa nts.
T he starti n g d ose le vel f or t his st u d y  will be 
 a d mi nistere d Q W f or 4 wee ks i n C o h ort 1. 
T he e x p os ure m ult i ples of t he rat n o -o bser ve d -a d verse-effect le vel ( N O A E L ) a n d m o n ke y 
N O A E L t o t his starti n g d ose are 0. 6 9 X a n d 5. 1 1 X , res pecti vel y. T he d ose le vel pr o p ose d f or 
of  L Y 3 4 9 3 2 6 9 a d mi nistere d Q W f or 4 wee ks.
If safety,  t olera bilit y, P K, a n d P D data are s u p p orti ve, a d ose ra n ge u p t o  
 of L Y 3 4 9 3 2 6 9 
ma y be st u die d. As state d earlier , a si n gle S C d ose of
 was p o orl y t olerate d i n St u d y 
G Z H A. H o we ver, d at a fr o m pri or i ncret i n pr o gra ms ha ve s h o w n t hat d ose le vels at least 2- f ol d
hi g her t ha n t h ose i n vest i gate d i n a S A D st u d y ca n be safel y attai ne d i n a M A D st u d y b y utilizi n g 
a ste p wise d ose -escalat i on a p pr oa c h ( C os k u n et al. 2 0 1 8; Frias et al. 2 0 1 8). I n t h ose st u dies, 
h i g her d ose le vels were better to lerate d usi n g a ste p wise d ose-escalati o n sc he me of 
a d mi nistrati o n a n d were a ble t o i ncrease e x p os ure c o m pare d t o a S A D st u d y . S af et y data fr o m 
St u d y  G Z H A s u p p ort t his a p pr oac h.
Wit h se vere wei g ht l oss bei n g t he d ose -li miti n g fact or i n a ni mals, t he mar gi n of safet y is less 
t ha n 1 at t he N O A E L b ut t he e x p os ure m ult i ple f or cli nical d oses will be ke pt t o a b o ve 1 f or t he 
hi g hest d ose teste d i n m o n ke ys . All effects o bs er ve d i n t he rats a n d m o n ke ys were c o nsiste nt 
wi t h L Y 3 4 9 3 2 6 9 p har mac ol o g y. Base d o n t he n o ncli nical t o xic ol o g y st u dies, p ote ntial ris ks for 
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clinical trial participants receiving LY3493269 include HR increase, body weight loss, GI 
effects, and appetite loss. All these identified risks are monitorable, manageable, and reversible.
The margin of safety for the proposed MAD is presented in Table 3.

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4.4.
End of Study Definition
A participant is considered to have completed the study if he or she has completed all required 
visits of the study including the last scheduled procedure shown in the Schedule of Activities
(SoA). Any participant who does not satisfy this definition but who has completed all the key 
assessments may be considered a completer at the discretion of the sponsor.
The end of the study is defined as the date of the last visit of the last participant in the study.

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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
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 nature of any 
conditions present at the time of the physical examination and any preexisting conditions will be 
documented.
Unless otherwise stated, the inclusion and exclusion criteria used to determine eligibility should 
be applied at screening only, and not continuously throughout the trial.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply at 
screening:
Informed consent
1. Are capable of giving signed informed consent as described in Section 10.1.2, which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol.
2. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures.
Participant characteristics
3. Are male or female not of childbearing potential from 18 to 70 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.
4. Have a body mass index of 23 to 50 kg/m2, inclusive, at screening.
5. Have had a stable body weight (<5% body weight change) for the 3 months prior to 
screening.
6. Have not modified their diet or adopted any nutritional lifestyle modification in the
3 months prior to screening.
Disease characteristics
7. Have T2DM controlled with diet and exercise alone or are on a stable dose of 
metformin for at least 3 months before screening. Patients with comorbid 
conditions commonly associated with diabetes (for example, hypertension, 
hypercholesterolemia, hypothyroidism) may be eligible for inclusion if conditions 
are assessed by the investigator to be well controlled and stable for at least
3 months prior to screening.
8. Have an HbA1c of at least 7.0% and no more than 10.5% at screening.

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9. Have clinical laboratory test results within the normal range for the population or 
investigative site, or with abnormalities deemed not clinically significant by the 
investigator.
10. Have venous access sufficient to allow blood sampling as per the protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply at screening:
Medical conditions
11. Have type 1 diabetes mellitus or latent autoimmune diabetes in adults.
12. Have uncontrolled diabetes, defined as an episode of ketoacidosis or hyperosmolar state 
requiring hospitalization in the 6 months prior to screening.
13. Have a history of proliferative diabetic retinopathy, diabetic maculopathy, or severe 
nonproliferative diabetic retinopathy that requires acute treatment.
14. Have had more than 1 episode of severe hypoglycemia, as defined by the American 
Diabetes Association criteria, within 6 months before screening or has a history of 
hypoglycemia unawareness or poor recognition of hypoglycemic symptoms.
Note: Any participant that cannot communicate an understanding of hypoglycemic 
symptoms and the appropriate treatment of hypoglycemia prior to the first dose of study 
drug should also be excluded.
15. Have a known clinically significant gastric emptying abnormality (for example, severe 
diabetic gastroparesis or gastric outlet obstruction), have undergone gastric bypass 
(bariatric) surgery or restrictive bariatric surgery (for example, Lap-Band®) or chronically 
take medications that directly affect GI motility.
16. Have a definitive diagnosis of autonomic neuropathy as evidenced by urinary retention, 
resting tachycardia, orthostatic hypotension, or diabetic diarrhea.
17. Have obesity induced by other endocrine disorders, such as Cushing’s syndrome or 
Prader-Willi syndrome.
18. Have an estimated glomerular filtration rate less than 60 mL/min/1.73 m2, as determined 
by the local laboratory at screening.
19. Have had any of the following within the past 6 months prior to screening:

myocardial infarction, 

unstable angina, 

coronary artery bypass graft, 

percutaneous coronary intervention (diagnostic angiograms are permitted), 

transient ischemic attack, 

cerebrovascular accident or decompensated congestive heart failure, or 

New York Health Association Class III or IV heart failure.
20. 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 QT data analysis, such as a QT interval corrected using Fridericia’s formula 
(QTcF) >450 msec for males and >470 msec for women, short PR interval (<120 msec), 

