Clinical trial NCT04178733
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-01-10; Completion date: 2020-05-11
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to determine the side effects related to LY3493269 given as a single injection to healthy participants. Blood tests will be performed to check how much LY3493269 gets into the bloodstream and how long the body takes to get rid of it. Each enrolled participant will receive a single dose of LY3493269 or placebo. The study will last up to approximately 71 days for each participant, including screening.

Detailed description:

Arms: arm 1: Participants received Placebo subcutaneously (SC). arm 2: Participants received 0.5 mg LY3493269 intravenously (IV). arm 3: Participants received 0.15 mg LY3493269 SC. arm 4: Participants received 0.5 mg LY3493269 SC. arm 5: Participants received 1.5 mg LY3493269 SC.
Interventions: intervention 1: LY3493269 - SC intervention 2: Placebo - SC intervention 3: LY3493269 - IV
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol J1X-MC-GZHA 
 
A Single-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 
LY3493269 in Healthy Participants 
 
NCT04178733 
 
Approval Date: 10-Oct-2019 


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1
L Y 3 4 9 3 2 6 9
Pr ot o c ol J 1 X -M C -G Z H A
A Si n gl e -A s c e n di n g D o s e St u d y  t o I n v e sti g at e t h e S af et y, 
T ol er a bilit y , a n d P h ar m a c o ki n eti c s of L Y 3 4 9 3 2 6 9 i n 
H e alt h y P arti ci p a nt s
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 pr ot o c ol 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 el 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.
A p pr o v al D at e: 1 0- O ct- 2 0 1 9 G M T
L Y 3 4 9 3 2 6 9
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Table of Contents
A Single-Ascending Dose Study to Investigate the Safety, 
Tolerability, and Pharmacokinetics of LY3493269 in Healthy 
Participants
Section
Page
Protocol J1X-MC-GZHA A Single-Ascending Dose Study to Investigate 
the Safety, Tolerability, and Pharmacokinetics of LY3493269 in 
Healthy Participants ............................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.1.1.
Inpatient Visit (Day -2/ Day -1 through Day 4) ....................................................22
5.1.2.
Outpatient Visits (Days 5, 6, 8, and 15)................................................................22
5.1.3.
Follow-Up Visits (Days 29 and 43)......................................................................23
5.2.
Number of Participants.................................................................................................23
5.3.
End of Study Definition ...............................................................................................23
5.4.
Scientific Rationale for Study Design...........................................................................23
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................28
6.1.
Inclusion Criteria..........................................................................................................28
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle and/or Dietary Requirements .........................................................................31
6.3.1.
Meals and Dietary Restrictions.............................................................................31
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................31
6.3.3.
Activity................................................................................................................32
6.3.4.
Contraception.......................................................................................................32
6.4.
Screen Failures.............................................................................................................33
7.
Treatment..........................................................................................................................34
7.1.
Treatment Administered...............................................................................................34


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LY3493269
7.1.1.
Injection Sites ......................................................................................................35
7.1.2.
Packaging and Labeling .......................................................................................35
7.2.
Method of Treatment Assignment ................................................................................35
7.2.1.
Selection and Timing of Doses.............................................................................35
7.3.
Blinding .......................................................................................................................35
7.4.
Dose Modification for Subcutaneous Cohorts Only......................................................36
7.4.1.
Dose Decision/Escalation.....................................................................................36
7.4.2.
Termination of Dosing/Dose Escalation ...............................................................37
7.4.2.1.
Premedication for IV Administration..............................................................37
7.4.2.2.
Management of IV Administration Reactions .................................................38
7.5.
Dose Modification for Intravenous Cohort ...................................................................38
7.6.
Preparation/Handling/Storage/Accountability...............................................................38
7.7.
Treatment Compliance .................................................................................................39
7.8.
Concomitant Therapy...................................................................................................39
7.9.
Treatment after the End of the Study............................................................................39
8.
Discontinuation Criteria ....................................................................................................40
8.1.
Discontinuation from Study Treatment.........................................................................40
8.1.1.
Discontinuation of Inadvertently Enrolled Participants.........................................40
8.2.
Discontinuation from the Study....................................................................................40
8.3.
Participants Lost to Follow-up......................................................................................40
9.
Study Assessments and Procedures ...................................................................................41
9.1.
Efficacy Assessments...................................................................................................41
9.2.
Adverse Events ............................................................................................................41
9.2.1.
Serious Adverse Events........................................................................................42
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................43
9.2.2.
Complaint Handling.............................................................................................43
9.3.
Treatment of Overdose.................................................................................................43
9.4.
Safety...........................................................................................................................43
9.4.1.
Laboratory Tests ..................................................................................................43
9.4.2.
Physical Examination/Medical Assessments.........................................................43
9.4.3.
Body Weight........................................................................................................43
9.4.4.
Vital Signs ...........................................................................................................44
9.4.5.
Electrocardiograms ..............................................................................................44
9.4.5.1.
Single/Triplicate ECGs...................................................................................44
9.4.5.2.
Safety Monitoring...........................................................................................45
9.4.5.3.
Nausea, Vomiting, and Diarrhea .....................................................................45
9.4.5.4.
Pancreatic Safety (Elevated Lipase or Amylase) .............................................46
9.4.5.5.
Hepatic Safety................................................................................................46


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LY3493269
9.4.5.6.
Injection Site Reactions ..................................................................................46
9.4.5.7.
Hypersensitivity Reactions .............................................................................47
9.4.6.
Glucose Monitoring .............................................................................................47
9.5.
Immunogenicity Assessments.......................................................................................49
9.6.
Pharmacokinetics .........................................................................................................49
9.6.1.
Bioanalysis...........................................................................................................49
9.7.
Pharmacodynamics ......................................................................................................50
9.7.1.
Oral Glucose Tolerance Test ................................................................................50
9.7.2.
Pharmacodynamic Markers..................................................................................50
9.8.
Genetics .......................................................................................................................50
9.9.
Biomarkers...................................................................................................................51
9.10. Appetite Analysis.........................................................................................................51
9.11. Health Economics ........................................................................................................52
10.
Statistical Considerations and Data Analysis.....................................................................53
10.1. Sample Size Determination ..........................................................................................53
10.2. Populations for Analyses..............................................................................................53
10.2.1.
Study Participant Disposition ...............................................................................53
10.2.2.
Study Participant Characteristics ..........................................................................53
10.3. Statistical Analyses ......................................................................................................53
10.3.1.
Safety Analyses....................................................................................................54
10.3.1.1.
Clinical Evaluation of Safety..........................................................................54
10.3.1.2.
Statistical Evaluation of Safety.......................................................................54
10.3.2.
Pharmacokinetic Analyses....................................................................................54
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................54
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................55
10.3.3.
Pharmacodynamic Analyses.................................................................................55
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................55
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................55
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................55
10.3.5.
Evaluation of Immunogenicity .............................................................................56
10.3.6.
Data Review During the Study.............................................................................56
10.3.7.
Interim Analyses..................................................................................................56
11.
References ........................................................................................................................57
12.
Appendices .......................................................................................................................58


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
List of Tables
Table
Page
Table GZHA.1.
Objectives and Endpoints .......................................................................19
Table GZHA.2
Margin of Safety for Subcutaneous Administration of LY3493269 
Based on Administered Dose and Predicted Exposure ............................27
Table GZHA.3.
Treatments Administered........................................................................34


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
List of Figures
Figure
Page
Figure GZHA.1.
Illustration of study design for Protocol J1X-MC-GZHA........................21


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LY3493269
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................59
Appendix 2.
Clinical Laboratory Tests........................................................................64
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................65
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............68
Appendix 5.
Blood Sampling Summary......................................................................69
Appendix 6.
Pancreatic Monitoring ............................................................................71
Appendix 7.
Hypersensitivity Event Tests ..................................................................74
Appendix 8.
Guidance on Clinically Significant Events..............................................75


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
1. Protocol Synopsis
Title of Study:
Protocol J1X-MC-GZHA A Single-Ascending Dose Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of LY3493269 in Healthy Participants.
Rationale: 
LY3493269 is a dual-agonist peptide that combines actions of glucose-dependent insulinotropic polypeptide (GIP)
and glucagon-like peptide-1 (GLP-1).  LY3493269 is being developed for the treatment of type 2 diabetes mellitus 
(T2DM) as a once-weekly (QW) subcutaneous (SC) administration.
Study J1X-MC-GZHA is designed to assess the safety, tolerability, and pharmacokinetics (PK) of single doses of 
LY3493269 when administered in healthy participants, as single SC doses, and as a single IV dose.  
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To evaluate the safety and tolerability of LY3493269 
following single SC and IV doses in healthy 
participants
TEAEs and SAEs
Secondary
To characterize the PK of LY3493269 following single 
SC and IV doses in healthy participants
AUC, Cmax, and tmax
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum observed drug 
concentration; IV = intravenous; PK = pharmacokinetic(s); SAE = serious adverse event; SC = subcutaneous; 
TEAE = treatment-emergent adverse events; tmax = time to maximum observed drug concentration
Summary of Study Design:  
Study J1X-MC-GZHA is a single center, randomized, placebo controlled study with 6 cohorts receiving SC doses 
and 1 cohort receiving IV doses.  The investigator and participants will be blinded to treatments administered via the 
subcutaneous route.  
Treatment Arms and Planned Duration for an Individual Healthy Participant:  
Up to 6 cohorts of approximately 8 participants each (6 LY3493269 and 2 placebo) receiving a SC dose and 1 
cohort of approximately 6 participants receiving an IV dose of LY3493269 are planned. Screening may occur up to 
28 days prior to enrollment; each participant may be in the study for up to 71 days including the screening period.


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Number of Healthy Participants:
Approximately 70 healthy participants may be enrolled so that approximately 54 participants complete the study.
Statistical Analysis:
Safety analyses will be conducted for all enrolled participants who receive 1 dose of the investigational product (IP), 
whether they completed all protocol requirements. Pharmacokinetic analyses will be conducted on data from all 
participants who receive 1 dose of the IP and have evaluable PK data.  
Safety and tolerability: All IP and protocol procedure-related adverse events will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.  Safety parameters that will be 
assessed include safety laboratory parameters, vital signs, injection site reactions, and electrocardiogram parameters.  
All serious adverse events will be reported.
Pharmacokinetics: Pharmacokinetic parameter estimates for LY3493269 will be calculated by standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum observed drug 
concentration (Cmax) and area under the concentration-time curve (AUC).  Other noncompartmental parameters, 
such as half-life, apparent clearance, time to Cmax (tmax), and apparent volume of distribution may also be reported.  


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
2. Schedule of Activities


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Study Schedule Protocol J1X-MC-GZHA – for Subcutaneous Cohorts
Procedure
Screening
Treatment Period: SC Cohort 
Follow-up
Comments/ Notes
Days
-28 to -2
−2
−1
1
2
3
4
5
6
8
15 
± 1
29
± 3
43 
± 3
ET
Study informed consent
X
Medical history
X
Physical examination/ 
Medical assessment
X
X
P
X
X
X
X
X
X
X
X
Complete physical 
examination at screening.  
Symptom-directed
physical examination
across study at other 
timepoints.
Height and weight
X
P
X
X
X
X
X
Height at Screening only.
Confirmation of eligibility
followed by randomization
X
Admit to CRU
X
Discharge from CRU – on 
completion of inpatient 
procedures
X
Participants may remain 
inpatient longer than 
Day 4, at the 
investigator’s discretion.
Administer study drug
X
Refer to Section 7.1.
AEs/ concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs: supine BP and PR
(h)
X
P, 
1, 4, 
6, 12
24
48
72
96
120 168
X
X
X
X
For Day 15 and 
subsequent visits, vital 
signs should be measured 
within 30 min of the 
scheduled PK sample.
Body temperature (h)
X
P, 
6, 12
24
ECG – single
X
X
X
X


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Procedure
Screening
Treatment Period: SC Cohort 
Follow-up
Comments/ Notes
Days
-28 to -2
−2
−1
1
2
3
4
5
6
8
15 
± 1
29
± 3
43 
± 3
ET
ECG – triplicate (m, h)
-30m, 
-15m, 
0, 
1, 4,
6, 12h
24
48
72
96
120 168
X
Day 1 Predose ECGs will 
be taken in triplicates at -
30, -15 and 0 min to 
establish a baseline.
Day 15 ECG should be 
measured within 
approximately 30 min of 
the PK sample.
Clinical safety lab tests (fasted)
X
P
X
X
X
X
X
X
X
Collected following ≥8h 
overnight fast.  
See Appendix 2, Clinical 
Laboratory Tests, for 
details.  
Serology
• Hepatitis B surface antigen, 
Hepatitis B core antibody
• Hepatitis C antibody 
• HIV
X
Point of care safety glucose 
samples
Days 1 – 3:
Pre-meals (breakfast, 
lunch and dinner)
and before bedtime
X
X
X
Days 4 -6: Fasted samples
collected before 
breakfast.
PK sampling (h)
P, 
6, 12
24
48
72
96
120 168
X
X
X
X
Days 15, 29, 43 and ET: 
Samples collected 
anytime during visit.
The ET sample is not 
required for participants 
who discontinued without 
receiving IP.
OGTT – 75 g glucose challenge 
(h)
X
24 
Conducted following 
overnight fast.


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 3
L Y 3 4 9 3 2 6 9
Pr oce d ure
Scree n i n g
Tre at me nt Peri o d : S C C o h ort 
F oll o w -u p
C o m me nts/ N otes
D a ys
-2 8 t o - 2
−2
−1
1
2
3
4
5
6
8
1 5 
± 1
2 9
± 3
4 3 
± 3
E T
P D bi o mar kers ( h):
• Gl uc ose
• I ns uli n a n d C- pe pti de
•
Pr e -O G T T, 
0. 5, 1, 1. 5, 
a n d 2 h
p ost -
O G T T
P
Pr e -O G T T, 
0. 5, 1, 1. 5, 
a n d 2 h
p ost -
O G T T
4 8 
7 2
X  
X  
X
Da ys 1, 3, 4, 8 , 1 5 a n d 2 9: 
Sa m ples dra w n after 
mi ni m u m 8 -h o ur fast.
 
I m m u n o ge nicit y
P
X  
X  
X  
X
A p petite V A S ( h)
P 
2 4 
4 8  
X  
X  
X  
X
O btai ne d after a n 
o ver ni g ht fast.
P har mac o ge netic sa m ple
X
Sa m ple ma y be o btai ne d 
at a n y ti me on D a y 1.
N o n p har mac o ge netic sa m pli n g 
(st ora ge) ( h)
P 
2 4 
4 8
X
Sa m ples dra w n after 
mi ni m u m 8 -h o ur fast.
C CI
A b bre viati o ns: C R U = cli nical researc h u nit; E C G = electr ocar di o gra m; E T = earl y ter mi nati o n; h = h o ur; I G F B P 2 = ins uli n -li ke g r owt h fact or b i n di n g pr otei n 2;
m = mi n ute s; P = p re d ose; P D = p har mac o d y na mics; P K = p har mac o ki netics ; S C = s u bc uta ne o us
N ote s:  If m ulti ple pr oce d ures ta ke place at t he sa me ti me p oi nt, E C Gs a n d vital si g ns m ust be o btai ne d pri or t o a n y bl o o d sa m ple c ollecti o n .
U n less ot her wise state d:
•
pre d ose st u d y assess me nts a n d pr oce d ures s h o ul d be perf or me d wit hi n 3 h o urs pri or t o pla n ne d d osi n g ,
•
p ost d ose assess me nts a n d pr oce d ures u p t o a n d i ncl u di n g 2 4 h o urs s h o ul d be perf or me d wit hi n ± 1 0 % of t he sc he d ule d ti me , a n d
•
p ost d ose assess me nts a n d pr oce d ures sc h e d ule d after t he 2 4 -h o ur ti me p oi nt s h o ul d be perf or me d wit hi n ± 3 h o urs of t he sc he d ule d ti me .
C CI


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Study Schedule Protocol J1X-MC-GZHA – Intravenous Cohort
Procedure
Screening
Treatment Period: IV Cohort
Follow-up
Comments/ Notes
Days
-28 to -2
−1
1
2
3
4
5
6
8
15 
± 1
29
± 3
43 
± 3
ET
Study informed consent
X
Medical history
X
Physical examination/ 
Medical assessment
X
P
X
X
X
X
X
X
X
X
Complete physical examination at 
screening.  Symptom-directed physical 
examination across study at other 
timepoints.
Height and weight
X
P
X
X
X
X
X
Height at Screening only.
Confirmation of eligibility
followed by randomization
X
Admit to CRU
X
Discharge from CRU – on 
completion of inpatient 
procedures
X
Participants may remain inpatient
longer than Day 4, at the investigator’s 
discretion.
Administer study drug
X
Refer to Section 7.1.
AEs/ concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs: supine blood 
pressure and pulse rate (m, h)
X
P, 5m, 15m, 
and 30m, 8h, 
12h
24
48
72
96
120 168
X
X
X
X
For Day 15 and subsequent visits, vital 
signs should be measured within 
30 min of the scheduled PK sample.
Body temperature (h)
X
P, 0.5, 8, 12 
24
ECG – single
X
X
X
X
ECG – triplicate (m, h)
-30m, -15m, 
P, 0.5, 8, 12h
24
48
72
96
120 168
X
Day 15 ECG should be measured 
within 30 min of the PK sample.
Day 1 Predose ECGs will be taken in 
triplicates at -30, -15 and 0 min to 
establish a baseline.
Clinical safety lab tests
(fasted)
X
P
X
X
X
X
X
X
X
Collected following ≥8h overnight fast.  
See Appendix 2, Clinical Laboratory 
Tests, for details.  


