A Randomized, Placebo-Controlled, Subject- and Investigator-Blind, Single and Multiple Dose, Safety, Tolerability, and Pharmacokinetics Study of LY3463251 in Healthy and Overweight Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

J1D-MC-GZAA Protocol (e) 
 
A Randomized, Placebo-Controlled, Subject- and Investigator-Blind, Single and Multiple Dose, 
Safety, Tolerability, and Pharmacokinetics Study of LY3463251 in Healthy and Overweight 
Healthy Subjects 
 
NCT03764774 
 
Approval Date: 09-Oct-2020 

J 1 D -M C -G Z A A ( e) 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 6 3 2 5 1
Pr ot o c ol J 1 D -M C -G Z A A ( e)
A R a n d o mi z e d, Pl a c e b o -C o ntr oll e d, S u bj e ct - a n d 
I n v e sti g at or-Bli n d, Si n gl e a n d M ulti pl e D o s 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 St u d y  of L Y 3 4 6 3 2 5 1 i n 
H e alt h y a n d O v er w ei g ht H e alt h y S u bj e ct 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 u l 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 6 3 2 5 1 , 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 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 .  
L Y 3 4 6 3 2 5 1
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 : 
2 5 S e p 2 0 1 8
A m e n d m e nt ( a) 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 :  1 1 O ct 2 0 1 8
A m e n d m e nt ( b) 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:  0 2 D e c 2 0 1 8
A m e n d m e nt ( c) 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:  0 6 S e p 2 0 1 9
A m e n d m e nt ( d) 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:  0 2 D e c 2 0 1 9
A m e n d m e nt ( e ) 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.
A p pr o v al D at e: 0 9- O ct- 2 0 2 0 G M T

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LY3463251
Table of Contents
A Randomized, Placebo-Controlled, Subject- and 
Investigator-Blind, Single and Multiple Dose, Safety, 
Tolerability, and Pharmacokinetics Study of LY3463251 in 
Healthy and Overweight Healthy Subjects
Section
Page
Protocol J1D-MC-GZAA(e) A Randomized, Placebo-Controlled, Subject-
and Investigator-Blind, Single and Multiple Dose, Safety, 
Tolerability, and Pharmacokinetics Study of LY3463251 in Healthy 
and Overweight Healthy Subjects........................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
2.1.
Part A (Single-Ascending Dose)...................................................................................12
2.2.
Part B (Multiple-Ascending Doses)..............................................................................14
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.1.1.
Part A (Healthy Subjects).....................................................................................24
5.1.2.
Part B (Overweight Healthy Subjects)..................................................................24
5.2.
Number of Participants.................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................26
5.5.
Justification for Dose ...................................................................................................27
6.
Study Population...............................................................................................................32
6.1.
Inclusion Criteria..........................................................................................................32
6.2.
Exclusion Criteria ........................................................................................................33
6.3.
Lifestyle and/or Dietary Requirements .........................................................................36
6.3.1.
Meals and Dietary Restrictions.............................................................................36
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................36
6.3.3.
Activity................................................................................................................37
6.3.4.
Contraceptive Requirements.................................................................................37

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LY3463251
6.4.
Screen Failures.............................................................................................................37
7.
Treatment..........................................................................................................................38
7.1.
Treatment Administered...............................................................................................38
7.1.1.
Packaging and Labeling .......................................................................................38
7.2.
Method of Treatment Assignment ................................................................................38
7.2.1.
Selection and Timing of Doses.............................................................................38
7.3.
Blinding .......................................................................................................................38
7.4.
Dose Modification........................................................................................................39
7.4.1.
Dose-Escalation ...................................................................................................39
7.4.1.1.
Part A.............................................................................................................39
7.4.1.2.
Part B .............................................................................................................40
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................42
7.8.
Treatment After the End of the Study...........................................................................42
8.
Discontinuation Criteria ....................................................................................................43
8.1.
Discontinuation from Study Treatment.........................................................................43
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Subjects Lost to Follow-Up..........................................................................................45
9.
Study Assessments and Procedures ...................................................................................46
9.1.
Efficacy Assessments...................................................................................................46
9.2.
Adverse Events ............................................................................................................46
9.2.1.
Serious Adverse Events........................................................................................47
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................48
9.2.2.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Laboratory Tests ..................................................................................................48
9.4.1.1.
Fasting Plasma Glucose, Lipoprotein, Cholesterol, and 
Triglycerides ..................................................................................................48
9.4.2.
Body Weight........................................................................................................48
9.4.3.
Vital Signs ...........................................................................................................49
9.4.4.
Electrocardiograms ..............................................................................................49
9.4.5.
Physical Examination...........................................................................................50
9.4.6.
Safety Monitoring ................................................................................................50
9.4.6.1.
Hepatic Safety................................................................................................50
9.4.6.2.
Columbia-Suicide Severity Rating Scale.........................................................53

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9.4.6.3.
Injection Site Reactions ..................................................................................53
9.4.6.4.
Allergic/Hypersensitivity Events ....................................................................53
9.5.
Pharmacokinetics .........................................................................................................54
9.5.1.
Bioanalysis...........................................................................................................54
9.6.
Pharmacodynamics ......................................................................................................54
9.6.1.
Fasting Plasma Glucose, Lipoprotein, Cholesterol and 
Triglycerides (Part B)...........................................................................................54
9.6.2.
Serum Insulin and C-Peptide (Part B)...................................................................55
9.6.3.
Oral Glucose Tolerance Test (Part B)...................................................................55
9.6.4.
Gastric Emptying (Part B)....................................................................................55
9.6.4.1.
Bioanalysis.....................................................................................................55
9.6.5.
Visual Analog Scale for Assessment of Appetite (Part B).....................................55
9.6.6.
Immunogenicity Assessments ..............................................................................56
9.7.
Genetics .......................................................................................................................56
9.8.
Biomarkers...................................................................................................................57
9.9.
Health Economics ........................................................................................................57
10.
Statistical Considerations and Data Analysis.....................................................................58
10.1. Sample Size Determination ..........................................................................................58
10.2. Populations for Analyses..............................................................................................58
10.2.1.
Study Participant Disposition ...............................................................................58
10.2.2.
Study Participant Characteristics ..........................................................................58
10.3. Statistical Analyses ......................................................................................................58
10.3.1.
Safety Analyses....................................................................................................58
10.3.1.1.
Clinical Evaluation of Safety..........................................................................58
10.3.1.2.
Statistical Evaluation of Safety.......................................................................59
10.3.2.
Pharmacokinetic Analyses....................................................................................59
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................59
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................59
10.3.3.
Pharmacodynamic Analyses (Part B Only)...........................................................59
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................59
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................60
10.3.4.
Evaluation of Immunogenicity .............................................................................60
10.3.5.
Data Review During the Study.............................................................................60
10.3.6.
Interim Analyses..................................................................................................61
11.
References ........................................................................................................................62

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List of Tables
Table
Page
Table GZAA.1.
Objectives and Endpoints .......................................................................21
Table GZAA.2.
Dosing Scheme in Part B........................................................................25
Table GZAA.3.
Margin of Safety for Subcutaneous Administration of LY3463251 
in Part A Based on Administered Doses in 1-Month Toxicity and 
Toxicokinetic Studies .............................................................................29
Table GZAA.4.
Exposure Multiples for Subcutaneous Administration of 
LY3463251 in Part A Based on Exposures Measured in 1-Month 
Toxicity and Toxicokinetic Studies and Predicted Human 
Exposures...............................................................................................30
Table GZAA.5.
Exposure Multiples for Subcutaneous Administration of 
LY3463251 in Part B Based on Exposures Measured in 3-Month 
Toxicity and Toxicokinetic Studies and Human Exposures from 
Part A.....................................................................................................31

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List of Figures
Figure
Page
Figure GZAA.1.
Planned treatment periods.......................................................................22
Figure GZAA.2.
Dose-escalation. .....................................................................................23

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................65
Appendix 2.
Safety Laboratory Tests (Fasting)...........................................................70
Appendix 3.
Hypersensitivity Tests ............................................................................71
Appendix 4.
Study Governance, Regulatory, and Ethical Considerations....................72
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............75
Appendix 6.
Blood Sampling Summary......................................................................76
Appendix 7.
Protocol Amendment J1D-MC-GZAA(e) Summary ..............................77

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1.
Protocol Synopsis
Title of Study:
A Randomized, Placebo-Controlled, Subject- and Investigator-Blind, Single and Multiple Dose, Safety, Tolerability,
and Pharmacokinetics Study of LY3463251 in Healthy and Overweight Healthy Subjects
Rationale: 
New antihyperglycemic agents for the treatment of type 2 diabetes mellitus (T2DM) offering significant 
improvements in glycemic control, which would result in improved health outcomes, are highly desired.  
LY3463251 is being developed to improve glycemic control in adult patients with T2DM, as an adjunct to diet and 
exercise.
This is the first-in-human study of LY3463251, which will investigate the safety, tolerability, and pharmacokinetics 
(PK) of LY3463251 in healthy subjects after a single dose and overweight healthy subjects after multiple doses.  
Additionally, the pharmacodynamic (PD) effects of multiple doses of LY3463251 on glycemic parameters
(including fasting plasma glucose, fasting serum insulin, glucose and insulin during an oral glucose tolerance test 
[OGTT]), gastric emptying using acetaminophen, appetite (measured using a visual analog scale), and body weight 
in overweight healthy subjects will be explored.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To determine the safety and tolerability of single doses 
of LY3463251 in healthy subjects and multiple doses of 
LY3463251 in overweight healthy subjects.
Incidence of treatment-emergent adverse events and 
serious adverse events.
Clinically significant changes in vital signs data, safety
laboratory parameters, and electrocardiograms.
Secondary
To determine the pharmacokinetics of LY3463251 
following single doses in healthy subjects and multiple 
doses in overweight healthy subjects.
Area under the concentration versus time curve from 
time 0 to infinity (AUC[0-∞]), area under the 
concentration versus time curve during 1 dosing interval 
(AUC[0-τ]; multiple doses only), area under the 
concentration versus time curve from time 0 to the time 
of the last quantifiable concentration (AUC[0-tlast]),
maximum observed concentration (Cmax), and time of 
Cmax (Tmax).
To determine the pharmacodynamic effects of 
LY3463251 following multiple doses of LY3463251 in 
overweight healthy subjects.
Glycemic effects (including fasting plasma glucose, 
fasting serum insulin, C-peptide, and glucose and insulin 
during an OGTT), gastric emptying using 
acetaminophen, appetite (measured using a visual analog 
scale), and body weight.
Summary of Study Design:  
Study J1D-MC-GZAA is a single-site, randomized, placebo-controlled, dose-escalation study in healthy and 
overweight healthy subjects.  The subjects and investigator will be blinded to the treatment assignment.

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Part A (Single-Ascending Dose [SAD] in Healthy Subjects):  Subjects with a body mass index (BMI) of ≥18.5
and <32 kg/m2 will be randomized to receive a single dose of LY3463251 or placebo on Day 1.  Six subjects will be 
randomized to LY3463251 and 2 subjects will be randomized to placebo in each cohort.  It is planned for subjects to
be followed for up to approximately 6 weeks post-dose for:  safety assessments, including measurements of blood 
pressure and body weight; and collection of safety laboratory, PK, and immunogenicity samples.  
It is planned for 8 single subcutaneous (SC) doses of LY3463251 to be evaluated in 8 dose-escalating cohorts.  
However, doses may be adjusted and the number of cohorts reduced based on ongoing review of the PK, safety, and 
tolerability data.

Cohort 1:  0.01 mg LY3463251 or placebo

Cohort 2: 0.03 mg LY3463251 or placebo

Cohort 3:  0.1 mg LY3463251 or placebo

Cohort 4:  0.3 mg LY3463251 or placebo

Cohort 5:  1 mg LY3463251 or placebo

Cohort 6:  3 mg LY3463251 or placebo

Cohort 7:  10 mg LY3463251 or placebo

Cohort 8: 24 mg LY3463251 or placebo
Dose-escalation decisions will primarily be based on safety and tolerability data; for Cohorts 1 to 3, decisions will 
be made based on data obtained up to Day 7 from at least 7 subjects in the previous cohort and all available safety 
and tolerability data from previous cohorts.  For Cohorts 4 to 8, decisions will be made based on data obtained up to 
Day 14 from at least 7 subjects in the previous cohort and all available safety and tolerability data from previous 
cohorts.  Following completion of Cohorts 1 to 3, an interim PK analysis will be conducted.  Depending on those 
PK results, dose escalation decisions for Cohorts 4 and 5 may be based on data available at 7 rather than 14 days 
post-dose.
Part B (Multiple-Ascending Dose [MAD] in Overweight Healthy Subjects):  Subjects with a BMI ≥27 and 
<40 kg/m2, will be randomized to receive 12 once-weekly (QW) SC doses of LY3463251 or placebo.  Nine subjects 
will be randomized to LY3463251 and 3 subjects will be randomized to placebo in each cohort.  It is planned for 
subjects to be followed for up to 45 (±3) days following their last dose for safety assessments, including 
measurement of blood pressure; collection of safety laboratory, PK, fasting plasma glucose (PD), fasting serum 
insulin (PD), OGTT (PD), and immunogenicity samples; and measurements of appetite and body weight (PD).
The dose levels of LY3463251 planned for Part B include 1, 3, 9, and 24 mg, and will be evaluated in 4 
dose-escalating cohorts.  An additional cohort (Cohort 5) may be initiated after reviewing at least 4 weeks of 
tolerability data obtained from Cohort 4.  If the Cohort 5 is initiated, it will evaluate a dose lower than 24 mg 
(maximum dose administered in Part A) or assess an alternate dose up-titration scheme that does not exceed 24 mg.  
Escalation or titration of doses in a cohort may be adjusted based on the safety and tolerability data obtained from at 
least 7 subjects in the previous cohort.