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Protocol J1X-MC-GZHC(c)
31
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.
21. Have a supine HR less than 50 bpm or greater than 100 bpm. If a repeat measurement 
shows values within the range, the patient can be included in the trial.
22. Have a mean supine systolic blood pressure higher than 160 mmHg and a mean supine
diastolic blood pressure 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.
23. Have donated blood in the amount of 450 mL or more in the past 3 months or any blood 
donation within the last month from screening, or have had a blood transfusion or severe 
blood loss within the prior 3 months, or have known hemoglobinopathy (alpha 
thalassemia), hemolytic anemia, sickle cell anemia, or have a hemoglobin value less than 
11 g/dL in males or 10 g/dL in females, or any other condition known to interfere with 
HbA1c methodology.
24. Have liver disease, obvious clinical signs or symptoms of liver disease, acute or chronic 
hepatitis, or have elevations in aminotransferase levels (alanine aminotransferase [ALT]
and aspartate aminotransferase [AST]) greater than 3X upper limit of normal (ULN) at 
screening.
25. Have a history of Gilbert’s syndrome or have total bilirubin level (TBL) above 1.5X 
ULN at screening.
26. Have a history of acute or chronic pancreatitis.
27. Have a fasting serum triglyceride level greater than 500 mg/dL at screening.
28. Have a history of atopy or clinically significant multiple or severe drug allergies, 
intolerance to topical corticosteroids, or severe posttreatment hypersensitivity reactions 
(including, but not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).
29. Have a history of or ongoing psychiatric disorders considered clinically significant in the 
opinion of the investigator.
30. History of drug or alcohol abuse.
31. Have a self or family history (first-degree relative) of multiple endocrine neoplasia type 
2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid carcinoma.
32. Have calcitonin levels of 20 pg/mL or more at screening.
33. Have an active or untreated malignancy or have been in remission from a clinically 
significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas 
of the cervix, or in situ prostate cancer) for 5 years prior to screening.
34. Have a history or presence of clinically relevant conditions constituting a risk while 
taking the study medication; or of interfering with the interpretation of data.
Prior/concomitant therapy
35. Have taken any glucose-lowering medications other than metformin, including insulin, in 
the past 3 months before screening.

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36. Have been treated or plan to be treated with prescription medications that promote weight 
loss within 3 months prior to screening. Examples include

Saxenda® (liraglutide 3.0 mg)

Xenical® (orlistat)

Meridia® (sibutramine)

Acutrim® (phenylpropanolamine)

Sanorex® (mazindol)

Adipex® (phentermine)

BELVIQ® (lorcaserin)

Qsymia™ (phentermine/topiramate combination)

Contrave® (naltrexone/bupropion), or

other similar body weight loss medication including over-the-counter (OTC)
medications (for example, allī®).
37. Have received chronic (lasting more than 14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-ocular, intra-articular, intranasal, or inhaled 
preparations) in the past year or have received any glucocorticoid therapy within 30 days 
before screening.
38. Are currently taking central nervous system stimulant(s) (for example, Ritalin-SR®) with 
the exception of caffeinated beverages, at screening.
39. Intend to use OTC or prescription medication 4 weeks before planned dosing, apart from 
occasional intake of vitamin/mineral supplements and allowable concomitant therapies 
provided in Section 6.5.
Prior/concurrent clinical study experience
40. Have completed or withdrawn from this study or any other study investigating 
LY3493269, and have previously received the study intervention.
41. Are currently enrolled in a clinical trial involving a study intervention or any other type 
of medical research judged not to be scientifically or medically compatible with this 
study.
42. Are currently enrolled in or past participation, within the 30 days prior to screening, in a 
clinical study involving a study intervention for which at least 5 half-lives or 30 days 
(whichever is longer) have not passed.
Diagnostic assessments
43. Have positive findings on drug screening.
44. Show evidence of human immunodeficiency virus (HIV) and/or positive HIV antibodies 
at screening.
45. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive hepatitis 
B surface antigen.
46. Show evidence of hepatitis C and/or positive hepatitis C antibody.

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Other exclusions
47. 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 from 24 hours 
prior to dosing day, until the patient has been discharged from the clinical research site (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).
48. Smoke more than 10 cigarettes, or cigarette equivalent (as determined by investigator), 
per day or are unable to abide by investigative site restrictions on smoking and nicotine-
containing products.
49. Are females who are breastfeeding.
50. Have known allergies to LY3493269, GLP-1 analogs, or related compounds, or 
acetaminophen.
51. Are investigative site personnel directly affiliated with this study and their immediate 
families, defined as a spouse, parent, child, or sibling, whether biological or legally 
adopted.
52. Are employees of the sponsor or the investigative site.
53. Are otherwise unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor.
5.3.
Lifestyle Considerations
Throughout the study, participants will undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
As specified in Section 1.3, participants are required to fast for at least 8 hours before

receiving study intervention

each study day when clinical safety laboratory and PD samples are collected, and

OGTTs are administered.
Water may be consumed freely.
Standard meals will be administered in the investigative site.
While outpatient, participants are encouraged to follow their usual dietary regimen that is a part 
of their diabetes management, as agreed with the investigator or his/her designee.
5.3.2.
Caffeine, Alcohol, and Tobacco
Caffeine
Participants are allowed to maintain their regular caffeine consumption throughout the study.
Alcohol
No alcohol is allowed

at least 24 hours before each weekly dosing,

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Protocol J1X-MC-GZHC(c)
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
at least 24 hours before each investigative site admission or outpatient visit, and

throughout the duration of each investigative site visit.
A maximum of 21 units per week for males and 14 units per week for females is permitted at all 
other times.
Tobacco
Participants will be questioned about their nicotine consumption habits at screening.
Smoking, and the use of other tobacco or nicotine-containing products, will

be limited during the study confinement according to investigative site guidelines, and

not be permitted for 1 hour before assessments of vital signs and ECG.
5.3.3.
Activity
Participants will be advised to maintain their regular levels of physical activity/exercise during 
the study.
Participants will abstain from strenuous exercise within 24 hours prior to admission to the 
investigative site.
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 enrolled in the study.
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 randomly assigned for nonmedical reasons, may be reassessed. Additional medical 
assessments and clinical measurements must include clinical laboratory tests, vital signs, and 
ECG to confirm their eligibility. Repeat of laboratory tests will be acceptable if judged pertinent 
by the investigator.

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6.
St u d y I nter ve nti o n
St u d y  i nter ve ntio n is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), 
pl ace b o , or m e dical de vice(s) i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol .
T he i n vest i gat or or desi g nee is res p o nsi ble f or

e x plai ni n g t he c orrect use of t he st u d y int er ve nt i ons t o t he site pers o n nel ,

verif yi n g t hat i nstr ucti o ns are f o ll owe d pr o perl y ,

mai ntai ni n g acc urate rec or ds of st u d y  int er ve ntio n di s pe nsi n g a n d c ollect i on, a n d

ret ur ni n g all u n use d me dicati ons t o t he s p o ns or or its desi g nee at t he e n d of t he st u d y .
N ote: I n s o me cases, sites ma y destr o y t h e mat erial if, d uri n g t he i n vest i gati ve site selecti on, t he 
e val uat or has verifie d a n d d oc u me nte d t hat t he site has a p pr o priate facilit ies a n d writte n 
pr oce d ures t o dis p ose of t he cli nical materials
6. 1. 1.
A d mi nistr ati o n Det ails
All i njectio ns will be a d mi nistere d i nt o t he S C tiss ue of t he a b d o mi nal wall. I nject i on sites will 
be alter nate d wee kl y  a mo n g 4 si tes (t hat is, rig ht a n d left u p per q ua dra nts a n d ri g ht a n d left lo wer 
q ua dra nts) o n t he a b d o mi nal wall. W he ne ver p ossi ble, st u d y dr u g a d mi nistrati o n s h o ul d be 
carrie d o ut b y t he sa me pers o n nel.
6. 2.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
Pre p ar ati o n
I n vesti gat ors s h o ul d c o ns ult t he i nf or mati on pr o vi de d i n t he P har mac y  I nstr uctio ns f or s pecific 
pre parati o n a n d a d mi nistrati o n i nf or mat i on of L Y 3 4 9 3 2 6 9 a n d place b o. T he st u d y i nter ve nt i on 
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must be prepared by an unblinded pharmacist or other unblinded qualified designee who is not 
involved in any other study-related procedures.
Handling and storage
Only authorized site staff may supply or administer study intervention. Study interventions 
should be stored in an 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.
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 intervention and only authorized site 
staff may supply or administer study intervention. 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 (that is,
receipt, reconciliation, and final disposition records).
In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. Otherwise, the investigator or designee will return all 
unused study interventions to the sponsor or designee at the end of the study.
Further guidance and information for handling, storage, accountability, and final disposition of 
unused study interventions are provided in the Pharmacy Manual.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Interactive web-response system
All participants will be centrally assigned to randomized study intervention using an 
interactive-web response system (IWRS) prior to or on Day 1. Before the study is initiated, the 
log in information and directions for the IWRS will be provided to each site. Study intervention 
will be dispensed at the study visits summarized in the SoA. Returned study interventions should 
not be re-dispensed to the participants.
Blind break
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding 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. The date and reason that the blind was broken 
must be recorded in the source documentation and case report form (CRF), as applicable.