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
Procedure
Screening
Treatment Period: IV Cohort
Follow-up
Comments/ Notes
Days
-28 to -2
−1
1
2
3
4
5
6
8
15 
± 1
29
± 3
43 
± 3
ET
Serology
• Hepatitis B surface antigen, 
Hepatitis B core antibody
• Hepatitis C antibody 
• HIV
X
Point of care safety glucose 
samples
Days 1- 3:
Pre-meals (breakfast, 
lunch and dinner)
and before bedtime
X
X
X
Days 4 -6: Samples collected before 
breakfast, following ≥8h overnight fast.
PK sampling (m, h)
P, EI, 
15m, 30m, 
1, 2, 4, 8, 12 h
24
48
72
96
120 168
X
X
X
X
Days 15, 29, and 43 and ET: samples 
are collected anytime during visit.
The ET sample shall be omitted for 
participants who discontinued without 
receiving IP.
Immunogenicity
P
X
X
X
X
Pharmacogenetic sample
X
Nonpharmacogenetic 
sampling (storage) (h)
P
24
48
X
Collected following ≥8h overnight fast.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; EI = end of study drug administration; ET = early termination; h = hour; 
IV = intravenous; m = minutes; P = predose; PD = pharmacodynamics; PK = pharmacokinetics; SC = subcutaneous
Notes:  If multiple procedures take place at the same time point, ECGs and vital signs must be obtained prior to any blood sample collection.
Unless otherwise stated:
•
predose study assessments and procedures should be performed within 3 hours prior to planned dosing,
•
postdose assessments and procedures up to and including 24 hours should be performed within ±10% of the scheduled time, and
•
postdose assessments and procedures scheduled after the 24-hour timepoint should be performed within ±3 hours of the scheduled time.


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
3. Introduction
3.1.
Study Rationale
LY3493269 is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like 
peptide-1 (GLP-1) receptor agonist being developed as a treatment for type 2 diabetes mellitus 
(T2DM).  This first-in-human study of LY3493269, J1X-MC-GZHA (GZHA), will investigate 
the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY3493269
administered as single subcutaneous (SC) doses in healthy participants. In addition, a cohort of 
healthy participants will receive a single intravenous (IV) dose of LY3493269, to allow
estimation of the absolute bioavailability of LY3493269.
3.2.
Background
Type 2 diabetes mellitus is characterized by impaired glycemic control due to insulin resistance 
and inadequate insulin secretion due to beta-cell failure. Frequently, T2DM is associated with 
comorbidities such as obesity, hypertension, and dyslipidemia resulting in increased 
cardiovascular (CV) risk. LY3493269 is being developed as a once-weekly (QW) subcutaneous 
treatment for T2DM; a once-daily oral formulation of LY3493269 is also being developed.
LY3493269 is a dual-agonist peptide that combines actions of glucose-dependent insulinotropic 
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). 
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. 
A well-characterized incretin hormone, GLP-1 potentiates insulin 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 
cells and in some non-islet cells. For example, GLP-1Rs (GLP-1 receptors) are expressed 
throughout the brain, in regions that control glucose homeostasis, gut motility, food intake, 
aversive signaling, and CV function (Campbell and Drucker 2013).  Currently, there are several 
approved GLP-1 receptor agonists (GLP-1RAs) for the treatment of diabetes and obesity.  The 
dosing of GLP-1RAs in humans is limited by gastrointestinal (GI) adverse effects, such as 
nausea and vomiting.  
Available preclinical and clinical data indicate that co-stimulation of GIP and GLP-1 receptors 
may enhance insulin secretion, improve insulin sensitivity, and reduce body weight beyond the 
effect of selective GLP-1R stimulation (Frias et al. 2018; Coskun et al. 2018). For example, 
Lilly is currently developing tirzepatide, a dual GIPRA (GIP receptor agonist)/GLP-1RA, now in 
Phase 3 development, targeted as a subcutaneous once-weekly (QW) therapy, to improve
glycemic control in adults with T2DM, as an adjunct to diet and exercise.  
Nonclinical safety of LY3493269 was evaluated in a CV safety pharmacology study in monkeys 
and 1-month repeat-dose toxicology studies in rats and monkeys. Important LY3493269-related 


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
findings in the rat and monkey repeat-dose toxicity studies were generally consistent with, or 
secondary to, GIP and/or GLP-1 pharmacology and included body weight loss and/or reduced 
body weight gain and decreased food consumption.  Additional findings from the monkey
studies, including changes in CV parameters (such as increases in heart rate and blood pressure),
were attributed to on target GLP-1 and/or GIP pharmacology. More information about the 
toxicologic profile of LY3493269 is available in the Investigator’s Brochure (IB).
3.3.
Benefit/Risk Assessment
The nonclinical safety information for LY3493269 adequately supports the transition from 
preclinical status to a clinical, single-dose study.  
The sponsor has evaluated the risks associated with LY3493269 and does not consider it to be a 
high-risk or high uncertainty compound based on the nonclinical data, published criteria (Butler 
et al. 2017) and other factors described below:
•
Findings in the toxicology studies were consistent with, or secondary to, the expected 
pharmacology for the drug class.
•
The animal toxicity models are believed to adequately reflect human toxicity for the GIP 
receptor (GIPR) and GLP-1R target.
•
Target engagement and activity will be clinically measurable with biomarkers employed 
during the study; anticipated effects on CV parameters, body weight loss, gastrointestinal 
effects, appetite loss are clinically monitorable and reversible.
This protocol reflects the fact that LY3493269 has not been administered to humans previously, 
and to mitigate this risk, the study has been designed to be conducted in accordance with 
principles outlined in the European Medicines Agency (EMA) Guideline (2017) on strategies to 
identify and mitigate risks for first-in-human clinical trials with investigational medicinal 
products.  
Any identified risks from preclinical studies (for example CV effects, gastrointestinal [GI] 
effects, decreased/loss of appetite, and weight loss) are similar to those noted during 
development of GIP and GLP-1 agonists; these are considered to be monitorable and manageable 
at the planned dose range of 0.15 to 7.5 mg for LY3493269 in healthy participants. To further 
minimize any potential risk, study participants will remain at least 3 days in the clinical research 
unit (CRU) where they will be monitored for safety and tolerability until discharge, at the 
discretion of the investigator.  During the 3-day CRU residence and through 7 days postdose, 
participants will be closely monitored with scheduled medical assessments, vital signs and 
triplicate ECG measurements.  The investigator will have the discretion to extend the participant
inpatient stay if necessary, for further safety monitoring.
There is no anticipated therapeutic benefit for the healthy participants in this study. However, it
is well known that co-administration of a GIPR mono-agonist and a GLP-1R mono-agonist, as 
well as the administration of a unimolecular dual-acting GIPR and GLP-1R agonist, has shown 
profound weight-lowering benefits that exceed that of either agent alone (Finan et al. 2016).  


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LY3493269
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3493269 are to be found in the IB.


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1 9
L Y 3 4 9 3 2 6 9
4. O bj e cti v e s a n d E n d p oi nt s
Ta ble G Z H A . 1 s h o ws t he o bjecti ves a n d e n d p oi nts of t he st u d y.
T a bl e G Z H A . 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y
T o e val uate t he safet y a n d t olera bilit y of L Y 3 4 9 3 2 6 9 
f oll o wi n g si n gle S C a n d I V d ose s i n healt h y  partici pa nts
T E A Es a n d S A Es
Sec o n d ar y
T o c haracterize t he P K of L Y 3 4 9 3 2 6 9 f oll o wi n g si ngle 
S C a n d I V d oses i n healt h y partici pa nts
A U C, C ma x , a n d tma x
  
E x pl or at or y
T o i n vesti gate t he P D effects of L Y 3 4 9 3 2 6 9 f oll o wi n g 
si n gle S C d oses i n healt h y  partici pa nts
C ha n ge s fr o m baseli ne le vels of

fasti n g gl uc ose , i ns uli n a n d C-pe pti de

gl uc ose, i ns uli n a n d C -pe pti de A U C d uri n g a n 
O G T T

b o d y w ei g ht , 
T o e x pl ore i m m u n o ge nicit y of L Y 3 4 9 3 2 6 9 f oll o wi n g 
si n gle d oses i n healt h y partici pa nts
I nci de nce of T E-A D A
T o e x pl ore t he effect of L Y 3 4 9 3 2 6 9 o n a p petite a n d 
f o o d i nta ke f oll o wi n g si n gle S C d oses i n healt h y 
partici pa nts
C ha n ge i n V A S sc ore f or a p petite assess me nt i n a faste d 
state
A b bre viati o ns:  A U C = area u n der t he c o nce ntrati o n vers us ti me c ur ve; C ma x = ma xi m u m o bser ve d dr u g 
c o nce ntrati o n; I G F B P 2 = ins uli n -li ke g r owt h f act or b i n di n g pr otei n 2; I V = i ntra ve n o us; O G T T = oral gl uc ose 
t olera nce test; P D = p har mac o d y na mic(s); P K = p har mac o ki netic(s); S A E = seri o us a d verse e ve nt; 
S C = s u bc uta ne o us; T E-A D A = treat me nt -e mer ge nt a nti dr u g a nti b o dies; T E A E = treat me nt -e mer ge nt a d verse 
e ve nts; T ma x
C CI
= ti me t o ma xi m u m o bser ve d dr u g c o nce ntrati o n ; V A S = vis ual a nal o g scale 


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LY3493269
5. Study Design
5.1.
Overall Design
Study GZHA is a Phase 1, single-site, randomized, placebo controlled, single-ascending dose 
(SAD) study in healthy participants, to evaluate the safety, tolerability, and PK of LY3493269
administered as single SC doses and as a single IV dose.  The PD effects of SC doses of 
LY3493269 on glycemic effects (including fasting glucose, insulin, and glucose and insulin 
during an OGTT) and appetite will be explored. For the SC cohorts, the investigator and 
participants will be blinded.  The IV Cohort is open-label with no placebo.  
The planned LY3493269 SC doses for this study range from 0.15 mg to 7.5 mg (Section 5.5).  
These dose levels may be adjusted (for example, dose increments may be reduced, a dose level 
may be repeated, or a lower/intermediate dose may be administered) based on ongoing review of 
available safety, tolerability, PK, and PD data (Section 7.4). Any proposal to adjust SC or IV 
doses from those planned and stated in the protocol, together with supporting data, will be 
reviewed by an independent safety review panel (SRP).  
Participants will undergo safety (including but not limited to AEs, medical assessments, clinical 
laboratory tests, body weight, vital signs and ECGs), PK and PD assessments according to the 
Schedule of Activities (Section 2).  
Study governance considerations are described in detail in Appendix 3.
Subcutaneous Administration Cohorts 1 through 6
Study GZHA includes up to 6 planned SC cohorts:

SC Cohort 1: 0.15 mg (6 LY3493269: 2 Placebo)

SC Cohort 2: 0.5 mg (6 LY3493269: 2 Placebo)

SC Cohort 3: 1.5 mg (6 LY3493269: 2 Placebo)

SC Cohort 4: 3.0 mg (6 LY3493269: 2 Placebo)

SC Cohort 5: 5.0 mg (6 LY3493269: 2 Placebo)

SC Cohort 6: 7.5 mg (6 LY3493269: 2 Placebo)
Cohorts 2 to 6 will be initiated only if the investigator and the Eli Lilly and Company (Lilly) 
clinical pharmacologist deem the safety results (AEs, clinical safety laboratory tests, vital signs,
12-lead ECGs, and medical assessments) in the preceding cohort to be acceptable through Day 8
(that is, 7 days postdose) from at least 6 participants dosed. In addition, all planned participants 
in the current cohort should have been dosed prior to escalation to the next cohort.
Intravenous Administration Cohort 
Study GZHA includes a single IV cohort (IV Cohort), where up to 6 healthy participants should 
complete dosing at the same dose level to provide sufficient PK sampling. The IV Cohort will


J1X-MC-GZHA Clinical Pharmacology Protocol
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LY3493269
be initiated based on review of safety and tolerability data from SC Cohort 3 (SC dose 1.5 mg) 
and available 7-day PK data and/or PD data from at least 2 preceding SC cohorts. 
All participants will receive LY3493269 only (that is no placebo group), as a single IV bolus 
dose.  The planned dose is 0.5 mg.  This dose is expected to be safe while providing plasma 
concentrations that can be adequately measured over the sampling time period enabling adequate 
characterization of the PK profile. The IV dose may be increased to a maximum of 1.5 mg or 
decreased to a minimum of 0.25 mg depending on emerging data (see details in Sections 5.5 and 
7.5). It is intended that the IV dose will be administered sequentially, with 1 participant having 
completed the dosing and observed for at least 20 minutes before the next participant is dosed.
In the IV Cohort, 2 participants will initially receive the planned 0.5 mg dose. An additional 4
participants will receive IP following joint investigator and sponsor review of safety and 
tolerability data through at least 4 days postdose (including Day 5 safety labs and assessments)
from the 2 initial participants.  
Figure GZHA.1 illustrates the study design.
Abbreviations: IV = intravenous; LY = LY3493269; PL = Placebo; SC = subcutaneous.
Figure GZHA.1.
Illustration of study design for Protocol J1X-MC-GZHA.


