Clinical trial NCT05794243
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2023-03-23; Completion date: 2023-06-20
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to conduct blood tests to measure how much LY3493269 is in the bloodstream and how the body handles and eliminates LY3493269 when administered orally as test compared to reference formulations in healthy participants in fed and/or fasted states. The study will also evaluate the safety and tolerability of LY3493269 in these participants. The study will last up to 43 days excluding the screening period.

Detailed description:

Arms: arm 1: * Participants were administered oral doses of 4 milligram (mg) LY3493269 test capsule formulation 1, co-administered with 280 mg of sodium caprate (C10).
* This regimen was administered once daily on Days 1, 2, and 3, following an overnight fast. arm 2: * Participants were administered oral doses of 4 mg LY3493269 test capsule formulation 2, co-administered with 280 mg of C10.
* This regimen was administered once daily on Days 1, 2, and 3, following an overnight fast. arm 3: * Participants were administered oral doses of 4 mg LY3493269 reference tablet formulation, co-administered with 300 mg of salcaprozate sodium (SNAC).
* This regimen was administered once daily on Days 1, 2, and 3, following an overnight fast. arm 4: The formulation of the LY3493269 test capsule (1,2) or reference tablet were planned to be determined based on the initial review of safety and pharmacokinetic data from Part A.
Interventions: intervention 1: LY3493269 intervention 2: Sodium Caprate (C10) intervention 3: Salcaprozate Sodium (SNAC)
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally.

Protocol documents:
Prot_000.pdf: 
 
 
Protocol: J1X-MC-GZHI (Initial Version) 
 
 
An Open-Label, Multiple-Dose Study to Investigate the Pharmacokinetics of LY3493269 
Oral Formulations Administered in a Fed or Fasted State in Healthy Participants 
 
 
NCT05794243 
 
 
Approval Date: 18-Sep-2022 
 


CONFIDENTIAL 
J1X-MC-GZHI 
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Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3493269, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: An Open-Label, Multiple-Dose Study to Investigate the Pharmacokinetics of 
LY3493269 Oral Formulations Administered in a Fed or Fasted State in Healthy Participants 
Protocol Number: J1X-MC-GZHI 
Amendment Number: This is the initial protocol.  
Compound: LY3493269 
Brief Title: Pharmacokinetics of LY3493269 Oral Formulations in Healthy Participants  
Study Phase: 1 
Acronym:  GZHI 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below. 
 
 
 
 
 
Document ID: VV-CLIN-023691 
 
 
 
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Medical Monitor Name and Contact Information will be provided separately  
 
 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................14 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
3. 
Objectives and Endpoints ............................................................................................17 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
Scientific Rationale for Study Design ............................................................................19 
4.3. 
Justification for Dose ......................................................................................................20 
4.4. 
End of Study Definition ..................................................................................................20 
5. 
Study Population ...........................................................................................................22 
5.1. 
Inclusion Criteria ............................................................................................................22 
5.2. 
Exclusion Criteria ...........................................................................................................23 
5.3. 
Lifestyle Considerations .................................................................................................25 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................25 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................26 
5.3.3. 
Activity ...........................................................................................................................26 
5.4. 
Screen Failures ................................................................................................................27 
5.5. 
Criteria for Temporarily Delaying Enrollment/ Randomization/ 
Administration of Study Intervention of a Participant....................................................27 
6. 
Study Interventions and Concomitant Therapy ........................................................28 
6.1. 
Study Interventions Administered ..................................................................................28 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................29 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
6.4. 
Study Intervention Compliance ......................................................................................30 
6.5. 
Dose Modification ..........................................................................................................30 
6.5.1. 
Data Review during the Study ........................................................................................30 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................31 
6.7. 
Treatment of Overdose ...................................................................................................31 
6.8. 
Concomitant Therapy .....................................................................................................31 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................32 
7.1. 
Discontinuation of Study Intervention ............................................................................32 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................32 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................33 
7.3. 
Lost to Follow-up............................................................................................................34 
8. 
Study Assessments and Procedures.............................................................................35 
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8.1. 
Efficacy Assessments .....................................................................................................35 
8.2. 
Safety Assessments .........................................................................................................35 
8.2.1. 
Physical Examinations ....................................................................................................35 
8.2.2. 
Vital Signs .......................................................................................................................35 
8.2.3. 
Electrocardiograms .........................................................................................................36 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................36 
8.2.5. 
Safety Monitoring ...........................................................................................................37 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................42 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................43 
8.3.2. 
Pregnancy ........................................................................................................................44 
8.3.3. 
Adverse Events of Special Interest .................................................................................45 
8.4. 
Pharmacokinetics ............................................................................................................45 
8.4.1. 
Bioanalysis ......................................................................................................................46 
8.5. 
Pharmacodynamics .........................................................................................................46 
8.6. 
Genetics ..........................................................................................................................46 
8.7. 
Biomarkers ......................................................................................................................47 
8.8. 
Immunogenicity Assessments.........................................................................................47 
8.9. 
Health Economics ...........................................................................................................48 
9. 
Statistical Considerations .............................................................................................49 
9.1. 
Statistical Hypotheses .....................................................................................................49 
9.1.1. 
Multiplicity Adjustment ..................................................................................................49 
9.2. 
Analyses Populations ......................................................................................................49 
9.2.1. 
Study Participant Disposition .........................................................................................49 
9.2.2. 
Study Participant Characteristics ....................................................................................49 
9.2.3. 
Treatment Compliance ....................................................................................................50 
9.3. 
Statistical Analyses .........................................................................................................50 
9.3.1. 
General Considerations ...................................................................................................50 
9.3.2. 
Pharmacokinetic Analyses ..............................................................................................50 
9.3.3. 
Safety Analyses ...............................................................................................................51 
9.3.4. 
Evaluation of Immunogenicity .......................................................................................52 
9.4. 
Interim Analysis ..............................................................................................................52 
9.5. 
Sample Size Determination ............................................................................................52 
10. 
Supporting Documentation and Operational Considerations ..................................53 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................53 
10.1.1. Regulatory and Ethical Considerations ...........................................................................53 
10.1.2. Informed Consent Process ..............................................................................................53 
10.1.3. Data Protection................................................................................................................54 
10.1.4. Dissemination of Clinical Study Data.............................................................................54 
10.1.5. Data Quality Assurance ..................................................................................................55 
10.1.6. Source Documents ..........................................................................................................56 
10.1.7. Study and Site Start and Closure ....................................................................................57 
10.1.8. Publication Policy ...........................................................................................................57 
10.1.9. Sample Retention ............................................................................................................57 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................59 
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10.2.1. Blood Sampling Summary ..............................................................................................61 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................62 
10.3.1. Definition of AE .............................................................................................................62 
10.3.2. Definition of SAE ...........................................................................................................63 
10.3.3. Definition of Product Complaints ...................................................................................64 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................64 
10.3.5. Reporting of SAEs ..........................................................................................................66 
10.3.6. Regulatory Reporting Requirements ...............................................................................66 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................68 
10.4.1. Definitions.......................................................................................................................68 
10.4.2. Contraception Guidance..................................................................................................68 
10.5. 
Appendix 5: Genetics......................................................................................................71 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................72 
10.7. 
Appendix 7: Pancreatic Monitoring ................................................................................73 
10.8. 
Appendix 8: Hypersensitivity Event Tests .....................................................................73 
10.9. 
Appendix 9: Provisions for Changes in Study Conduct during 
Exceptional Circumstances .............................................................................................75 
10.10. 
Appendix 10: Abbreviations and Definitions .................................................................78 
11. 
References ......................................................................................................................81 
 