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Blinded study with unblinded site pharmacist who is dispensing drug
Participants will be randomly assigned to receive study intervention. Investigators will remain 
blinded to each participant’s assigned study intervention throughout the course of the study. 
To maintain this blind, an otherwise uninvolved third party (for example, the pharmacist) will be 
responsible for the reconstitution and dispensing of all study interventions and will endeavor to 
ensure that there are no differences in time taken to dispense following randomization. In 
addition, the site personnel administering the study interventions will not be blinded and will not 
perform other protocol assessments to avoid bias. 
The dosing team may blindfold the study participant to maintain the blind at the time of dose 
administration. The participant will be instructed to avoid discussing the packaging of the study 
intervention with the investigator.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
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 investigative site personnel.
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 investigative site personnel other than the person administering the study 
intervention.
6.5.
Concomitant Therapy
Recording of concomitant therapy
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements or other specific categories of interest) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with

reason for use

route of administration, and

dates of administration, including start and end dates.
Participants will be instructed to consult the investigator or other appropriate investigative site 
personnel before taking any new medications or supplements during the study. The sponsor’s 
medical monitor should be contacted if there are any questions regarding concomitant or prior 
therapy.

C O N FI D E N TI A L
Pr ot oc ol  J 1 X-M C -G Z H C (c)
3 8
All o we d c o nc o mit a nt t her a p y
P arti cipa nts will mai ntai n t heir us ual me dicati o n re gi me n t hr o u g h o ut t he st u d y u nless 
s pecificall y e xcl u de d i n t he pr ot oc ol ( Secti o n 5. 2 ). D oses m ust be sta ble as state d i n t he 
e xcl usi o n cri teria. Partici pa nts w h o ha ve bee n o n sta ble d oses of O T C or prescri pt i on 
me dicat i ons f or at least 4 wee ks f or t he treat me nt of c o nc urre nt me dical c o n dit i ons are per mitte d 
t o c o nti n ue t hese me dicati o ns d uri n g t he st u d y. T hese me dicatio ns ma y i ncl u de

a nt i h y perte nsi ve a ge nts

as pirin

li pi d-l oweri n g a ge nts, a n d

met f or mi n.
P arti cipa nts m ust be o n a sta ble d ose of metf or mi n f or at  least 3 mo nt hs pri or t o scree ni n g. D oses 
of  met f or mi n m ust re mai n sta ble bet wee n scree ni n g a n d ra n d omizat i on. D oses of metf or mi n ma y 
be a dj uste d after ra n d omizat i on per la bel, if re q uire d f or safety reas o ns. P artici pa nts o n 
met f or mi n m ust meet l ocal la bel re q uire me nts.
A d dit i onal c o nc o mit a nt me dicat i ons f or treat me nt of T 2 D M are n ot per mitte d d uri n g t he st u d y.
Na usea a n d/ or v o mit i n g d uri n g t his st u d y ma y be treate d wit h a nti-e met ics b ut t hese me dicati o ns 
s h o uld n ot be use d pr o p h ylact icall y.
Aceta mi n o p he n, at d oses of ≤2 g/ da y , is per mitte d f or use a n y ti me d uri n g t he st u d y. H o we ver, 
aceta mi n o p he n s h o ul d n ot be all o we d after mi d ni g ht a n d u nt il t he last aceta mi n o p he n P K sa m ple 
is ta ke n f or t he gastric- e m pt yi n g test.
Ot her c o nc o mita nt me dicat i on ma y be c o nsi dere d o n a case - b y-case basis b y t he i n vest i gat or i n 
c o ns ultati o n wit h t he s p o ns or’ s me dical mo ni t or, if re q uire d.
6. 6.
D ose M o dific ati o n
B y  nat ure of bei n g a d ose -escalat i on st u d y , data will be e val uate d o n a n o n g oi n g basis u ntil t he 
ma xi m u m d ose is deter mi ne d or w he n st o p pi n g criteria are met. Safet y data, i n partic ular A Es, 
S A Es, a n d cli nicall y  i m p orta nt la b orat or y a b n or malities, are t he pri mar y crit eria for d ose 
escalat i on. I nteri m access t o st u d y d at a is sc he d ule d t o occ ur d uri n g t he st u d y t o i nf or m d ose-
escalat i on decisi o ns, as s pecifie d i n Sect i on 6. 6. 1 .
T his pr ot oc ol all o ws s o me alterati o n fr o m t he c urre nt l y o utli ne d d osi n g sc he d ule, b ut t he 
ma xi m u m d ose will n ot e xcee d 
 of L Y 3 4 9 3 2 6 9 . If c o nsi dere d a p pr o priate i n vie w of 
e mer gi n g safet y,  t olera bilit y,  or P K data,

act ual d oses, i ncre me nts, an d/ or d urati o n of d osi n g i n eac h c o h ort at eac h d ose le vel ma y 
be a dj uste d.

the ti mi n g of t he sa m pli n g ma y be a dj uste d a n d a d dit i onal l y t he n u m ber of sa m ples t o be 
c ollecte d ma y be a dj uste d, as descri be d i n Secti o n 8. 5 .

the d urati o n of t he i n pat ient  sta y or t he d uratio n of  s afet y f oll ow- u p ma y  be i ncrease d b ut 
n ot decrease d.
N o d ose decisi o n ca n occ ur wit h o ut pri or disc ussi o n a n d a gree me nt bet wee n t he i n vesti gat or a n d 
s p o ns or. C ha n ges m ust be a p pr o priatel y d oc u me nte d a n d c o m m u nicate d b y t he s p o ns or t o t he 
C CI