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LY3493269
Participant eligibility for this study will be determined at a screening visit; participants will be 
required to attend the CRU on at least 8 occasions:

A screening visit (may occur up to 28 days prior to enrollment)

An inpatient stay comprising admission on Day -2 for SC administration cohorts or 
Day -1 for the IV administration cohort, with subsequent dosing on Day 1 followed by 
inpatient monitoring up to Day 4

Four outpatient visits on Days 5, 6, 8, and 15

Two outpatient follow-up visits on Days 29 and 43
If the investigator decides not to administer the planned dose to a participant or not to enroll a 
participant on a certain day, the participant may be rescheduled to participate in a subsequent 
dose cohort if he/she consents to doing so.  If this situation arises:

The investigator documents the agreement by the participant to proceed

Any procedures performed up to that point may be repeated to obtain predose 
measurements and/or to confirm eligibility of the participant for the study
5.1.1. Inpatient Visit (Day -2/ Day -1 through Day 4)
Eligible participants will be admitted to the CRU on Day -2 or Day -1 (for SC or IV 
administration cohorts, respectively) and adhere to an overnight fast.  
Participants in the SC administration cohorts will undergo baseline assessments on Day -1, 
including an oral glucose tolerance test (OGTT), blood sampling for PD/biomarker assessments, 
and an appetite assessment using a visual analog scale (VAS).  
On the morning of Day 1, participants will receive a single-dose of their assigned treatment 
(either LY3493269 or placebo) in the fasted state.  The IP will be administered either as a SC or 
IV dose, per treatment assigned for each participant.
Pharmacokinetic and PD sampling and safety assessments, including AE, medical assessments, 
clinical laboratory tests, vital signs and ECGs, will be performed according to the Schedule of 
Activities (Section 2).  Pharmacokinetic and PD sampling schedules may be modified based on 
the available safety and PK/PD data.
If deemed medically fit by the investigator, participants will be discharged from the CRU on 
Day 4 after completing the scheduled assessments.  Participants may remain as needed at the 
CRU for safety monitoring based on the investigator’s judgement. 
5.1.2. Outpatient Visits (Days 5, 6, 8, and 15)
Participants will return to the CRU for outpatient visits on Days 5, 6, 8 and 15, for safety 
assessments, PK, PD and/or immunogenicity (antidrug antibody [ADA]) sampling at the times 
specified in the Schedule of Activities (Section 2).  Participants may remain as needed at the 


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LY3493269
CRU for safety monitoring based on the investigator’s judgement or to facilitate participant
compliance.
5.1.3. Follow-Up Visits (Days 29 and 43)
On Days 29 and 43, two follow-up visits will occur where participants will undergo study 
assessments specified in the Schedule of Activities (Section 2).  
Participants who received IP and who discontinue early will be encouraged to return for follow-
up visit(s) for safety monitoring, including but not limited to 28 days after IP administration.  All 
enrolled participants who discontinue without receiving IP will observe an early termination visit 
with procedures performed as shown in the Schedule of Activities (Section 2).
Participants will be discharged after the investigator has completed review of all final safety 
assessments from the last follow-up visit.
5.2.
Number of Participants
Up to 70 participants may be enrolled so that approximately 54 participants complete the study.  
For purposes of this study, a participant completes the study when all scheduled procedures 
shown in the Schedule of Activities have been finished.  
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last participant.
5.4.
Scientific Rationale for Study Design
A population of healthy participants is selected to assess the safety and tolerability at the initial 
starting doses in humans.  Using this participant population mitigates possible confounding 
effects of comorbidities and concomitant medications.  Therefore, Study GZHA provides an
unbiased assessment of safety, tolerability, and PK of LY3493269.
The study is intended to estimate a maximum tolerated exposure or establish that exposures
exceeding the expected therapeutic range are tolerated.  Additionally, the study will inform the 
target exposure range for subsequent oral dosing of LY3493269.  Safety, tolerability, PK, and 
preliminary PD data will assist in identifying an appropriate dose range for subsequent clinical 
studies regardless of administration route.
A single cohort of participants will be administered LY3493269 via the IV route. This approach
provides an estimate of the absolute SC bioavailability of LY3493269 and enables estimation of 
bioavailability for alternative routes of administration, including oral dosing.
While European Medicines Agency guidelines (EMA 2017) recommend using sentinel dosing in 
first-in-human studies, it allows for flexibility in dosing approaches based on the available 
scientific and preclinical assessments of a given molecule. The intended and exaggerated 
pharmacological responses of LY3493269 have been well characterized in multiple preclinical 
pharmacology models. Toxicology studies have suggested that non-monitorable or clinically 


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 4
L Y 3 4 9 3 2 6 9
u n ma na gea ble c o ncer ns w o ul d be u nli kel y t o occ ur i n h u ma ns treate d wit h L Y 3 4 9 3 2 6 9 . Base d 
o n t he a vaila ble data, L Y 3 4 9 3 2 6 9 d oes n ot prese nt a n u ncertai nt y pr ofile necessitat i n g a se nti nel 
d osi n g a p pr oac h. 
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 ol og 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 mp 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 re peat-d ose t o xicit y s t u dies were ge nerall y c o nsiste nt wit h, or 
sec o n dar y t o, i ncreti n p har mac ol og y a n d i ncl u de d b o d y wei g ht loss a n d/ or re d uce d b o d y  wei g ht 
gai n a n d decrease d f o o d c o ns u m pt i on. A d dit i on al  fi n di n gs i n mo n ke ys i ncl u de d c ha n ges i n C V
para m eters (f or e xa m ple, i ncreases i n heart rate a n d bl o o d press ure) were attri b ute d t o o n tar get 
G L P -1 p har mac o l og y a n d are cli nical l y m o nit ora ble. D ue t o t he effects o n b o d y wei g ht, f o o d 
c o ns u m pti o n, a n d cli nical c o n dit i on, d osi n g h o li da ys were re q uire d i n or der t o a v oi d t he nee d t o 
r e mo ve a ni mals fr o m  t he st u dies; t hese effects were c o nsi dere d a d verse i n b ot h rats a n d 
m o n ke ys.  T hese p har mac o l ogi cal effects decli ne d as s yste mic e x p os ure dec rease d i n a ni mal 
m o dels, a n d t he y are cli nical l y m o nit ora bl e.
S af et y a n d t olera bilit y asses s me nts will be ma de acr oss all d ose l e vels, i nclu di n g i nci de nce of 
na usea a n d/ or v o mit i n g, a n d e val uati on of E C Gs a n d vital si g ns c o n d ucte d d uri n g t he st u d y 
( Sectio n 2 ).  A preli mi nar y assess me nt of t he P D effects of L Y 3 4 9 3 2 6 9 will be base d o n t he 
c o nce ntrati o ns of  fast i n g gl uc ose, i ns uli n, a n d C -pe pti de u p t o Da y  2 9 p ost d ose.  T he effect of 
L Y 3 4 9 3 2 6 9 o n a p peti t e se nsati o ns will als o be e x pl ore d.  T he deci sio n  t o escalate t he d ose will 
be base d pri maril y o n safet y  a n d t olera bility d at a ( Secti o ns 5. 1 a n d 7. 4 ) a n d all a vaila ble P K data 
will als o be re vie we d .  
5. 5.
J u stifi c ati o n f or D o s e
C CI
T he pl a n ne d d ose ra n ge of L Y 3 4 9 3 2 6 9 i n G Z H A is i nte n de d t o pr o vi de a n a de q uate e val uat i on 
of  safety a n d t olera bilit y.
B ase d o n c urre nt precli nical p har mac o l og y  a n d t o xic o l og y  data, a d ose 
ra n ge of 0. 1 5 m g t o 7. 5 m g a d mi nistere d as si n gle S C d oses is pl a n ne d. T he a nt ici pate d d ose-
li miti n g safety a n d t olera bilit y pr ofile ( na usea a n d v o miti n g) of L Y 3 4 9 3 2 6 9 is e x pecte d t o be 
c o nsiste nt wit h t hat de m o nstrate d b y t he G L P- 1 rece pt or a g o nists a n d GI P/ G L P- 1 d ual a g o nist
dr u g classes a n d s h o ul d be re versi ble as P K e x p os ures decli ne .
D ose were selecte d b y e val uat in g precli nical p har mac o l og y  a ni mal data (i ns uli n secreti on fr o m 
I V gluc ose t ol era nce tests in rats a n d wei g ht l oss fr o m diet -i n d uce d o bese mice) a n d t hr o u g h 
be nc h mar ki n g a gai nst t he precli nical a n d cli nical d at a of  tirze pati de ( L Y 3 2 9 8 1 7 6), a n ot her 
GI P/ G L P - 1 d ual a g o nist .
H u m a n efficacio us d ose s f or L Y 3 4 9 3 2 6 9 were pr ojecte d t hr o u g h a nc h ori n g t he r elat i ve p ote nc y 
of  L Y 3 4 9 3 2 6 9 fr o m precli nical efficac y m o dels t o tirze pati de a n d acc o u nti n g f or tra nslat i onal 
differe nces bet wee n a ni mals a n d h u ma n t o ac hie ve c o mpara ble cli nical efficac y  for H b A 1c a n d 
w eig ht re d ucti o n i n h u ma ns ( Fri as et al 2 0 1 8). 
 
 
 


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 5
L Y 3 4 9 3 2 6 9
 
 
 
S u bc uta ne o us d oses m a y be i ncrease d or decrease d acc or di n g t o e mer gi n g P K data, b ut S C d ose 
escalat i ons will n ot e xcee d a half -l og ( 3. 3 -f ol d) i ncrease i n d ose bet wee n 2 S C c o h orts. T he 
A U C e x p os ure i n healt h y part ici pa nts at t he ma xi m u m d ose s h o ul d n ot e xcee d t he pre dicte d 
A U C of  1 2 5 0 0 0 0 n g . h/ m L, c orres p o n di n g t o t he e x p os ure f or t he hi g hest d ose teste d ( H D T) i n 
t he m o n ke y  t o xic o l og y st u d y. A d versit y at t his d ose le vel i n t he m o n ke y t o xic o l og y  st u d y was 
base d o n t he e x pecte d p har mac ol o gical effects of decrease d f o o d c o ns u m pt i on/ b o d y  wei g ht, an d 
t he nee d f or a d osi n g h o li da y.  As t hese effects are k n o w n t o re verse base d o n e x perie nce wit h 
ot her m e m bers of t he i ncreti n class, it is dee me d acce pta ble t o use t his d ose le vel t o calc ulate 
cli nical e x p os ure m ult i ples.  T hi s is a n ar bitrary e x p os ure li mit base d o n m o n ke y  data w here b y 
t o xic o l og y  fi n di n gs were attri b ute d t o e x pecte d p har mac ol og y . It is a ntici pate d t hat cli nical 
safety a n d t olera bilit y data will  inf or m  t he decisi o n f or t he ma xi m u m d ose t o be teste d. 
C ar dio vasc ular effects (i ncreases i n heart rate a n d bl o o d press ure) were o bser ve d i n b ot h t he 
sta n dal one C V safet y p har mac o l og y  st u d y a n d t he re peat-d ose t o xicit y st u d y in m o n ke ys.  T hese 
fi n di n gs ha ve bee n o bser ve d wit h ot her G L P-1 R A a n d GI P / G L P- 1 R A m o lec ules.  T he cli nical 
starti n g d ose will mai ntai n a 7. 6 x d ose m ult i ple a n d a 1 5. 8 x e x p os ure m ulti ple t o t he l owest -
o bser ve d -effect le v el (L O E L ) i de ntifie d i n t he C V safet y p har mac o l og y  st u d y.  Parti ci pa nts will 
be cl osel y m o nit ore d f or effects o n C V para meters.  
P har mac o ki net ic pr o perti es of L Y 3 4 9 3 2 6 9 are e x pecte d t o be c o nsiste nt wit h t hat of ac ylate d 
pe pti des.  H u m a n P K para meters were scale d with all o metr y usi n g c y n o m o l g o us mo n ke y  P K.  
 
T o e ns ure t he m ost c o nser vat i ve h u ma n e x p os ure m ulti ple esti mate, t he hi g hest S C 
bi oa vaila bilit y o bser ve d i n a ni mals  
 was a d o pte d f or calc ulat i ng h u ma n e x p os ure 
para m eters. T he pl a n ne d S C d oses t o be e val uate d are: 0. 1 5 m g, 0. 5 m g, 1. 5 m g, 3. 0 m g, 5. 0 m g 
a n d 7. 5 m g. 
A si n gle I V d ose of 0 . 5 mg is pl a n n e d for o ne d osi n g c o h ort, t o be a d mi nistere d a p pr o xi matel y  
after t he t hird S C c o h ort ( pl a n ne d S C d ose of 1 . 5 m g) .  A n I V d ose of 0 . 5 mg is a ntici pate d t o 
yiel d L Y 3 4 9 3 2 6 9 e x p os ures cl ose t o or sli g ht l y hi g her t ha n S C 0 . 5 mg. D osi n g of t he I V C o h ort 
will o nl y pr ocee d w he n P K e x p os ures fr o m at least 2 prece di n g S C c o h ort s e xcee ds pre dicte d 
e x p os ures f or t he pla n ne d I V d ose. T he I V d ose ma y be i ncrease d t o a ma xi m u m of 1. 5 m g or 
decrease d t o a mi ni m u m of 0. 2 5 m g de pe n di n g o n e mer gi n g safety a n d P K data fr o m prece di n g 
S C d oses . Criteria f or I V d ose i ncre ase or re d ucti o n ca n be f o u n d i n Sect i on 7. 5 . 
D ose m ul tiples a n d pre dicte d e x p os ure m ult i ples relat i ve t o t he n o -o bser ve d -a d verse-effect 
le vels (N O A E Ls ) i n rats a n d m o n ke ys are liste d i n Ta ble G Z H A. 2
C CI
bel o w. E x p os ure m ult i ples 
base d o n t he N O A E L are > 1 f or t he starti n g d ose a n d < 1 f or t he re mai ni n g pl a n ne d d ose s, wit h 
C CI
C CI


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severe weight loss being the dose-limiting factor in animals which is an expected 
pharmacological effect.
Participants will be closely monitored and LY3493269 doses may be adjusted before each dose
escalation based on safety, tolerability and available PK data throughout the course of the study.


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Table GZHA.2
Margin of Safety for Subcutaneous Administration of LY3493269
Based on Administered Dose and Predicted Exposure
Dose 
(mg/kg)
Dose 
(mg/m2)
Dose multiple a
AUC 
(ng.hr/mL)
Maximum
Con-
centration 
(ng/mL)
Exposure multiple b
Starting 
dose
Maximum 
dose 
Starting 
Dose
Maximum 
dose
Human 
starting 
dose  
(0.15mg)c
0.00214
0.0793
7670
31.2
Human 
Maximum 
dose 
(7.5mg)c
0.11
3.96
386000d
1580
Rat 
NOAELe
0.05
0.3
3.8
0.076
8020
1.83
0.036
Rat HDTe
1
6
75.7
1.52
154000
35.1
0.70
Monkey 
NOAELf
0.05
0.6
7.6
0.15
59800
7.8
0.15
Monkey 
HDTf
1
12
151.3
3.03
1250000
163
3.24
Monkey 
CV LOELg
0.05
0.6
7.6
0.15
-
494
15.8
0.3
Abbreviations:  AUC = area under the plasma concentration-time curve; CV = cardiovascular; LOEL = lowest-
observed-effect level; NOAEL = no-observed-adverse-effect level; HDT = highest dose tested; 
PK = pharmacokinetics.
a
Dose multiple (based on body surface area) is calculated as dose in animals (mg/m2)/dose in humans (mg/m2). 
b Exposure multiple is the calculated as time-adjusted AUC in animals/predicted AUC in humans; 
(1) ([AUC(0-96) in rats Day 29]/96hr)/ ([AUC(0-inf) in humans]/168 hr) OR 
(2) ([AUC(0-168) in monkeys Day 29]/168hr)/([AUC(0-inf) in humans]/168 hr)
c
Typical body weight of 70 kg was assumed for a healthy participant.
d Plasma PK parameter (AUC) was computed based on PK model-predicted LY3493269 clearance. 
e
Rat NOAEL and HDT was determined in a 1-month repeat-dose toxicity study (130-735).  It is mean Male 
+Female from Study 130-735 Day 29 toxicokinetic data. All findings in the study were considered secondary to 
stress and/or pharmacology (decreased body weights and/or decreased food consumption).  The only adverse 
finding in the 1 mg/kg group (HDT) was the need for a single dosing holiday on Day 5 due to pharmacology.
f
Monkey NOAEL and HDT was determined in a 1-month repeat-dose toxicity study (130-739).  It is mean Male 
+Female from Study 130-739, Day 29 toxicokinetic data.  All findings in the study were considered secondary to 
stress and/or pharmacology (decreased body weights and/or decreased food consumption).  The only adverse 
finding in the 1-mg/kg group (HDT) was the need for dosing holidays in 1 male and 2 females (of a total of 
6 monkeys in the group) due to pharmacology (i.e. body weight loss and decreased body condition score).
g Monkey CV LOEL was determined in a single-dose safety pharmacology study (130-738).  Cardiovascular 
findings at 0.05 mg/kg were limited to increases in heart rate, blood pressure and QRS duration. The effects 
declined as the systemic exposure decreased, but still notable by the end of the monitor phase (88 - 96 hrs 
postdose). The mean exposure at 18 hours postdose (approximate Cmax) from Study 130-738.