 
 
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List of Tables 
Table 
Page 
Table GZHI.6.1. Fasting or Fed Conditions and Water Consumption for Dosing ...................... 29 
 
 
 
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List of Figures 
Figure 
Page 
Figure GZHI.1.1 Illustration of Parts A and B for Protocol J1X-MC-GZHI. ...............................10 
 
 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
An Open-Label, Multiple-Dose Study to Investigate the Pharmacokinetics of LY3493269 Oral 
Formulations Administered in a Fed or Fasted State in Healthy Participants 
Brief Title: Pharmacokinetics of LY3493269 Oral Formulations in Healthy Participants 
Rationale: 
LY3493269 is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like 
peptide (GLP)-1 receptor agonist being developed as a treatment for type 2 diabetes mellitus 
(T2DM). In addition to subcutaneous treatment, an oral formulation of LY3493269 is being 
developed for once-daily administration to improve patient convenience and therapy adherence. 
The aim of developing an oral formulation is to provide an effective oral incretin for patients 
with T2DM with inadequately managed blood glucose goals. This study of LY3493269, Study 
J1X-MC-GZHI (GZHI), will investigate the pharmacokinetics (PK) of LY3493269 administered 
as multiple once-daily oral doses in healthy participants.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 To evaluate and compare the PK of up to 3 test capsule 
formulations with a reference tablet formulation of LY3493269 
following 3 consecutive once-daily oral doses in healthy 
participants  
 AUC and Cmax  
Secondary 
 
 To evaluate the PK of up to 2 LY3493269 formulations when 
administered in a fed condition following 3 consecutive once-
daily oral doses in healthy participants 
 
AUC and Cmax  
 To assess the safety and tolerability of up to 3 test capsule 
formulations of LY3493269 with that of a reference tablet 
formulation following 3 once-daily oral doses in healthy 
participants 
 
TEAEs 
Abbreviations:  AUC = area under the concentration versus time curve; Cmax = maximum observed drug 
concentration; PK = pharmacokinetics; TEAE = treatment-emergent adverse event. 
 
 
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J1X-MC-GZHI 
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Overall Design 
Study GZHI is a Phase 1, single-center, open-label, multiple-dose study in 5 planned treatment 
groups targeting 10 healthy participants in each treatment group to complete. The study will be 
conducted in 2 parts (Part A and Part B). 
Brief Summary: 
The purpose of this study is to evaluate and compare the PK of up to 3 test capsule formulations 
with a reference tablet formulation of LY3493269 following 3 consecutive once-daily oral doses 
in healthy participants.   
Study details include: 
● The study duration will be up to 71 days. 
● The treatment duration involves consecutive once-daily dosing up to 3 days. 
● The visit frequency will be one inpatient stay (Day -1 through Day 5) and 5 outpatient 
visits. 
Number of Participants: 
Up to approximately 70 participants may be enrolled to ensure approximately 10 evaluable 
participants from each of the 5 planned treatment groups complete the study. Participants who 
are enrolled but not administered treatment prior to discontinuation may be replaced to ensure 
that the target number of participants complete the study.   
Participants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant. 
Intervention Groups and Duration: 
In each part of the study, eligible participants will be assigned to a study treatment (Test or 
Reference formulation) and will receive 3 once-daily doses of study intervention. 
The maximum total duration of study participation for each participant may be up to 71 days, 
across the following study intervals: 
 Screening, approximately 28 days 
 Study period, approximately 15 days 
 Follow up, approximately 28 days after the last dose of study intervention 
Data Monitoring Committee: No 
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1.2. 
Schema 
 
 
 
Formulations “X” and “Y” will be determined after review of interim data from Part A.  If appropriate, Formulation “Y” may be determined after review 
of data from Treatment B1. 
 
Figure GZHI.1.1 
Illustration of Parts A and B for Protocol J1X-MC-GZHI. 
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J1X-MC-GZHI 
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1.3. 
Schedule of Activities (SoA) 
Schedule of activities for Parts A and B 
Study Activities 
Scrn 
Study Period (Parts A and B) 
Follow-up 
Comments/Notes 
CRU Inpatient Stay 
Outpatient 
Outpatient 
Days 
-28 
to  
-2 
−1 
1 
2 
3 
4 
5 
6 
8 
15 
±1 
29 
±3 
43 
±3 
ET  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical assessment 
 
 
P 
P 
P 
 
X 
X 
X 
X 
X 
X 
X 
Medical review and symptom-
directed physical examination, as 
appropriate. 
Height and weight 
X 
 
P 
 
X 
 
 
 
X 
X 
X 
X 
X 
Height at screening only. 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
X 
 
 
 
 
 
 
At the investigator’s discretion, 
participants may remain inpatient 
after Day 5. 
Outpatient visit to CRU 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Administer study drug 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Refer to Section 6.1 for details 
AEs/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG – single (h)   
X 
 
P, 1, 4, 
12 
P, 1, 4, 
12 
P, 1, 4, 
12 
 
 
 
 
X 
X 
X 
X 
ECGs must be recorded 
approximately within 30 minutes 
before collection of any blood 
samples (applicable for study visits). 
Vital signs: supine 
BP/PR (h) 
X 
 
P, 1, 4, 
12 
P, 1, 4, 
12 
P, 1, 4, 
12 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body temperature 
X 
 
P 
P 
P 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
(fasted) 
X 
 
P 
 
 
 
X 
 
X 
X 
X 
X 
X 
See Appendix 2 for details. 
Point-of-care safety 
glucose samples 
(glucose analyzer)   
 
 
Days 1 – 4: Pre-meals (breakfast, 
lunch, and dinner) and before bedtime 
X 
X 
 
 
 
 
 
Day 5: Fasted sample collected 
before breakfast. 
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Study Activities 
Scrn 
Study Period (Parts A and B) 
Follow-up 
Comments/Notes 
CRU Inpatient Stay 
Outpatient 
Outpatient 
Days 
-28 
to  
-2 
−1 
1 
2 
3 
4 
5 
6 
8 
15 
±1 
29 
±3 
43 
±3 
ET  
LY3493269 PK 
sampling (h) 
 
 
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
5, 6, 8, 9, 
10, 12, 
14 
P, 1, 2, 
3, 4, 8, 
14 
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
5, 6, 8, 9, 
10, 12, 
14 
X 
X 
X 
X 
X 
X 
X 
X 
Days 15, 29, 43, and ET: Samples 
collected anytime during visit. 
SNAC (Reference 
Formulation) or 
C10 (Test Formulations) 
PK sampling (h) 
 
 
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
5, 6, 8, 9, 
10, 12, 
14 
P, 1, 2, 
3, 4, 8, 
14 
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
5, 6, 8, 9, 
10, 12, 
14 
X 
X 
 
 
 
 
 
 
 
Immunogenicity 
 
 
P 
 
 
 
 
 
 
X 
X 
X 
X 
Day 1: Samples are collected within 
30 min of the predose PK samples.  
Pharmacogenetic 
sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Obtained any time on Day 1. 
Nonpharmacogenetic 
biomarker stored 
samples – (fasted) 
 
 
P 
 
P 
 
X 
 
X 
X 
X 
 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination (applicable only to 
study participants who have received study intervention); P = predose; PK = pharmacokinetics; PR = pulse rate; Scrn = Screening Visit; SNAC = salcaprozate 
sodium; SoA = schedule of activities.  
 