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39
investigator. Because these adjustments to timing or dose levels are allowable changes permitted 
by the protocol, they would not require a protocol amendment.
6.6.1.
Dose Escalation
Dose Decisions between Cohorts
Preliminary safety and tolerability data from the current dose level, and any available data from 
preceding doses, are the primary criteria for decisions jointly made by the investigator and 
sponsor on
1) a dose escalation between successive cohorts, and
2) starting doses for Cohorts 2 to 4.
The initiation of each cohort shall be scheduled such that a planned escalated dose is supported 
by a review of 2-week safety and tolerability data from at least 5 participants who received 
LY3493269 through Day 15 at the preceding lower dose (Figure 1).
If available at the time of the dose-escalation decision, PK and PD results may be used as 
supporting data. Initiation of dosing for the last 2 planned cohorts will be based on review of the 
following:
1) All available PK data from Cohort 1, prior to initiation of Cohort 3 
2) All available PK data from Cohort 2, prior to initiation of Cohort 4.
Dose Decisions within Cohorts 3 and 4
For Cohorts 3 and 4, progression of planned doses from Weeks 1 through 4 shall be based on the 
ongoing evaluation of individual patient-level safety and tolerability data. Any available safety 
and PK data from preceding cohorts will also be considered.
If individual participants on LY3493269 in either Cohort 3 or 4 experience tolerability issues 
after dose escalation, these participants may receive the previously tolerated dose for the 
remainder of the treatment period. The planned dose for escalation between cohorts and within 
cohorts may be further reduced if warranted by safety or tolerability data. Any subsequent dose 
increments will not be greater than those originally planned.
6.6.2.
Dose-Escalation Stopping Criteria
If any of the following scenarios occur, dosing at the current level and further dose escalation 
within a cohort and to the next cohort may be discontinued after a discussion between the 
sponsor and the investigator:
1. One treatment-emergent SAE believed to be associated with LY3493269; For more 
details see Section 7.1.2.
2. One or more participants on active drug experience 2 or more clinically significant events 
(CSEs) deemed related to LY3493269. Clinically significant events are 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 

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Protocol J1X-MC-GZHC(c)
40
by the investigator or suitable designee and may include findings that do not fulfill the 
criteria for SAEs.
3. Three or more participants at the same dose level experience any of the following deemed 
related to LY3493269 administration: 
o
drug-related GI effects (for example emesis, diarrhea) causing severe distress 
(prevents daily activities or requires an emergency department visit or 
hospitalization); and/or 
o
clinically significant cardiovascular AE.
4. 40 % or more of participants in a dose level experience 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]) and these events are deemed to be related to 
LY3493269 administration (see Section 7.1.2), or
5. 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.
6.6.3. Data Review during the Study
Interim access to safety, tolerability, and any available PK and PD data is scheduled to occur 
after every dosing session. This schedule may be modified as applicable, based on emerging 
safety and tolerability data. The purpose of these reviews is to guide and confirm dose selection 
for the next dosing cohort.
The decision to proceed to the next cohort will be made by the sponsor and the investigator 
based on safety, tolerability data (including but not limited to AEs, concomitant medications, 
clinical laboratory tests, vital signs, ECGs) from at least 5 participants who have received 
LY3493269 through Day 15 at the prior dose level. If available, PK and PD data will be 
reviewed.  In addition, these data may be used to guide dose selection and inform the need to 
adjust timing of procedures and sampling schedules for the current study.
6.7.
Intervention after the End of the Study
Not applicable.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.7.
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 early termination safety assessments and 
follow-up. 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.
Participants experiencing CSEs thought to be related to the study intervention will be encouraged 
to complete a 28-day follow-up period before study discharge.
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 for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.1.1.
Liver Enzymes and Other Laboratory
Discontinuation of the study intervention for abnormal liver tests 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 >8X ULN

ALT or AST >5X ULN sustained for more than 2 weeks 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%).
Participants who discontinue from study intervention due to the abnormal liver tests 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:

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
lipase and/or amylase ≥3X ULN (Section 8.2.5.1 should be considered by the 
investigator).
7.1.2.
Persistent Hyperglycemia/Hypoglycemia
Discontinuation of the study intervention should be considered for participants with any 
persistent severe hyperglycemia, defined as a persistent fasting PG level above 240 mg/dL, 
without an identified cause (for example, intercurrent illness).
Discontinuation of the study intervention should be considered for participants with any severe 
hypoglycemia (Level 3 according to Section 8.2.6.1), or persistent hypoglycemic events (Level 
2), for example 3 or more hypoglycemic events over any 7-day period.
7.1.3.
Hypersensitivity Reactions
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity reaction has occurred related to study drug administration, the 
participant should be permanently discontinued from using the study intervention.
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 investigational product 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.

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7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor CRP agree it is 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 investigational product. 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.

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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 
(that is, outside stipulated time allowances) to perform procedures or obtain samples within the 
stipulated time allowances due to legitimate clinical issues (for example, equipment technical 
problems, venous access difficulty) will not be considered protocol deviations. However, the 
clinical research unit is required to notify the sponsor in writing using a file note.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
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 
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.

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8.2.2.
Vital Signs
Vital signs, blood pressure, PR, and body temperature, should be measured as specified in 
Section 1.3 and as clinically indicated. Additional vital signs may be measured during each study 
period if warranted.
Blood pressure and PR should be measured twice 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.
8.2.3.
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.
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, baseline, at early termination, and follow-up on Days 
36 and 57 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.

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Triplicate electrocardiograms
Triplicate 12-lead ECGs will be obtained as specified in Section 1.3. Collection of triplicate 
ECGs on Days 23, 24, 29, and 30 should be time matched to the predose triplicate ECG collected 
on Day 22.
Collection of more ECG replicates than expected at a certain time point will be permitted to 
ensure high-quality records. At each time point at which triplicate ECGs are required, 3
individual ECG tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 4 minutes.
Scheduled and unscheduled digital ECGs will be electronically transmitted to a central ECG 
laboratory designated by the sponsor. The central ECG laboratory will perform a basic quality 
control check, for example, demographics and study details, then store the ECGs in a database.
At a future time, the stored ECG data may be overread at the central ECG laboratory for further 
evaluation of machine-read measurements or to meet regulatory requirements.
8.2.4.
Clinical Safety Laboratory Assessments
See 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 approximately 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 (for example, SAE or AE or dose 
modification), then the results must be recorded in the CRF.
8.2.5.
Safety Monitoring
The sponsor clinical pharmacologist or CRP/scientist will monitor safety data throughout the 
course of the study.
The sponsor will review SAEs within time frames mandated by company procedures. The 
sponsor’s clinical pharmacologist or CRP will periodically review

trends in safety data

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
laboratory analytes, and

AEs.
When appropriate, the sponsor’s 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 one 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; 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 OTC), herbal and dietary supplements, history of 
alcohol drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:

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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; 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

liver biopsy.
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver test results during the study

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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.
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 
investigational product and protocol procedure will be captured.
8.2.5.3.
Pancreatic Safety
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 
(MRI).
If acute pancreatitis is suspected, the investigator should

obtain appropriate laboratory tests, including p-amylase and lipase

perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal MRI

evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications.

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Discontinuation for acute pancreatitis
If acute pancreatitis is diagnosed, the participant must discontinue use of the study intervention.
8.2.5.4.
Injection-Site Reactions
Symptoms of a local injection-site reaction may include

erythema

induration

pain

pruritus, and

edema.
If an injection-site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the electronic case report form (eCRF).
8.2.5.5.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided 
to the sponsor in the eCRF.
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines.
In case of anaphylaxis or generalized urticaria, additional blood samples should be collected as 
described in Section 10.8. The laboratory results are provided to the sponsor via the central 
laboratory.
8.2.6.
Glucose Monitoring
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).