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6. Study Population
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests and electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Participants who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Participants are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment as applicable, or as otherwise indicated:
[1]
are overtly healthy males or females, as determined through medical history 
and physical examination
[1a] male participants:
agree to use an effective method of contraception for the duration of the 
study (see Section 6.3.4) and for 5 months following the last dose of the IP.
[1b] female participants:
Women not of childbearing potential may participate and include those who 
are

infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), or congenital anomaly such as 
mullerian agenesis; or 

those who are postmenopausal, defined as either:
o
a woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has cessation of menses for at least 1 
year without an alternative medical cause, AND with a 
follicle-stimulating hormone of >40 mIU/mL; women in this 
category must test negative in pregnancy test prior to study 
entry.
o
a woman 55 years of age or older not on hormone therapy 
who has had at least 12 months of spontaneous amenorrhea; or
o
a woman of at least 55 years of age with a diagnosis of 
menopause before starting hormone replacement therapy.
[2]
are between the ages of 21 and 65 years, inclusive at screening


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[3]
have a body mass index of ≥19 and ≤40.0 kg/m2 at screening
[4]
have clinical laboratory test results within normal reference range for the 
population or CRU, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator
[5]
have blood pressure of <150/90 mmHg and pulse rate of between 50 to 100 
bpm, supine (at screening), or with minor deviations judged to be acceptable 
by the investigator
[6]
have hemoglobin A1c level of <5.7% at screening
[7]
have venous access sufficient to allow blood sampling as per the protocol
[8]
are reliable and willing to make themselves available for the duration of the 
study and who will comply with the required study and dosing visits and abide 
by the clinical research site policy and procedure and study restrictions
[9]
are able and willing to give signed informed consent and have given written 
informed consent to participate in this study in accordance with local 
regulations and the ethical review board (ERB) governing the site
6.2.
Exclusion Criteria
Participants will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment as applicable, or as otherwise indicated:
[10]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[11]
are Lilly employees 
[12]
are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study
[13]
have participated within the past 30 days of screening in a clinical study 
involving an IP; at least 5 half-lives or 30 days, whichever is longer, should 
have passed
[14]
have previously completed or withdrawn from this study 
[15]
have a history of atopy (severe or multiple allergic manifestations) or 
clinically significant multiple or severe drug allergies, or intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, 
but not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, anaphylaxis, angioedema, or 
exfoliative dermatitis)


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[16]
have an abnormality in the 12-lead ECG at screening that, in the opinion of 
the investigator, increases the risks associated with participating in the study 
or may confound ECG (QT) data analysis, such as a corrected QT interval 
using Fridericia’s formula (QTcF) >450 msec, PR >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 [Note: the QTcF and PR criteria are applicable at 
screening only]
[17]
have a significant history of or current CV (e.g. myocardial infarction, congestive 
heart failure, cerebrovascular accident, venous thromboembolism, etc.), respiratory, 
renal, GI, endocrine, hematological (including history of thrombocytopenia), or 
neurological disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the IP; or of interfering with 
the interpretation of data
[18]
have undergone any form of bariatric surgery
[19]
have a personal or family history of medullary thyroid carcinoma or have 
multiple endocrine neoplasia syndrome type 2
[20]
have a history of acute or chronic pancreatitis, or elevation in serum lipase 
and/or amylase greater than 1.5 times the upper limit of normal (ULN)
[21]
have obvious clinical signs or symptoms of liver disease, acute or chronic 
hepatitis
[22]
have serum aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >2X the ULN or total bilirubin (TBL) >1.5X ULN
[23]
have been treated with prescription drugs that promote weight loss (e.g. 
Meridia® [sibutramine], Sanorex® [mazindol], Adipex-P® [phentermine], 
BELVIQ® [lorcaserin], Mysimba® [naltrexone/bupropion], Saxenda®
[liraglutide] or similar other body weight loss medications including over-the-
counter medications (e.g. Alli®) within 3 months prior to screening
[24]
have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy in the past year, or have received any glucocorticoid therapy within 
1 month before screening (topical, intra-articular, and inhaled preparations
such as steroid nasal spray are permitted in the study)
[25]
have fasting triglyceride levels ≥5 mmol/L (≥442.5 mg/dL) at screening
[26]
have evidence of significant active neuropsychiatric disease as determined by 
the investigator 
[27]
regularly use known drugs of abuse 
[28]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[29]
show evidence of hepatitis C and/or positive hepatitis C antibody


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[30]
show evidence of hepatitis B, positive hepatitis B core antibody, and/or 
positive hepatitis B surface antigen 
[31]
intended to use over-the-counter or prescription medication within 7 or 
14 days, respectively, prior to planned dosing (apart from vitamin/mineral 
supplements, occasional paracetamol, and thyroid replacement medication) 
and throughout the study period.  If this situation arises, inclusion of an 
otherwise suitable participant may be at the discretion of the investigator and 
sponsor
[32]
have donated blood of more than 450 mL, or have participated in a clinical 
study that required similar blood volume drawn within the past 3 calendar 
months
[33]
have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females) or are unwilling to stop alcohol consumption 
as required during the study (Section 6.3.2) (1 unit = 12 oz or 360 mL of beer; 
5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
[34]
smoke >10 cigarettes per day or the equivalent, or are unable or unwilling to 
refrain from nicotine during CRU admission
[35]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Participants will be required to fast overnight for at least 8 hours before taking a SC or IV dose 
of LY3493269 (or placebo) on Day 1 and for each subsequent study day when clinical safety 
laboratory and PD samples are taken and OGTTs are administered.  Water may be consumed 
freely. Subjects will receive a standard meal shortly after dosing. Throughout the inpatient 
period, standard meals will be administered in the CRU.  While not resident in the CRU, 
participants will be encouraged to follow their normal diet.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed at least 24 hours before each CRU admission and each outpatient 
visit and throughout the duration of each CRU visit.  Between CRU visits, daily alcohol should 
not exceed 3 units for males and 2 units for females (a unit is defined in Exclusion Criterion 
[35]).  No nicotine use will be permitted while at the CRU.  While not resident in the CRU, 
participants must consume no more than 10 cigarettes or equivalent per day. Participants will be 
allowed to maintain their regular caffeine consumption throughout the study period.


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6.3.3. Activity
Participants will be advised to maintain their regular levels of physical activity/exercise during 
the study.  When certain study procedures are in progress at the site, participants may be required 
to remain recumbent or sitting.
6.3.4. Contraception
Men, 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 (less than 1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted contraceptives or 
intrauterine device) or effective method of contraception (such as diaphragms with 
spermicide or cervical sponge).
They must agree to do this for the duration of the study plus 105 days, which corresponds to
approximately 5 months.
Additional notes:

Men and their partners may choose to use a double-barrier method of contraception.  
(Barrier protection methods without concomitant use of a spermicide are not an effective 
or acceptable method of contraception.  Thus, each barrier method must include use of a 
spermicide.  It should be noted, however, that the use of male and female condoms as a 
double-barrier method is not considered acceptable due to the high failure rate when 
these barrier methods are combined). 

Periodic abstinence (for example, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 

Men with pregnant partners should use condoms during intercourse for the duration of 
the study plus 105 days, which corresponds to approximately 5 months following the last 
dose of IP – for example, until the end of estimated relevant potential exposure in women 
of childbearing potential. 

Men 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. 

Men who are in exclusively same sex relationships (as their preferred and usual lifestyle) 
are not required to use contraception.


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6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened, although screening tests such as clinical laboratory tests and vital signs/ECGs may 
be repeated at the discretion of the investigator. 


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7. Treatment
7.1.
Treatment Administered
The doses to be administered are presented in Section 5.1.1.
The IP will be administered either via a SC injection or as a slow IV bolus (over at least 1
minute).  A maximum of 2 injections may be necessary to achieve higher planned dose levels.
•
For SC cohorts, LY3493269 and placebo will be administered at a maximum volume of 
2 mL per injection.  
•
Participants in the IV Cohort will be dosed one at a time, at least 20 minutes apart. 
For IV doses, investigative sites must have resuscitation equipment, emergency drugs, and 
appropriately trained staff available during IV dosing and for at least 6 hours after participants 
have completed their IV dose.
Table GZHA.3 shows the treatment regimens.
Table GZHA.3.
Treatments Administered
Treatment Name
LY3493269
Placebo
Dosage 
Formulation
Lyophilized powdera
0.9% sodium chloride injection
Unit dose strength
5mg/vial LY3493269
N.A.
Route of 
Administration
SC injection
or IV dose
SC injection
Dosing instructions
Single injection or IV dose
(at the assigned dose level)
Single injection
(volume matched with active drug)
Abbreviations:  IV = intravenous, SC = subcutaneous.
a
Reconstituted with sterile water for injection.
The investigator or designee is responsible for:

explaining the correct use of the IPs to the participant and site personnel 

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.


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7.1.1. Injection Sites 
All injections will be administered into the SC tissue of the abdominal wall, in the right or left
upper or lower quadrant.  Where more than 1 injection is required to deliver a full dose, it is 
recommended that the injections are administered in opposite quadrants, such as upper right and 
lower left or upper left and lower right.  Whenever possible, IP administration should be carried 
out by the same personnel and at approximately the same time of day in all cohorts.  The actual 
time of dosing and the site(s) of injection(s) will be recorded in the participant’s case report form 
(CRF).  
7.1.2. Packaging and Labeling
The drug product LY3493269 is supplied for clinical trial use as 5 mg lyophilized powder in a 
glass vial.  Further dilution may be needed for IV administration.  Detailed instructions for the 
preparation of LY3493269 will be included in the Pharmacy Instructions provided by the 
sponsor.
Placebo will be provided as sterile saline (0.9% NaCl) in a 50 mL vial. Placebo doses should be 
held in the pharmacy for an equivalent amount of time as is required to prepare doses of 
LY3493269. 
Both materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Randomization tables for allocation of LY3493269 or placebo to participants will be prepared by 
the statistician for the study and provided to the site pharmacists involved in dose preparation.  
The allocation and dispensing of the IPs will be fully documented and verified by a second 
person.  Detailed records of the amounts of the IP received, dispensed, and remaining at the end 
of the study will be maintained by the site pharmacist.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the participant’s CRF.
7.3.
Blinding
This is an investigator- and participant-blind study for SC Cohorts 1 through 6.  To preserve the 
blinding of the study for LY3493269 and placebo, all study site personnel, except pharmacy staff 
who prepare and dispense study medication, will be blinded to treatment allocation.
Blinding will be maintained throughout the conduct of the study as described in the 
Blinding/Unblinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study participant, may be opened during the study only if the participant’s well-being 
requires knowledge of the participant’s treatment assignment.


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If the study treatment assignment for participants in the SC cohorts is unblinded, the participant
must be discontinued from the study, unless the investigator obtains specific approval from a 
Lilly clinical pharmacologist or clinical research physician (CRP) for the study participant to 
continue in the study.  During the study, emergency unblinding should occur only by accessing 
the study participant’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event.  The 
participant’s safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification for Subcutaneous Cohorts Only
In cohorts receiving SC doses, dose levels or increments, sampling schedule, and length of stay 
at the CRU may be adjusted in view of emerging safety, tolerability, or PK/PD data during the 
study.  
If considered appropriate:

Dose increments for SC doses may be reduced, a dose level may be repeated, or a 
lower/intermediate dose may be administered, but dose escalations will not exceed a half-
log (3.3-fold) increase in dose.  

The timing of the sampling may be adjusted and additional samples may be collected, as 
described in Section 9.6.  

The duration of the CRU stay or the duration of safety follow-up may be increased (for 
example if the half-life of LY3493269 is longer than anticipated) but not decreased.  
These changes must be appropriately documented and communicated by the sponsor to the 
investigator.  Because these adjustments to timings or dose levels are allowable changes 
permitted by the protocol, they would not require a protocol amendment.  However, any changes 
to the planned dose levels, together with the supporting data, will be reviewed by a SRP, 
composed of members independent of the study team and investigative site.
7.4.1. Dose Decision/Escalation
By nature of being a dose escalation study, data will be evaluated on an ongoing basis until the 
maximum tolerated dose (MTD) is determined or when stopping criteria are met. The highest 
dose level that is tolerated will be designated as the MTD for single SC doses in healthy 
participants.  Interim access to study data is scheduled to occur during the study to inform dose
escalation decisions, as specified in Section 10.3.6.  
Safety data will be the primary criteria for the dose escalation.  In addition, if available at the 
time of dose escalation decision, PK and/or PD results may be used as supporting data for dose


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escalation, but such data are not required.  No dose decision can occur without prior discussion 
and agreement between the investigator and the Lilly clinical pharmacologist.  
Prior to dose escalation, all planned participants in the current cohort should have been dosed 
prior to escalation to next cohort.  The investigator and sponsor must review safety and 
tolerability data up to at least 7 days postdose from at least 6 participants receiving IP at the 
current dosing level, including but not limited to ECGs, clinical laboratory tests, vital signs, body 
weight, appetite VAS scores and AEs.  After review of these data, an escalation to the next dose 
level will be jointly decided by the investigator and sponsor.  The magnitude of dose escalation
may be reduced following data review, but subsequent escalations cannot be increased by more 
than approximately 3.3 fold (a half-log increment); dose levels may be repeated if warranted 
following data review.
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the IP unless there 
is clear evidence that the event is not related.  
7.4.2. Termination of Dosing/Dose Escalation
If any of the following scenarios occur, dosing at the current level and further dose escalation
will be discontinued:
1) One or more participants on active drug experience an SAE considered to be related to 
LY3493269
2) One or more participants on active drug experience 2 clinically significant events defined 
as moderate to severe symptoms, clinical signs, and clinical laboratory findings that could 
cause harm to health. CSEs will be determined 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 
to be related to LY3493269 administration: 
•
drug-related GI effects (for example emesis, diarrhea) causing severe distress 
(prevents daily activities or requires an emergency department visit or 
hospitalization); and/or
•
clinically significant cardiovascular AEs
•
a symptomatic hypoglycemic episode with BG values <2.7 mmol/L (48.6 mg/dL; 
corresponding to plasma glucose levels of <3.0 mmol/L [54 mg/dL])
4) Two or more participants on active drug develop persistent (>1 week) symptoms 
suggestive of acute pancreatitis.  Refer to algorithm for the monitoring of asymptomatic 
hyperenzymemia in Appendix 6.
7.4.2.1.
Premedication for IV Administration
Premedication for the IV administration is not planned.  However, if a reaction occurs after 
dosing the first 2 participants (Section 5.1), appropriate medication may be used in subsequent


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participants in the cohort.  If postdose reactions are observed in the first 2 participants, but 
review of the data suggests that dosing of subsequent participants may continue, administration 
of acetaminophen, 500 to 1000 mg, and/or an antihistamine may be administered orally 30 to 60 
minutes prior to the start of the IV injection for subsequent participants.
The decision to implement premedication for IV injections in subsequent participants will be 
made by the investigator and sponsor and recorded in the study documentation.
Any premedications given will be documented as a concomitant therapy (see Section 7.8).
7.4.2.2.
Management of IV Administration Reactions
There is a risk of reaction with any biological agent administered intravenously; therefore, all 
participants should be monitored closely.  Symptoms and signs that may occur as part of an IV 
injection reaction include, but are not limited to: fever, chills, nausea, headache, bronchospasm, 
hypotension, angioedema, throat irritation, rash, pruritus, myalgia, and dizziness.  In the event 
that a significant IV injection reaction occurs, the following guidance should be followed:

Supportive care should be employed in accordance with the symptoms/signs

If a participant’s injection reaction is sufficiently severe, subsequent injections in the 
cohort may be administered with premedication at the discretion of the investigator
following agreement with the Lilly CRP or clinical pharmacologist
7.5.
Dose Modification for Intravenous Cohort 
If tolerability precludes dosing of the IV 0.5 mg cohort, the IV dose will be reduced to a 
minimum of 0.25 mg. Based on preclinical data, SC bioavailability for LY3493269 is expected 
to be close to 100%. If PK exposures from the SC 0.5 mg dose yields largely concentrations 
below quantification, the IV 0.5 mg dose is likely to be at risk for unmeasurable concentrations. 
Under such circumstances, the IV dose may be increased to a maximum of 1.5 mg and be 
initiated only after 7-day safety data is available from the SC 3.0 mg dose and 7-day PK data 
from at least 2 preceding SC cohorts. Any proposal to adjust IV doses from those planned and
stated in the protocol, together with supporting data, will be reviewed by an independent SRP.  
7.6.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
CRU staff may supply or administer IP. All IP 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 CRU staff.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).


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7.7.
Treatment Compliance
The IP will be administered at the CRU, and documentation of treatment administration (date 
and time of drug administration) will occur at the CRU.
7.8.
Concomitant Therapy
Participants on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.
In general, concomitant medication should be avoided; however, acetaminophen (1g, maximum 
4g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the participant may be at the discretion of the investigator after consultation with 
a Lilly clinical pharmacologist or CRP.  Any medication used during the course of the study 
must be documented.
7.9.
Treatment after the End of the Study
Not Applicable.