Notes:  
1) Fasted samples or assessments should be collected or performed after a minimum 8-hour overnight fast. If multiple procedures take place at the same time 
point, ECGs and vital signs must be obtained prior to any blood sample collection.  
2) For vital signs and ECGs 
 
time points on Days 1 to 3 are relative to scheduled dosing at “0 h”. Assessments scheduled at “0” are conducted predose (P).  
 
on Day 15, ECG should be measured within approximately 30 min prior to the scheduled PK sample. 
 
on Day 15 and subsequent visits, vital signs should be measured within approximately 30 min prior to the scheduled PK sample. 
3) PK and immunogenicity samples are not required at ET for participants who discontinue without receiving study intervention. 
4) The following requirements are not applicable for urinalysis samples. Unless otherwise stated, 
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J1X-MC-GZHI 
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 
predose study assessments and procedures should be performed within 3 hours prior to planned dosing, 
 
postdose assessments and procedures on Days 1, 2, and 3, up to and including 24 hours post-Day 3 dose should be performed within ±10% of the 
scheduled time, and 
 
postdose assessments and procedures on Days 4 to 8, scheduled after 24 hours post-Day 3 dose should be performed within ±3 hours of the scheduled 
time,  
 
windows for postdose assessments and procedures on Days 15 and later are indicated in the SoA. 
 
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2. 
Introduction 
2.1. 
Study Rationale 
LY3493269 is a dual GIP and GLP-1 RA being developed as a treatment for T2DM. In addition 
to SC treatment, an oral formulation of LY3493269 is being developed for once-daily 
administration to improve patient convenience and therapy adherence. The aim of developing an 
oral formulation is to provide an effective oral incretin for patients with T2DM with inadequately 
managed blood glucose goals. This study of LY3493269, Study J1X-MC-GZHI (GZHI), will 
evaluate and compare the PK of different test capsule formulations of LY3493269 administered 
as multiple once-daily oral doses in healthy participants with that of a reference tablet 
formulation.  
2.2. 
Background 
T2DM is characterized by impaired glycemic control due to insulin resistance and inadequate 
insulin secretion due to the pancreatic beta-cell failure. T2DM is frequently associated with 
comorbidities such as obesity, hypertension, and dyslipidemia resulting in increased risk of 
microvascular and macrovascular complications. 
Synthesized and secreted in the proximal intestine, GIP is primarily regulated by nutrients, 
especially fats, and is responsible for the majority of the insulinotropic incretin effect in humans. 
In addition, distinct from GLP-1, GIP promotes glucagon secretion at low blood glucose levels to 
augment endogenous glucose production. It stimulates lipolysis and inhibits insulin-induced 
lipogenesis in human adipocytes. 
GLP-1 is a well-characterized incretin hormone that potentiates insulin secretion and reduces 
glucagon secretion in a glucose-dependent manner after meal ingestion. GLP-1 exerts its 
insulinotropic action through distinct G protein-coupled receptors highly expressed on islet β 
cells and in some non-islet cells. For example, GLP-1 receptors are expressed throughout the 
brain, in regions that control 
 glucose homeostasis 
 gut motility 
 food intake 
 aversive signaling, and 
 CV function (Campbell and Drucker 2013).  
Currently, there are several approved GLP-1 RAs for the treatment of diabetes and obesity. The 
dosing of GLP-1 RAs in humans is limited by GI adverse effects, such as nausea and vomiting. 
Available preclinical and clinical data indicate that co-stimulation of GIP and GLP-1 receptors 
may enhance insulin secretion, improve insulin sensitivity, and reduce body weight beyond the 
effect of selective GLP-1 receptor stimulation (Coskun et al. 2018; Frias et al. 2018).  
The LY3493269 reference tablet formulation in Study GZHI will include the permeation 
enhancer SNAC, to enable oral absorption of the LY3493269 peptide, while the LY3493269 test 
capsule formulations will include sodium caprate (C10) as a permeation enhancer. 
 
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J1X-MC-GZHI 
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 As 
peptides are otherwise poorly absorbed orally due to low permeability, an enabling excipient 
such as SNAC or C10 in an oral tablet formulation is expected to transiently increase local 
permeability (Twarog et al. 2019) and result in increased oral bioavailability for therapeutic use. 
2.3. 
Benefit/Risk Assessment 
There is no anticipated therapeutic benefit for the participants in this trial. 
The sponsor has evaluated the preclinical and clinical risks associated with LY3493269. 
Nonclinical safety of SC LY3493269 was evaluated in a CV safety pharmacology study in 
monkeys and 1-month repeat-dose toxicology studies in rats and monkeys. Important 
LY3493269-related findings in the rat and monkey included body weight loss and/or reduced 
body weight gain and decreased food consumption. Additional findings from the monkey studies 
included changes in CV parameters (such as increases in HR and BP). In the completed clinical 
studies where LY3493269 was administered SC (Studies GZHA and GZHC) or orally with C10 
(Study GZHB) or SNAC (Study GZHF), similar findings were observed, which include  
 nausea 
 vomiting 
 loss of appetite, and 
 increased HR. 
SNAC has generally regarded as safe status and is contained in FDA-approved medical food 
(Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA; Twarog et al. 2019). Rybelsus® tablet, 
which is approved by FDA, European Medicines Agency and Japan Pharmaceuticals and 
Medical Devices Agency, also contains SNAC (daily dose of 300 mg). In addition, in a first-in-
human trial, up to 600 mg SNAC was evaluated with oral semaglutide with no safety concerns 
reported (Granhall et al. 2019).  
C10 has a long history of use in humans and has food additive status in the US and EU with no 
daily limits on consumption (Twarog et al. 2019). In the completed nonclinical safety 
pharmacology and toxicology studies, LY3493269 orally co-administered with C10, produced 
increased HR, body weight loss and/or decreased body weight gain, and decreased food 
consumption, which are consistent with, or secondary to, incretin pharmacology. The effects on 
body weight were dose limiting and resulted in dosing suspension at the highest dose levels 
tested in monkeys. No adverse C10-related effects were observed up to 350 mg/kg in any of the 
toxicology studies/assessments. 
In the completed nonclinical safety pharmacology and toxicology studies, LY3493269 orally 
co-administered with SNAC produced body weight loss and/or decreased body weight gain, and 
decreased food consumption, which are consistent with, or secondary to, incretin pharmacology. 
The effects on body weight were dose limiting and resulted in dosing suspension in monkeys. No 
adverse SNAC-related effects were observed up to 600 mg/kg in any of the toxicology 
studies/assessments. Refer to the IB for more information.   
Based on the completed clinical Studies GZHA, GZHB, GZHC, and GZHF, potential risks for 
clinical trial participants receiving orally administered LY3493269 are similar to those for 
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participants receiving SC administered LY3493269 and include CV effects, GI disturbances, 
inappetence, skin burning sensation and related events, and weight loss. 
All identified risks from the nonclinical and clinical studies are considered monitorable and 
manageable at the planned once-daily oral dose of 4 mg LY3493269. To further minimize any 
potential risk, participants will remain at the CRU for at least 5 days for safety and tolerability 
monitoring until discharge. Participants will be closely monitored with scheduled medical 
assessments, vital signs, and triplicate ECG measurements. The investigator will have the 
discretion to extend the participant inpatient stay for further safety monitoring. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3493269 may be found in the IB. 
 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
 To evaluate and compare the PK of up to 3 test capsule 
formulations with a reference tablet formulation of 
LY3493269 following 3 consecutive once-daily oral doses 
in healthy participants  
 AUC and Cmax  
Secondary 
 