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
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).

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.
8.2.6.2.
Self-Monitoring of Blood Glucose
Prior to the first outpatient visit after the first SC dose, participants will receive training on 
routine BG monitoring and paper diary completion required during the study.

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When outpatient, participants should measure their fasting BG daily during the study. In 
addition, participants should test their glucose whenever they experience symptoms of 
hypoglycemia.
Participants will be trained to record their results in their diaries. The investigator or designee 
must review the diaries at each return visit to the site.
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be collected from the signing of the ICF until the participation in study has ended.
All AEs will be collected from the signing of the ICF until the follow-up visit.
Adverse events that begin before the start of study intervention but after signing 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 patient 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 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 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.

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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.6),
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 Appendix 10.3.1.
8.3.4.
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.
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 (for example, summary or listing of SAEs) from the sponsor will review and 
then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
Pregnancy (maternal or paternal exposure to study intervention) does not meet the definition of 
an AE. However, to fulfill regulatory requirements, any pregnancy should be reported following 
the SAE process described in Section 10.4.3 to collect data on the outcome for both mother and 
fetus.

Details of all pregnancies in female participants and female partners of male participants
will be collected after the start of study intervention and for the duration of the study plus 
105 days, which corresponds to approximately 5 months following the last dose of study 
intervention.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.4.

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Adverse Events of Special Interests
Adverse events of special interest for this program include

CV events

GI events

injection-site reactions

hypersensitivity reactions, and

hypoglycemic events.

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Each occurrence will be recorded as a separate AE in the CRF. For each event assessment of 
severity, duration (actual date, time of onset, and end times), and investigator’s opinion of 
relatedness to study intervention and protocol procedure will be captured.
8.3.7. 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 investigational products 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 investigational product so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Appendix 10.3.3 of the protocol.
8.3.7.1.
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.
8.3.7.2. Prompt Reporting of Product Complaints to 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.
8.3.7.3.
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 dose assigned through randomization 
will be considered an overdose. Treatment for overdose is supportive care. For additional details, 
refer to the LY3493269 IB.

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In the event of an overdose, the investigator or treating physician 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.
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.
8.5.
Pharmacokinetics
Plasma samples will be collected for measurement of plasma concentrations of LY3493269 as 
specified in Section 1.3.
A maximum of 3 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 (for example, 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 investigative 
sites or blinded personnel until the study has been unblinded.
8.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
The retention period for bioanalytical samples collected to measure LY3493269 concentrations 
is provided in Section 10.1.9. 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.
8.5.1.1.
Bioanalysis of Study Intervention
Concentrations of LY3493269 will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method. Analyses of samples collected from participants who 
received either placebo or dulaglutide are not planned.
8.5.1.2.
Bioanalysis of Acetaminophen
Concentrations of acetaminophen will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method.

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8.6.
Pharmacodynamics
8.6.1.
Oral Glucose Tolerance Test
Glucose, C-peptide, glucagon, and insulin will be measured in an OGTT to assess effects of 
LY3493269 on glycemic control, disposition index, insulin secretion and insulin sensitivity. The 
schedule for OGTTs is indicated in Section 1.3.
1. Participants will maintain adequate carbohydrate intake (125 to 150 g/day) 3 days before 
the scheduled OGTT and fast for approximately 8 hours overnight before administration 
of the OGTT.
2. A 75-g glucose dose will be given orally. Participants should consume the glucose load 
within 5 minutes.
3. Blood samples will be drawn for assessment of glucose, C-peptide, glucagon, and insulin 
concentrations pre-test and at 0.5, 1, 1.5, and 2 hours after the initiation of the glucose 
load.
4. If participants develop symptoms of hypoglycemia, bedside BG concentration may be 
measured. The participant will be treated per investigator’s discretion.
8.6.2.
Gastric-Emptying Test
Acetaminophen is a well-established marker of gastric emptying (Young 2005). It is rapidly 
absorbed from the duodenum upon release from the stomach. A delay in gastric emptying is 
reflected in the alterations to the concentration versus time profile of acetaminophen, 
specifically, decreasing its maximum observed drug concentration (Cmax) and likely delaying tmax
without altering the extent (total drug amount) absorbed.
The acetaminophen dose should be given approximately 30 minutes after the 75-g glucose dose 
for the OGTT.
A dose of approximately 1 g acetaminophen is considered to be sufficient for bioanalytical 
detection and will be administered at the times specified in Section 1.3.
Venous blood samples of approximately 2 mL each will be collected to determine the plasma 
concentrations of acetaminophen.
8.6.3.
Six-Point Plasma Glucose Profiles
The samples for the 6-point glucose profiles will be collected as specified in the Section 1.3 and 
analyzed at a central laboratory.
Six-point glucose profiles consisting of PG measurements should be obtained at investigative site 
before each meal (breakfast, lunch, and dinner) and approximately 2 hours after the end of each 
meal.
8.6.4.
Pharmacodynamic Markers
Samples for PD markers will be collected at the times specified in Section 1.3.

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Fasting serum samples for glucose, insulin, and C-peptide will be evaluated as PD biomarkers. 
Fasting lipids (triglycerides, cholesterol, very low-density lipoproteins, low-density lipoproteins,
and high-density lipoproteins) 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 samples for these analyses will be 
provided by the sponsor.
8.6.5.
Appetite Analysis with a Visual Analog Scale
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 visual analog scale (VAS) for parameters 
of hunger, fullness, satiety, and prospective food consumption prior to dosing and in the fasted 
state while inpatient as well as on scheduled outpatient visits, according to 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?”
Investigative site personnel will use a caliper to measure the distance from 0 to the mark that the 
participant placed on the VAS and record the measurement in the source document. Overall 
appetite score is calculated as the average of the 4 individual scores: satiety + fullness + (100-
prospective food consumption) + (100-hunger) / 4 (van Can et al. 2014). The higher overall 
appetite score indicates less appetite, and the lower score indicates more appetite.
8.6.6.
Body Weight
Weight will be measured as indicated in the SoA. 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. 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 at 
each scheduled timepoint or visit, and after an overnight fast and evacuation of bowel and 
bladder, if possible.
8.6.7.
Waist Circumference
Waist circumference will be measured twice on each scheduled occasion according to 
Section 1.3. The mean of the 2 measurements will be recorded in the source document and the 
eCRF.

Waist circumference should be measured at the midpoint between the lower margin of 
the least palpable rib and the top of the iliac crest.

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
The patient should stand with feet close together, arms at the side and body weight evenly 
distributed, and should wear little clothing.

The patient should be relaxed, and the measurements should be taken at the end of a 
normal expiration.
8.7.
Genetics
A blood sample for DNA isolation will be collected from participants. 
See Appendix 10.5 for information regarding genetic research and Section 10.1.9 for details 
about sample retention and custody. 
8.8.
Biomarkers
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in Section 1.3 where local regulations allow.
Sample use
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.
Samples will be used for exploratory 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.
Exploratory biomarker measures may include potential markers of GIP and GLP-1R target 
engagement and mechanism of action.
Confidentiality
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigative site personnel.
Sample retention
The purpose of retention, the maximum duration of retention, and facility for long-term storage 
of samples are described in Section 10.1.9.
8.9.
Immunogenicity Assessments
At the visits and times specified in 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.