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8. Discontinuation Criteria
Participants discontinuing from the study prematurely for any reason must complete adverse 
event and follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Participants will only receive 1 dose of IP and hence cannot be discontinued from the study 
treatment.
8.1.1. Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist
and the investigator to determine if the participant may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist to allow the inadvertently enrolled participant to continue in the 
study.  
8.2.
Discontinuation from the Study
Participants will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the participant should be discontinued from the study
o
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

Participant Decision
o
the participant, or legal representative, requests to be withdrawn from the study.
The replacement strategy for discontinued participants is described in Section 10.1.  If deemed 
appropriate by the investigator, early discontinuation procedures will be performed as shown in 
the Schedule of Activities (Section 2).
8.3.
Participants 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 CRU.  Personnel at the CRU 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 CRU.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical (safety and/or PK) information. The scheduled time points may be 
subject to minor alterations; however, the actual time must be recorded correctly in the CRF. 
Unless otherwise stated in the Schedule of Activities (Section 2):

For predose study assessments and procedures, these should be performed within 3 hours 
prior to planned dosing

For postdose assessments and procedures up to and including 24 hours, these should be 
performed within ±10% of the scheduled time

For postdose assessments and procedures scheduled after the 24-hour timepoint, these 
should be performed within ±3 hours of the scheduled time
Failure or delays (i.e. outside stipulated time allowances) in performing procedures or obtaining 
samples must be notified to the sponsor in writing via a file note to facilitate data reconciliation.
If multiple procedures take place at the same time point, ECGs and vital signs must be obtained 
prior to any venipuncture.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the anticipated number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 


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or that caused the participant to discontinue the IP before completing the study.  The participant
should be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or 
is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
The investigator will record all relevant AE and SAE information in the CRF.  After the ICF is 
signed, study site personnel will record, via CRF, the occurrence and nature of each participant’s 
preexisting conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study.  Additionally, site personnel will record any change in the condition(s) 
and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, study device and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the participant or may require intervention to 
prevent one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.


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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Participants should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3493269 is considered any dose higher than the 
dose assigned through randomization.  Treatment for overdose is supportive care.  Refer to the 
IB for LY3493269.
9.4.
Safety
9.4.1. Laboratory Tests
For each participant, laboratory tests detailed in Appendix 2 should be conducted according to 
the Schedule of Activities (Section 2).
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Physical Examination/Medical Assessments
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities and as clinically indicated (Section 2).
9.4.3. Body Weight
Weight will be measured as indicated in the Schedule of Activities (Section 2).  Wherever 
possible, the same scale will be used for all weight measurements throughout the study and the 
scale will not be moved or recalibrated.
Participants will be weighed in light clothing at approximately the same time in the morning 
before dosing (on Day 1 only) and after an overnight fast and evacuation of bowel and the 
bladder, if possible.  Weight will be measured twice on each scheduled occasion, with the 
participant stepping off the scale between measurements.  The mean of the 2 weight 
measurements will be recorded in the source document and the CRF.  


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9.4.4. Vital Signs
For each participant, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2), and as clinically indicated.  
Blood pressure and pulse rate should be measured after at least 5 minutes in a supine position.
If orthostatic measurements are required, participants should be supine for at least 5 minutes and 
stand for at least 2 minutes.
If the participant feels unable to stand, only supine vital signs will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
Body temperature will be measured, as specified in the Schedule of Activities (Section 2), and as 
clinically indicated.
9.4.5. Electrocardiograms
For each participant, ECGs should be collected according to the Schedule of Activities 
(Section 2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
participant receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE 
via CRF.
9.4.5.1.
Single/Triplicate ECGs
For each participant:
•
A single 12-lead digital electrocardiogram (ECG) will be collected screening, and at 
follow-up (Days 29 and 43).  All single ECGs recorded should be stored at the 
investigational site.  Single ECGs will not be transmitted.  
•
At all other scheduled times (Section 2), consecutive replicate ECGs will be obtained in 
triplicate at approximately 1-minute intervals.  
Electrocardiograms (single) may be obtained at additional times when deemed clinically 
necessary (e.g. to assess participants’ safety).  Collection of more ECG replicates than expected 
at a certain timepoint will be permitted to ensure high-quality records.
Electrocardiograms must be recorded before collecting any blood samples.  Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  
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, and ideally while the 
participant is still present, to determine whether the participant meets entry criteria at the relevant 


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visit(s) and for immediate participant management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the participant can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
adverse event.
Digital ECGs (scheduled and unscheduled) will be electronically transmitted to a central ECG 
laboratory designated by Lilly.  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.  
The machine-read ECG intervals and heart rate 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).
9.4.5.2.
Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes

serious and non-SAEs including monitoring of GI events, hypoglycemia, injection site 
reactions, and hypersensitivity reactions and reported and adjudicated pancreatitis
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
In the event safety monitoring uncovers an issue that needs to be addressed by unblinding at the 
group level, additional analyses of the safety data will be conducted by the personnel included in 
the unblinding/blinding plan.
9.4.5.3.
Nausea, Vomiting, and Diarrhea
Nausea, vomiting, and diarrhea events are considered AEs of interest; each occurrence will be 
recorded as a discrete AE in the CRF. For each event assessment of severity, duration (actual 
date together with onset and end times) and investigator’s opinion of relatedness to IP and 
protocol procedure will be captured.


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9.4.5.4.
Pancreatic Safety (Elevated Lipase or Amylase) 
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing at time points specified in the Schedule of Activities (Section 2).  Additional 
measurements may be performed at the investigator’s discretion.
Further diagnostic assessments will be recommended whenever lipase and/or amylase are 
confirmed to be ≥3X ULN at any visit post-treatment sequence allocation even if the participant
is asymptomatic (as per the algorithm for the monitoring of pancreatic events in Appendix 6).  If 
pancreatitis is suspected, the case will be further defined during an adjudication process.
To ensure participant safety and compliance with regulatory guidance, the investigator is to 
consult with the Lilly-designated Clinical Pharmacologist or CRP regarding collection of 
specific recommended clinical information and follow-up laboratory tests.
9.4.5.5.
Hepatic Safety
If a study participant experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If the 
abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly clinical pharmacologist or CRP.  Monitoring 
should continue until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ 5X ULN on two or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥ 2X ULN on 2 or more consecutive blood tests 

participant discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE.
9.4.5.6.
Injection Site Reactions
Injection site assessments for local tolerability will be conducted, when reported as

an AE from a participant, or

a clinical observation from an investigator.
If an AE of injection site reaction is reported, the investigator will complete a supplemental 
injection site reaction form in the eCRF.  The injection site reaction form documents the 
presence of erythema, induration, pain (mild, moderate, or severe), pruritis, and edema.  If more 
than 1 characteristic of ISR (for example erythema and pain) are recorded for a specific injection, 
a single AE will be reported. The severity of the AE will be that of the highest severity from the 


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various components, at all assessed timepoints. All injection site reactions reported as AEs 
should be closely monitored until resolution. 
A clinically significant AE of injection site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation.
9.4.5.7.
Hypersensitivity Reactions
Clinical manifestations of allergic/ hypersensitivity reactions may include but are not limited to:

skin rash

pruritus (itching)

dyspnea

urticaria (hives)

angioedema (for example, swelling of the lips and/or tongue)

hypotension

anaphylactic reaction
Participants with clinical manifestations of systemic allergic/hypersensitivity reactions should be 
treated per local standard of care.  Additional data describing each symptom should be provided
to the sponsor in the eCRF. 
In case of anaphylaxis or generalized urticaria, additional blood samples should be collected as 
close as possible to the onset of the event (Appendix 7). Follow-up samples should be obtained 
at the next regularly scheduled visit or 4 weeks after the event, whichever is later.  The lab 
results are provided to the sponsor via the central laboratory.
9.4.6. Glucose Monitoring
Site personnel will collect information on episodes of hypoglycemia at each study visit according 
to the Schedule of Activities.  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 when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma glucose [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.  


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9.5.
Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected for analysis to determine antibody production against LY3493269. Antibodies 
may be further characterized for cross-reactive binding to native GIP and GLP-1. To interpret 
the results of immunogenicity, a venous blood sample will be collected at the same time points to 
determine the plasma concentrations of LY3493269.  
Treatment-emergent (TE)-ADAs are defined in Section 10.3.5.  If the immunogenicity sample at 
the last scheduled assessment or discontinuation visit is TE-ADA positive [and if available, the 
ADA cross-reactively binds to native GIP and GLP-1], additional samples may be taken every 3 
months for up to one year from dosing or until the ADA signal returns to baseline (for example,
no longer TE-ADA positive).
A PK sample will continue to be collected at each time point at the investigator’s discretion.  
Participants followed for at least 1 year since last dose, whose titer has not returned to within 2-
fold of the baseline, will be assessed for safety concerns.  If no clinical sequelae are recognized 
by the clinical team, then no further follow-up will be required.
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor.  The 
duration allows the sponsor to respond to future regulatory requests related to the IP.  Any 
samples remaining after 15 years will be destroyed.
9.6.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 5 mL each will be collected to determine the plasma concentrations of 
LY3493269.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling as well as the date and 24-hour 
clock time of LY3493269 dosing will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
9.6.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3493269 will be assayed using a validated LC-MS/MS method.  Analyses 
of samples collected from placebo-treated participants are not planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last participant visit for the study. During this time, samples remaining after the 


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 5 0
L Y 3 4 9 3 2 6 9
bi oa nal yses ma y  be use d f or e x plorat or y  meta b o lis m st u dies or e x plorat or y  a nal yses s uc h as 
bi oa nal yt ical assa y vali datio n or cr oss -vali dati o n e xercises.
9. 7.
P h ar m a c o d y n a mi c s
P har mac o d y na mic sa m ples will be st ore d f or u p t o a ma xi m u m of 1 year after t he last partici pa nt
visit f or t he st u d y  at a facilit y selecte d b y t he s p o ns or.
9. 7. 1.
Or al Gl u c o s e T ol er a n c e T e st
Gl uc ose , C-pe pti de a n d i ns uli n will be meas ure d i n a n O G T T t o assess effects of L Y 3 4 9 3 2 6 9 o n 
gl yce mic c o ntr ol, dis p osit i on i n de x, i ns uli n secreti o n a n d i ns uli n se nsit i vity.  T he sc he d ule f or 
O G T Ts is i n dicate d i n t he Sc he d ule of Act i vities ( Secti o n 2 ).
P arti cip a nts will mai ntai n a de q uate car b o h y drate i nta ke 3 da ys bef ore t he sc he d ule d O G T T a n d 
fast f or a p pr o xi matel y 8 h o urs o ver ni g ht bef ore a d mi nistrati o n of t he O G T T.  A 7 5 -gra m gl uc ose 
d ose will be gi ve n orall y.  Parti ci pa nt s s h o uld c o ns u m e t he gluc ose l o a d wi t hi n 5 mi n utes.  If 
pa rtici pa nt s de vel o p s y m pt o ms of h y p o gl yce mia, be dsi de B G c o nce ntrati o n ma y be meas ure d.
T he parti ci pa nt will be treate d per i n vest i gat or discreti o n.  
Bl o o d sa m ples will be dra w n f or assess me nt of g l uc ose, i ns uli n a n d C- pe pti de c o nce ntratio ns 
pre -test a n d at 0. 5, 1, 1. 5 a n d 2 h o urs aft er t he i nit iatio n of  t he gluc ose l oa d.
9. 7. 2.
P h ar m a c o d y n a mi c M ar k er s 
Fast i n g ser u m sa m ples f or gl uc ose, i ns uli n, a n d C- pe pti de will be e val uate d as P D bi o mar kers. 
 
 
Pl as ma/ser u m c o nce ntratio ns of  t hese mar kers will be assa ye d usi n g vali date d a nal yt ical 
met h o ds.  I nstr ucti o ns f or t he c ollect i on a n d ha n dli n g of bl o o d sa m ples f or t hese a nal yses will be 
pr o vi de d b y t he s p o ns or.
T he sa m ples will be st ore d f or u p t o a ma xi m u m of 1 year after t he last partici pa nt visit f or t he 
st u d y at a facilit y selecte d b y t he s p o ns or.
9. 8.
G e n eti c s
C CI
A bl o o d sa m ple will be c ollecte d f or p har mac o ge netic a nal ysis as s pecifie d i n t he Sc he d ule of 
Act i vities, w here l o c al  re g ulatio ns all o w.  
S a mples will n ot be use d t o c o n d uct u ns pecif ie d disease or p o p ulati on ge net ic researc h eit her 
n o w or i n t he f ut ure.  Sa m ples ma y be use d t o i n vesti gate varia ble e x p os ure or res p o nse t o 
L Y 3 4 9 3 2 6 9 a n d t o i n vesti gate ge netic varia nts t h o u g ht t o pla y a r ole i n T 2 D M , o besit y, or 
di a betes c o mplicati o ns i n cl u di n g n o nalc o h o lic steat o he patitis (N A S H ).  Assess me nt of varia ble 
res p o nse ma y i ncl u de e val uati on of A Es or differe nces i n efficac y.  
All sa m ples will be c o de d wit h t he partici pa nt n u m ber.  T hese sa m ples a n d a n y data ge nerate d 
ca n be li n ke d bac k t o t he parti ci pa nt o nl y  b y t he i n vestig at i ve site pers o n nel.  


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Samples will be retained for a maximum of 15 years after the participant visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of LY3493269 or after LY3493269 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.
9.9.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of participant response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules including DNA, 
RNA, proteins, lipids, and other cellular elements. Exploratory biomarker measures may include 
potential markers of GIP and GLP-1 receptor target engagement.
Serum and plasma samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3493269, pathways associated with T2DM, obesity, or diabetes complications including 
NASH, mechanism of action of LY3493269, and/or research method, or for validating diagnostic 
tools or assay(s) related to T2DM, obesity, or diabetes complications including NASH.
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and/or ERBs impose shorter time limits, at a facility selected 
by Lilly or its designee.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3493269 or after LY3493269 or is commercially available.  
9.10. Appetite Analysis
To explore the effects of LY3493269 on meal intake and appetite sensation, participants will be
asked to rate their appetite sensations using a 100-mm VAS for parameters of hunger, fullness, 
satiety, and prospective food consumption prior to dosing on Day 1, and in the fasted state while 
inpatient as well as on scheduled outpatient visits.  These measurements shall be performed
according to the Schedule of Activities (Section 2).
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 


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“not at all”. Participants are required to rate their subjective sensations on four 100-mm scales 
combined with questions similar to the following: 
1. “How hungry do you feel?”
2. “How satisfied do you feel?”
3. “How full do you feel?”
4. “How much do you think you could eat?”
A staff member will use a caliper to measure the distance from 0 to the mark that the participant
placed on the VAS and record the measurement in the source document. Overall appetite score 
is calculated as the average of the 4 individual scores:  satiety + fullness + (100-prospective food 
consumption) + (100-hunger) / 4 (van Can et al. 2014). The higher overall appetite score 
indicates less appetite, and the lower score indicates more appetite.  
9.11. Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety and PK and is not powered on 
the basis of statistical hypothesis testing.
Participants who are randomized but not administered treatment prior to discontinuation may be 
replaced to ensure that approximately 8 participants may complete each SC Cohort, and 6 to 
complete the IV cohort.
Participants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
All participants who discontinue from the study will be identified and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. A detailed description of participant disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The participant’s age, sex, weight, height, or other demographic characteristics will be recorded 
and may be used in the PK, PD, and safety analyses as quantitative or classification variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all participants who receive a dose of 
the IP and have evaluable PK. 
Pharmacodynamic analyses will be conducted on the full analysis dataset.
Safety analyses will be conducted for all enrolled participants, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate. Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses. Statistical analyses 
will be fully detailed in the statistical analysis plan.