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Treatment Arms and Planned Duration for an Individual Subject:  
Part A (SAD):  Subjects will participate in a screening period of up to 28 days prior to Day -1 and it is planned that 
subjects will be followed for approximately 41 days after receiving a single dose of investigational product.  The 
total study duration for each subject is planned to be approximately 10 weeks.
Part B (MAD):  Subjects will participate in a screening period of up to 28 days prior to Day 1, will receive multiple 
doses of investigational product over a period of approximately 12 weeks, and it is planned that subjects will be 
followed up for 45 (±3) days after the last dose.  The total duration for each subject is planned to be approximately 
23 weeks.
Number of Subjects:
In Part A, up to 75 subjects may be enrolled such that approximately 64 subjects have evaluable data.
In Part B, up to 85 subjects may be enrolled such that approximately 60 subjects have evaluable data.
Subjects who are randomized and who are discontinued from the study (providing that discontinuation did not result 
from a safety finding) may be replaced to ensure that enough subjects complete the study.
Statistical Analysis:
Safety and tolerability:  Treatment-emergent adverse events and safety laboratory and vital signs data will be 
summarized using descriptive statistics.
Pharmacokinetics:  The degree of dose proportionality for LY3463251 will be assessed by fitting the power model 
to area under the concentration versus time curve (AUC) from time 0 to infinity (AUC[0-∞]), area under the 
concentration versus time curve over a dosing interval (AUC[0-τ]) and maximum observed concentration (Cmax) 
versus dose for each dose level of LY3463251.  The estimated ratio of dose-normalized geometric means of PK 
parameters between the highest and lowest doses will be used to assess dose proportionality.  In addition, the slope 
and its 90% confidence interval (CI) and the geometric least-square means for each dose level tested will be 
produced.  The analysis will be performed separately for Parts A and B.  In the event that the power model is not a 
good representation of the data over the entire dose range tested, alternative models may be investigated.  Log-
transformed Cmax and AUC least-squares means, and 90% CI estimates for each dose will be back-transformed to 
provide the geometric means and the corresponding 90% CIs.
Pharmacodynamics (Part B only):  Fasting plasma glucose concentrations, fasting serum insulin concentrations,
C-peptide, OGTT-derived parameters, gastric-emptying rate, appetite, and body weight will be summarized using 
descriptive statistics.

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2.
Schedule of Activities

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2.1.
Part A (Single-Ascending Dose)
Screening
Days
FUa
EDb
Comments
Procedure
Up to 
28 days prior 
to Day 1
-1
1
2 to 6
8
11, 15, 22, 
29
42 (±3)
Informed Consent
X
Subject Admission to CRU
X
Subject Discharge from CRU
X
Non-Residential Visit
X
X
X
X
IP Administration
X
Medical History
X
Height
X
Weight
X
X
X
Days 
2 and 5
Days 15, 
22, 29
X
X
Body weight will be recorded for safety analysis.  
Blood Pressure and Pulse Rate 
(Supine)
X
P, 6, 
12 h
24, 48, 72, 
96, 120 h
168 h
X
X
Where possible, measurements of blood pressure and pulse rate 
should be performed at approximately the same time of day at each 
scheduled timepoint.  Time points may be added for each study 
period, if warranted and agreed upon between Lilly and the 
investigator.  
Ambulatory Blood Pressure 
Monitoring
Day -1 to Day 4
For 24 h prior to and 72 h post IP administration.  Measurements of 
blood pressure will be collected every 30 min between 0800 and 
2200 h and every 60 min between 2201 and 0759 h.
Body Temperature and 
Respiratory Rate
X
P
24
168 h
X
X
Time points may be added for each study period, if warranted and 
agreed upon between Lilly and the investigator.
Safety Lab Testsc
X
X
P
Days 
2 and 5
X
Days 15, 
22, 29
X
See Appendix 2, Safety Laboratory Tests, for details.  
Fasting Plasma Glucosec
X
X
P
Days 
2 and 5
X
Days 15, 
22, 29
X
X
Fasting plasma glucose will be recorded for safety analysis.
Serum Pregnancy Test 
X
Female subjects only.
Physical Exam
X
X
After screening, medical assessment only performed to include 
medical review and targeted examination, as appropriate.
12-Lead ECG
X
P, 6, 
12 h
24, 48, 72, 
96, 120 h
168 h
X
X
Single ECGs.  Additional single ECGs may be obtained if clinically 
indicated.
Genetic Sample
P
Single sample for pharmacogenetic analysis taken prior to/on Day 1.
Fasting Biomarker Sample
X
Day 15
Sample for storage only.
Adverse Event Recording
X
Plasma PK samples
P, 6, 
12 h
24, 48, 72, 
96, 120 h
168 h
X
X
X
Sampling times are relative to the time of study treatment 
administration (0 min).
Immunogenicity Samples
P
Days 15 
X
X
All samples for immunogenicity should be taken predose, when 

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Screening
Days
FUa
EDb
Comments
Procedure
Up to 
28 days prior 
to Day 1
-1
1
2 to 6
8
11, 15, 22, 
29
42 (±3)
and 29
applicable and possible.  Also, a time matched PK should be taken at 
each immunogenicity sample time point.  Additional samples may be 
collected approximately every 3 months for up to 1 year after dose
(Section 9.6.6)
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = hour(s); min = minutes; IP = investigational product; P = 
predose; PK = pharmacokinetics.  
Note:  if multiple procedures take place at the same time point, the following order of the procedures should be used: ECG, vital signs, and venipuncture.
a
Additional FU visits may occur depending upon emerging PK and/or safety data.
b
At the discretion of the investigator, subjects may be requested to return to the CRU for safety monitoring at additional visits following completion of the ED procedures.  At 
the discretion of the investigator, assessments may include, but will not be limited to, those presented for the FU visit (Day 42) with the addition of safety lab tests.
c
Samples collected at screening and on Day -1 will be analyzed at a local laboratory.  Samples collected at all other time points will be analyzed by a central laboratory.

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2.2.
Part B (Multiple-Ascending Doses)
Screening
Days
FUa EDb
Comments
Procedure
Up to 
28 days 
prior to 
Day 1
-2
-1
1
2 to 7
8
9
15, 22, 29, 36, 
43, 50, 57, 64, 
71, 78 
16, 23, 30, 
37, 44, 51, 
58, 65, 72, 
79
80
81
85 86
92 107 123 
(±3)
The timepoints need to be noted 
in conjunction with the comments 
below.
Informed Consent
X
Subject Admission to 
CRU
X
X
X
X
Subjects may be admitted the night 
before the day of dosing.
Subject Discharge from 
CRU
X
X
X
X
Subjects may be discharged on any 
day between Day 4 and Day 7 at 
the investigator’s discretion.
Non-Residential Visit
X
Day 6 
X
X
X
X
If the subjects are discharged before 
Day 6, the subjects will attend the 
non-residential visit on Day 6.
IP Administration
X
X
X
IP administration on Day 1 
indicates time = 0 h.
Medical History
X
Height
X
Body Weight
X
X
X
P
P
X
X
X
X
Body weight will be recorded twice 
first thing in the morning for PD 
analysis. See Section 9.4.2.
Blood Pressure and 
Pulse Rate (Supine)
X
X
P, 6, 
12 h
24, 48, 
72, 120 
h
P, 6, 
12 h
24 
h
P, 6, 12 h
24 h
X
X
X
X
X
X
Where possible, measurements of 
blood pressure and pulse rate 
should be performed at 
approximately the same time of day 
at each scheduled time point.  Time 
points may be added for each study 
period, if warranted and agreed 
upon between Lilly and the 
investigator.  
Ambulatory Blood 
Pressure Measurement
Day -1 to 
Day 2
X
Days 15, 29, 
and 57 only
X
ABPM will be monitored for 24 h
prior to and 24 h following the first 
dose, and for 24 h following 
subsequent doses.  Measurements 
of blood pressure will be collected 
every 30 min between 0800 and 
2200 h and every 60 min between 
2201 and 0759 h.
Body Temperature
X
X
P
24 h
P
24 
h
P
24 h
X
X

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
Screening
Days
FUa EDb
Comments
Procedure
Up to 
28 days 
prior to 
Day 1
-2
-1
1
2 to 7
8
9
15, 22, 29, 36, 
43, 50, 57, 64, 
71, 78 
16, 23, 30, 
37, 44, 51, 
58, 65, 72, 
79
80
81
85 86
92 107 123 
(±3)
The timepoints need to be noted 
in conjunction with the comments 
below.
Clinical Laboratory
Tests (fasting)
X
X
P
Day 6
P (Days 15, 
22, 29, 36, 43, 
57, and 71 
only)
X
X
X 
X See Appendix 2, Clinical
Laboratory Tests, for details.
Fasting Plasma Glucose
X
Samples will be analyzed at a 
central laboratory.
Fasting Serum Insulin
P
P (Day 57 
only)
X Samples will be analyzed at a 
central laboratory.
C-Peptide Samples
P
P (Day 57 
only)
X Samples will be analyzed at a 
central laboratory.
OGTT (fasting 
overnight)
X
Day 30
X
Blood sample collected for glucose, 
C-peptide, and insulin 
concentrations prior to and at 30, 
60, 90, and 120 min after glucose 
administration.
Samples will be analyzed at a 
central laboratory.
OGTT includes samples for FPG, 
fasting serum insulin, and fasting 
C-peptide, corresponding to 0 min.
Acetaminophen test for 
gastric emptying
X
Day 3
X
Acetaminophen PK sampling 
schedule on each day specified in 
the table:  Pre-acetaminophen dose 
and 0.5, 0.75, 1, 2, 3, 4, 6, 9, 12, 
and 24 hours after acetaminophen 
dose.  Acetaminophen can be 
administered after completion of 
OGTT on Day -2 and after 
overnight fast on Days 3 and 80.  
Food is not allowed for 2 hours 
after acetaminophen dose.
Standardized Meal
X
X
Days 15, 22, 
29, and 57 
only
X
Standardized breakfast and lunch 
should be provided at the same time 
of day on each occasion.
Visual Analog Scale 
(Appetite) (Fasting)
X
X
X
X
Administered at 30 min (±20 min) 
prior to the start of standardized 
breakfast and lunch.

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LY3463251
Screening
Days
FUa EDb
Comments
Procedure
Up to 
28 days 
prior to 
Day 1
-2
-1
1
2 to 7
8
9
15, 22, 29, 36, 
43, 50, 57, 64, 
71, 78 
16, 23, 30, 
37, 44, 51, 
58, 65, 72, 
79
80
81
85 86
92 107 123 
(±3)
The timepoints need to be noted 
in conjunction with the comments 
below.
Visual Analog Scale 
(Postprandial)
X
X
Days 15, 22, 
29, and 57 
only
X
Administered at 30 min (±15 min) 
and 5 h (±30 min) after 
standardized breakfast and lunch.
C-SSRS Baseline and 
Screening
X
X
C-SSRS Since Last 
Visit
X
Days 15, 22, 
29, 43, and 57 
only
X
X
C-SSRS may be performed around
the same time of the day with a 
time window of ±2 h for a subject 
before or after dosing, at the 
discretion of the investigator.
Self-Harm Supplement 
Form and Self-Harm 
Follow-up Form
X
X
X
Days 15, 22, 
29, 43, and 57 
only
X
X
Self-Harm Follow-up form is 
required only if triggered by the 
Self-Harm Supplement Form.
Serum Pregnancy Test 
X
X
Female subjects only.  Additional 
serum pregnancy tests may be 
performed at the discretion of 
investigator.
Physical Examination
X
At screening, complete physical 
examination (except genital and 
rectal).   After screening, physical 
examination should be only 
symptom directed.
12-lead ECG
X
P
24, 48,
72 h
P
P (Days 15, 
29, and 57 
only)
Day 79
X
X
X
X
Single ECGs.  Additional single 
ECGs may be obtained if clinically 
indicated.  The ECGs should be 
obtained prior to collection of the 
PK samples, and closer to the PK 
sampling time points.
Genetic Sample
P
Single sample for pharmacogenetic 
analysis taken on Day 1 or Day -1.
Fasting Biomarker 
Sample
X
Day 29 only
X
X
Biomarker sample for storage.
Adverse Event 
Recording
X
Plasma PK Samples
P, 6, 
12 h
24, 48,
72, 120
h
P
P (Days 15, 
29, 57, and 78 
only)
24 h 
postdose on 
Day 79 
X
X
X
X
X
X
Sampling times are relative to the 
time of the last IP administration (0 
min).

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
Screening
Days
FUa EDb
Comments
Procedure
Up to 
28 days 
prior to 
Day 1
-2
-1
1
2 to 7
8
9
15, 22, 29, 36, 
43, 50, 57, 64, 
71, 78 
16, 23, 30, 
37, 44, 51, 
58, 65, 72, 
79
80
81
85 86
92 107 123 
(±3)
The timepoints need to be noted 
in conjunction with the comments 
below.
only
Immunogenicity 
Samples
P
P (Days 15 
and 29 only)
X
X
X
All samples for immunogenicity 
should be taken predose, when 
applicable and possible.  Also, a 
time-matched PK should be taken 
at each immunogenicity sample 
time point.  Additional samples 
may be collected approximately 
every 3 months for up to 1 year 
after dose (Section 9.6.6).
Abbreviations:  CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = 
hour; IP = investigational product; min = minutes; OGTT = oral glucose tolerance test; P = predose; PD = pharmacodynamic; PK = pharmacokinetic.  
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: ECG, vital signs, and venipuncture.
a
Additional FU visits may occur depending upon emerging PK, PD, and/or safety data.
b
At the discretion of the investigator, subjects may be requested to return to the CRU for safety monitoring at additional visits following completion of the ED procedures.  At 
the discretion of the investigator, assessments may include, but will not be limited to, those presented for the FU visit (Day 123).