 To evaluate the PK of up to 2 LY3493269 formulations 
when administered in a fed condition following 3 
consecutive once-daily oral doses in healthy participants 
 AUC and Cmax  
 To assess the safety and tolerability of up to 3 test capsule 
formulations of LY3493269 with that of a reference tablet 
formulation following 3 once-daily oral doses in healthy 
participants 
 TEAEs 
Exploratory 
 
 To assess PK of SNAC and C10 following oral 
administration in healthy participants  
 AUC and Cmax 
Abbreviations:  AUC = area under the concentration versus time curve; C10 = sodium caprate; Cmax = maximum 
observed drug concentration; PK = pharmacokinetics; SNAC = salcaprozate sodium; TEAE = treatment-
emergent adverse event. 
 
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4. 
Study Design 
4.1. 
Overall Design 
This is a 2-part, open-label study with a parallel design to be conducted in healthy participants.  
The purpose of this study is to evaluate and compare the PK of up to 3 test capsule formulations 
with a reference tablet formulation of LY3493269 following 3 consecutive once-daily oral doses 
in healthy participants.   
Study details include: 
 The study duration will be up to 71 days. 
 The treatment duration involves consecutive once-daily dosing up to 3 days. 
 The visit frequency will be one inpatient stay (Day -1 through Day 5) and 5 outpatient 
visits. 
In Parts A and B, eligible participants will receive 3 once-daily doses of study intervention. 
The maximum total duration of study participation for each participant may be up to 71 days, 
across the following study intervals: 
 Screening, approximately 28 days 
 Study period, approximately 15 days, and 
 Follow up, approximately 28 days after the last dose of study intervention. 
The study shall target 10 participants completing each treatment – that is, these participants must 
complete Day 8 PK assessments after receiving all 3 consecutive daily doses of the study 
treatment. 
Part A 
Part A of the study is an initial characterization of 2 test capsule formulations, compared with a 
reference tablet formulation. Participants will be randomly assigned to receive 1 of the 3 possible 
treatments as follows: 
 Treatment A1: Test capsule formulation 1 
 Treatment A2: Test capsule formulation 2 
 Treatment A3: Reference tablet formulation 
Test formulations 1 and 2 and the reference formulation will be administered in the fasted state.  
Part B 
Part B of the study will investigate the test capsule formulations 1, 2, or 3 or the reference tablet 
formulation.  
An initial review of safety and PK data from Part A will be conducted to determine the test or 
reference formulation(s) to be evaluated in Part B. Participants will be assigned to 1 of the 2 
possible treatments as follows: 
 Treatment B1: Test formulations 1, 2, or 3 (referred to as “X” from this point forward) 
 Treatment B2: Test formulations 1, 2, or 3 or reference formulation (referred to as “Y” 
from this point forward). 
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The 3 test formulations will be administered in either the fasted or fed state depending on the 
review of safety and PK data from Part A. If the reference formulation is selected as Treatment 
B2, it will be administered in the fasted state.   
Depending on the review results, the selected formulation(s) will be administered in either the 
fed or fasted state.   
Treatments B1 and B2 may be initiated concurrently if the formulations “X” and “Y” and 
administration conditions are determined for both treatment groups after the first review. 
Otherwise, a second review of available PK data from Treatment B1 may be conducted prior to 
the initiation of Treatment B2.  
4.2. 
Scientific Rationale for Study Design 
The study is intended to estimate the relative oral bioavailability of various LY3493269 4-mg 
oral formulations with 280 mg C10 versus a LY3493269 4 mg with 300 mg SNAC oral 
formulation. A population of healthy participants is selected to assess the safety and tolerability 
of LY3493269 co-formulated with 280 mg C10 as a capsule for oral administration with an 
intended lower intestinal release mechanism. An LY3493269 tablet co-formulated with 300 mg 
SNAC will be used as the reference treatment. Using a healthy participant population mitigates 
possible confounding effects of comorbidities and concomitant medications. Therefore, Study 
GZHI provides an unbiased assessment of safety, tolerability, and PK of LY3493269 
administered as oral doses. 
A study design of once-daily oral dosing for 3 days will be employed to characterize oral PK 
behavior of LY3493269. The dosing duration of 3 days was selected after taking into 
consideration the following factors: 
 low oral bioavailability expected from oral peptide formulations 
 the exceptionally high inter- and intra-individual variabilities in oral bioavailability 
expected of oral peptide formulations 
 the sensitivity of the bioanalytical assay, and  
 once absorbed via the oral route of administration, LY3493269 systemic PK disposition 
should be similar regardless of route of administration, hence safety, tolerability, and PK 
data from past LY3493269 studies (GZHA, GZHB, GZHC, and GZHF) should be 
applicable to this study. 
To predict the oral PK profiles for each treatment, extensive PK simulations were conducted. 
The PK profile following a single oral dose was deemed to be at risk of being highly variable and 
potentially returning lower than quantifiable concentrations at multiple time points. The 
simulation results did suggest that 3 days was adequate for a majority of PK profiles from 
participants in each treatment group to remain above the quantification limit of 
 to yield 
meaningful PK results. Therefore, PK exposures from a short dosing duration of 3 days from this 
study are not expected to reach steady state for the respective doses.  
Strict oral administration conditions such as controlling the duration of fasting before and after 
dosing and water volume for oral administration of LY3493269 will be imposed. These are 
necessary to reduce any potential variability arising from oral administration conditions that may 
affect oral bioavailability of LY3493269. 
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Safety and tolerability assessments will be made, including incidence of nausea and/or vomiting, 
skin burning sensation, and other related events and evaluation of ECGs and vital signs 
conducted during the study (Section 8.2). The decisions to proceed from Part A to Part B and 
from Treatments B1 to B2, and the selection of LY3493269 formulations for Part B will be 
based primarily on safety and tolerability data (Sections 6.5.1) and all available PK data. 
4.3. 
Justification for Dose 
The proposed LY3493269 oral dose of 4 mg once daily is selected based on safety, tolerability, 
and PK data from oral administration of this same dose in combination with the permeation 
enhancers C10 and SNAC from Studies GZHB and GZHF. Based on past PK data, a 4-mg once-
daily dose is likely still adequate to enable quantification of LY3493269 concentrations for PK 
analysis assuming oral bioavailability in the range of 
 as observed from Study 
GZHB when co-administered with the permeation enhancer C10. Oral bioavailability for 
LY3493269 was calculated to be 
 when co-administered with the SNAC 
permeation enhancer in Study GZHF. Should oral bioavailability reach preclinical values of 
 (relative to SC administration) in dogs or 
 (absolute oral bioavailability) observed in 
monkeys for the current co-formulation with C10, anticipated PK concentrations from the 
proposed 4-mg dose are not expected to exceed concentrations from the 
dose tested in 
Study GZHF. When the highest preclinical relative oral availability of 
 in dogs is applied to 
simulate anticipated mean exposures of LY3493269 4 mg for this enteric formulation, Cmax and 
AUC from time zero to 24 hours after the third daily oral dose are expected to be approximately 
1.0x and 0.9x, respectively, of that for LY3493269 
 + SNAC 600 mg SNAC. Exposures 
from the 4-mg dose are also expected to be well below exposures from the SC multiple-
ascending dose study (Study GZHC). At this 4-mg dose, all of the expected safety findings 
(including skin burning sensation and related AEs) as evaluated in GZHF are monitorable. 
SNAC has generally regarded as safe status and is contained in FDA-approved medical food 
(Eligen-Vitamin B12, Emisphere, Roseland, NJ, USA). Rybelsus tablet, which is approved by 
FDA, European Medicines Agency and Japan Pharmaceuticals and Medical Devices Agency, 
contains SNAC at 300 mg. The SNAC reference dose in this study has been administered in 
GZHF without SNAC-specific safety concerns. 
While C10 has food additive status with no daily limits on consumption, up to 550 mg per day 
has been evaluated in an 8-week Phase 2 trial with oral insulin in patients with T2DM, with no 
safety concerns reported (Halberg et al. 2019). In the proposed study, C10 will be dosed at 
280 mg, which is 1.7-fold below the top dose in Study GZHB. In Study GZHB, a top dose of 
500 mg C10 was administered without C10-specific safety concerns. 
All of the identified risks in Section 2.3 are considered to be reversible, monitorable, and 
manageable and will continue to be monitored closely in clinic. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all required 
phases of the study including the last scheduled procedure shown in the SoA (Section 1.3). 
Any participant who does not satisfy this definition but who has completed all the key 
assessments may be considered a completer at the discretion of the sponsor. 
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The end of the study is defined as the date of the last visit of the last participant in the study. 
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5. 
Study Population 
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only, and not continuously throughout the trial. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Screening may occur up to 28 days prior to enrollment. Participants who are not enrolled within 
28 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. Parameters repeated for screening include clinical 
laboratory tests, body weight, ECGs, and vital signs. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 21 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2. Participants who are overtly healthy as determined through medical evaluation including 
screening medical history, physical examination, vital signs, clinical laboratory tests, and 
ECG. 
3. Have clinical laboratory test results within normal reference range for the population or 
CRU, or results with acceptable deviations that are judged to be not clinically significant 
by the investigator. 
4. Have venous access sufficient to allow blood sampling as per the protocol. 
5. Are able and willing to consume the high-fat, high-calorie breakfast meal provided on 
dosing days (Part B only). 
6. Are reliable and willing to make themselves available for the duration of the study and 
who will comply with the required study and dosing visits and abide by the clinical 
research site policy and procedure and study restrictions. 
Weight 
7. Body mass index within the range 19.0 to 40.0 kg/m2 (inclusive), at screening. 
 