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10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator. Symptoms reported to occur prior to the first dose of IP
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 regulatory dictionary.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include laboratory tests, vital signs, body weight, 
immunogenicity, hypoglycemic events, injection site reactions and ECG parameters. The 
parameters will be listed and summarized using standard descriptive statistics. Additional 
analyses may be performed if warranted based upon review of the data.
Laboratory measurements will be summarized regarding observed values and change from 
baseline by treatment group, at each time point, using descriptive statistics. In addition, all 
clinical chemistry, hematology, and urinalysis data outside the reference ranges will be tabulated 
by parameter and treatment group.
Vital signs will be summarized regarding observed values and change from baseline values by 
treatment at each time point using descriptive statistics. For change from baseline values, a 
mixed-model repeated-measure model with treatment, time (of measurement), and treatment-by-
time interaction as fixed effects, participant as random effect, and baseline as covariate will be 
used to determine the effects of LY3493269. Least squares means as well as 90% confidence 
intervals (CIs) will be reported.
Electrocardiogram parameters will be summarized, including the PR, QT, RR, and QTcF 
intervals, QRS duration, and heart rate. Outliers for these parameters may be summarized by 
dose groups. 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 
exposures on QTcF and other intervals.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3493269 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be maximum drug concentration (Cmax), time to 
maximum concentration (tmax) and area under the concentration versus time curve (AUC) of 
LY3493269. Other noncompartmental parameters, such as half-life, clearance, and volume of 
distribution may be reported. Subcutaneous bioavailability will also be reported. All PK 


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parameters will be summarized using descriptive statistics. If necessary, additional population 
PK modeling may be performed. 
The relationship between LY3493269 doses and/or concentrations and key safety (such as QT 
interval, blood pressure, heart rate, PR), tolerability (such as nausea, vomiting) and efficacy 
(fasting glucose) measures may be assessed via PK/PD analyses or graphical explorations. 
Endpoints may include but are not necessarily limited to those listed above. 
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetics dose proportionality will be assessed. 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. 
The parameter Tmax of LY3493269 will be analyzed using a nonparametric method. All PK 
parameters will be summarized using descriptive statistics.
10.3.3. Pharmacodynamic Analyses 
10.3.3.1. Pharmacodynamic Parameter Estimation
Inferences will be sought regarding the effect of LY3493269 on the PD endpoints of fasting 
glucose, and insulin. Exploratory PD may include, but are not limited to, OGTT-derived 
glycemic control parameters. Such effects will be explored over different doses of LY3493269
and at applicable time points as per the Schedule of Activities (Section 2).
10.3.3.2. Pharmacodynamic Statistical Inference
Pharmacodynamic parameters may be transformed before statistical analyses, if deemed
necessary. Absolute values as well as change from baseline in each parameter will be analyzed
using mixed-effects models to evaluate treatment effects as well as treatment comparisons. The
model will include treatment, day, and treatment-by-day interaction as fixed effects, and 
participant as a random effect. Baseline values, as well as other influencing variables, may be 
used as covariates.
All PD parameters, including baseline-corrected parameters, will be summarized and tabulated
by treatment group and day. Summary statistics will be provided. The individual observed and
mean time profile of the postdose PD parameters will be plotted by treatment group.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
The relationships between LY3493269 doses or concentrations and key safety, tolerability and 
efficacy endpoints and their time-course profiles may be evaluated via modeling, or graphically 
if there is sufficient data. 


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10.3.5. Evaluation of Immunogenicity 
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.
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.
10.3.6. Data Review During the Study
Interim access to safety and tolerability (and any available PK and PD) data is scheduled to occur 
after every dosing session as described in Section 5.1.  This schedule may be modified as 
applicable, based on emerging safety and/or tolerability data.  The purpose of these reviews is to 
guide dose selection for the next dosing cohort.  Prior to confirming the dose and initiating the 
IV Cohort, preliminary PK data from at least 1 preceding SC cohort must be reviewed. 
The investigator and the Lilly sponsor team will jointly make the determination regarding dose 
escalation, based upon their review of the safety and tolerability data, and PK or PD results if 
available.  In addition, these data may be used to guide dose selection and inform the need to 
adjust timing of procedures/sampling schedules for the current study.  
A SRP will be established and composed of experts in early phase medicine independent of the 
study team and investigative site.  Any changes to the planned dose levels, together with the 
supporting data, will be reviewed and approved by the SRP.
10.3.7. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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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.
Butler LD, Guzzie-Peck P, Hartke J, Bogdanffy MS, Will Y, Diaz D, Mortimer-Cassen E, Derzi 
M, Greene N, DeGeorge JJ. Current nonclinical testing paradigms in support of safe clinical 
trials: An IQ Consortium DruSafe perspective. Regul Toxicol Pharmacol. 2017;87 Suppl 3:S1-
S15.
Campbell JE, Drucker DJ. Pharmacology, physiology and mechanisms of incretin hormone 
action. Cell Metabolism. 2013;17(6):816-837.
Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a 
novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From 
discovery to clinical proof of concept. Mol Metab 2018;18: 3-14.
Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia – assessed using continuous glucose monitoring – in 125 
preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the 
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. Erratum in: Pediatr Diabetes. 
2015;16(6):462.
[EMA] European Medicines Agency. Guideline on strategies to identify and mitigate risks for 
first-in-human and early clinical trials with investigational medicinal products. July 2017. 
Available at: https://www.ema.europa.eu/documents/scientific-guideline/guideline-strategies-
identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf. Accessed 
September 01, 2019.  
Finan B, Müller TD, Clemmensen C, Perez-Tilve D, DiMarchi RD, Tschöp MH. Reappraisal of 
GIP Pharmacology for Metabolic Diseases. Trends Mol Med 2016; 22(5): 359-376.
Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue 
scales in assessment of appetite sensations in single test meal studies. Int J Obes. 2000; 
24(1):38 48. 
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, 
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor 
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active
comparator-controlled phase 2 trial. Lancet. 2018; 17;392(10160):2180-2193.
van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. 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 (Lond). 2014;38(6):784-793.
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes Sci 
Technol. 2010;4(3):577-582.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
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.
ADA
Anti-drug antibody
ALP
Alkaline Phosphatase 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
BG
Blood glucose
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
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 participants are aware of the treatment 
received
BP
Blood pressure
CBC
Complete blood count
CK
Creatine kinase
CNS
Central nervous system
CIOMS
Council for International Organizations of Medical Sciences
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 the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.


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confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
CRF
Case report form
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
Clinical research unit
CSE
Clinically significant events
CV
Cardiovascular 
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the study 
are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FSH
Follicle-stimulating hormone
GCP
good clinical practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal 
GIP
Glucose-dependent insulinotropic polypeptide
GIPR
Glucose-dependent insulinotropic polypeptide receptor
GIPRA
Glucose-dependent insulinotropic polypeptide receptor agonist
GLP-1
Glucagon-like peptide-1
HCV
Hepatitis C virus
HIV
Human Immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
ICF
informed consent form


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ICH
International Council for Harmonization
Ig
immunoglobulin
IGFBP2
Insulin-like growth factor binding protein 2 (IGFBP2)
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.
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, 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.
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.
ISR
injection site reaction
IV
intravenous
LDL
low-density lipoprotein
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective participant, to the participant’s participation in the clinical study.
LOEL
Lowest-observed-effect level
MTD
maximum tolerated dose
NASH
nonalcoholic steatohepatitis
NOAEL
No-observed-adverse-effect levels
OGTT
Oral glucose tolerance test
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
randomize
the process of assigning participants/s to an experimental group on a random basis
PK/PD
pharmacokinetic/pharmacodynamic
PG
Plasma glucose


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PR
pulse rate
QW
once-weekly
RBC
red blood cell
SAD
single-ascending dose
SAE
serious adverse event
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.  
SRP
safety review panel
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
T2DM
Type 2 diabetes mellitus 
TEAE
treatment-emergent adverse event:  Any 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 to maximum observed drug concentration
ULN
upper limit of normal
VAS
visual analog scale
WBC
white blood cell


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry (fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphate
Leukocytes (WBC)
Magnesium
Absolute Counts of
Creatinine
Neutrophils
Glucose (fasting)
Lymphocytes
Urea
Monocytes
Uric acid
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysis
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Lipase
Protein
Amylase
Glucose
Triglycerideb
Ketones
Total cholesterolb
Bilirubin
HbA1cb
Urobilinogen
Nitrite
Serology
Blood 
Hepatitis B surface antigenb,c
Leukocytes
Hepatitis C virus serology (Anti-HCV)b,c
Microscopya
Human immunodeficiency virus (HIV)b,c
Follicle-stimulating hormone (FSH)b,d
Pregnancy teste
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
FSH = follicle-stimulating hormone; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; RBC = 
red blood cells; WBC = white blood cell.
a
If clinically indicated, per investigator’s discretion.
b
Performed at screening only.
c
Tests may be waived if they have been performed within 6 months before screening with reports available for review.
d
To be performed for women at screening, if needed to confirm postmenopausal status.
e
For females only:  A serum pregnancy test will be performed at screening and urine pregnancy test at the Day 43 
follow-up. 
Note:  Results of these assays will be validated by the local laboratory at the time of testing.  Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed.  Some of the 
above parameters are calculated from measured values.  Inclusion or omission of calculated values will not be 
considered as a protocol deviation.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the participant understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each participant or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

answering any questions the participant may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the participant’s willingness 
to continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for participants.  
Individual investigators may have additional local requirements or processes.  Study specific 
recruitment material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by ICH guidelines and other applicable laws and 
regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF 

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:


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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly 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 Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 


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applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
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 Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of participant personal information collected will be provided in a written 
document to the participant by the ponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time, INR
WBC
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, IgG
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody, total
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; GGT = 
gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; 
WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability


J 1 X -M C -G Z H A Cli ni c al P h ar m a c ol o g y Pr ot o c ol
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T his ta ble s u m marizes t he a p pr o xi mate n u m ber of ve ni p u nct ures a n d bl o o d v ol u mes f or all 
bl o o d sa m pli n g (scree ni n g, safet y lab orat ori es, a n d bi oa nal ytical assa ys) d uri n g t he st u d y.  
Pr ot oc ol J 1 X- M C -G Z H A
S u bc ut a ne o us D osi n g C o h orts
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( m L)
A p pr o xi m ate
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A p pr o xi m ate
T ot al V ol u me 
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Scree ni n g tests a (l ocal la b orat or y)
2 3
1
2 3
Cli nical la b orat or y testsa (l ocal la b orat or y)
St u d y visits
1 0
5
5 0
F oll o w -u p/ Earl y  disc o nti n uati o n visit
8
3
2 4
L Y 3 4 9 3 2 6 9 p har mac o ki netics
5
1 2
6 0
P ote ntial a d diti o nal L Y 3 4 9 3 2 6 9
p har mac o ki netic sa m ples
5
3
1 5
Bl o o d discar d f or ca n n ula pate nc y
0. 3
1 3
3. 9
P oi nt -of -care safet y gl uc ose ( o n-site)
0. 3
1 5
4 . 5
P har mac o d y na mics (ce ntral la b orat or y)
•  
Gl uc ose
2
1 6
3 2
•
I ns uli n, C-pe pti de
3
1 6
4 8
•
 
 
P har mac o ge netic sa m ple (st ore d)
1 0
1
1 0
N o n -p har mac o ge netic sa m ple (st ore d)
•
Plas ma
2
4
8
• 
Ser u m
2. 5
4
1 0
•
P 8 0 0 
2
4
8
I m m u n o ge nicit y
1 0
4
4 0
T otal
3 9 0. 9
T otal f or cli nical p ur p oses (r o u n de d u p t o t he nearest 1 0 m L)
4 0 0
a
C CI
A d diti o nal sa m ples ma y be dra w n if nee de d f or safet y p ur p oses.


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LY3493269
Intravenous Dosing Cohort
Purpose
Blood Volume per 
Sample 
(mL)
Approximate
Number of Blood 
Samples
Approximate
Total Volume 
(mL)
Screening testsa (local laboratory)
23
1
23
Clinical laboratory testsa (local laboratory)
Study visits
10
5
50
Follow-up/Early discontinuation visit
8
3
24
LY3493269 pharmacokinetics
5
18
90
Potential additional LY3493269
pharmacokinetic samples
5
3
15
Blood discard for cannula patency
0.3
13
3.9
Point-of-care safety glucose (on-site)
0.3
15
4.5
Pharmacogenetic sample (stored)
10
1
10
Non-pharmacogenetic sample (stored)
Plasma
2
4
8
Serum
2.5
4
10
P800 
2
4
8
Immunogenicity
10
4
40
Total
263.4
Total for clinical purposes
270
a
Additional samples may be drawn if needed for safety purposes.


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LY3493269
Appendix 6.
Pancreatic Monitoring
Glucagon-like peptide 1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the United States (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 LY3437943 on the exocrine pancreas, 
amylase and lipase values will be monitored in all current and future clinical trials with 
LY3437943.
Additional monitoring will be requested for amylase or lipase values ≥3X the ULN at any visit 
after randomization, even in asymptomatic participants (see figure below).  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 computed tomography scan or magnetic 
resonance imaging
Most participants with acute pancreatitis experience abdominal pain that is located generally in 
the epigastrium and radiates to the back in approximately one-half of the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some participants asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  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.


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LY3493269
Abbreviations:  CBC = complete blood count; CT = computed tomography; LFT = liver function 
test; MRI = magnetic resonance imaging; ULN = upper limit of normal.
Pancreatic Enzymes:  Safety Monitoring Algorithm
In Patients without Symptoms of Pancreatitis1,2
Follow this algorithm when the value(s) for serum amylase and/or lipase are = 3x upper limit of normal (ULN)
Test A/L every 4 Weeks 
(More Frequently if Protocol Visit  
Schedule is < 4 weeks)
Negative Imaging Results
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis 
Notify Lilly
Retest within 24 - 72 hours
Send sample to Laboratory
Amylase and/or Lipase (A/L3) = 3X ULN
A/L Not Decreasing
4.  Abdominal imaging is most valuable when performed 
at the time of elevated enzyme values.  If in the opinion 
of the radiologist or investigator, it is safe for the 
patient/subject to receive contrast, an enhanced 
abdominal CT is preferred. MRI is also an acceptable 
imaging modality.
3. A/L = amylase and/or lipase. Either or both 
enzymes can be used to meet the algorithm criteria.   
5. At a minimum, order a CBC and a pancreatic 
panel (which includes LFTs, calcium and 
triglycerides). Record all concomitant 
medications.
A/L Decreasing
Repeat Abdominal Imaging4
as Soon as Possible After 
Confirmation of Laboratory Values  
1. Symptomatic – related primarily to abdominal pain 
consistent with pancreatitis; however, in the opinion of 
the investigator severe nausea and vomiting plus
other symptoms consistent with pancreatitis may be
considered symptomatic as well.  
2. If in the opinion of the investigator, the patient 
has symptoms of acute pancreatitis:
(a) Stop injectable study drug 
(b) Consult for assessment and management 
(c) Assess for causes of pancreatitis 
(d) Notify Lilly
If A/L = 3X ULN, perform 
Abdominal Imaging4
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis
Notify Lilly
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
Positive Imaging Results
Negative Imaging Results
Positive Imaging Results
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
5
5


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LY3493269
Participants diagnosed with pancreatitis will be discontinued from the study.  Investigators will 
be responsible for following, through an appropriate health care option, these pancreatitis AEs 
until the events resolve or are explained.  Adverse events that meet the diagnostic criteria of 
acute pancreatitis will be captured as SAEs.  For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to IP.


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LY3493269
Appendix 7.
Hypersensitivity Event Tests
This table list 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.
Hypersensitivity Testsa
Anti-LY antibodies (immunogenicity)
Tryptase
LY concentration (PK)
N-methylhistamine
Drug Specific IgEb
Basophil Activation Testb
Complements
Cytokine Panel
Abbreviations:  PK = pharmacokinetic; LY = LY3493269
a
Assayed by Lilly-designated laboratory
b Basophil Activation test will be performed if a drug specific IgE assay is unavailable.


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LY3493269
Appendix 8.
Guidance on Clinically Significant Events
The table below summarizes the type and severity of symptoms, clinical signs, and clinical 
laboratory findings that may qualify as a CSE.  These are intended as a guideline to the 
investigator(s), not as a set of absolute criteria.  The underlying principle is to define a level of 
moderate to severe abnormality in safety findings that could cause harm to health and which 
should trigger consideration of whether or not it would be appropriate to continue dosing of a 
participant who experiences this effect.  Safety parameters not included in this table may be 
interpreted in a similar manner according to investigators’ judgment.