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TE-ADAs are defined in Section 9.4.6. In the case that ADA samples are tested before end of 
study and if the immunogenicity sample at the last scheduled assessment or discontinuation visit 
is TE-ADA positive, additional samples may be taken every 3 months until the ADA signal 
returns to baseline (that is, 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.
The purpose of retention, the maximum duration of retention, and facility for long-term storage 
of samples are described in Section 10.1.9.
8.10.
Health Economics
Not applicable.

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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The primary study objective is to determine the safety and tolerability LY3493269 following 4 
QW doses. Additional hypotheses will include the comparison of study intervention with placebo 
and/or dulaglutide for the prespecified objectives and endpoints defined in Section 3.
9.2.
Sample Size Determination
Approximately 64 participants may be randomly assigned to study intervention such that 
approximately 12 evaluable participants from each of the 4 cohorts complete the study. In each 
cohort, participants will be randomly assigned to

8 LY3493269

2 dulaglutide, and

2 placebo.
If participants are discontinued during the study, additional participants may be enrolled as 
replacements for these participants.
The sample size is considered sufficient for evaluating the primary objective of this study.
Participant replacement
A total of 12 participants are aimed to complete the study in each cohort.
Participants who discontinue from the study, for reasons other than an AE suspected to be related 
to study drug, may be replaced as agreed between the sponsor and investigator. The replacement 
participant will be assigned to the same treatment as the participant being replaced.
Participants who discontinue from the trial due to an AE considered by the investigator to be 
probably or most likely related to study intervention will not be replaced.

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9.3.
Populations for Analyses
The following populations are defined:
Population
Definition
Entered
All participants who sign the ICF.
Enrolled
All participants randomly assigned to study intervention. 
Safety
All participants randomly assigned to study intervention and who received 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 dose of LY3493269 and have evaluable PK 
sample.
Pharmacodynamic 
Analysis
All participants who received at least 1 dose of study intervention and have evaluable 
PD sample.
Abbreviations: ICF = informed consent form; PD = pharmacodynamics; PK = pharmacokinetics.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Statistical analyses will be conducted on the populations as described in Section 9.3. Safety 
analyses will be conducted on the safety population whether or not they completed all protocol 
requirements.
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.
The SAP will be finalized prior to the first patient visit and it will include a more technical and 
detailed description of the statistical analyses provided in this section.
9.4.1. General Considerations
Data listings will be provided for all data that are databased. 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 analysis will only be presented for data where detailed in the 
SAP. Summary statistics and statistical analyses will generally only be performed for 
participants included in the relevant analysis population. For the calculation of summary 
statistics and statistical analysis, unrounded data will be used (Table 4).

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Table 4.
Data Presentation Methods
Parameters
Summary Statistics

demography

clinical laboratory

vital signs

ECG

appetite analysis, and

PD data

arithmetic mean

arithmetic standard deviation

median

minimum

maximum, and

the number of observations

PK data
o
AUC(0-τ), and
o
Cmax

geometric mean and

CV%

adverse event data

hypoglycemic classification data, and

injection-site reaction data

frequency count and

percentages
Abbreviations: AUC(0-τ) = area under the concentration versus time curve during 1 dosing interval; Cmax = 
maximum observed drug concentration; CV% = geometric coefficient of variation; ECG = electrocardiogram; 
PD = pharmacodynamics; PK = pharmacokinetics.
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 
participant’s baseline value from the value at the time point. Baseline is defined to be Day 1 
predose measurements unless otherwise stated.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.4.2.
Safety Analyses
All safety analyses will be made on the safety population.
All SAEs will be reported. 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.
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.
Analysis for clinical laboratory tests
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.

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Analysis for vital signs
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 for repeated measurement with treatment, visit of measurement, and treatment-by-
visit 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.
Analysis for electrocardiograms
Electrocardiogram parameters will be summarized, including the PR, QT, RR, and QTcF 
intervals, QRS duration, and HR. A concentration-response analysis will also be performed to 
assess the effect of LY3493269 on QTcF. Additional analyses may be performed to determine 
the effects of PK and PD parameters on QTcF and other intervals.
9.4.3.
Pharmacokinetic Analyses
Pharmacokinetic parameter estimates for LY3493269 will be calculated using standard 
noncompartmental methods of analysis. The primary parameters for analysis will be Cmax and 
area under the concentration versus time curve (AUC) of LY3493269 after the first and last dose.
Other parameters, such as tmax, half-life, apparent clearance, apparent volume of distribution, and 
accumulation ratio, may be reported. If deemed necessary, additional population PK modeling
may be performed or data may be combined with other studies for further analysis.
Pharmacokinetic dose proportionality will be explored for the first dose of each cohort. Log-
transformed Cmax and AUC of LY3493269 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 will be analyzed using a nonparametric method. All PK 
parameters will be summarized using descriptive statistics.
9.4.4.
Pharmacodynamic Analyses
All PD parameters, including the change from baseline 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.
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 model for repeated measurement 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.

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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 
Section 1.3.
Differences between each LY3493269-treated group and dulaglutide group will be estimated. 
Participants who received dulaglutide will be pooled across all cohorts.
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.
Acetaminophen parameters will be calculated using standard noncompartmental methods of 
analysis. The primary parameters for analysis will be Cmax, AUC, and tmax of acetaminophen. 
Other PK parameters of acetaminophen may be reported where appropriate. Baseline-adjusted 
Cmax of acetaminophen (ratio to Day -1 value) will be calculated and log transformed to compare 
the gastric-emptying effect of LY3493269 to that of dulaglutide and placebo. A mixed model for 
repeated measurement with treatment, day, and treatment-by-day interaction as fixed effects, 
participant as random effect, and baseline (Day -1) as covariate will be used to perform the 
analysis. Least-squares means as well as 95% CIs will be reported. The parameter tmax of 
acetaminophen will be analyzed using a nonparametric method.
9.4.5.
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
blood pressure
o
HR, and
o
PR interval,

tolerability parameters, such as 
o
nausea and
o
vomiting, and

PD parameters, such as 
o
fasting glucose
o
HbA1c, and
o
weight.
Endpoints may include but are not necessarily limited to those listed earlier.
9.4.6.
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

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
a 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 for reasons other than a safety concern, the protocol must be amended.
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)
Not applicable.

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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
International Ethical Guidelines

applicable International Council for Harmonisation (ICH) good clinical practice (GCP)
Guidelines

applicable laws and regulations
The protocol, protocol amendments, ICF, IB, and other relevant documents (for example,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and approved 
by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 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.
10.1.2.
Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, 
where applicable, and the IRB/IEC or study center.

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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 and is kept on file.
10.1.3.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets,
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The sponsor has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach.
10.1.4.
Dissemination of Clinical Study Data
Communication of suspended or terminated dosing
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, through phone and/or 
email) as soon as possible. It will be a requirement that investigators respond upon receipt to 
confirm that they understand the communication and have taken the appropriate action prior to 
further dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.
Reports
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.
Data
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.