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Sex and contraceptive/barrier requirements 
8. Males who agree to use highly effective/effective methods of contraception may 
participate in this trial. Please refer to Appendix 4 for definitions and additional guidance 
related to contraception. 
9. Only women not of childbearing potential (WNOCBP) may participate in this trial  
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Appendix 10.4. 
Informed consent 
10. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
11. Have a history of atopy (severe or multiple allergic manifestations) or clinically 
significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or 
severe posttreatment hypersensitivity reactions (including, but not limited to, erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
anaphylaxis, angioedema, or exfoliative dermatitis). 
12. Have a significant history of or current CV (for example, myocardial infarction, 
congestive heart failure, cerebrovascular accident, venous thromboembolism, etc.), 
respiratory, renal, GI (including involving the liver, gallbladder or gallbladder surgery), 
endocrine, hematological (including history of thrombocytopenia), or neurological 
disorders capable of significantly altering the absorption, metabolism, or elimination of 
drugs; of constituting a risk while taking the IP; or of interfering with the interpretation of 
data. 
13. Have a mean supine HR less than 45 bpm or greater than 100 bpm from 2 assessments at 
screening. If a repeat measurement (mean of 2 assessments) shows values within the 
range of 45 to 100 bpm, the participant may be included in the trial. 
14. Have a mean supine systolic BP higher than 160 mmHg and a mean supine diastolic BP 
higher than 95 mmHg from 2 assessments at screening; therefore, if a repeat 
measurement (mean of 2 assessments) shows values within the range (systolic BP ≤160 
mmHg and /or diastolic BP ≤95 mmHg), the participant can be included in the trial. 
15. Have undergone any form of bariatric surgery. 
16. Have a history of GI bleeding, or gastric or duodenal ulcers. 
17. Have a personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2. 
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18. Have a history of acute or chronic pancreatitis, or elevation in serum lipase and/or 
amylase levels greater than 1.5 times the ULN. 
19. Have clinical signs or symptoms of liver disease, acute or chronic hepatitis. 
20. Have evidence of significant active neuropsychiatric disease as determined by the 
investigator. 
Prior/concomitant therapy 
21. Have been treated with prescription drugs that promote weight loss within 3 months prior 
to screening. Examples include  
 Meridia® (sibutramine) 
 Sanorex® (mazindol) 
 Adipex-P® (phentermine) 
 BELVIQ® (lorcaserin) 
 Mysimba® (naltrexone/bupropion) 
 Saxenda® (liraglutide), or  
 similar other body weight loss medications including any over-the-counter 
medications or supplements (for example, alli®). 
22. Have received chronic (lasting >14 consecutive days) systemic glucocorticoid therapy in 
the past year, or have received any glucocorticoid therapy within 1 month before 
screening (topical, intra-articular, and inhaled preparations such as steroid nasal spray are 
permitted in the study). 
Prior/concurrent clinical study experience 
23. Are currently enrolled in a clinical study involving an IP or any other type of medical 
research judged not to be scientifically or medically compatible with this study. 
24. Have participated within the past 30 days of screening in a clinical study involving an IP; 
at least 5 half-lives or 30 days, whichever is longer, should have passed. 
Diagnostic assessments 
25. Have an abnormality in the 12-lead ECG at screening that, in the opinion of the 
investigator, increases the risks associated with participating in the study or may 
confound ECG (QT) data analysis, such as a QTcF >450 msec for males and >470 msec 
for females, short PR interval (<120 msec), or PR interval >220 msec, second- or third-
degree atrioventricular block, intraventricular conduction delay with QRS >120 msec, 
right bundle branch block, left bundle branch block or Wolff-Parkinson-White syndrome. 
26. Have serum AST or ALT >1.5x ULN or TBL >1.5x ULN. 
27. Show evidence of human immunodeficiency virus infection and/or positive human 
immunodeficiency virus antibodies. 
28. Show evidence of hepatitis C and/or positive hepatitis C antibody. 
29. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive hepatitis 
B surface antigen. 
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Other exclusions 
30. Are 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 
31. Are Lilly employees. 
32. Have previously completed or withdrawn from this study.  
33. Have donated blood of more than 450 mL or have participated in a clinical study that 
required similar blood volume withdrawn within the past 3 calendar months. 
34. Women who are lactating. 
35. Women of childbearing potential 
36. Have known allergies to LY3493269, related compounds, or any components of the 
formulation (including C10 or SNAC), or a history of significant atopy. 
37. Regularly use known drugs of abuse. 
38. Have an average weekly alcohol intake that exceeds 21 units per week (males) and 
14 units per week (females) or are unwilling to stop alcohol consumption as required 
during the study (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). 
39. Smoke >10 cigarettes per day or the equivalent or are unable or unwilling to refrain from 
nicotine during CRU admission. 
40. Are unwilling to comply with the dietary restrictions required for this study. 
41. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
5.3. 
Lifestyle Considerations 
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
5.3.1. 
Meals and Dietary Restrictions 
All participants will observe an overnight fast of at least 8 hours prior to the scheduled dosing 
time and for each subsequent study day when clinical safety laboratory fasting samples are taken. 
Further requirements on water and meal restrictions related to administration of study 
intervention are found in Section 6.1.  
Throughout the inpatient period, apart from the high-fat, high-calorie meal served at dosing, and 
the standardized breakfast meal for Treatment B2 [dosing condition B2(b)], standard meals will 
be administered in the CRU. While not resident in the CRU, participants will be encouraged to 
follow their normal diet. 
5.3.1.1. 
High-Fat, High-Calorie Breakfast 
For Treatments B1 and B2, participants may receive study intervention in the fed state. A high-
fat, high-calorie breakfast will be served to participants prior to dosing to achieve a fed state. 
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Participants will be encouraged to finish the meal, including milk or milk substitute. The amount 
of the meal consumed by the participant will be documented by the CRU. 
The high-fat, high-calorie breakfast should consist of approximately 800 to 1000 calories.  This 
meal derives approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and 
fat, respectively. At least approximately 50% of the calories should be derived from fat. An 
example of a high-fat, high-calorie breakfast is as follows:  
 two eggs fried in butter 
 two strips of bacon 
 two slices of toast with butter 
 four ounces of hash brown potatoes, and  
 240 mL of whole milk or substitute.  
Appropriate substitutions of meal components that match the fat- and calorie-content may be 
made to accommodate an individual participant’s dietary restrictions or requirements. 
Participants will receive each dose with approximately 240 mL of water.  
5.3.1.2. 
Standardized Breakfast 
Under dosing conditions in Treatment B2(b) as described in Table GZHI.6.1, a standardized 
breakfast will be served 30 minutes after dosing.  This meal should consist of approximately 558 
calories, composed of approximately 49% carbohydrate, 34% fat, and 17% protein.  
Apart from the restrictions listed above and in Table GZHI.6.1, there are no other beverage 
restrictions. Water ad libitum is allowed only until 1 hour before dosing and following the 2-hour 
postdose fast. 
Further requirements on water and timing of the high-fat, high-calorie breakfast and standardized 
breakfast meals are found in Section 6.1. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco 
Participants are allowed to maintain their regular caffeine consumption throughout the study.  
No alcohol will be allowed at least 24 hours before each CRU admission and each outpatient 
visit and throughout the duration of each CRU visit. Between CRU visits, daily alcohol should 
not exceed 3 units for males and 2 units for females (a unit is defined in Section 5.2, 
criterion [38]).  
No nicotine use will be permitted while at the CRU. While not resident in the CRU, participants 
must consume no more than 10 cigarettes or equivalent per day. 
5.3.3. 
Activity 
Participants will be advised to maintain their regular levels of physical activity/exercise during 
the study, and to abstain from strenuous exercise for at least 24 hours before each blood 
collection for clinical laboratory tests.  
When certain study procedures are in progress at the site, participants may be required to remain 
recumbent or sitting. 
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5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. However, participants who were eligible for inclusion in previous treatment groups, 
but were not randomly assigned for nonmedical reasons, may be reassessed. Additional medical 
assessments and clinical measurements include clinical laboratory tests, vital signs, and ECG to 
confirm their eligibility. This is applicable for both Parts A and B. 
Repeating of laboratory tests during the screening period or repeating screening tests to comply 
with the protocol-designated screening period does not constitute rescreening. Abnormal 
screening laboratory tests may be repeated if the investigator considers that the abnormality is 
likely related to a sampling or handling issue, or to a technical error.  
5.5. 
Criteria for Temporarily Delaying Enrollment/ Randomization/ 
Administration of Study Intervention of a Participant 
Not applicable in this study. 
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6. 
Study Interventions and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Interventions Administered 
The following table shows the planned study interventions in this study.  
 