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LY3493269
Parameter
CSE level
Symptoms
Dizziness/hypotension
Orthostatic CNS symptoms (dizziness, confusion) that are not vasovagal responses 
to provocative stimuli (for example, phlebotomy, nausea, bowel, or bladder 
function), and are associated with orthostatic SBP decrease >20 mm Hg or DBP 
decrease >10 mm Hg or heart rate >105 bpm, for >3 hours 
Sensorium
Disorientation to time, place, or identity.  Any abnormal ideation
Mood
Feelings of grief or loss that interfere with study procedures or activities of daily 
living.  Any suicidal ideation
Headache/pain
Any focal or generalized head pain that disrupts normal activities and is not 
responsive to medical therapies
Pruritus
Generalized itching over >24 hours unresponsive to oral antihistamine
Signs
Systolic blood pressure
>30 mm Hg increase from baseline values and an absolute level >190 mm Hg
Diastolic blood pressure
>20 mm Hg increase from baseline values and an absolute level >115 mm Hg
Heart rate
Resting (sitting or recumbent) HR >120 bpm
Cardiac rhythm
Any symptomatic rhythm other than sinus rhythm, mild sinus bradycardia, or mild 
sinus tachycardia
QTc
>500 msec and >60 msec increase from baseline value
QRS morphology
Significant prolongation of QRS interval or new onset of bundle branch block
Tremor
Readily visible tremor during normal movement deemed unrelated to hypoglycemia
Reflexes
New onset of clonic reflexes
Clinical Laboratory
(if confirmed by repeat measurements within 48 hours)
Hemoglobin
Absolute value <10 g/dL and >2 g/dL reduction from baseline
Neutropenia
Absolute neutrophils <1,500/μL and >1,000 L decrease from baseline
Lymphopenia
Absolute lymphocyte count <800/μL and >500/L decrease from baseline
Platelet count
<75,000/μL and >50,000/L decrease from baseline
Creatinine
>180 µmol/L and >30 µmol/L increase from baseline value
Urea
>8 mmol/L and >3 mmol/L increase from baseline value
Alanine aminotransferase
≥5-fold above laboratory reference upper limit value [also see section 9.4.5.2 
Hepatic Safety]
Potassium
<2.5 or >5.5 mmol/L and >0.5 mmol/L change from baseline value
Sodium
<130 or >150 mmol/L and >10 mmol/L change from baseline value
Abbreviations:  CNS = central nervous system; CSE = clinically significant event; DBP = diastolic blood pressure; 
HR = heart rate; QTc = corrected QT interval; SBP = systolic blood pressure.


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

SAP_001.pdf: 
Statistical Analysis Plan J1X-MC-GZHA (v2) 
 
A Single-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 
LY3493269 in Healthy Participants 
 
NCT04178733 
 
Approval Date: 28-Jan-2020 


Fi nal V 2 , 2 2 Ja n 2 0 2 0
             Pa ge 1 of 2 5
S T A TI S TI C A L A N A L Y SI S P L A N
A Si n gle- Asce n di n g D ose St u d y t o I n vesti g ate t he S afet y, T oler a bilit y, a n d 
P h ar m ac o ki netics of L Y 3 4 9 3 2 6 9 i n He alt h y P artici p a nts
A p pr o v al D at e: 2 8- J a n- 2 0 2 0 G M T
Stati stical A nal ysis Pla n Stat us : Fi nal Versi o n  2
Stati stical A nal ysis Pla n Date : 2 2- Ja n uar y- 2 0 2 0
St u d y  Dr u g: L Y 3 4 9 3 2 6 9
S p o ns or Refere nce : J 1 X-M C -G Z H A
C o va nce C R U St u d y : 1 0 0 1 2 1 5- 8 4 1 5 5 3 4
Cli nical P hase I


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 9
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 14
9.4
Pharmacodynamic Assessment .............................................................................. 15
9.4.1
Pharmacodynamic Analysis.......................................................................... 15
9.5
Safety and Tolerability Assessments...................................................................... 18
9.5.1
Adverse events ............................................................................................. 18
9.5.2
Glucose Monitoring and Hypoglycemia........................................................ 18
9.5.3
Concomitant medication............................................................................... 19
9.5.4
Clinical laboratory parameters...................................................................... 19
9.5.5
Vital signs .................................................................................................... 19
9.5.6
Electrocardiogram (ECG)............................................................................. 20
9.5.7
Immunogenicity Assessments....................................................................... 21
9.5.8
Injection-Site Reactions................................................................................ 21
9.5.9
Appetite Analysis ......................................................................................... 22
9.5.10
Body Weight ................................................................................................ 23
9.5.11
Hypersensitivity reactions............................................................................. 23
9.5.12
Hepatic Monitoring ...................................................................................... 23
9.5.13
Pancreatic Safety.......................................................................................... 23
9.5.14
Other assessments......................................................................................... 24


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10. INTERIM ANALYSES ............................................................................................... 24
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 24
12. REFERENCES ............................................................................................................ 24
13. DATA PRESENTATION ............................................................................................ 25
13.1 Derived Parameters ............................................................................................... 25
13.2 Missing Data ......................................................................................................... 25
13.3 Insufficient Data for Presentation .......................................................................... 25


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Statistical Analysis Plan 
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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ADA
Anti-drug antibody
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-168 h)
Area under the concentration versus time curve from time zero to 168 
hours postdose
%AUC(tlast-)
Percentage of AUC(0-∞) extrapolated
BQL
Below the lower limit of quantitation
CI
Confidence interval
CL
Total body clearance of drug calculated after intravenous 
administration
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects repeated measures
OGTT
Oral glucose tolerance test
PD
Pharmacodynamic
PG
Plasma Glucose
PK
Pharmacokinetic
QTcF
The QT interval corrected using Fridericia’s formula


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8415534
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RA
Accumulation ratio (AUC(0-∞))/AUC(0-168 h))
SAD
Single ascending dose
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
t½
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vz
Volume of distribution during the terminal phase after intravenous 
administration 
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss
Volume of distribution at steady state after intravenous 
administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
WHO
World Health Organization


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Statistical Analysis Plan 
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
10 October 2019) and SAP version 1 (dated 02 December 2019).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical, PK and PD analyses of data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Eli Lilly and Company. A limited amount of information 
concerning this study (e.g., objectives, study design) is given to help the reader’s interpretation. 
When the SAP and TFL shells are agreed upon and finalized, they will serve as the template for 
this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
Primary

To evaluate the safety and tolerability of LY3493269 following single subcutaneous (SC)
and intravenous (IV) doses in healthy participants. 
Secondary 

To characterize the PK of LY3493269 following single SC and IV doses in healthy 
participants.
Exploratory 

To investigate the PD effects of LY3493269 following single SC doses in healthy 
participants. 

To explore immunogenicity of LY3493269 following single doses in healthy participants.

To explore the effect of LY3493269 on appetite and food intake following single SC 
doses in healthy participants.


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Statistical Analysis Plan 
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5. STUDY DESIGN
Study GZHA is a Phase 1, single-site, randomized, placebo controlled, single-ascending dose 
(SAD) study in healthy participants, to evaluate the safety, tolerability, and PK of LY3493269 
administered as single SC doses and as a single IV dose. The PD effects of SC doses of 
LY3493269 on glycemic effects (including fasting glucose, insulin, and glucose and insulin 
during an oral glucose tolerance test [OGTT]) and appetite will be explored. For the SC cohorts, 
the investigator and participants will be blinded. The IV Cohort is open label with no placebo.
The planned LY3493269 SC doses for this study range from 0.15 mg to 7.5 mg. These dose 
levels may be adjusted (for example, dose increments may be reduced, a dose level may be 
repeated, or a lower/intermediate dose may be administered) based on ongoing review of 
available safety, tolerability, PK, and PD data. Any proposal to adjust SC or IV doses from those 
planned and stated in the protocol, together with supporting data, will be reviewed by an 
independent safety review panel.
Participants will undergo safety (including but not limited to adverse events [AEs], medical 
assessments, clinical laboratory tests, body weight, vital signs and ECGs]), PK and PD 
assessments. 
Subcutaneous Administration Cohorts 1 through 6
This study includes up to 6 planned SC cohorts: 

SC Cohort 1: 0.15 mg (6 LY3493269: 2 Placebo)

SC Cohort 2: 0.5 mg (6 LY3493269: 2 Placebo)

SC Cohort 3: 1.5 mg (6 LY3493269: 2 Placebo)

SC Cohort 4: 3.0 mg (6 LY3493269: 2 Placebo)

SC Cohort 5: 5.0 mg (6 LY3493269: 2 Placebo)

SC Cohort 6: 7.5 mg (6 LY3493269: 2 Placebo)
Cohorts 2 to 6 will be initiated only if the investigator and Eli Lilly and Company clinical 
pharmacologist deem the safety results in the preceding cohort to be acceptable through Day 8 
from at least 6 participants dosed. In addition, all planned participants in the current cohort 
should have been dosed prior to escalation to the next cohort.
Intravenous Administration Cohort
This study includes a single IV cohort (IV Cohort), where up to 6 healthy participants should 
complete dosing at the same level to provide sufficient PK sampling. The IV Cohort will be 
initiated based on review of safety and tolerability data from SC Cohort 3 and available 7-day 
PK data and/or PD data from at least 2 preceding SC cohorts. 
All participants will receive LY3493269 only (that is no placebo group), as a single IV bolus 
dose. The planned dose is 0.5 mg. This dose is expected to be safe while providing plasma 
concentrations that can be adequately measured over the sampling time period enabling adequate 
characterization of the PK profile. The IV dose may be increased to a maximum of 1.5 mg or 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8415534
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decreased to a minimum of 0.25 mg depending on emerging data. It is intended that the IV dose 
will be administered sequentially, with 1 participant having completed the dosing and observed 
for at least 20 minutes before the next participant is dosed. 
In the IV Cohort, 2 participants will initially receive the planned 0.5 mg dose. An additional 
4 participants will receive investigational product following joint investigator and sponsor 
review of safety and tolerability data through at least 4 days postdose (including Day 5 safety 
labs and assessments) from the 2 initial participants.
Figure GZHA.1 illustrates the study design.
Abbreviations: IV = intravenous; LY = LY3493269; PL = Placebo; SC = subcutaneous.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
Placebo SC
1
0.15 mg LY3493269 SC
2
0.5 mg LY3493269 SC
3
0.5 mg LY3493269 IV
4
1.5 mg LY3493269 SC
5
3.0 mg LY3493269 SC
6
5.0 mg LY3493269 SC
7


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7.5 mg LY3493269 SC
8
7. SAMPLE SIZE JUSTIFICATION
Up to 70 participants may be enrolled so that approximately 54 participants complete the study.
The sample size is customary for Phase 1 studies evaluating safety and PK and is not powered on 
the basis of statistical hypothesis testing. 
Participants who are randomized but not administered treatment prior to discontinuation may be 
replaced to ensure that approximately 8 participants complete each SC Cohort, and 6 to complete 
the IV cohort. 
Participants who discontinue early mat be replaced after consultation with the investigator and
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant. 
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug 
or placebo.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data. 
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug or placebo and have evaluable PD data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 


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Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed. All other demographic 
variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 8.1 or later).
Plasma concentrations of LY3493269 will be used to determine the following PK parameters, 
when possible:  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
Parameter
Units
Definition
AUC(0-tlast)
h*ng/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-168 h)
h*ng/mL
area under the concentration versus time curve from time zero to
168 hours postdose
AUC(0-∞)
h*ng/mL
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL
L/h
total body clearance of drug calculated after intravenous 
administration
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
RA
N/A
Accumulation ratio (AUC(0-∞))/AUC(0-168 h))
Vz
L
volume of distribution during the terminal phase after intravenous 
administration 
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss
L
volume of distribution at steady state after intravenous 
administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate.  
The software and version used for the final analyses will be specified in the clinical study report. 
Any exceptions or special handling of data will be clearly documented within the final study 
report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 


Final V2, 22 Jan 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive concentrations above the LLOQ, with at least one of these concentrations 
following Cmax.

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on predicted last observed drug concentration will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a 
subsequent dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.


Final V2, 22 Jan 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA

For multiple-dosing data, when pre-dose concentrations are missing, the value to be 
substituted will be the minimum observed drug concentration for the dosing interval.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) 
sampling times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will 
be used to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.

Concentrations excluded from the mean calculation will be documented in the 
final study report.

A concentration average will be plotted for a given sampling time only if 2/3 of 
the individual data at the time point have quantifiable measurements that are 
within the sampling time window specified in the protocol or ± 10%. An average 
concentration estimated with less than 2/3 but more than 3 data points may be 
displayed on the mean concentration plot if determined to be appropriate and will 
be documented within the final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:


Final V2, 22 Jan 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
PK dose proportionality will be assessed. Log-transformed Cmax, AUC(0-tlast) and AUC(0-∞) 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% 
confidence intervals (CIs). The estimated ratio of dose-normalized geometric means of PK 
parameters between the highest and lowest doses will be used to assess dose proportionality. A 
subinterval within the highest and lowest doses may also be considered for assessment of dose 
proportionality using the same approach. 


 
Final V2, 22 Jan 2020 
 
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Statistical Analysis Plan  
 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534 
Sponsor Reference J1X-MC-GZHA
A statistical analysis using the Kruskal-Wallis test3 will be conducted to investigate the dose 
proportionality (independence) of tmax. The p-value will be calculated for the overall dose 
comparison. 
All PK parameters will be summarized using descriptive statistics. Geometric means of the IV 
dose group and corresponding SC dose group will be used to discuss absolute bioavailability.   
Examples of the SAS code that will be used are as follows: 
proc mixed data=xxx; 
model log_pk = log_dose / alpha=0.1 cl solution outpred=resids ddfm=kr; 
estimate 'xx mg' intercept 1 log_dose yy / alpha=0.1 cl; /*Log value of xx*/ 
estimate 'zz mg - xx mg' log_dose pp / alpha=0.1 cl; /*Difference in log 
values of zz and xx*/ 
ods output solutionf=est; 
ods output estimates=estims; 
run; 
 
Kruskal-Wallis Test 
 
proc npar1way data=xxx 
  class dose; 
  var pk; 
  output out=krusk; 
run; 
 
9.4 
Pharmacodynamic Assessment 
9.4.1 
Pharmacodynamic Analysis 
The oral glucose tolerance test (OGTT) will be used to derive the following PD 
endpoints/biomarkers by Covance: 
 Fasting (Pre-OGTT) glucose, insulin, C peptide and glucagon. Baseline for these 
parameters will be the Day -1 Pre-OGTT concentration. 
 Concentrations of glucose, insulin, C peptide and glucagon during the OGTT. Baseline 
for these parameters will be the time-matched Day -1 Pre-OGTT concentration. 
 AUC(0-2h) for glucose, insulin, C peptide and glucagon during the OGTT, derived using 
the trapezoidal rule. Baseline for these parameters will be the Day -1 AUC. 
In addition, the following OGTT derived parameters will also be derived: 
 HOMA-IR and HOMA-B based on fasting insulin and fasting glucose4,5 
 
ܪܱܯܣെܫܴൌሺܨܲܫൈܨܲܩሻ/22.5 
 
ܪܱܯܣെܤൌሺ20 ݔܨܲܫሻ/ሺܨܲܩെ3.5ሻ 
 


 
Final V2, 22 Jan 2020 
 
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Statistical Analysis Plan  
 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534 
Sponsor Reference J1X-MC-GZHA
where FPI = fasting plasma insulin in U/mL, FPG = fasting plasma glucose in mmol/L 
Or alternatively, 
 
ܪܱܯܣെܫܴൌሺܨܲܫൈܨܲܩሻ/405 
 
ܪܱܯܣെܤൌሺ360 ݔܨܲܫሻ/ሺܨܲܩെ63ሻ 
where FPI = fasting plasma insulin in U/mL, FPG = fasting plasma glucose in mg/dL 
 Insulinogenic index4,5 
 
ܫܩܫൌΔܫ݊ݏݑ݈݅݊଴ିଷ଴௠௜௡
Δܩ݈ݑܿ݋ݏ݁଴ିଷ଴௠௜௡
 
where glucose is in mg/dL and insulin is in U/mL 
 Insulin sensitivity (Matsuda Index)6 
 
ISI ൌ
10000
ටܩ0 ∗ܫ0 ∗ܩ݈ݑܿ݋ݏ݁ܣܷܥሺ0 െ2݄ሻ
2݄
∗ܫ݊ݏݑ݈݅݊ܣܷܥሺ0 െ2݄ሻ
2݄
 
where glucose is in mg/dL and insulin is in U/mL 
 OGIS7 
 
 
ܱܩܫܵൌ1
2 ൈሺܤ൅ݏݍݎݐሺܤଶ൅4 ൈ݌5 ൈ݌6 ൈሺܩ90 െܩ݈ܿሻൈܥ݈ைீ்்ሻሻ 
 
where, ܤൌሺ݌5 ൈሺܩ90 െܩ݈ܿሻ൅1ሻൈܥ݈ைீ்் 
 
ܥ݈ைீ்்ൌ ݌4 ൈ
݌1 ൈܦ଴െܸൈܩ120 െܩ90
ܶ
ܩ90
൅݌3
ܩ0
ܫ90 െܫ0 ൅݌2
 
 
                    ݌1 ൌ 6.50, ݌2 ൌ1951, ݌3 ൌ4514, ݌4 ൌ792, ݌5 ൌ11.8 ൈ10ିଷ, ݌6 ൌ173  
D0, glucose dose of OGTT normalized for body surface area (mmol/m2) 
V = 104 (glucose distribution volume, ml/m2) 
T = 30 (time interval between G120 and G90, min) 
Gcl = 5 (typical clamp glucose concentration, mmol/L) 
OGIS (ml/min.m2) 