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10.1.5.
Data Quality Assurance
Investigator responsibilities
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (for example, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 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.
Data monitoring and management
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques 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 (for example,
contract research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; 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 retention and audits
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement unless 
local regulations or institutional policies require a longer retention period. No records may be
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
In addition, sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by 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. The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data collected via the sponsor-provided data capture systems 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 systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse.
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.6.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
Definition of what constitutes source data can be found in Section 10.1.5.
10.1.7.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to

failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

inadequate recruitment of participants by the investigator

discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 

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regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.8.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.
10.1.9.
Long-Term Sample Retention
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3493269 or after LY3493269 becomes commercially available.
The following table lists the maximum retention period for sample types. The retention period 
begins after the last participant visit for the study.
The maximum retention times may be shorter, if specified in local regulations and/or if ethical 
review boards/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 in the Safety Laboratory Tests table will be performed by the local 
laboratory at screening, and at the central laboratory for all scheduled assessments from 
Day -3 through the treatment period and follow-up.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests (for example, drug/alcohol screen) may be performed at any time during 
the study as determined necessary by the investigator or as required by local regulations.

Pregnancy testing will occur as indicated in the SoA.
Investigators must document their review of each laboratory safety report.
Laboratory and analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel.

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Safety Laboratory Tests (Screening - Local Laboratory)
Hematology
Clinical Chemistry (fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphate
Leukocytes (WBC)
Magnesium
Absolute Counts of
Creatinine
Neutrophils
Glucose (fasting)
Lymphocytes
Urea
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Urinalysis
Alanine aminotransferase (ALT)
Specific gravity
Lipase
pH
Amylase
Protein
Triglyceride
Glucose
Total cholesterol
Ketones
HbA1c
Bilirubin
Calcitonin
Urobilinogen
Nitrite
Blood
Serology
Leukocytes
Hepatitis B surface antigena
Microscopyb
Hepatitis B core antibody, totala
Hepatitis C virus serology (anti-HCV)a
Follicle-stimulating hormone (FSH)c
Human immunodeficiency virus (HIV)a
Serum pregnancy test (females only)
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell.
a
Tests may be waived if they have been performed within 6 months before screening with reports available for 
review.
b
If clinically indicated, per investigator’s discretion.
c
Performed for females at screening, if needed to confirm postmenopausal status.

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Safety Laboratory Tests (Central Laboratory - from Day -3 through Follow-up)
Hematology
Clinical Chemistry (fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphate
Leukocytes (WBC)
Magnesium
Absolute Counts of
Creatinine
Neutrophils
Glucose (fasting)
Lymphocytes
Urea
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Urinalysis
Alanine aminotransferase (ALT)
Specific gravity
Lipase
pH
Amylase
Protein
Triglyceride
Glucose
Total cholesterol
Ketones
HbA1cc
Bilirubin
Urobilinogen
Nitrite
Blood
Leukocytes
Microscopya
Pregnancy testb
Tests will be performed at a central laboratory unless otherwise specified.
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell.
a
If clinically indicated, per investigator’s discretion.
b
Local laboratory test for females only: urine pregnancy test at the Day 57 follow-up or early discontinuation.
c
HbA1c samples obtained according to the Schedule of Activities (Section 1.3).

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10.2.1.
Blood Sampling Summary
These tables summarize the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Blood Sampling Summary Table (Cohorts 1 and 2) 
Purpose
Blood Volume 
per Sample (mL)
Approximate 
Number of Blood 
Samples
Approximate 
Total Volume 
(mL)
Screening tests (local laboratory)a
25
1
25
Clinical laboratory testsa (central laboratory)

HbA1c
3
3
9

Study Visits
10
8
80

Follow-up
10
1
10
LY3493269 pharmacokinetics
3
19
57
Potential additional LY3493269
pharmacokinetic samples
3
3
9
Blood discard for cannula patency
0.5
19
9.5
Fasting plasma glucose
2
7
14
6-point glucose
2
30
60
OGTT (central laboratory)

Glucose
2
20
40

Insulin, C-peptide
3
20
60

Glucagon
2
20
40
Gastric-emptying test (acetaminophen PK)
2
33
66
Biomarkers (central laboratory)

Lipid panel 
(triglycerides, total cholesterol, low-
density lipoprotein-cholesterol, very 
low-density lipoprotein-cholesterol, 
and high-density lipoprotein-
cholesterol)
3.5
2
7
Pharmacogenetic sample (stored)
10
1
10
Nonpharmacogenetic sample (stored)

Plasma
2
5
10

Serum
2.5
5
12.5

P800
2
5
10
Immunogenicity
10
4
40
Total
569
Total for clinical purposes (rounded up to the nearest 10 mL)
570
a
Additional samples may be drawn if needed for safety purposes.

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Blood Sampling Summary Table (Cohorts 3 and 4) 
Purpose
Blood Volume 
per Sample (mL)
Approximate 
Number of Blood 
Samples
Approximate 
Total Volume 
(mL)
Screening tests (local laboratory)a
25
1
25
Clinical laboratory testsa (central laboratory)

HbA1c
3
3
9

Study Visits
10
8
80

Follow-up
10
1
10
LY3493269 pharmacokinetics
3
21
63
Potential additional LY3493269 
pharmacokinetic samples
3
3
9
Blood discard for cannula patency
0.5
21
10.5
Fasting plasma glucose
2
7
14
6-point glucose
2
30
60
OGTT (central laboratory)

Glucose
2
20
40

Insulin, C-peptide
3
20
60

Glucagon
2
20
40
Gastric-emptying test (acetaminophen PK)
2
33
66
Biomarkers (central laboratory)

Lipid panel 
(triglycerides, total cholesterol, low-
density lipoprotein-cholesterol, very 
low-density lipoprotein-cholesterol, 
and high-density lipoprotein-
cholesterol)
3.5
2
7
Pharmacogenetic sample (stored)
10
1
10
Nonpharmacogenetic sample (stored)

Plasma
2
5
10

Serum
2.5
5
12.5

P800
2
5
10
Immunogenicity
10
4
40
Total
576
Total for clinical purposes (rounded up to the nearest 10 mL)
580
a
Additional samples may be drawn if needed for safety purposes.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting 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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

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
Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 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 preexisting condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

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
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 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records 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.

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

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 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information.

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10.3.4.
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.
10.3.5.
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
10.4.1.
Definitions
Females of Childbearing Potential
A female is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Females NOT of Childbearing Potential
Females in the following categories are not considered women of childbearing potential
1. Premenarchal
2. Premenopausal female with 1 of the following:

documented hysterectomy

documented bilateral salpingectomy

documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (for example, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel: review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with

12 months of amenorrhea for women >55 years, with no need for follicle-stimulating 
hormone (FSH)

12 months of amenorrhea for women >40 years with FSH of ≥40 mIU/mL and no 
other medical condition such as anorexia nervosa and not taking medications during 
the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing 
hormone, anti-estrogens, selective estrogen receptor modulators, or chemotherapy 
that induced amenorrhea)

hormone levels consistent with a post-menopausal state per the local laboratory 
reference range
10.4.2.
Contraception Guidance
10.4.2.1.
Female Participants
Female participants of childbearing potential are excluded from this study.