Intervention Name 
LY3493269 Test Capsule formulation 
1, 2, or 3  
LY3493269 Reference Tablet 
formulation 
Type  
Drug 
Drug 
Dose Formulation 
Capsule 
Tablet 
Unit Dose Strength 
4 mg LY3493269 with 280 mg C10 
4 mg LY3493269 with 300 mg SNAC 
Dosage Level 
Single 4-mg dose 
Single 4-mg dose 
Route of Administration 
Oral 
Oral 
Use 
Test formulation 
Reference formulation 
IMP and NIMP 
IMP  
IMP  
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and Labeling 
Study intervention will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement 
Study intervention will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement 
Abbreviations: C10 = sodium caprate; IMP = investigational medicinal product; NIMP = noninvestigational 
medicinal product; SNAC = salcaprozate sodium.  
All participants in Part A will observe an overnight fast of at least 8 hours prior to the scheduled 
dosing time.  
If dosing is to be done in the fed state, participants in Part B will observe an overnight fast of at 
least 8 hours prior to the administration of the high-fat, high-calorie breakfast. If dosing is to be 
done in the fasted state, participants will observe an overnight fast of at least 8 hours prior to the 
scheduled dosing time.  
Water can be allowed as desired except as described in Table GZHI.6.1 and the following 
sections (dosing in the fasted or fed state). Any additional water required by the participant to 
complete the dose must be recorded in the CRF.  
LY3493269, as Test Capsule formulations 1, 2, or 3, or the Reference tablet will be administered 
orally with 
 water in the morning of each dosing day in a sitting position.   
Participants will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated 
or for study procedures.  
Dosing in the fasted state  
Participants will take each dose of LY3493269 on Days 1, 2, and 3 after the overnight fast. After 
each daily dose, participants must continue to fast for 2 hours or 30 mins, as described in Table 
GZHI.6.1. Water ad libitum is allowed only until 1 hour before dosing and following the 2-hour 
postdose fast.  
Dosing in the fed state  
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For each participant, a high-fat, high-calorie breakfast meal shall be administered at the same 
time on each scheduled dosing day, to be consumed within 30 minutes.  
Participants should be administered their assigned treatment 30 minutes after the start of the 
high-fat, high-calorie breakfast meal on each of the 3 dosing days. No food is allowed for at least 
4 hours after the LY3493269 dose. 
Table GZHI.6.1. 
Fasting or Fed Conditions and Water Consumption for Dosing 
Treatment  Formulation 
Dosing 
Conditionsa 
Overnight 
Fast? 
Water for Dosing 
(Approximate 
Volumes) 
Dosing vs. Meal Timing 
A1 
Test 1 
Fasted 
Yes 
120 mL 
Postdose fast duration:  
2 hours 
A2 
Test 2 
Fasted 
Yes 
120 mL 
Postdose fast duration:  
2 hours 
A3 
Reference 
Fasted 
Yes 
120 mL 
Postdose fast duration:  
2 hours 
B1 
“X” 
B1(a) Fasteda 
Yes 
120 mL 
Postdose fast duration:  
2 hours 
B1(b) Fasteda 
Yes 
240 mL 
Postdose fast duration:  
2 hours 
B1(c) Feda 
Yes 
240 mL 
Dosing is scheduled  
30 minutes after the start 
of the high-fat, high-
calorie breakfast meal  
B2 
“Y” 
B2(a) Fed 
Yes 
240 mL 
Dosing is scheduled  
30 minutes after the start 
of the high-fat, high-
calorie breakfast meal 
B2(b) Fastedb 
Yes 
120 mL 
Standardized breakfast 
meal provided 30 minutes 
postdosing 
Abbreviations: vs = versus; X = test formulation 1, 2, or 3; Y = test formulation 1, 2, or 3 or reference formulation.  
a Dosing conditions for Treatment B1 will be dependent on which Test Formulation is selected: 
 