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LY3463251
3.
Introduction
3.1.
Study Rationale
With the prevalence of type 2 diabetes mellitus (T2DM) increasing world-wide, new 
antihyperglycemic agents offering significant improvements in glycemic control and secondary 
benefits, which would result in improved health outcomes, are highly desired.  LY3463251 is a 
growth and differentiation factor 15 (GDF15) variant that is being developed with an aim to 
fulfill these unmet needs, potentially leading to improvements in clinical outcomes.  
This is the first-in-human study of LY3463251, which will investigate the safety, tolerability, 
and pharmacokinetics (PK) of LY3463251 in healthy subjects after a single dose and overweight 
healthy subjects after multiple doses.  Additionally, the pharmacodynamic (PD) effects of 
multiple doses of LY3463251 on glycemic parameters (including fasting plasma glucose, fasting 
serum insulin, and glucose and insulin during an oral glucose tolerance test [OGTT]), appetite 
(measured using visual analog scale [VAS]), and body weight in overweight healthy subjects 
will be explored.
3.2.
Background 
GDF15 (also known as macrophage inhibitory cytokine-1 or MIC-1 or nonsteroidal 
anti-inflammatory drug-activated gene-1 [NAG-1]) is a cysteine knot protein belonging to the 
transforming growth factor-beta (TGFβ) superfamily (Bootcov et al. 1997). Among the many 
reported biological functions of GDF15, the regulation of energy homeostasis has gained 
significant attention due to its potential for the treatment of obesity and T2DM (Tsai et al. 2016). 
The connection between GDF15 and alterations in body weight was initially postulated based on 
the observation that increasing serum GDF15 levels correlate with weight loss in individuals 
with advanced prostate cancer (Johnen et al. 2007). Increasing GDF15 levels in mice through 
administration of recombinant protein or via secretion from tumor xenografts illustrated that 
GDF15 induces weight loss via its ability to decrease food intake and enhance energy 
expenditure (Johnen et al. 2007; Tsai et al. 2018). Furthermore, transgenic mice overexpressing 
GDF15 were found to be resistant to diet-induced obesity and to exhibit improved glucose 
tolerance (Macia et al. 2012; Chrysovergis et al. 2014), whereas GDF15 knockout mice had 
increased body weight and fat mass (Tsai et al. 2013). 
Recent work indicates that GDF15 elicits these effects through action on the brainstem, localized 
to the area postrema (Tsai et al. 2014). The area postrema is a circumventricular organ and has 
been specifically shown to be involved in the control of food intake and body weight (Young 
2012). The orphan receptor glial cell derived neurotrophic factor receptor alpha–like (GFRAL) 
was identified as the ligand binding receptor for GDF15 (Emmerson et al. 2017; Mullican et al.
2017; Yang et al. 2017; Hsu et al. 2017). GDF15 was found to induce signaling by stimulating 
the interaction of GFRAL with a coreceptor rearranged during transfection (RET; Mullican et al. 
2017; Hsu et al. 2017).  GFRAL was found to be expressed specifically in the area postrema
located outside the blood-brain barrier and the neighboring nucleus tractus solitarius. 

J 1 D -M C -G Z A A ( e) 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 6 3 2 5 1
F urt her m ore, G F R A L l ocaliz atio n was s h o w n t o be hi g hl y c o nser ve d acr oss s pecies i ncl u di n g 
m o use, rat, m o n ke y , a n d h u ma n ( E m mer s o n et al. 2 0 1 7; M ullica n et al. 2 0 1 7). 
L Y 3 4 6 3 2 5 1 was
 
 f o u n d t o de m o nstrate si gnifica nt l y pr ol o n ge d P K pr ofile r elat i ve t o t he nati ve 
f or m, s u p p orti n g p ote ntial o nce-wee kl y ( Q W) a d mi nistrati o n.
  
 
 
 
T here are n o n o ncli nical safet y assess me nt fi n di n gs precl u di n g cli nical de vel o p me nt. 
As of 1 1 J ul y 2 0 1 9 , 6 4 healt h y s u bjects e ntere d Part A; 4 8 s u bjects recei ve d si n gle asce n di n g 
s u bc uta ne o us ( S C) d oses of  0. 0 1, 0. 0 3, 0. 1, 0. 3, 1, 3, 1 0, or 2 4 m g L Y 3 4 6 3 2 5 1, a n d 1 6 s u bjects 
recei ve d place b o.  
I n Part A, there were n o deat hs, serio us a d verse e ve nts (S A Es ), or disc o nti n uati ons d ue t o 
a d verse e ve nts (A Es ).  Si n gle d oses of L Y 3 4 6 3 2 5 1 t hr o u g h 3 m g were well t olerate d ( C o h orts 1 
t hr o u g h 6).  At d oses of 1 0 m g ( C o h ort 7) a n d 2 4 m g ( C o h ort 8), L Y 3 4 6 3 2 5 1 treat me nt was 
c o m m o nl y  ass ociate d wit h ma na gea ble a n d re versi ble treat me nt -e mer ge nt a d verse e ve nts
(T E A Es ) of  na usea a n d v omit i n g.  T hese T E A Es were of mil d or mo derate se verity a n d re q uir e d 
treat me nt wit h o n da nsetr o n i n 4 of 6 s u bjects recei vi n g 2 4 m g L Y 3 4 6 3 2 5 1.  
T he m ai n la b orat or y fi n di n g was a n i ncrease i n ser u m tra nsa mi nase le vels, o bser ve d i n 9 o ut of 
4 8 s u bjects recei vi n g L Y 3 4 6 3 2 5 1 a n d 1 o ut of 1 6 s u bjects recei vi n g place b o, wit ho ut a n y  
i n dicati on of a d ose -res p o nse relati ons hi p.  T hese fi n di n gs were o bser ve d wit hi n C o h orts 1 
t hr o u g h 6 b ut were n ot detecte d i n C o h orts 7 or 8.  N o ne of t hese c ha n ges were ass ociate d wit h 
a b n or malities i n t otal bilir u bi n le vel ( T B L) or al kali ne p h os p hatase ( A L P), a n d n o s u bject ha d 
cli nical si g ns or s y m pt o ms s u g gest i ve of li ver i nj ur y or ot her m e dical c o n dit i ons .  T w o s u bjects 
i n C o h ort 4 ( L Y 3 4 6 3 2 5 1 0. 3 m g) ha d i ncrease d ala ni ne a mi n otra nsferase ( A L T ) be y o n d 2 -f ol d 
t he u p per li mit  of nor m al ( U L N), pea ki n g at 3. 8 × U L N f or 1 s u bject, a n d 2. 5× U L N f or t he ot her 
s u bject.  I n b ot h s u bjects, pea ks were o bser ve d at o nl y 1 time p oi nt a n d ha d re verse d b y  t he ne xt 
visit. 
N o rele va nt treat me nt -e mer ge nt a b n or malities were n ote d f or bl o o d p ress ure, p ulse rate, b o d y 
t e mperat ure, bl o o d press ure assesse d b y a m b ulat or y  mo ni t orin g, or electr ocar di o gra ms ( E C Gs) .  
D ose -de pe n de nt b o d y wei g ht decreases were n ote d f or s u bjects recei vi n g L Y 3 4 6 3 2 5 1 i n C o h orts 
7 a n d 8 , wit h a na dir ge nerall y o n Da y 5, reversi n g o n s u bse q ue nt da y s.  S u bje cts i n C o h orts 7 
C CI
C CI

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
and 8 lost an average of approximately 1 kg body weight compared with subjects who received 
placebo who gained approximately 0.1 kg and 0.85 kg body weight, respectively.  The loss of 
body weight in subjects who received LY3463251 was generally associated with the 
gastrointestinal (GI) TEAEs observed in Cohorts 7 and 8. Another TEAE of interest is a case of 
moderate generalized urticaria without any associated signs of anaphylaxis, that occurred 106 
minutes after dosing, and resolved within 2 days after it started, following a single dose of 
antihistamine. The subject did not have detectable baseline or treatment-emergent anti-drug 
antibodies.
Based on the preliminary PK data available from Cohorts 1 to 6 (all days) and Cohort 7 (up to 
Day 15), the exposures to LY3463251 (maximum observed concentration [Cmax] and area under 
the concentration versus time curve (AUC) appeared to increase proportionally in the dose range 
evaluated. The median time to maximum observed concentration (Tmax) occurred between 
48 and 96 hours after dose administration. The mean half-life of LY3463251 was approximately 
7 days, thus supporting once-weekly administration. More details about these preliminary 
clinical and laboratory results can be found in the Investigator’s Brochure (IB).
3.3.
Benefit/Risk Assessment
Based on the available nonclinical and single-ascending dose (SAD) clinical data, LY3463251 
continues to be considered a low-risk compound.  Anticipated risks are those associated with GI
events, mainly nausea and vomiting, elevations of liver enzyme levels, and urticarial allergic 
reactions. These risks are considered to be monitorable and manageable at the planned dose 
range of 1 to 24 mg in Part B and with updated discontinuation criteria based on the SAD results.  
Analyses of the frequency and magnitude of the cluster of differentiation (CD4)+ T-cell 
responses indicated that LY3463251 is predicted to have a very low to low risk of clinical 
immunogenicity. Results from SAD assessments confirm this status. 
Based on observations from the SAD study, subjects may benefit from a therapeutic weight loss.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY3463251 is to be found in the IB.  

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LY3463251
4.
Objectives and Endpoints
Table GZAA.1 shows the objectives and endpoints of the study.
Table GZAA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine the safety and tolerability of single doses 
of LY3463251 in healthy subjects and multiple doses of 
LY3463251 in overweight healthy subjects.
Incidence of TEAEs and SAEs.
Clinically significant changes in vital signs data, safety
laboratory parameters, and electrocardiograms.
Secondary
To determine the pharmacokinetics of LY3463251
following single doses in healthy subjects and multiple 
doses in overweight healthy subjects.
AUC(0-∞), AUC(0-τ) [Part B only], AUC(0-tlast), Cmax, 
and Tmax.
To determine the pharmacodynamic effects of 
LY3463251 following multiple doses of LY3463251 in 
overweight healthy subjects.
Glycemic effects (including fasting plasma glucose, 
fasting serum insulin, C-peptide, and glucose and insulin 
during an oral glucose tolerance test), gastric emptying 
using acetaminophen, appetite (measured using a VAS),
and body weight.
Exploratory
To determine the immunogenicity of LY3463251
following single and multiple doses.
Incidence of TEADA.
To evaluate the pharmacodynamic effect on the lipid 
profile of multiple doses of LY3463251 in overweight 
healthy subjects.
Low- and high-density lipoproteins, cholesterol, and 
triglycerides.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time 0 to infinity; AUC(0-τ) = 
area under the concentration versus time curve during 1 dosing interval; AUC(0-tlast) = area under the 
concentration versus time curve from time 0 to the time of the last quantifiable concentration; Cmax = maximum 
observed concentration; SAE = serious adverse event; TEADA = treatment-emergent antidrug antibodies; TEAE 
= treatment-emergent adverse event; Tmax = time of maximum observed concentration; VAS = visual analog 
scale.

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LY3463251
5.
Study Design
5.1.
Overall Design
This is a single-site, randomized, placebo-controlled, dose-escalation study in healthy and 
overweight healthy subjects to evaluate the safety, tolerability, and PK of LY3463251 following 
single doses in healthy subjects and multiple doses in overweight healthy subjects. Additionally, 
the PD effects of multiple doses of LY3463251 on glycemic effects (including fasting plasma 
glucose, fasting serum insulin, and glucose and insulin during an OGTT), appetite, and body 
weight in overweight healthy subjects will be explored.  The subjects and investigator will be 
blinded to the treatment assignment; the sponsor will not be blinded.  The study will be 
conducted in 2 parts:  Part A (SAD) and Part B (multiple-ascending dose [MAD]).  
Screening will occur up to 28 days prior to Day 1 in both parts of the study.
Study governance considerations are described in detail in Appendix 3.  Schematic 
representations of the study are presented in Figure GZAA.1.
Abbreviation:  CRU = clinical research unit.
Figure GZAA.1.
Planned treatment periods.

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LY3463251
Part B may be initiated following review of all available safety data up to Day 14 post-dose from the last cohort, and of all safety 
data available at this time (including antidrug antibody data) from the preceding cohorts.  An optional Cohort 5 may be initiated after
reviewing at least 4 weeks of tolerability data obtained from Cohort 4.  The number of cohorts in both parts may be reduced based 
on review of PK, safety, and/or tolerability data.
Figure GZAA.2.
Dose-escalation.

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LY3463251
5.1.1.
Part A (Healthy Subjects)
Subjects, with a body mass index (BMI) of ≥18.5 and <32 kg/m2, will be admitted to the clinical 
research unit (CRU) on Day -1 and will be randomized to receive a single dose of LY3463251 or 
placebo on Day 1.  Six subjects will be randomized to LY3463251 and 2 subjects will be 
randomized to placebo in each cohort.  At the discretion of the investigator, subjects may be 
discharged from the CRU on Day 8 after all study procedures have been completed.  Subjects 
will return to the CRU as outpatients at predetermined visits for up to approximately 6 weeks 
post-dose for: safety assessments, including measurements of blood pressure and body weight;
and collection of safety laboratory, PK, and immunogenicity samples.  Sampling schedules may 
be adjusted and the duration of the residential period may be increased (but not decreased) based 
on ongoing review of the PK and/or safety data.  Additional follow-up visits may occur 
depending upon the PK and/or safety data.
It is planned for 8 single SC doses of LY3463251 to be evaluated in 8 dose-escalating cohorts.  
However, doses may be adjusted and the number of cohorts reduced based on ongoing review of 
the PK, safety, and tolerability data.