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10.4.2.2.
Female participants who are not of childbearing potential may participate in this 
study. 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.
10.4.3.
Collection of Pregnancy Information
Male participants with partners who become pregnant
●
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive LY3493269.
●
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed up to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported including fetal status (presence or absence of anomalies) and
indication for the procedure. 
Female participants who become pregnant
●
The investigator will collect pregnancy information on any female participant
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant’s pregnancy. 
●
The participant will be followed up to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, including fetal status 
(presence or absence of anomalies) or indication for the procedure.
●
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
●
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

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●
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. 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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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 or analysis of the entire 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 multi-study 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:
IgA (quantitative)
  HAV total antibody
IgG (quantitative)
  HAV IgM antibody
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 normalization ratio; PT = prothrombin time.
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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10.7.
Appendix 7: Pancreatic Monitoring
Glucagon-like peptide 1 agonists have been associated with a possible risk of acute pancreatitis. 
In 2006, the US 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

characteristic findings of acute pancreatitis on the CT scan or MRI
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. 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 
investigational product.

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Abbreviations: CT = computed tomography; MRI = magnetic resonance imaging; ULN = upper limit of normal.

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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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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
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not.
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
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.
CSE
clinically significant events
CT
computed tomography
CV
cardiovascular

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ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
FSH
follicle-stimulating hormone
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
HbA1c
glycated hemoglobin
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed, and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigator
A person responsible for the conduct of the clinical study at a study site. If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB
institutional review board

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IWRS
interactive web-response system
MRI
magnetic resonance imaging
NASH
nonalcoholic steatohepatitis
NOAEL
no-observed-adverse-effect level
OGTT
oral glucose tolerance test
OTC
over the counter
p-amylase
pancreatic amylase
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
PD
pharmacodynamics
PG
plasma glucose
PK
pharmacokinetics
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
QW
once weekly
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
study intervention
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
TBL
total bilirubin

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T2DM
type 2 diabetes mellitus
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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10.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment [a]: 11-July-2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
For Cohorts 3 and 4, the following timepoints were added:

Visits on Days 9 and 16,

Drug/alcohol screen on Days 8 and 15,

Triplicate ECGs and vital signs at 1, 4, 6, and 12 hours 
post dose on Days 8 and 15, at 24 hours postdose on 
Days 9 and 16, and at 1 and 4 hours postdose on Day 
22, and

Pharmacokinetic samples at 4 hours postdose on Days 8 
and 15.
Based on feedback 
from the FDA
1.3 Schedule of 
Activities
Table 1 shows Assessment Schedules for Oral Glucose 
Tolerance and Gastric Emptying Tests with separate 
sampling schedules for each test.
Original table revised 
for clarity.
4.3 Justification 
of Dose
In Table 3, an error in the human maximum dose (mg/kg) 
was corrected from 0.556 to 0.0556.  
Based on feedback 
from the FDA.
5.1 Inclusion 
Criteria
Upper age limit for participants reduced to 65 years.
Based on feedback 
from the FDA.
6.6.2 Dose-
Escalation 
Stopping 
Criteria
Added the follow stopping criteria:  
Three or more participants at the same dose level 
experience drug-related GI effects causing severe distress 
and/or clinically significant cardiovascular AE deemed 
related to LY3493269 administration. 
Based on feedback 
from the FDA.
7.1.2 Persistent 
Hyperglycemia/ 
Hypoglycemia
Added details on the number and duration of hypoglycemic 
events to be considered for discontinuation of study 
intervention.
Based on feedback 
from the FDA.
8.9 
Immunogenicity 
Assessments
Removed that ADA cross-reactively binds to native GIP ad 
GLP-1 would necessitate additional ADA samples 
Based on feedback 
from the FDA.
10.4.2.1 Female 
participants
Removed the contraception restriction for female 
participants not of childbearing potential.
These restrictions did 
not provide the 
participant with any 
additional safety 
benefit.

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Amendment [b]: 13-October-2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment:
This amendment serves to clarify that dose escalation between cohorts will be based on a review 
of 2-week safety and tolerability data from participants who received LY3493269 through Day 
15 at the preceding lower dose.
Section # and 
Name
Description of Change
Brief Rationale
1.2. Schema
Diagram was updated to reflect 
data reviews for dose-escalation 
decisions.
4.2. Scientific 
Rationale for 
Study Design
Text updated to allow “up to 2” 
from “2” participants to be assigned 
to dulaglutide or placebo treatment
per cohort.
Deleted the redundant text “The 
decision to escalate doses between 
and within the cohorts will be based 
primarily on safety and tolerability 
data from preceding dose cohorts 
and within the cohort”. This text 
was reported in Section 6.6.1.
Editorial change to align with 
intended completion of 
“approximately” 12 evaluable 
participants in each cohort.
5.1. Inclusion 
Criteria
Upper age limit for participants 
revised to 70 years.
The protocol is amended to 
increase the age limit to 70 years 
for the following reasons: 
(1) No relevant differences with 
regard to safety between 
individuals aged <65 years and 
those >65 years have been observed 
with incretin agents
(Boustani et al. 2016, 
Warren et al. 2018);
(2) One common concern in elderly 
population is the risk of severe 
hypoglycemia (Warren et al. 2018); 
(3) Severe hypoglycemia occurs 
rarely with incretin therapy as these 
agents are not insulin 
secretagogues;

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Section # and 
Name
Description of Change
Brief Rationale
(4) There were no events of severe 
hypoglycemia after single dose of 
LY3493269 in healthy participants;
(5) To enable enrolment during the 
current COVID-19 pandemic;
(6) To allow for a broader 
population to be safely studied.
6.6.1. Dose 
Escalation
Text updated to describe dose-
escalation decisions between 
successive cohorts, which would be 
based on data from preceding 
doses.
Clarified language describing dose 
adjustments for participants with 
tolerability issues after dose 
escalations within Cohorts 3 and 4.
Dose escalations between 
successive dose levels are based on 
data from preceding lower doses, 
and not “cohorts”.
Dose adjustments will be based on 
individual patient-level safety and 
tolerability data.  

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11.
References
[ADA] American Diabetes Association. Glycemic targets: standards of medical care in diabetes -
2019. Diabetes Care. 2019;42(Suppl 1):S61–S70.
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
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Boustani, M. A., Pittman Iv, I., Yu, M., Thieu, V. T., Varnado, O. J., & Juneja, R. (2016). 
Similar efficacy and safety of once‐weekly dulaglutide in patients with type 2 diabetes aged≥ 
65 and< 65 years. Diabetes, Obesity and Metabolism, 18(8), 820-828.
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 
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Danne T, Philotheou A, Goldman D, et al. A randomized trial comparing the rate of 
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Pediatr Diabetes. 2013;14(8):593-601. Erratum in: Pediatr Diabetes. 2015;16(6):462.
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. 
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Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and 
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active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota 
M, Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S. JPN guidelines for the management of 
acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
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Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon‑like peptide‑1 receptor 
agonists on heart rate. Cardiovasc Diabetol. 2017;16:6.
Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Co.; 2019.
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.
Warren, M., Chaykin, L., Trachtenbarg, D., Nayak, G., Wijayasinghe, N., & Cariou, B. (2018). 
Semaglutide as a therapeutic option for elderly patients with type 2 diabetes: Pooled analysis 
of the SUSTAIN 1‐5 trials. Diabetes, Obesity and Metabolism, 20(9), 2291-2297.
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.

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Young A. Inhibition of gastric emptying. Adv Pharmacol. 2005;52:99-121.

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