If Test Formulation 3 (not tested previously) is selected as Formulation “X”, the dosing condition will be 
either B1(a), B1(b), or B1(c). 
 
If Test Formulation 1 or 2 is selected as Formulation “X”, the dosing condition will be either B1(b) or 
B1(c). 
b   This condition applies only to a scenario that further evaluates the Reference tablet formulation as Treatment B2. 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
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interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study.  Prior to the first dose, participants will be assigned a unique number 
(randomization number), which encodes the participant’s assignment to 1 of the treatment arms 
of the study.  
6.4. 
Study Intervention Compliance 
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the site personnel.  
Study intervention will be administered under medical supervision by either the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. Study site staff shall confirm completion of dose administration by 
visual inspection of each participant’s mouth.  The date and time of each dose administered will 
be recorded in the source documents and will be provided to the sponsor as requested.   
6.5. 
Dose Modification 
No modification of the dosage is planned in this study.  
6.5.1. 
Data Review during the Study 
Part A  
A review of available safety and PK data will be conducted to determine the test formulation(s) 
to be evaluated in Part B.  
This review will include data from at least 8 participants who have completed 3 consecutive 
doses of the study intervention in each of the 3 planned treatment groups, and who have 
completed protocol assessments up to Day 8. 
Part B  
Emerging PK data from Part A will determine the formulations to be tested as Treatments B1 
and B2, as well as the conditions (fed or fasted) under which the test or reference formulations 
are administered.  If deemed appropriate, an interim review of PK data from Treatment B1 may 
be conducted prior to the initiation of Treatment B2. This review will include data from at least 8 
participants who have completed 3 consecutive doses of the study intervention, and who have 
completed protocol assessments up to Day 8. 
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6.6. 
Continued Access to Study Intervention after the End of the Study 
There is no planned/continued intervention after the end of the study. 
6.7. 
Treatment of Overdose 
For this study, any dose of study intervention greater than daily dose assigned through 
randomization will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should 
● contact the medical monitor immediately. 
● evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
● closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically, and 
● document the quantity of the excess dose as well as the duration of the overdose 
in the CRF. 
6.8. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or analgesics that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with 
 reason for use 
 dates of administration including start and end dates, and 
 dosage information including dose and frequency for concomitant therapy of special 
interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (apart from 
vitamin/mineral supplements and thyroid replacement medication) within 7 days or 5 half-lives 
(whichever is longer) before the start of study intervention until completion of the follow-up 
visit, unless, in the opinion of the investigator and sponsor, the medication will not interfere with 
the study. 
Paracetamol/acetaminophen, at doses not to exceed 3 g/day, is permitted for use any time during 
the study. Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
Participants discontinuing from study intervention prematurely for any reason should complete 
AE and other follow-up procedures per Section 1.3 of this protocol. 
7.1. 
Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA.  
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons 
 an AE that is considered to be intolerable 
 an abnormal safety laboratory test result, determined to be clinically significant by the 
investigator, or 
 QTcF >500 msec and an increase from baseline in QTcF >60 msec, from at least 2 
consecutive readings. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study drug based on liver test elevations in participants with normal or 
near-normal baseline liver tests 
In study participants with normal or near normal baseline liver tests (ALT, AST, ALP <1.5x 
ULN), the study drug should be interrupted and close hepatic monitoring initiated (see  
Section 8.2.5.1) if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >5x ULN 
 
ALT or AST >3x ULN and either TBL >2x ULN or 
international normalized ratio (INR) >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
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ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
and other consensus guidelines, with minor modifications 
Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, ALP ≥1.5x ULN), the study 
drug should be interrupted if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >3x baseline 
 
ALT or AST >2x baseline and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >2.5x baseline, when the source of increased ALP is the liver 
 