Cohort 1:  0.01 mg LY3463251 or placebo

Cohort 2:  0.03 mg LY3463251 or placebo

Cohort 3:  0.1 mg LY3463251 or placebo

Cohort 4:  0.3 mg LY3463251 or placebo

Cohort 5:  1 mg LY3463251 or placebo

Cohort 6:  3 mg LY3463251 or placebo

Cohort 7:  10 mg LY3463251 or placebo

Cohort 8:  24 mg LY3463251 or placebo
Data to be reviewed prior to dose-escalation decisions, including the timing and scope of these 
reviews, are described in Section 7.4.1.
Safety and tolerability will be assessed throughout Part A of the study by means of vital sign 
measurements, safety laboratory tests, ECGs, physical examinations, and AE recording.
5.1.2.
Part B (Overweight Healthy Subjects)
Subjects, with a BMI ≥27 and <40 kg/m2, will be admitted to the CRU on Day -2 and will be 
randomized to receive QW SC doses of LY3463251 or placebo on Days 1, 8, 15, 22, 29, 36, 43, 
50, 57, 64, 71, and 78.  Nine subjects will be randomized to LY3463251 and 3 subjects will be 
randomized to placebo in each cohort.
Subjects will receive their first dose of LY3463251 or placebo on Day 1.
Subjects may be discharged from the CRU on Day 4 after all study procedures have been 
completed or remain until Day 9 at the discretion of the investigator.  

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LY3463251
Subjects will return to the CRU for a series of residential visits over a period of approximately 
12 weeks for administration of LY3463251 or placebo, and will subsequently return as 
outpatients at predetermined visits for up to 45 (±3) days following their last dose for: 

safety assessments, including measurements of blood pressure; collection of safety
laboratory, 

pharmacokinetics,

pharmacodynamics:  fasting plasma glucose, insulin, OGTT, C-peptide, gastric emptying
and measurement of appetite and body weight, and

immunogenicity samples.
Sampling schedules may be adjusted, and the duration of the residential period may be increased 
(but not decreased) based on ongoing review of the PK, PD, and/or safety data.  Additional 
follow-up visits may occur depending upon the PK, PD, and/or safety data.
The target dose levels of LY3463251 planned for Part B include 1, 3, 9, and 24 mg, and will be 
evaluated in 4 dose-escalating cohorts.  Cohorts 2 and 3 will be initiated following review of all 
available data from the previous cohort through at least 22 days and Cohort 4 to be initiated after 
at least 36 days.  
An additional cohort (Cohort 5) may be initiated after reviewing at least 4 weeks of tolerability 
data obtained from Cohort 4. If the Cohort 5 is initiated, it will evaluate a dose lower than 24 mg 
(maximum dose administered in Part A) or assess an alternate dose up-titration scheme that does 
not exceed 24 mg (Table GZAA.2).  
Escalation or titration of doses in a cohort may be adjusted based on the safety and tolerability 
data from at least 7 subjects in the previous cohort.
Table GZAA.2.
Dosing Scheme in Part B
Study Day
1
8
15
22
29
36
43
50
57
64
71
78
Dose (mg)
Cohort 1
1
1
1
1
1
1
1
1
1
1
1
1
Cohort 2
3
3
3
3
3
3
3
3
3
3
3
3
Cohort 3
3
3
6
6
9
9
9
9
9
9
9
9
Cohort 4
3
3
9
9
15
15
24
24
24
24
24
24
Cohort 5
(Optional)
Dose level(s) to be determined after reviewing 4-week data from Cohort 4.

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LY3463251
The timing for initiation of Part B of the study and the data to be reviewed prior to 
dose-escalation decisions, including the timing and scope of these reviews, are described in 
Section 7.4.1.
Safety and tolerability will be assessed throughout Part B of the study by means of vital sign 
measurements, safety laboratory tests, ECGs, physical examinations, and AEs. 
5.2.
Number of Participants
It is planned to enroll 64 subjects into Part A and 60 subjects into Part B.  For purposes of this 
study, a subject completes the study when all scheduled procedures shown in the Schedule of 
Activities have been finished.
Subjects who are randomized and who are discontinued from the study (providing that 
discontinuation did not result from a safety finding) may be replaced to ensure that enough 
subjects complete the study. To allow for replacement in case of discontinuation, up to 
75 subjects may be enrolled into Part A and up to 85 subjects may be enrolled into Part B.  
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 subject.
5.4.
Scientific Rationale for Study Design
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients, and therefore provides the most unbiased 
assessment of the safety and tolerability in this first-in-human study.  Overweight healthy 
subjects have been chosen for Part B in order to conduct a preliminary PD evaluation of change 
in fasting plasma glucose, fasting serum insulin, OGTT-derived parameters, appetite, and body 
weight.
In Part B, gastric emptying rate will be assessed using acetaminophen to evaluate if the observed 
GI intolerability after single dose of LY3463251 in Part A was associated with delay in gastric 
emptying.
A subject- and investigator-blinded, randomized, placebo-controlled design has been chosen to 
minimize bias in the primary objective of the study.  A parallel-group design was chosen because 
a crossover design is impractical for compounds that have long half-lives.  Additionally, a 
crossover design could confound PK data if subjects developed neutralizing antidrug antibodies 
(ADA).
The study is intended to estimate a maximum tolerated dose (MTD) or establish that doses 
exceeding the expected therapeutic dose are tolerated. Safety, tolerability, PK, immunogenicity 
and preliminary PD data in healthy subjects and overweight healthy subjects will assist in 
identifying an appropriate dose range for subsequent clinical studies.
The 12-week duration of the treatment period in the Part B has been planned

J 1 D -M C -G Z A A ( e) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 7
L Y 3 4 6 3 2 5 1

t o e val uate t he safety a n d t olera bilit y of L Y 3 4 6 3 2 5 1, c o nsi deri n g t he ti me nee de d t o 
u p- titrate d oses > 3 m g ( ~ 1 mo nt h or l o n ger), w hile p ote ntiall y decreasi n g t he e xte nt of 
na usea a n d v o mit i n g o bser ve d i n st u d y s u bjects,

f or a relia ble assess me nt of c ha n ges i n b o d y w eig ht a n d i ns uli n se nsit i vity i n t he prese nce 
of  L Y 3 4 6 3 2 5 1, a n d

f or a more pre dicti ve assess me n t of a p ote nti al he p atic safet y ris k c o mpare d wi t h a st u d y 
of  a s h orter d urati o n ( F D A 2 0 0 9; H o of na gle a n d Bj ӧr n ss o n 2 0 1 9).
P eri o dic tri al-le vel s afet y re vie ws d uri n g t he M A D (i n a d diti on t o t he S A D) will e ns ure t hat a n y  
s u bject ca n be disc o nti n ue d earl y, or t he d ose escalati o n ca n be ter mi nate d , i n case of a n y A E
re q uirin g s uc h a decisi o n.
W hile rece nt l y p u blis he d E ur o pea n Me dici nes A ge nc y ( E M A) g ui deli ne ( E M A 2 0 1 7) 
rec o m me n ds use of se nti nel d osi n g i n first-i n-h u ma n st u dies, it als o all o ws f or fle xi bilit y i n a 
pr o p ose d d osi n g a p pr oac h base d o n t he a vaila ble scie ntific data a n d precli nical assess me nt of a 
gi ve n m o lec ule. T he i nte n de d a n d e xa g gerate d p har mac o l ogi cal res p o nses of  L Y 3 4 6 3 2 5 1 ha ve 
bee n well c haracterize d i n m ult i ple precli nical p har mac ol og y  mo dels.  L Y 3 4 6 3 2 5 1 was 
eval uate d i n t he w h ole bl o o d c y t o ki ne release assa y in dicati n g t hat L Y 3 4 6 3 2 5 1 d oes n ot acti vate 
bl o o d i n nate i m m u ne cells , t h us s u g gesti n g a l o w ris k of a c yt o ki ne release s y n dr o me. M ore o ver, 
t o xic o l og y  st u dies ha ve s u g geste d t hat cli nicall y 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 6 3 2 5 1 .  Base d o n t he a vaila ble data o n t he L Y 3 4 6 3 2 5 1
m o lec ule, it d oes n ot prese nt an u ncertai nt y  pr ofile necessitat i n g a se nti nel d osi n g a p pr oac h.  
F urt her m ore, se nti nel d osi n g wit h l ow- ris k c o m p o u n ds, s uc h as L Y 3 4 6 3 2 5 1, ma y lea d t o 
i na bility t o int er pret data d ue t o false p osit i ve A E fi n di n gs i n t he a bse nce of data fr o m all c o h orts 
or place b o -treate d s u bjects.  
 
 
5. 5.
J u stifi c ati o n f or D o s e
H u m a n efficacio us d oses were esti mate d b y scali n g L Y 3 4 6 3 2 5 1 P K i n m o n ke ys t o h u ma ns a n d 
usi n g wei g ht l oss data i n diet -i n d uce d o bese mice a n d lea n rats. 
 
  
 
 
 
 
C CI
C CI
C CI

J 1 D -M C -G Z A A ( e) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 8
L Y 3 4 6 3 2 5 1
 
T he safet y mar gi ns f or t he ma xi m u m a nt ici pate d h u ma n d ose i n 
P hase 1 st u dies ar e a p pr o xi matel y 0. 0 9- f ol d (rats) a n d 5 2 5- f ol d ( mo n ke ys) , base d o n 
a d mi nistere d d oses ( d ose m ulti ples) a n d n o ncli nical N O A E L data (Ta b le G Z A A .3 ).  Alt h o u g h 
t he rat e x p os ure mar gi ns at t he N O A E L d o se d o n ot c o ver t he c o m plete d osi n g ra n ge pla n ne d, 
a d verse fi n di n gs i n t he rat st u d y were li mit e d t o decreases i n b o d y  wei g ht a n d f oo d c o ns u m pti o n , 
w hic h are e x pecte d p har mac o l ogi c al effects of L Y 3 4 6 3 2 5 1, a n d s h o ul d n ot restrict t he pla n ne d 
cli nical d oses.
 
P lan ne d
d oses u p t o 2 4 mg will all o w e v al u ati o n of  P D effects across a wi de ra n ge of L Y 3 4 6 3 2 5 1 
e x p os ures.  T his e val uati on will ai d i n p erf or m i n g d ose -e x p os ure-res p o nse a nal yses a n d selecti n g
d oses f or f ut ure cli nical st u dies. E x peri e nce wit h ot her dr u gs has s h o w n t hat sl o wer d ose 
escalat i on has i m pr o ve d t olera bilit y (Petr o ne et al . 1 9 9 9; Ki m et al. 2 0 1 5; Na uc k et al . 2 0 1 6); 
t heref ore, i ncl usi on of d ose u p -titr atio n ste ps i n C o h orts 3 a n d 4 ma y p ote ntiall y miti gate t he GI 
t olera bilit y iss ues o bser ve d f or hig her d oses i n Part A. D o ses i n Part B ma y be titrate d or 
a djuste d bef ore eac h d ose escalati o n base d o n t he a vaila ble s afet y,  t olera bilit y, a n d P K data
d uri n g t he st u d y . 
I n a d diti on, data fr o m rece ntl y c o m p lete d 3-m o nt h rat a n d m o n ke y t o xic o l og y  st u dies pr o vi de 
a p pr o priate safet y mar gi ns f or t he d oses pr o p ose d i n Part B ( Ta b le G Z A A. 5 ).
C CI
C CI

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LY3463251
Table GZAA.3.
Margin of Safety for Subcutaneous Administration of LY3463251 in
Part A Based on Administered Doses in 1-Month Toxicity and 
Toxicokinetic Studies
Species/Dose
Dose (mg/kg)
Margin of Safetya
Starting Dose
Maximum Dose
Humanb
Starting dose (0.01 mg)
0.00014c
Maximum dose (24 mg)
0.343c
Rat
NOAELd
0.03
214×
0.09×
High dosed
1
7,143×
2.9×
Monkey 
NOAELe
180
1,285,714×
525×
Abbreviation: NOAEL = no-observed-adverse-effect level.  
a
The margin of safety is the administered dose in animals/administered dose in humans on a mg/kg basis.
b
The human doses shown are the anticipated starting dose and the maximum dose for Part A.  
c
Human doses were adjusted for body weight assuming a 70-kg person.
d
The rat NOAEL and high dose are from a 1-month repeat-dose toxicology study (Study Number 130-655). 
e
The monkey NOAEL was determined in a 1-month repeat-dose toxicology study (Study Number 130-657).
NOTE:  Although the rat NOAEL was 0.03 mg/kg, adverse findings in rats at the mid and high doses (0.3 and 
1 mg/kg, respectively) were limited to excessive decreases in body weight and food consumption.  These are 
expected pharmacologic effects of LY3463251.  There were no other adverse findings in rats that would affect 
clinical dosing limits.