 
Fi nal V 2, 2 2 Ja n 2 0 2 0 
 
             Pa ge 1 7 of 2 5 
Statistical A nal ysis Pla n  
 
C O N FI D E N TI A L
C o va nce Cli nical St u d y N o. 1 0 0 1 2 1 5- 8 4 1 5 5 3 4 
S p o ns or Refere nce J 1 X- M C- G Z H A
B MI ( k g/ m 2) 
Fasti n g gl uc ose ( m m ol/ L) 
Fasti n g i ns uli n ( p m ol/ L) 
2 h Gl uc ose ( m m ol/ L) 
 Pre dicte d cla m p- deri ve d i ns uli n se nsiti vit y ( M val ue) 8 
 
 
  
2
 
 
 
      2. 8 8 4 6 2 1 9,      0. 5 2 08 5 2 0,       0. 8 2 2 3 3 6 3,       0. 4 1 9 1 2 4 2 ,
      0. 2 4 2 7 8 9 6 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
I n di vi d ual o bser ve d (s pa g hetti pl ots) a n d mea n ti me pr ofile of  t he p ost d ose P D para meters, 
i ncl u di n g baseli ne c orrecte d para meters, will be pl otte d b y treat me nt gr o u p.  
A bs ol ute val ues as well as c ha n ge fr o m baseli ne fasti n g gl uc ose, i ns uli n a n d C- pe pti de will be 
a nal yze d statisticall y. Para meters will be u nt ra nsf or me d bef ore statistical a nal yses. T he 
para meters will be a nal yze d usi n g mi xe d-effects re peate d meas ures ( M M R M) m o dels t o e val uate 
treat me nt effects as well as treat me nt c o m paris o ns. T he m o del will i ncl u de treat me nt, ti me p oi nt, 
a n d treat me nt- b y-ti me p oi nt i nteracti o n as fi xe d e ffects, a n d s u bject as a ra n d o m effect. Baseli ne 
val ues will be i ncl u de d as a c o variate f or t he c ha n ge fr o m baseli ne a nal ysis. A n u nstr uct ure d 
c o varia nce str uct ure will be use d a n d a c o m p o u n d s y m metr y str uct ure ma y be use d if t his fails t o 
c o n ver ge. Least-s q uares mea ns as well as 9 0 %  CIs f or t he differe nce of L Y 3 4 9 3 2 6 9 c o m pare d 
wit h place b o will be re p orte d. 
E xa m ple of S A S c o de (f or t he c ha n ge fr o m baseli ne a nal ysis) as f oll o ws. 
p r o c  m i x e d  d a t a = x x x ;  
c l a s s  t r e a t m e n t  t i m e p o i n t  s u b j e c t ;  
m o d e l  c h a n g e  =  b a s e l i n e  t r e a t m e n t  t i m e p o i n t  t r e a t m e n t * t i m e p o i n t  
/ r e s i d u a l  d d f m = k r ;  
r e p e a t e d  t i m e p o i n t  /  s u b j e c t = s u b j e c t  t y p e = U N ;  
l s m e a n s  t r e a t m e n t * t i m e p o i n t  /  c l  p d i f f  a l p h a = 0 . 1 ;  
o d s  o u t p u t  l s m e a n s = l s m  d i f f s = e s t i m s ;  
r u n ;  
C CI
 


Final V2, 22 Jan 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
9.5
Safety and Tolerability Assessments
9.5.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug by the investigator.
Any serious AEs will be listed. 
Discontinuations due to AEs will be listed.
9.5.2
Glucose Monitoring and Hypoglycemia
During the study, blood glucose concentrations will be monitored for safety assessments.
Glucose data will be listed, and if sufficient data is collected, summarized by treatment together 
with changes from baseline, where baseline is defined as Day 1 predose.
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:
Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/dL (3.9 mmol/L):
‒ Symptomatic hypoglycemia:  an event during which typical symptoms of   hypoglycemia are 
accompanied by PG ≤70 mg/dL (3.9 mmol/L)
‒ Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms of    
hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
‒ Unspecified hypoglycemia:  an event during which PG ≤70 mg/dL (3.9 mmol/L) but   no 
information relative to symptoms of hypoglycaemia
Documented Clinically Significant Hypoglycemia (Level 2) PG <54 mg/dL (3.0 mmol/L):
‒ Symptomatic hypoglycemia:  an event during which typical symptoms of    hypoglycemia are 
accompanied by PG <54 mg/dL (3.0 mmol/L)


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
‒ Asymptomatic hypoglycemia:  an event not accompanied by typical symptoms of    
hypoglycemia but with PG <54 mg/dL (3.0 mmol/L)
‒ Unspecified hypoglycemia:  an event during which PG ≤<4 mg/dL (3.0 mmol/L) but   no 
information relative to symptoms of hypoglycemia was recorded.
Severe hypoglycemia (Level 3):  an event requiring the assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. During these episodes, the 
subject has an altered mental status and cannot assist in their care, is semiconscious or 
unconscious, or experienced coma with or without seizures and may require parenteral therapy. 
Plasma glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of blood glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low PG concentration (≤70 mg/dL [3.9 
mmol/L]).
Other Hypoglycemia:
Nocturnal hypoglycemia:  any hypoglycemic event (documented symptomatic, asymptomatic, 
probable symptomatic, or severe hypoglycemia) that occurs between bedtime and waking
Investigator review of glucose results clinically indicative of hypoglycemia will be required.
9.5.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2019). 
Concomitant medication will be listed.
9.5.4
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment
group together with changes from baseline, where baseline is defined as the Day 1 predose
assessment, and listed. Urinalysis data will be listed. Additionally, clinical chemistry, 
hematology and urinalysis data outside the reference ranges will be listed and flagged on 
individual subject data listings.
9.5.5
Vital signs
Vital signs data will be summarized by treatment group together with changes from baseline, 
where baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual subjects will be listed.
For change from baseline values, a mixed-model repeated-measure model with treatment, time 
(of measurement), and treatment-by-time interaction as fixed effects, subject as a random effect, 
and baseline as covariate will be used to determine the effects of LY3493269. Least-squares 
means as well as 90% CIs for the difference of LY3493269 compared with placebo will be 


Final V2, 22 Jan 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
reported. An unstructured covariance structure will be used and a compound symmetry structure 
may be used if this fails to converge. 
Example of SAS code (for the change from baseline analysis) as follows.
proc mixed data=xxx;
class treatment timepoint subject;
model change = baseline treatment timepoint treatment*timepoint 
/residual ddfm=kr;
repeated timepoint / subject=subject type=UN;
lsmeans treatment*timepoint / cl pdiff alpha=0.1;
ods output lsmeans=lsm diffs=estims;
run;
The relationship between the time-matched LY3493269 concentrations and changes from 
baseline and mean time-matched placebo for all vital signs parameters will be explored 
graphically using a scatter plot. A regression analysis using a linear mixed-effects model will be 
performed. A plasma LY3493269 concentration- vital signs data analysis will be performed to 
assess the changes from baseline (Day 1 predose) and mean time-matched placebo for each vital 
sign relative to plasma LY3493269 concentrations across all active treatments. The change from 
baseline adjustment will be based on each individual subject’s Day 1 predose value, and an 
additional placebo adjustment will be based on mean time-matched placebo values. The analysis 
will be performed by plotting double delta vital signs measurement against LY3493269 
concentrations, including all post dosing timepoints. A linear mixed-effects model will be 
performed on the double delta vital signs values and will include LY3493269 concentration as a 
covariate. The estimated regression line and associated 90% CI will be fitted on the plot and the 
p-value for the slope reported. Estimated delta vital signs result and 90% CI at the geometric 
mean Cmax will also be presented. 
Example of SAS code as follows:
proc mixed data=xxx;
  class subject; 
  model DDchg = concentration / solution cl alpha=0.1 ddfm=kr; 
  random subject;  
  ods output estimates=est;
  ods output solutionf=sol;  
run;
9.5.6
Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR, 
QT, RR, QRS duration and heart rate. In addition, QT interval corrected using Fridericia’s 
formula (QTcF) will be calculated as follows:


3 60 HR
QT
QTcF 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
The mean of triplicate data will be used for reporting. The ECG data will be summarized by 
treatment group together with changes from baseline, where baseline is defined as the mean of 
the triplicate Day 1 predose assessments (-30, -15 and 0 minute). Figures of mean ECG data and 
mean changes from baseline will be presented by treatment. The frequency of subjects with a 
maximum increase from baseline in QTcF interval will be summarized for each treatment
according to the following categories: >30 ms and >60 ms. In addition, the frequency of subjects 
QTcF postdose values, according to the following categories: >450 ms, >480 ms and >500 ms, 
will be summarized by treatment. 
The relationship between the time-matched LY3493269 concentrations and changes from 
baseline and mean time-matched placebo on QTcF will be explored graphically using a scatter 
plot. A regression analysis using a linear mixed-effects model will be performed. A plasma 
LY3493269 concentration-QTcF analysis will be performed to assess the changes from baseline 
(Day 1 predose) and mean time-matched placebo in the QTcF interval relative to plasma 
LY3493269 concentrations across all active treatments. The change from baseline adjustment 
will be based on each individual subject’s Day 1 predose value, and an additional placebo 
adjustment will be based on mean time-matched placebo values. The analysis will be performed 
by plotting double delta QTcF against LY3493269 concentrations, including all post dosing 
timepoints. A linear mixed-effects model will be performed on the double delta QTcF values and 
will include LY3493269 concentration as a covariate. The estimated regression line and 
associated 90% CI will be fitted on the plot and the p-value for the slope reported. Estimated 
delta QTcF and 90% CI at the geometric mean Cmax will also be presented. The analysis will also 
be produced for heart rate and PR.
Example of SAS code as follows:
proc mixed data=xxx;
  class subject; 
  model DDchg = concentration / solution cl alpha=0.1 ddfm=kr; 
  random subject;  
  ods output estimates=est;
  ods output solutionf=sol;  
run;
9.5.7
Immunogenicity Assessments
The frequency and percentage of subjects with pre-existing antidrug antibody (ADA) and with 
treatment-emergent ADAs (TE ADA) to LY3493269 may be tabulated and listed if available. 
For subjects who are ADA negative at baseline, TE ADAs are defined as those with a signal 
increase, greater than assay variability, compared to baseline. The frequency of cross-reactive 
binding to native GIP, GLP-1 or neutralizing antibodies may also be tabulated in TE ADA+ 
participants, when available.
9.5.8
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as

an AE from a subject, or


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA

a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

pruritus

pain
In case of an AE of injection-site reaction, pain data will be listed.
Injection-site reaction data will be listed and summarized by treatment in frequency tables.
9.5.9
Appetite Analysis
To explore the effects of LY3493269 on meal intake and appetite sensation, subjects 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 on Day 1, and in 
the fasted state while inpatient as well as on scheduled outpatient visits.
The VAS is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually 
“extremely” and “not at all”. Subjects are required to rate their subjective sensations on four 
100 mm scales combined with questions similar to the following:
1. “How hungry do you feel?”
2. “How satisfied do you feel?”
3. “How full do you feel?”
4. “How much do you think you could eat?”
A staff member will use a caliper to measure the distance from 0 to the mark that the subject
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.
The individual VAS measurements and overall appetite score will be listed and summarized by 
treatment and timepoint, alongside change from baseline (Day 1 predose).
The individual parameters, and overall score, will be analyzed using an MMRM model to 
evaluate treatment effects as well as treatment comparisons. The model will include treatment, 
timepoint, and treatment-by-timepoint interaction as fixed effects, and subject as a random 
effect. An unstructured covariance structure will be used and a compound symmetry structure 
may be used if this fails to converge. Least-squares means as well as 90% CIs for the difference 
of LY3493269 compared with placebo will be reported. The distribution of the data will be 
tested prior to analyses and should the distribution indicate a parametric analysis not to be 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
appropriate, a non-parametric analysis will be used instead. Change from baseline (Day 1 
predose) will also be analysed, with a covariate for baseline added to the model.
9.5.10
Body Weight
Body weight data will be listed and summarized by treatment group, alongside changes from 
baseline (Day 1 predose).
Change from baseline body weight will be analyzed using an MMRM model to evaluate 
treatment effects as well as treatment comparisons. The model will include treatment, timepoint, 
and treatment-by-timepoint interaction as fixed effects, and subject as a random effect. Baseline 
values will be included as a covariate for the change from baseline analysis. An unstructured 
covariance structure will be used and a compound symmetry structure may be used if this fails to 
converge. Least-squares means as well as 90% CIs for the difference of LY3493269 compared 
with placebo will be reported.
9.5.11 Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to
assess the patient’s medical history, alternative causes, and symptoms.
These data will be listed.
9.5.12 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase ≥3× upper limit of normal (ULN), 
alkaline phosphatase ≥2× ULN, or elevated total bilirubin ≥2× ULN, liver tests will be 
performed to confirm the abnormality. Additional safety data may be collected if required, as 
defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant that have potential for hepatotoxicity, including acetaminophen will be listed. 
Results from any hepatic monitoring procedures, such as a magnetic resonance elastography 
scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.5.13 Pancreatic Safety
Serum amylase and lipase measurements will be collected as part of the clinical laboratory
testing at time points specified in the protocol Additional measurements may be performed at the 
investigator’s discretion.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8415534
Sponsor Reference J1X-MC-GZHA
Further diagnostic assessments will be recommended whenever lipase and/or amylase are
confirmed to be ≥3× ULN at any visit post-treatment sequence allocation even if the participant
is asymptomatic. If pancreatitis is suspected, the case will be further defined during an 
adjudication process.
These data will be listed.
9.5.14
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
10.
INTERIM ANALYSES
Interim access to safety and tolerability (and any available PK or PD) data is scheduled to occur 
after every dosing session. This schedule may be modified as applicable, based on emerging 
safety and/or tolerability data. The purpose of these reviews is to guide dose selection for the 
next dosing cohort. Prior to confirming the dose and initiating the IV Cohort, preliminary PK 
data from at least 2 preceding SC cohort must be reviewed.
The investigator and the Lilly sponsor team will jointly make the determination regarding dose 
escalation based upon their review of the safety and tolerability data, and PK or PD results if 
available. In addition, these data may be used to guide dose selection and inform the need to 
adjust timing of procedures/sampling schedules for the current or future studies.
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. San Francisco, CA: 
Holden-Day; 1975.
4. Seltzer et al, 1967: Seltzer et al, Insulin Secretion in Response to Glycemic Stimulus: 
Relation of Delayed Initial Release to Carbohydrate Intolerance in Mild Diabetes Mellitus. 
The Journal of Clinical Investigation. 1967; 46(3):323-335.


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Sponsor Reference J1X-MC-GZHA
5. Utzschneider et al, 2009: Utzschneider et al. Oral disposition index predicts the development 
of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009 Feb; 
32(2):335-41.
6. Matsuda et al 1999, based on 2h OGTT: Insulin sensitivity indices obtained from oral 
glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 
1999; 22(9):1462-1470.
7. Tura et al. Prediction of clamp-derived insulin sensitivity from the oral glucose insulin 
sensitivity index. Diabetologia. 2018 May; 61(5):1135-1141
8. Tura et al 2018, based on 2h OGTT: Prediction of clamp-derived insulin sensitivity from the 
oral glucose insulin sensitivity index. Diabetologia. 2018 May; 61(5):1135-1141.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


P P D
L e o  D o c u m e n t  I D  =  4 2 3 8 9 0 f d - c d 3 1 - 4 7 7 0 - 9 3 1 1 - 6 8 6 2 1 0 a f 7 1 e 0
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 8 - J a n - 2 0 2 0  1 5 : 1 2 : 3 1  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 8 - J a n - 2 0 2 0  1 5 : 1 8 : 0 2  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 8 - J a n - 2 0 2 0  1 5 : 2 7 : 3 1  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D