J 1 D -M C -G Z A A ( e) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 0
L Y 3 4 6 3 2 5 1
T a b l e G Z A A. 4.
E x p o s ur e M ulti pl e s f or S u b c ut a n e o u s Ad mi ni str ati o n of L Y 3 4 6 3 2 5 1 
i n P art A B a s e d o n E x p o s ur e s M e a s ur e d i n 1- M o nt h T o xi cit y a n d 
T o xi c o ki n eti c St u di e s a n d Pr e di ct e d H u m a n E x p o s u r es
S pecies/ D ose
A U C ( µ g• hr/ m L)
M ar gi n of S afet y
a
Starti n g D ose
Ma xi m u m D ose
H u m a n b
Starti n g d ose ( 0. 0 1 m g)
0. 1 4 7 c
Ma xi m u m d ose ( 2 4 m g)
3 5 2 c
R at
N O A E L d
1 4. 9 5 e
1 0 2 ×
0. 0 4 ×
Hi g h d ose d
3 9 2. 5 e
2, 6 7 0 ×
1. 1 ×
M o n ke y 
N O A E L f
9 3, 1 0 0
g
6 3 3, 3 3 3 ×
2 6 4 ×
A b bre viati o n: A U C = area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve; A U C 0- ∞
= area u n der t he 
c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 t o i nfi nit y; A U C 0- 1 6 8 h = area u n der t he c o nce ntrati o n vers us ti me 
c ur ve fr o m ti me 0 t o 1 6 8 h o urs p ost -d ose; N O A E L = n o -o bser ve d -a d verse-effect le vel.  
a
T he e x p os ure m ulti ple is calc ulate d as t he A U C 0- 1 6 8 h i n a ni mals/ A U C0- ∞ i n h u ma ns.
b
T he h u ma n d oses s h o w n are t he a ntici pate d starti n g d ose a n d t he ma xi m u m d ose f or Part A .  
c
H u ma n e x p os ures are pre dicte d va l ues.
d
T he rat e x p os ure val ues are fr o m t he N O A E L ( 0. 0 3 m g/ k g) a n d hi g h d ose ( 1 m g/ k g) i n a 1 -m o nt h re peat -d ose 
t o xic ol o g y st u d y ( St u d y N u m ber 1 3 0- 6 5 5).
e
Rat A U C 0 -1 6 8 h val ues are t he mea n male + fe male e x p os ures o n Da y 2 9 i n St u d y 1 3 0 - 6 5 5.
f
T he m o n ke y  NO A E L ( 1 8 0 m g/ k g) was deter mi ne d i n a 1 -m o nt h re peat -d ose t o xic ol o g y st u d y ( St u d y N u m ber 
1 3 0- 6 5 7).
g
T he m o n ke y A U C 0- 1 6 8 h val ue is t he mea n male + fe male e x p os ure o n Da y 2 9 i n St u d y 1 3 0 - 6 5 7.
N O T E:   Alt h o u g h t he rat N O A E L was 0. 0 3 m g/ k g, a d verse fi n di n gs i n rats at t he mi d a n d hi g h d oses ( 0. 3 a n d 
1 m g/ k g, res pecti vel y) were li mite d t o e xcessi ve decreases i n b o d y wei g ht a n d f o o d c o ns u m pti o n.  T hese are 
e x pecte d p har mac ol o gic effects of L Y 3 4 6 3 2 5 1.  T here were n o ot her a d verse fi n di n gs i n rats t hat w o ul d affect 
cli nical d osi n g li mits.

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
Table GZAA.5.
Exposure Multiples for Subcutaneous Administration of LY3463251 
in Part B Based on Exposures Measured in 3-Month Toxicity and 
Toxicokinetic Studies and Human Exposures from Part A
Species/Dose
AUC (µg•hr/mL)
Margin of Safetya
Starting Dose
Maximum Dose
Humanb
Starting dose (1 mg)
17.6c
Maximum dose (24 mg)
590c
Rat
NOAELd
29.9e
1.7×
0.1×
High dosed
221e
12.6×
0.4×
Monkey 
NOAELf
83200
g
4727×
141×
Abbreviations: AUC = area under the plasma concentration versus time curve; AUC0-∞= area under the 
concentration versus time curve from time 0 to infinity; AUC0-168h = area under the concentration versus time 
curve from time 0 to 168 hours postdose; NOAEL = no-observed-adverse-effect level.  
a
The exposure multiple is calculated as the AUC0-168h in animals/AUC0-∞ in humans.
b
The human doses shown are the starting dose and the maximum dose for Study GZAA Part B.  
c
Steady state human exposures based on the preliminary PK data from Study GZAA Part A.
d
The rat exposure values are from the NOAEL (0.1 mg/kg) and high dose (1 mg/kg) in a 3-month repeat-dose 
toxicology study (Study Number 130-695).
e
Rat AUC0-168h values are the mean male + female exposures on Day 85 in Study 130-695.
f
The monkey NOAEL (180 mg/kg) was determined in a 3-month repeat-dose toxicology study (Study Number 
130-694).
g
The monkey AUC0-168h value is the mean male + female exposure on Day 85 in Study 130-694.
NOTE: Although the rat NOAEL was 0.1 mg/kg, adverse findings in rats at the high doses (1 mg/kg) were limited 
to excessive decreases in body weight and food consumption.  These are expected pharmacologic effects of 
LY3463251.  There were no other adverse findings in rats that would affect clinical dosing limits.

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
6.
Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, safety laboratory tests, and ECGs. 
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. Subjects 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
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] male subjects must agree to adhere to contraception restrictions specified in 
Section 6.3.4
[1b] female subjects must be of non-childbearing potential, and include those who 
are:

infertile due to surgical sterilization (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), congenital anomaly such as 
mullerian agenesis, or 

those who are post-menopausal, defined in Part A as either:
o
a woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had cessation of menses for at least 1 
year, or at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone of >40 mIU/Ml
o
a woman of at least 55 years of age not on hormone therapy who 
has had at least 6 months of spontaneous amenorrhea
o
a woman of at least 55 years of age who has a diagnosis of 
menopause before starting hormone replacement therapy

those who are post-menopausal, defined in Part B as either:

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
Page 33
LY3463251
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 aged between 18 and 65 years, inclusive
[3]
have a BMI of ≥18.5 and <32 kg/m2 (Part A [SAD]) or a BMI ≥27 and 
<40 kg/m2 (Part B [MAD])
[4]
have had a stable weight for the 3 months prior to screening and enrollment 
(<5% body weight change), and have not received dietary intervention in the 
3 months prior to screening and enrollment
[5]
have safety laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[6]
have venous access sufficient to allow for blood sampling as per the protocol
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[8]
are able and willing to give signed informed consent
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[9]
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
[10]
are Lilly or Covance employees
[11]
are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study 
[12]
have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed
[13]
have previously completed or withdrawn from this study and have previously 
received the investigational product 

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
[14]
have known allergies to related compounds of LY3463251 or any components 
of the formulation, or history of significant atopy
[15]
have clinically significant abnormal ECG results constituting a risk when 
taking the investigational product, as determined by the investigator
[16]
have clinically significant abnormal blood pressure and/or pulse rate
constituting a risk when taking the investigational product, as determined by 
the investigator
[17]
have a history or presence of cardiovascular (including hypertension), 
respiratory, hepatic, renal, GI, endocrine, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the investigational 
product; or of interfering with the interpretation of data.  Appendectomy is 
permitted.
[18]
have been diagnosed with type I diabetes mellitus or TD2M, or have any of 
the following at screening:

a fasting plasma glucose concentration ≥126 mg/dL (7.0 mmol/L)

glycated hemoglobin ≥6.5% (48 mmol/mol)
Note:  assessments performed on Day 1 will not be used to confirm eligibility.
[19]
have a history or presence of psychiatric disorders.  Attention deficit disorder 
(ADD)/attention deficit hyperactivity disorder (ADHD) is permitted provided
it is not severe, does not require treatment, and does not jeopardize the ability 
to adhere to the study requirements.  At least 5 half-lives following 
discontinuation of any treatment for ADD/ADHD should have passed

For Part B only:
o
in the judgment of the investigator, subjects are actively suicidal and 
deemed to be at significant risk for suicide
o
have answered “yes” to either Question 4 or Question 5 on the 
“Suicidal Ideation” portion of the Columbia Suicide Severity Rating 
Scale (C-SSRS)
[20]
regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies
[22]
show evidence of hepatitis C and/or positive hepatitis C antibody
[23]
show evidence of hepatitis B, hepatitis B core antibody, and/or positive 
hepatitis B surface antigen
[24]
are women who are lactating

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
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LY3463251
[25]
intend to use over-the-counter medication in the 7 days, or prescription 
medications in the 14 days prior to dose administration (including any 
medications for the treatment of obesity), with the exception of vitamin and 
mineral supplements and occasional use of acetaminophen.  If the situation 
arises, an otherwise suitable subject may be included following agreement 
between the investigator and the sponsor
[26]
have donated blood of more than 500 mL within the previous 3 months of 
study screening, or intend to donate blood during the course of the study
[27]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (females and males aged 65), or are 
unwilling to stop alcohol consumption from 48 hours prior to admission to 
and while resident at the CRU (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)
[28]
have used any tobacco product within 3 months of Day -1, or are unwilling to 
refrain from the use of tobacco during the study.  Results from cotinine tests 
performed as part of the urine drug screen that are consistent with passive 
smoking are not exclusionary
[29]
are immunocompromised
[30]
have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing.
[31]
have significant allergies to humanized monoclonal antibodies 
[32]
have 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, or exfoliative 
dermatitis)
[33]
have had lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years
[34]
have had breast cancer within the past 10 years
[35]
are unwilling to abide by the lifestyle and dietary requirements in Section 6.3
[36]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
[37]
have a history or presence of a GI disorder that impacts gastric emptying (for 
example, relevant esophageal reflux or gall bladder disease, gastric bypass 
surgery, pyloric stenosis).
[38]
prior (within 5 years) or planned (during the study) surgical treatment or 
device-based treatment use for obesity.

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LY3463251
[39]
have obesity induced by other endocrinologic disorders (for example, Cushing 
syndrome) or diagnosed monogenetic or syndromic forms of obesity (for 
example, Melanocortin 4 Receptor deficiency or Prader Willi syndrome)
[40]
have evidence of acute or chronic liver disease or Gilbert’s disease, including 
any of the following:
o
aspartate aminotransferase (AST) or ALT >1.5× ULN; or
o
ALP >1.5× ULN; or
o
TBL >2× ULN.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1.
Meals and Dietary Restrictions
Subjects will be provided with standardized meals while resident at the CRU, and the same 
standardized breakfast and lunch will be provided on each day for all subjects when appetite will 
be assessed by VAS (Section 9.6.4).  The macronutrient composition of the standardized meals 
should be targeted to provide approximately 50% of the calories from carbohydrate, 30% of the 
calories from fat, and 20% of the calories from protein.  Subjects will be instructed to consume 
meals within approximately 30 minutes.  Detailed guidance related to meal standardization will 
be provided to the investigative site.
Subjects should be fasted for 8 hours prior to blood sampling, performing ECGs, and dose 
administration.  Post-dose ECG measurements should be taken prior to any food intake.
Subjects should maintain adequate carbohydrate intake for the 3 days before the scheduled 
OGTT and will be fasted for at least 10 hours before administration of the 75-g oral glucose dose.
On days where assessment of subjects’ appetite is to be measured (Section 2), standardized 
breakfast and lunch will be provided approximately 30 minutes after the first VAS assessment.  
Additional food should not be consumed until after the 5-hour VAS assessment.  With the 
exception of water, drinks are not permitted until after the 5-hour VAS assessment.  If the subject 
is unable to consume the standardized meal completely, the leftover amount (as percentage of 
total meal) will be recorded in the electronic case report form (eCRF).
At all other times, subjects should maintain their standard diet.
6.3.2.
Caffeine, Alcohol, and Tobacco
Subjects will be allowed to maintain their regular caffeine consumption.
Tobacco use is not permitted for 3 months prior to Day -1 and during the study.
Alcohol consumption is not permitted from 48 hours prior to admission to and while resident at 
the CRU.

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6.3.3.
Activity
Subjects should avoid exercise during the screening visit, and should avoid strenuous exercise 
3 days prior to each admission to and while at the CRU.  Subjects should maintain their normal 
levels of activity at other times.
6.3.4.
Contraceptive Requirements
Male subjects (regardless of their fertility status) with non-pregnant female partners of 
childbearing potential must agree to either remain abstinent (if this is their preferred and usual 
lifestyle), or to use condoms as well as one additional highly effective (< 1% failure rate) method 
of contraception (such as combination oral contraceptives, implanted contraceptives, or 
intrauterine devices) or effective method of contraception (such as diaphragms with spermicide 
or cervical sponges) from the time of first administration of the investigational product until the 
last study visit or 90 days following the last dose of investigational product, whichever is longer.  
Men and their partners may choose to use a double-barrier method of contraception; however, 
barrier protection methods without concomitant use of a spermicide are not an effective or 
acceptable method of contraception (each barrier method must include use of a spermicide).  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.
Male subjects with pregnant partners should use condoms during intercourse from the time of 
first administration of the investigational product until the last study visit or 90 days following 
the last dose of investigational product, whichever is longer.  Male subjects should refrain from 
sperm donation from the time of first administration of the investigational product until the last 
study visit or 90 days following the last dose of investigational product, whichever is longer. 
Male subjects who chose to remain abstinent (if this is their preferred and usual lifestyle) must
adhere to the contraception requirements indicated above should their circumstances change.
Male subjects who are in exclusively same-sex relationships (as their preferred and usual 
lifestyle) are not required to use contraception.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.

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LY3463251
7.
Treatment
7.1.
Treatment Administered
The investigational product will be administered as a SC injection into the abdomen while the 
subject is resident at the CRU.
LY3463251 will be provided at a concentration of 3 mg/mL.  The doses to be administered are 
presented in Sections 5.1.1 and 5.1.2.
Placebo will be normal saline (0.9% sodium chloride).
The investigator or designee is responsible for:

explaining the correct use of the investigational product to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, the site 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. 
7.1.1.
Packaging and Labeling
LY3463251 and placebo will be provided to the investigative site as bulk supply in vials by Lilly 
or its designee.  
Clinical trial materials will be labeled according to the country’s regulatory requirements, and 
will be stored, inventoried, reconciled, and destroyed according to applicable regulations.  
Clinical trial materials are manufactured in accordance with current good manufacturing 
practices.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Subjects will be randomized to a treatment using a computer-generated randomization schedule.
7.2.1.
Selection and Timing of Doses
The actual time of all dose administrations will be recorded in the subject’s eCRF.
The doses will be administered at approximately the same times on each day in Part B.  
7.3.
Blinding
Blinding will be maintained throughout the conduct of the study as described in the separate 
blinding plan.
The unblinded pharmacist or designee will prepare the study drug.

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Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study subject, may be opened during the study only if the subject’s well-being requires 
knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist (CP)
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 subject’s emergency 
code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’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.
7.4.
Dose Modification
7.4.1. Dose-Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
highest planned dose has been administered, or the MTD is determined.  If the highest planned 
dose is not reached, the highest dose level that is tolerated will be designated as the MTD.
Safety and tolerability data will be the primary criteria for the dose-escalation.  No dose decision 
can occur without prior discussion and agreement between the investigator and the Lilly 
CP/CRP/study team.  Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, 
will be independently assessed by the investigator, and will be considered related to the 
investigational product unless there is clear evidence that the event is not related.  
Any available PK data may be used to guide dose selection or to determine if the number of 
doses to be studied may be reduced.
After review of these data, an agreement on the appropriate dose will be made by the investigator 
and sponsor for the next cohort/dose level.  A lower dose may be administered; dose levels may 
be repeated providing that it is not the result of a safety finding; or the magnitude of dose 
escalations may be reduced following data review, providing that subsequent escalations do not
increase by more than approximately 3-fold (a half-log increment).
7.4.1.1.
Part A
Dose-escalation decisions will primarily be based on safety and tolerability data obtained up to 
Day 7 (in Cohorts 1 through 3) or Day 14 (in Cohorts 4 through 8) from at least 7 subjects in the 
previous cohort, and all safety and tolerability data from previous cohorts.  Additionally, any
available PK data may be used to guide dose selection or to determine if the number of doses to 
be studied may be reduced.

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If any of the following scenarios occur, dosing at the current level and further dose-escalation 
will be discontinued:

Five or more subjects develop AEs within 7/14 days (depending on the cohort; see 
Section 10.3.5) of dosing that are considered to be related to study treatment and graded 
as at least moderate, clinically significant and not responsive to supportive care

One or more subjects develop AEs within 7/14 days (depending on the cohort; see 
Section 10.3.5) of dosing that are considered to be related to study treatment and graded 
as severe

One or more subjects develop SAEs that are considered to be related to study treatment
7.4.1.2. Part B
Dose-escalation at the cohort level
Part B may be initiated following review of all available safety and tolerability data up to Day 14 
post-dose from all subjects in the last cohort of Part A, and all safety and tolerability data 
available at this time (including ADA data) from the previous cohorts.  
Dose-escalation decisions in Part B will primarily be based on safety and tolerability data 
obtained from at least 7 subjects up to and including Day 22 for Cohorts 2 and 3, and up to and 
including Day 36 for Cohort 4.  Additionally, any available PK data may be used to guide dose 
selection or to determine if the number of doses to be studied may be reduced.
If any of the following scenarios occur, dosing at the current level and further dose-escalation 
will be interrupted:

Four or more subjects develop AEs that are considered to be related to study treatment 
and graded as at least moderate and not responsive to supportive care

One or more subjects develop AEs that are considered to be related to study treatment 
and graded as severe

One or more subjects develop SAEs that are considered to be related to study treatment
Dose-escalation at the individual subject level
In case a subject interrupted the study drug and

more than 2 doses were missed, the subject should be discontinued from the study – this 
would be at least 25% of doses missed and may compromise data reliability. 

the number of consecutive missed doses is ≤2, the treatment can be restarted at the same 
dose, if the drug was well tolerated prior to interruption.

the number of consecutive missed doses is ≤2, then the treatment should be restarted at 3 
mg irrespective of the dose the subject was receiving if the dose was not well tolerated 
before the interruption and subsequently follow the assigned dose escalation scheme.

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Every effort should be made for a subject to adhere to the protocol dose escalations within a 
cohort.  However, it is possible that some subjects may not tolerate higher doses of the study 
drug.
All dose adjustments discussed below may only occur following agreement between the 
investigator and sponsor medical monitor. The dose administered to the subjects each week 
should be recorded on the case report form during titration and throughout the study.
Dose modification for Cohort 4 
Subjects who do not tolerate the 3 mg or 9 mg doses of study drug for at least 2 weeks will be 
discontinued from study drug but should continue to be monitored for safety for the duration of 
the study.  
If after 2 weeks at 15 mg, a subject still has gastrointestinal symptoms preventing dose escalation 
to 24 mg, the subject may be kept at 15 mg for 1 to 3 additional doses before escalating to 24 
mg.  
Subjects who cannot tolerate the 15 mg dose after at least 2 doses due to moderate or severe 
gastrointestinal symptoms may be discontinued from study treatment but should continue to be 
monitored for safety for the duration of the study.
If after at least 2 doses of 24 mg a subject has poorly tolerated nausea, vomiting, or diarrhea, and 
the investigator does not believe that the subject will tolerate additional injections of 24 mg 
despite the possibility of tachyphylaxis, then the investigator may reduce the dose to 15 mg.  If 
this dose of 15 mg is tolerated, the subject may remain at that dose level for the duration of the 
study or the investigator may increase the dose back to 24 mg.  Maintenance doses of less than 
15 mg will not be allowed. 
Dose Modification for Optional Cohort 5 
In case a subject has poorly tolerated nausea, vomiting, or diarrhea at a given dose, the 
investigator may decide to decrease the dose to a previous dose level.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all investigational product received 
and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).

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7.6.
Treatment Compliance
The investigational product will be administered at the clinical site and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (1 g, maximum 
4 g/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 subject may be at the discretion of the investigator after consultation with a 
Lilly CP or CRP.  Any medication used during the course of the study must be documented.
Acetaminophen should not be allowed from the day prior to gastric emptying assessment until 
24 hours after acetaminophen dosing.
7.8.
Treatment After the End of the Study
Not applicable.

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8.
Discontinuation Criteria
Subjects discontinuing from the treatment or study prematurely for any reason should complete 
early discontinuation procedures per Section 2 of this protocol.
Dose-escalation stopping criteria are presented in Section 7.4.1.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST ≥5× ULN on 2 consecutive occasions

ALT or AST ≥3× ULN and TBL ≥2× ULN or international normalized ratio ≥1.5

ALT or AST ≥3× ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP ≥3× ULN

ALP ≥2.5× ULN and TBL ≥2× ULN

ALP ≥2.5× ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
The following discontinuation criteria related to abnormal liver tests should be applied during the 
dose-escalation process. The occurrence of 1 or more cases meeting all the following criteria 
should be considered as a dose-limiting toxicity event:

ALT or AST ≥3× ULN

TBL ≥2× ULN

No initial cholestasis (ALP does not exceed 2× ULN), and

No other cause explaining the abnormality in liver tests.
Subjects who do not tolerate a given dose level due to gastrointestinal symptoms may be 
discontinued from study drug or may have their dose reduced depending on various parameters 
as described in Section 7.4.1.2 (dose level, severity of symptoms, investigator’s judgement, 
discussion between investigator and sponsor medical monitor). If they are discontinued from 
study drug, these subjects should continue to be monitored for safety for the duration of the 
study.
Additionally, subjects may be discontinued from the investigational product if any of the 
following occur:

An AE that is considered to be intolerable

An abnormal safety laboratory test result, as determined by the investigator

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
Corrected QT interval (QTc) >500 msec or an increase from baseline in QTc >60 msec

The investigator decides that the subject should be discontinued from using the
investigational product.
If the subject develops active suicidal ideation with some intent to act with or without a specific 
plan (yes to Question 4 or 5 on the “Suicidal Ideation” portion of the C-SSRS) or develops 
suicide-related behaviors as recorded on the C-SSRS, it is recommended that the subject be 
assessed by a psychiatrist or appropriately trained professional to assist in deciding whether the 
subject is to be discontinued from the study.
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions. Clinical 
manifestations of these reactions are described in Section 9.4.6.4.  Systemic allergic/
hypersensitivity reactions may possibly lead to a participant’s permanent discontinuation of 
investigational intervention.  The investigator, after consultation with the sponsor-designated 
medical monitor, determines that a clinically significant hypersensitivity reaction has occurred.  
A clinically significant systemic hypersensitivity reaction is 1 that occurs after administration of 
the investigational intervention (for example, drug-related symptomatic bronchospasm, allergy-
related edema/angioedema, or hypotension) and requires parenteral medication, does not respond 
to symptomatic medication, results in clinical sequelae, or is an anaphylactic reaction.
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

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:  the investigator decides that the subject should be discontinued
from the study

Subject decision:  the subject requests to be withdrawn from the study.

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8.3.
Subjects Lost to Follow-Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 6 provides a summary of the maximum 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 subjects 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 subject.
The investigator is responsible for the appropriate medical care of subjects 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 investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject 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.
After the informed consent form (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’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 investigational product 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.

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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
See Section 9.4.6.3 for monitoring injection site reactions and Section 9.4.6.4 for monitoring 
allergic/hypersensitivity events.
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 subject 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.  
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered reasonably possibly related to a study procedure then 
it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.

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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 investigational product 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 investigational products 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.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3463251 is considered any dose higher than the 
dose assigned through randomization. Therapeutic or monitoring measures should be 
implemented according to clinical presentation at the discretion of the investigator.
9.4.
Safety
9.4.1.
Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Samples collected at screening and on Day -1 will be analyzed at a local laboratory.  Samples 
collected at the remaining time points will be analyzed by a central laboratory. 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.
9.4.1.1. Fasting Plasma Glucose, Lipoprotein, Cholesterol, and Triglycerides
Part A:  Fasting plasma glucose, low- and high-density lipoprotein, cholesterol, and triglyceride 
concentrations will be measured as part of safety assessments. Samples for analysis of low- and 
high-density lipoprotein, cholesterol, and triglyceride concentrations will be collected as part of 
the safety laboratory tests, and venous blood samples of approximately 4 mL will be collected to 
determine plasma concentrations of glucose.
Part B:  Fasting plasma glucose, low- and high-density lipoprotein, cholesterol, and triglyceride 
concentrations will be measured for PD analysis (Section 9.6.1).
9.4.2.
Body Weight
Body weight will be measured as part of safety assessments in Part A and for PD analysis in 
Part B.  
Body weight will be measured as indicated in the Schedule of Activities (Section 2).  

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Subjects will be weighed in light clothing at approximately the same time in the morning before 
dosing, after an overnight fast and evacuation of bowel and the bladder, if possible.  
During the treatment period, weight will be measured twice on each scheduled occasion during 
Part B only, with the subject stepping off the scale between measurements.  Both weight 
measurements will be recorded in the source document and the eCRF.  Wherever possible, the 
same scale will be used for all weight measurements throughout the study and the scale will not 
be moved or recalibrated.
9.4.3.
Vital Signs
For each subject, vital signs (including blood pressure, pulse rate, and body temperature in 
Parts A and B, and respiratory rate in Part A only) measurements should be conducted according 
to the Schedule of Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 2 minutes.  If the subject feels unable to stand, supine vital signs only 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.
Ambulatory measurements of blood pressure will be collected every 30 minutes between 0800 
and 2200 hours and every 60 minutes between 2201 and 0759 hours according to the Schedule of 
Activities (Section 2).
9.4.4.
Electrocardiograms
For each subject, single ECGs should be collected according to the Schedule of Activities 
(Section 2), and may be obtained at additional times, when deemed clinically necessary.  
Electrocardiograms must be recorded before collection of any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  
Electrocardiograms will be interpreted by a qualified investigator (physician or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subjects for symptoms (e.g., palpitations, near 
syncope, syncope) to determine if the subject can continue in the study.  The investigator, or 
qualified designee, is responsible for determining if any change in subject management is 
needed, and must document his/her review of the ECG printed at the time of collection (from at 
least 1 of the replicate ECGs from each timepoint when replicate ECGs are collected).  Any new 
clinically relevant finding should be reported as an AE.  Any clinically significant findings from 

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ECGs that result in a diagnosis and that occur after the subject receives the first dose of the 
investigational product, should be reported to Lilly, or its designee, as an AE via eCRF. 
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (e.g.  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.
Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the
Schedule of Activities (Section 2) and as clinically indicated.
9.4.6.
Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.6.1. Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm 
the abnormality and to determine if it is increasing or decreasing, if 1 or more of these conditions 
occur:

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If a subject with baseline results of...
develops the following elevations:
ALT or AST <1.5X ULN
ALT or AST ≥3X ULN
ALP <1.5X ULN
ALP ≥2X ULN
TBL <1.5X ULN
TBL ≥2X ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline
ALP ≥1.5X ULN
ALP ≥2X baseline
TBL ≥1.5X ULN
TBL ≥2X baseline (except for patients with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver test results should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including symptoms, recent 
illnesses (e.g., heart failure, systemic infection, hypotension, or seizures), recent travel, history of 
concomitant medications (including OTC), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the subject’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
subject’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:

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If a subject with baseline results 
of...
develops the following elevation:
ALT or AST <1.5X ULN
ALT or AST ≥3X ULN with hepatic signs/symptomsa, or ALT or AST ≥5X
ULN
ALP <1.5X ULN
ALP ≥3X ULN
TBL <1.5 X ULN
TBL ≥2X ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline with hepatic signs/symptomsa, or ALT or AST 
≥3X baseline
ALP ≥1.5X ULN
ALP ≥2X baseline
TBL ≥1.5X ULN
TBL ≥1.5X baseline (except for patients with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
a
Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper-quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined earlier, as well as tests for prothrombin time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (e.g., ultrasound or 
computed tomography scan).
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for

hepatitis D virus

cytomegalovirus

Epstein-Barr virus

acetaminophen levels

acetaminophen protein adducts

urine toxicology screen

Wilson’s disease

blood alcohol levels

urinary ethyl glucuronide, and

serum phosphatidylethanol.
Based on the circumstances and the investigator’s assessment of the subject’s clinical condition, 
the investigator should consider referring the subject for a

hepatologist or gastroenterologist consultation

magnetic resonance cholangiopancreatography

endoscopic retrograde cholangiopancreatography

cardiac echocardiogram, or

liver biopsy.
Additional hepatic data collection (hepatic safety CRF) in study subjects who have 
abnormal liver test results during the study

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Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
subjects who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5X ULN)
a.
In subjects with baseline ALT ≥1.5X ULN, the threshold is ALT ≥3X baseline on 
2 or more consecutive tests
2. Elevation of TBL to ≥2X ULN (if baseline TBL <1.5X ULN) (except for cases of known 
Gilbert’s syndrome)
a.
In subjects with baseline TBL ≥1.5X ULN, the threshold should be TBL ≥2X 
baseline
3. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5X ULN)
a.
In subjects with baseline ALP ≥1.5X ULN, the threshold is ALP ≥2X baseline on 
2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study drug due to a hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days.
9.4.6.2.
Columbia-Suicide Severity Rating Scale
The C-SSRS (Columbia Lighthouse Project [WWW]) captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period.  The scale 
includes suggested questions to solicit the type of information needed to determine if a suicide-
related thought or behavior has occurred.  The C-SSRS will be administered by appropriately 
trained site personnel at the time points specified in the Schedule of Activities (Section 2.2).  
Subjects with any significant change must be referred to a psychiatrist.  If the investigator 
determines that suicide-related behaviors have occurred, the Lilly Self-Harm Supplement Form 
will be used to collect additional information to allow for a more complete assessment of these 
behaviors.  As noted earlier, subjects with any clinically significant change, as determined by the 
investigator, must be referred to a psychiatrist.
9.4.6.3.
Injection Site Reactions
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.  Injection 
sites may be inspected and photographically documented.
9.4.6.4. Allergic/Hypersensitivity Events
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions. Clinical 
manifestations of these reactions may include but are not limited to

skin rash

pruritus (itching)

dyspnea

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
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 (see Appendix 3). Follow-up samples should be 
obtained at the next scheduled visit or 4 weeks after the event, whichever is later.  The laboratory
results are provided to the sponsor via the central laboratory.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3463251.  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 will be recorded.  
Samples from placebo-treated subjects will not be analyzed.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
9.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3463251 will be assayed using a validated enzyme-linked immunosorbent 
assay method.  Analyses of samples collected from placebo-treated subjects are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as additional 
metabolism or exploratory analyses such as bioanalytical assay validation or cross-validation 
exercises.
9.6.
Pharmacodynamics
9.6.1.
Fasting Plasma Glucose, Lipoprotein, Cholesterol and 
Triglycerides (Part B)
Fasting plasma glucose, low- and high-density lipoprotein, cholesterol, and triglyceride
concentrations will be measured from venous blood samples.  Samples for analysis of low- and 

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high-density lipoprotein, cholesterol, and triglyceride concentrations will be collected as part of 
the safety laboratory tests, and venous blood samples of approximately 4 mL will be collected to 
determine plasma concentrations of glucose, as described in Section 9.4.1.  
9.6.2.
Serum Insulin and C-Peptide (Part B)
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3.5 mL each will be collected to determine C-peptide and serum concentrations 
of insulin.  Samples will be analyzed at a central laboratory.
9.6.3.
Oral Glucose Tolerance Test (Part B)
Subjects should maintain their regular dietary intake for 3 days before the scheduled OGTT.  
Subjects will be fasted for at least 10 hours before administration of a 75-g oral glucose dose, 
which should be consumed within 5 minutes.
Glucose, C-peptide, and insulin will be measured during an OGTT to assess effects of 
LY3463251 on glycemic control, OGTT index, and insulin sensitivity.  Samples will be analyzed 
at a central laboratory.
9.6.4.
Gastric Emptying (Part B)
Acetaminophen is a well-established marker for the rate and extent of gastric emptying (Young 
2005).  It is rapidly absorbed from the duodenum upon release from the stomach.  A delay in 
gastric emptying is reflected in the alterations to the concentration-time profile of 
acetaminophen, specifically, decreasing its Cmax and Tmax without altering the extent (total drug 
amount) absorbed. A dose of approximately 1 g acetaminophen is considered to be sufficient for 
bioanalytical detection and will be administered after overnight fast on Day -2 and about 48
hours after first and last LY3463251 doses in Part B (Section 2). 
Venous blood samples of approximately 2 mL each will be collected to determine the plasma 
concentrations of acetaminophen.
9.6.4.1.
Bioanalysis
Concentrations of acetaminophen will be assayed using validated liquid chromatography mass 
spectrometry method.  Analyses of samples collected from placebo-treated subjects are not 
planned.
9.6.5.
Visual Analog Scale for Assessment of Appetite (Part B)
At the times specified in the Schedule of Activities (Section 2), the subjective rating of appetite 
sensations will be measured by a 100-mm VAS for parameters of hunger, fullness, satiety, and 
prospective food consumption.
Dietary restrictions related to the measurements of appetite are described in Section 6.3.1.
The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000), and is 
presented as a 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 

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the questions: “How hungry do you feel right now?”, “How satisfied do you feel right now?”, 
“How full do you feel right now?”, and “How much food do you think you could eat right now?” 
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 (van Can et al. 
2014):
             satiety + fullness + (100 — prospective food consumption) + (100 — hunger) / 4
A higher overall appetite score indicates less appetite and a lower score indicates more appetite.
9.6.6.
Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 10 mL each will be collected to determine antibody production against 
LY3463251.  To interpret the results of immunogenicity, a venous blood sample will be 
collected at the same time points to determine the plasma concentrations of LY3463251. All 
samples for immunogenicity should be taken predose when applicable and possible. Sampling 
for drug hypersensitivity reactions is described in Section 9.4.6.4.  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 will be recorded.  
Treatment-emergent ADAs (TEADAs) are defined in Section 10.3.4.  Subjects who are TEADA 
positive at the end of the study or at early discontinuation may be followed up with samples
taken approximately every 3 months, until they return to 2-fold titer of baseline or for a 
maximum of 1 year.  
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3463251 at a laboratory approved by the sponsor.  Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of LY3463251.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and institutional review boards (IRBs) allow, at a facility selected by 
the sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY3463251.  Any samples remaining after 15 years will be destroyed.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3463251 and to investigate genetic variants thought to play a role in T2DM, diabetic 
complications, obesity, or the potential mechanism of action of LY3463251.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  

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All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs 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 LY3463251 or after LY3463251 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. 
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of subject 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.
Blood 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 
LY3463251, pathways associated with T2DM, diabetic complications, obesity, or the potential 
mechanism of action of LY3463251 and/or research method, or for validating diagnostic tools or 
assay related to T2DM, diabetic complications, obesity, or the potential mechanism of action of 
LY3463251.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs 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 LY3463251 or after LY3463251 is commercially available. 
9.9.
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 clinical studies evaluating safety and PK, and is not 
powered on the basis of statistical hypothesis testing.
Subjects who are randomized and who are discontinued from the study (providing that 
discontinuation was not as a result of a safety finding) may be replaced to ensure that enough 
subjects complete the study.
10.2. Populations for Analyses
10.2.1.
Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2.
Study Participant Characteristics
The subject’s age, sex, race, weight, height, and other demographic characteristics will be 
summarized.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic and PD analyses will be conducted on data from all subjects who receive at 
least 1 dose of the investigational product and have evaluable PK and PD data.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
10.3.1. Safety Analyses
10.3.1.1.
Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment 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 investigational product-related SAEs will be reported.

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10.3.1.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, C-SSRS scores, 
Lilly Self-Harm Supplement responses, and vital signs.  
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide 
(Columbia Lighthouse Project [WWW]). The parameters will be listed, and summarized using 
standard descriptive statistics.  Electrocardiogram data and physical examination will be 
performed for safety monitoring purposes and will not be listed or summarized.
Additional analysis will be performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1.
Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3463251 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be AUC from time 0 to infinity (AUC[0-∞]), AUC 
during 1 dosing interval (AUC[0-τ]), AUC from time 0 to the time of the last quantifiable 
concentration (AUC[0-tlast]), maximum drug concentration (Cmax) and time to reach Cmax
(Tmax).  Other noncompartmental parameters, such as half-life, apparent clearance, and apparent 
volume of distribution may be reported.  If deemed necessary, additional model based analyses 
may be performed.
10.3.2.2.
Pharmacokinetic Statistical Inference
The degree of dose proportionality for LY3463251 will be assessed by fitting the power model 
(Smith et al. 2000) to AUC[0-∞], AUC[0-τ] and Cmax versus dose for each dose level of 
LY3463251. The estimated ratio of dose-normalized geometric means of PK parameters 
between the highest and lowest doses will be used to assess dose proportionality. In addition, the 
slope and its 90% confidence interval (CI) and the geometric least-square means for each dose 
level tested will be produced. The analysis will be performed separately for Parts A and B. In 
the event that the power model is not a good representation of the data over the entire dose range 
tested, alternative models may be investigated. Log-transformed Cmax and AUC least-squares 
means, and 90% CI estimates for each dose will be back-transformed to provide the geometric 
means and the corresponding 90% CIs.
Additional analysis will be conducted if appropriate.
10.3.3. Pharmacodynamic Analyses (Part B Only)
10.3.3.1.
Pharmacodynamic Parameter Estimation
The primary parameters for analysis will be fasting plasma glucose concentrations, fasting serum 
insulin concentrations, OGTT-derived-parameters, gastric emptying rate, appetite, and body 
weight.  Baseline body weight will be computed as the average of the measurements taken on 

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Days -1 and 1.  Pharmacodynamic data will be summarized as reported values and as changes
from baseline using descriptive statistics.
10.3.3.2.
Pharmacodynamic Statistical Inference 
Pharmacodynamic parameters will be summarized with no statistical inference. Additional 
analysis will be conducted if appropriate.
10.3.4.
Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TEADA to 
LY3463251 will be tabulated. For subjects who are ADA negative at baseline, TEADAs are 
defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution of the 
assay.  For subjects who are ADA positive at baseline, TEADAs are defined as those with a 
4-fold (2 dilutions) increase in titer compared to baseline.  For subjects with TEADA, the
distribution of maximum titers will be described.  The frequency and percentage of subjects with 
neutralizing antibodies, if measured, may also be tabulated for subjects with TEADA.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3463251 may be assessed.
10.3.5.
Data Review During the Study
Access to safety data is scheduled to occur after Day 7 for Cohorts 1 through 3 in Part A, Day 14 
for Cohorts 4 to 8 in Part A, Day 22 for Cohorts 1 and 2, and Day 36 for Cohort 3 in Part B.  
Following completion of Cohorts 1 to 3 in Part A, an interim PK analysis will be conducted.  
Depending on those PK results in Part A, dose escalation decisions for Cohorts 4 and 5 may be 
based on data available at 7 rather than 14 days post-dose.
After the third SAD cohort, all available PK data obtained up to Day 14 from at least 7 subjects 
in the third cohort, and all available PK data from the preceding cohorts, will be reviewed to 
confirm the human dose projections established before study start. Depending on these results in 
Part A, the timing for dose escalation between Cohorts 4 and 5 may be reduced to 7 days.
The purpose of these reviews is to guide dose selection for the next dosing session, and/or to 
inform the design of subsequent studies.  The investigator and the Lilly sponsor team will make 
the determination regarding dose-escalation, based upon their review of the data.  The 
investigator will remain blinded, and the Lilly sponsor team will be unblinded during these 
reviews.  
Safety and tolerability data up to 14 days post-dose from all subjects in the last cohort of Part A, 
and all safety and tolerability data available at this time (including ADA data) from the 
preceding cohorts of Part A will be reviewed prior to initiation of Part B.
Interim access to PK and PD data may be scheduled during Part B to plan for future clinical 
studies.

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10.3.6.
Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, 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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Appendix 1.
Abbreviations and Definitions

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Term
Definition
ADA
antidrug antibody
ADHD
attention deficit hyperactivity disorder
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-168h
area under the concentration versus time curve from time 0 to 168 hours post-dose
AUC(0-∞)
area under the concentration versus time curve from time 0 to infinity
AUC(0-τ)
area under the concentration versus time curve during 1 dosing interval
AUC(0-tlast)
area under the concentration versus time curve from time 0 to the time of the last 
quantifiable concentration
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 subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
BMI
body mass index
CI
confidence interval
Cmax
maximum observed 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, 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
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
C-SSRS
Columbia Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
Fc
fragment crystallization region
GCP
good clinical practice
GDF15
growth and differentiation factor 15
GFRAL
glial cell derived neurotrophic receptor alpha–like
GI
gastrointestinal
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
informed consent
A process by which a subject 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 subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
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.

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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical 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.
IRB
institutional review board
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effects-level
OGTT
oral glucose tolerance test
PK/PD
pharmacokinetic/pharmacodynamic
QTc
corrected QT interval
QW
once-weekly
randomize
the process of assigning subjects/patients to an experimental group on a random basis
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.  
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TEADA
treatment-emergent antidrug antibodies
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 concentration
ULN
upper limit of normal

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VAS
visual analog scale

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Appendix 2.
Safety Laboratory Tests (Fasting)
Safety Laboratory Tests
Samples collected at screening and on Day -1 will be analyzed at a local laboratory.  Samples 
collected at all other time points will be analyzed by a central laboratory.
In addition, a 3.5-mL sample will be collected locally on Day 6 for analyzing the levels of AST, 
ALT, ALP, total bilirubin, and gamma glutamyl transferase during Part B of the study.
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Bicarbonate
Erythrocyte count (red blood cells)
Chloride
Mean cell volume
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Magnesium
Leukocytes (white blood cells [WBC]) 
Glucose (fasting)
Platelets
Blood urea nitrogen
Differential WBC [Absolute counts] of:
Uric acid
Neutrophils
Total cholesterol
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase
Urinalysis
Aspartate aminotransferase
Specific gravity
Alanine aminotransferase
pH
Creatinine
Protein
Gamma-glutamyl transferase
Glucose
Low-density lipoprotein
Ketones
High-density lipoprotein
Bilirubin
Triglycerides
Urobilinogen
Ethanol testinga
Blood
Urine drug screen (including cotinine)a
Nitrite
Hepatitis B surface antigenb
Microscopic examination (if protein, nitrite, or blood 
is positive)
Hepatitis B core antibodyb
Hepatitis C antibodyb
Human immunodeficiency virusb
Pregnancy testc
Follicle-stimulating hormonec
Glycated hemoglobinb
Abbreviation:  WBC = white blood cells.
a
Performed at screening and Day -1.  May be repeated at other times, at the discretion of the investigator.
b
Performed at screening only.
c
Females only.

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Appendix 3.
Hypersensitivity Tests
Selected tests may be obtained in the event of anaphylaxis or generalized urticaria.
Hypersensitivity Testsa
Anti-LY3463251 antibodies (immunogenicity)
Tryptase
LY3463251 concentration (PK)
N-methylhistamine
Drugs-specific IgEb
Basophil activation testb
Complements
Cytokine Panel
Abbreviations:  IgE = immunoglobulin E; PK = pharmacokinetics.
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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Appendix 4.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject 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 subject.  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 investigational product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  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 IRB was 
properly constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of IRB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s IRB should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae

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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences 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, each 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 eCRFs, 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 eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.

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In addition, Lilly or its representatives will periodically check a sample of the subject 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, 
applicable regulatory agencies, and applicable IRBs 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 subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the IRB 
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 5.
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 subjects in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
Red blood cells
Prothrombin Time
White blood cells
Prothrombin Time, International Normalized Ratio
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total and direct bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase
Anti-nuclear antibodya
Aspartate aminotransferase
Alkaline Phosphatase Isoenzymesa
Gamma-glutamyl transferase
Creatine phosphokinase
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviation:  Ig = immunoglobulin.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 6.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol J1D-MC-GZAA Sampling Summary (Part A [Single-Ascending Dose])
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
23.5
1
23.5
Safety laboratory testsa
12.5
8
100
Fasting plasma glucose
4
9
36
Pharmacokinetics 
5
14
70
Immunogenicity
10
5
50
Pharmacogenetics
10
1
10
Biomarkers
10
2
20
Total
309.5
Total for clinical purposes
310
a
Additional samples may be drawn if needed for safety purposes.
Protocol J1D-MC-GZAA Sampling Summary (Part B [Multiple-Ascending Dose])
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
23.5
1
23.5
Safety laboratory testsa
12.5
14
175
Liver function tests on Day 6b
3.5
1
3.5
Fasting plasma glucose
2
1
2
Fasting serum insulin and 
C-peptide
3.5
3
10.5
Oral glucose tolerance testc
5.5
15
82.5
Pharmacokinetics 
3
18
54
Acetaminophen test for gastric 
emptying
2
33
66
Immunogenicity
10
6
60
Pharmacogenetics
10
1
10
Biomarkers
10
4
40
Total
527
Total for clinical purposes
530
a
Additional samples may be drawn if needed for safety purposes.
b
Analyzed at a local laboratory.  Liver function tests include aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, total bilirubin, and gamma glutamyl transferase.
c
Includes 2-mL sample for measurement of glucose and 3.5 mL sample for measurement of insulin and C-peptide 
at a central laboratory.

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Appendix 7.
Protocol Amendment J1D-MC-GZAA(e) 
Summary 
A Randomized, Placebo-Controlled, Subject and Investigator-
Blind, Single and Multiple Dose, Safety, Tolerability, and 
Pharmacokinetics Study of LY3463251 in Healthy and 
Overweight Healthy Subjects Overview
Protocol J1D-MC-GZAA, A Randomized, Placebo-Controlled, Subject and Investigator-Blind, 
Single and Multiple Dose, Safety, Tolerability, and Pharmacokinetics Study of LY3463251, has 
been amended.  The new protocol is indicated by Amendment (e) will be used to conduct the 
study in place of any preceding version of the protocol.
This protocol amendment (e) is not a substantial amendment and will be used to conduct the 
study in place of any preceding version of the protocol.
Overall Rationale for the Amendment
Section # and 
Name
Description of Change
Brief Rationale
5.2 Number of 
Participants
The maximum number of 
subjects to be enrolled in part 
B was increased from 75 to 85
Objective is to consider the 
risk of dropouts due to the 
COVID-19 pandemic. 
7.4.1.2 Part B
Dose escalation at the cohort 
level and individual subject-
level was clarified.
Dose modification language 
was added for subjects in 
Cohort 4 or in optional Cohort 
5.
To allow dose modification in
Part B for subjects who do not 
tolerate or poorly tolerate 
doses of study drug.
8.1 
Discontinuation 
from Study 
Treatment
The previous dose 
modification language was 
replaced.
This dose modification
language was replaced by the 
changes to Section 7.4.1.2 Part 
B.
9.4.6.1. Hepatic 
Safety
The previous hepatic safety 
language was replaced with 
newer language.
The language was updated to 
stay current with hepatic safety 
monitoring procedures. 
The revisions are as follows:

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Note: All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.

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1.
Protocol Synopsis
Number of Subjects:
It is planned to enroll 64 subjects into Part A and 60 subjects into Part B.
In Part A, up to 75 subjects may be enrolled such that approximately 64 subjects have evaluable data.
In Part B, up to 85 subjects may be enrolled such that approximately 60 subjects have evaluable data.
Subjects who are randomized and who are discontinued from the study (providing that discontinuation did not result 
from a safety finding) may be replaced to ensure that enough subjects complete the study. To allow for 
replacements in case of discontinuation, up to 75 subjects may be enrolled into Part A and up to 75 subjects may be 
enrolled into Part B.
5.2.
Number of Participants
It is planned to enroll 64 subjects into Part A and 60 subjects into Part B.  For purposes of this 
study, a subject completes the study when all scheduled procedures shown in the Schedule of 
Activities have been finished.
Subjects who are randomized and who are discontinued from the study (providing that 
discontinuation did not result from a safety finding) may be replaced to ensure that enough 
subjects complete the study. To allow for replacement in case of discontinuation, up to 
75 subjects may be enrolled into Part A and up to 75 85 subjects may be enrolled into Part B.  
7.4.1.2.
Part B
Dose-escalation at the cohort level
Part B may be initiated following review of all available safety and tolerability data up to Day 14 
post-dose from all subjects in the last cohort of Part A, and all safety and tolerability data 
available at this time (including ADA data) from the previous cohorts.  
Dose-escalation decisions in Part B will primarily be based on safety and tolerability data 
obtained from at least 7 subjects up to and including Day 22 for Cohorts 2 and 3, and up to and 
including Day 36 for Cohort 4.  Additionally, any available PK data may be used to guide dose 
selection or to determine if the number of doses to be studied may be reduced.
If any of the following scenarios occur, dosing at the current level and further dose-escalation 
will be interrupted:

Four or more subjects develop AEs that are considered to be related to study treatment 
and graded as at least moderate and not responsive to supportive care

One or more subjects develop AEs that are considered to be related to study treatment 
and graded as severe

One or more subjects develop SAEs that are considered to be related to study treatment
Dose-escalation at the individual subject level

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In case a participant subject interrupted the study drug and

more than 2 doses were missed, the subject should be discontinued from the study – this 
would be at least 25% of doses missed and may compromise data reliability. 

the number of consecutive missed doses is ≤2, the treatment can be restarted at the same 
dose, if the drug was well tolerated prior to interruption.

the number of consecutive missed doses is ≤2, then the treatment should be restarted at 3 
mg irrespective of the dose the subject was receiving if the dose was not well tolerated 
before the interruption and subsequently follow the assigned dose escalation scheme.
Every effort should be made for a subject to adhere to the protocol dose escalations within a 
cohort.  However, it is possible that some subjects may not tolerate higher doses of the study 
drug.
All dose adjustments discussed below may only occur following agreement between the 
investigator and sponsor medical monitor. The dose administered to the subjects each week 
should be recorded on the case report form during titration and throughout the study.
Dose modification for Cohort 4 
Subjects who do not tolerate the 3 mg or 9 mg doses of study drug for at least 2 weeks will be 
discontinued from study drug but should continue to be monitored for safety for the duration of 
the study.
If after 2 weeks at 15 mg, a subject still has gastrointestinal symptoms preventing dose escalation 
to 24 mg, the subject may be kept at 15 mg for 1 to 3 additional doses before escalating to 24 
mg. Subjects who cannot tolerate the 15 mg dose after at least 2 doses due to moderate or severe 
gastrointestinal symptoms may be discontinued from study treatment but should continue to be 
monitored for safety for the duration of the study.
If after at least 2 doses of 24 mg a subject has poorly tolerated nausea, vomiting, or diarrhea, and 
the investigator does not believe that the subject will tolerate additional injections of 24 mg 
despite the possibility of tachyphylaxis, then the investigator may reduce the dose to 15 mg.  If 
this dose of 15 mg is tolerated, the subject may remain at that dose level for the duration of the 
study or the investigator may increase the dose back to 24 mg.  Maintenance doses of less than 
15 mg will not be allowed.  
Dose modification for optional Cohort 5 
In case a subject has poorly tolerated nausea, vomiting, or diarrhea at a given dose, the 
investigator may decide to decrease the dose to a previous dose level.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST ≥5× ULN on 2 consecutive occasions

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
ALT or AST ≥3× ULN and TBL ≥2× ULN or international normalized ratio ≥1.5

ALT or AST ≥3× ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP ≥3× ULN

ALP ≥2.5× ULN and TBL ≥2× ULN

ALP ≥2.5× ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
The following discontinuation criteria related to abnormal liver tests should be applied during the 
dose-escalation process. The occurrence of 1 or more cases meeting all the following criteria 
should be considered as a dose-limiting toxicity event:

ALT or AST ≥3× ULN

TBL ≥2× ULN

No initial cholestasis (ALP does not exceed 2× ULN), and

No other cause explaining the abnormality in liver tests.
Subjects who do not tolerate a given dose level due to gastro-intestinal symptoms may be 
discontinued from study drug or may have their dose reduced depending on various parameters 
as described in Section 7.4.1.2 (dose level, severity of symptoms, investigator’s judgement, 
discussion between investigator and sponsor medical monitor). If they are discontinued from 
study drug, these subjects should continue to be monitored for safety for the duration of the 
study.
In the presence of GI events, subjects

from 1-mg and 3-mg dose groups who are unable to tolerate their assigned dose level for 
≥2 weeks (have persistent vomiting or moderate to severe nausea) should be discontinued 
from using the study drug

in the remaining dose groups who have reached their target dose for ≥2 weeks and are 
still unable to tolerate that dose level (present persistent vomiting or moderate to severe 
nausea) may have the dose reduced to the previous dose and remain on the reduced dose 
for the remainder of the study.  The dose administered to the subjects each week should 
be recorded on the case report form during titration and throughout the study. 
9.4.6.1.
Hepatic Safety
If a study subject experiences elevated ALT or AST ≥3× ULN, ALP ≥2× ULN, or elevated 
TBL ≥2× ULN, liver tests (Appendix 5) should be repeated within 48 to 72 hours including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine 
phosphokinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator based on 

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consultation with the Lilly CP 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 ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests
hepatic event considered to be an SAE.
Close hepatic monitoring
Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm 
the abnormality and to determine if it is increasing or decreasing, if 1 or more of these conditions 
occur:
If a subject with baseline results of...
develops the following elevations:
ALT or AST <1.5X ULN
ALT or AST ≥3X ULN
ALP <1.5X ULN
ALP ≥2X ULN
TBL <1.5X ULN
TBL ≥2X ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline
ALP ≥1.5X ULN
ALP ≥2X baseline
TBL ≥1.5X ULN
TBL ≥2X baseline (except for patients with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver test results should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including symptoms, recent 
illnesses (e.g., heart failure, systemic infection, hypotension, or seizures), recent travel, history of 
concomitant medications (including OTC), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the subject’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
subject’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation

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A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:
If a subject with baseline results 
of...
develops the following elevation:
ALT or AST <1.5X ULN
ALT or AST ≥3X ULN with hepatic signs/symptomsa, or ALT or AST ≥5X 
ULN
ALP <1.5X ULN
ALP ≥3X ULN
TBL <1.5 X ULN
TBL ≥2X ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline with hepatic signs/symptomsa, or ALT or AST 
≥3X baseline
ALP ≥1.5X ULN
ALP ≥2X baseline
TBL ≥1.5X ULN
TBL ≥1.5X baseline (except for patients with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
a
Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper-quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined earlier, as well as tests for prothrombin time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (e.g., ultrasound or 
computed tomography scan).
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for

hepatitis D virus

cytomegalovirus

Epstein-Barr virus

acetaminophen levels

acetaminophen protein adducts

urine toxicology screen

Wilson’s disease

blood alcohol levels

urinary ethyl glucuronide, and

serum phosphatidylethanol.
Based on the circumstances and the investigator’s assessment of the subject’s clinical condition, 
the investigator should consider referring the subject for a

hepatologist or gastroenterologist consultation

magnetic resonance cholangiopancreatography

endoscopic retrograde cholangiopancreatography

cardiac echocardiogram, or

liver biopsy.

J1D-MC-GZAA(e) Clinical Pharmacology Protocol
Page 84
LY3463251
Additional hepatic data collection (hepatic safety CRF) in study subjects who have 
abnormal liver test results during the study
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
subjects who meet 1 or more of the following 5 conditions:
6. Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5X ULN)
a.
In subjects with baseline ALT ≥1.5X ULN, the threshold is ALT ≥3X baseline on 
2 or more consecutive tests
7. Elevation of TBL to ≥2X ULN (if baseline TBL <1.5X ULN) (except for cases of known 
Gilbert’s syndrome)
a.
In subjects with baseline TBL ≥1.5X ULN, the threshold should be TBL ≥2X 
baseline
8. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5X ULN)
a.
In subjects with baseline ALP ≥1.5X ULN, the threshold is ALP ≥2X baseline on 
2 or more consecutive blood tests
9. Hepatic event considered to be an SAE
10. Discontinuation of study drug due to a hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days.

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