ALP >2x baseline and TBL >2x ULN  
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited nondrug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study 
● at any time at the participant’s own request 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
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● if enrolled in any other clinical study involving an IP, or enrolled in any other 
type of medical research judged not to be scientifically or medically compatible 
with this study, and 
● if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and posttreatment follow-up, if applicable, as shown in the 
SoA. If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
Complete physical examinations and symptom-directed physical examinations will be conducted 
at the visits specified in the SoA (Section 1.3). Symptom-directed physical examinations may 
also be conducted at other visits, as determined by the investigator, if a participant presents with 
complaints. A complete physical examination will include, at a minimum, assessments of the 
CV, respiratory, GI, and neurological systems. 
Height and weight will also be measured and recorded as per SoA (Section 1.3). 
8.2.2. 
Vital Signs 
For each participant, vital sign measurements should be conducted according to the SoA 
(Section 1.3) and as clinically indicated. 
Vital sign measurements should be obtained before collection of blood samples (applicable for 
study visits). 
BP and pulse rate should be measured after at least 5 minutes in a supine position. 
Note: If white-coat hypertension is suspected at screening, the participant can be included in the 
trial if a repeated measurement (a mean of 2 measurements) shows values within the acceptable 
range. 
If orthostatic measurements are required, participants should be supine for at least 5 minutes and 
stand for at least 2 minutes. If the participant feels unable to stand, only supine vital signs will be 
recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Additional vital signs may be measured during each study period if 
warranted. 
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Body temperature will be measured, as specified in the SoA (Section 1.3), and as clinically 
indicated. 
8.2.3. 
Electrocardiograms 
Single 12-lead ECGs will be obtained as specified in the SoA (Section 1.3). ECGs must be 
recorded approximately within 30 minutes before collecting any blood samples (applicable for 
study visits). Participants must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. 
ECGs may be obtained at additional times, when deemed clinically necessary to assess 
participants’ safety. Collection of additional ECGs at a particular time point is allowed to ensure 
high-quality records. 
ECGs will be interpreted by a qualified physician, the investigator, or qualified designee at the 
site as soon after the time of ECG collection as possible. Ideally, the participant should be 
present 
 to determine whether the participant meets entry criteria at the relevant visit(s), and 
 for immediate participant management, should any clinically relevant findings be 
identified.  
All single ECGs recorded should be stored at the investigational site. Single ECGs will not be 
transmitted to a central laboratory.  
8.2.4. 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the timing 
and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the participant’s 
condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 28 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
 If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified 
and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2, 
must be conducted in accordance with the SoA, standard collection 
requirements, and applicable laboratory manual. 
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If laboratory values from nonprotocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE. 
8.2.5. 
Safety Monitoring 
The Lilly clinical pharmacologist or CRP will monitor safety data throughout the course of the 
study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or CRP will periodically review the following data: 
 trends in safety data 
 laboratory analytes 
 serious and non-SAEs including monitoring of GI events, hypoglycemia, and 
hypersensitivity reactions and reported and adjudicated pancreatitis 
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist. 
8.2.5.1. 
Hepatic Safety  
Close hepatic monitoring 
Laboratory tests (see Appendix 6; Section 10.6), including ALT, AST, ALP, TBL, creatine 
kinase, and direct bilirubin, should be repeated, with addition of gamma-glutamyl transferase, 
within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if 1 or more of these conditions occur: 
If a participant with baseline results 
of... 
 develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants 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 ≥1.5x baseline (except for participants with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.  
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver test results should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including symptoms, recent 
illnesses (for example, heart failure, systemic infection, hypotension, or seizures), recent travel, 
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history of concomitant medications (including over the counter), herbal and dietary supplements, 
and history of alcohol drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline 
results of... 
 develops the following elevation: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or ALT or AST 
≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants 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 ≥2x  baseline (except for participants with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a 
Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined earlier, as well as tests for prothrombin time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for 
 hepatitis D virus 
 cytomegalovirus 
 Epstein-Barr virus 
 acetaminophen levels 
 acetaminophen protein adducts 
 urine toxicology screen 
 Wilson’s disease 
 blood alcohol levels 
 urinary ethyl glucuronide, and 
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 blood phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a 
 hepatologist or gastroenterologist consultation 
 magnetic resonance cholangiopancreatography 
 endoscopic retrograde cholangiopancreatography 
 cardiac echocardiogram, or a 
 liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver test results during the study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT levels to ≥5x ULN on 2 or more consecutive blood tests (if 
baseline ALT <1.5x ULN) 
a. In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
2. Elevation of TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
a. In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL 
≥2x baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
a. In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.5.2. 
Pancreatic Safety (Elevated Lipase or Amylase)  
Diagnosis of acute pancreatitis 
Acute pancreatitis is an AE of interest in all studies with LY3493269, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 2006; 
Koizumi et al. 2006): 
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to the 
back, often associated with nausea and vomiting), and 
 serum amylase (total, pancreatic, or both) and/or lipase ≥3x ULN 
 characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging. 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase and lipase 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal magnetic resonance imaging, and  
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 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications. 
Discontinuation for acute pancreatitis 
If acute pancreatitis is diagnosed, the participant must discontinue use of the study intervention. 
Asymptomatic elevation of serum amylase and/or lipase 
Serial measures of pancreatic enzyme levels have limited clinical value for predicting episodes 
of acute pancreatitis in asymptomatic patients (Nauck 2016; Steinberg et al. 2017ab). Therefore, 
further diagnostic follow-up of cases of asymptomatic elevation of pancreatic enzymes (lipase 
and/or p-amylase ≥3x ULN) is not mandated but may be performed based on the investigator’s 
clinical judgment and assessment of the participant’s overall clinical condition.  
8.2.5.3. 
Hypoglycemia 
Participants will be trained by site personnel about signs and symptoms of hypoglycemia and 
how to treat hypoglycemia.  
Once a hypoglycemic event has started, the investigator should perform further bedside testing at 
regular intervals (for example, every 15 to 30 minutes) until normoglycemia (plasma glucose 
≥70 mg/dL) is documented. If symptoms are present during the hypoglycemic event, then the 
end time of the hypoglycemic event should be either the time of resolution of symptoms or when 
normoglycemia is achieved, whichever is later. 
Investigators should use the following classification of hypoglycemia based on plasma glucose 
measurements:  
Level 1 hypoglycemia:  
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L):  Level 1 hypoglycemia 
can alert a person to take action such as treatment with fast-acting carbohydrates. Providers 
should continue to counsel participants to treat hypoglycemia at this glucose alert value. 
Level 2 hypoglycemia:   
Glucose <54 mg/dL (3.0 mmol/L):  This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence of absence of symptoms of hypoglycemia.  
Level 3 hypoglycemia:   
Severe hypoglycemia (in adults):  A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia.  For example, participants 
had altered mental status, and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person was needed to actively administer carbohydrate, glucagon, or other resuscitative 
actions. Glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low glucose concentration. 
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 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia:  
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep.   
To avoid duplicate reporting, all consecutive plasma glucose values ≤70 mg/dL (3.9 mmol/L) 
occurring within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013) 
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated. The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established by the investigator. The participant should 
receive additional education, if deemed appropriate. If applicable, please refer to the protocol 
section regarding management of increased hypoglycemia risks. 
8.2.5.4. 
Hypersensitivity Reactions 
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom must be provided to 
the sponsor in the electronic CRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Appendix 8, Section 10.8. Laboratory results are provided to the sponsor via the 
central laboratory. 
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity reaction has occurred related to study intervention 
administration, the participant should be permanently discontinued from the intervention, and the 
sponsor’s designated medical monitor should be notified. If the investigator is uncertain about 
whether a systemic hypersensitivity reaction has occurred and whether discontinuation of study 
intervention is warranted, the investigator may consult the sponsor. 
8.2.5.5. 
Skin Burning Sensations and Related AEs 
Healthy participants in this short-exposure study may experience AEs of skin burning sensation 
and related AEs. Skin burning sensation and related AEs were reported in a total of 28 
participants from 2 of the four Phase 1 studies. If this AE does occur within the present study, a 
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dedicated CRF will be used by site personnel to collect detailed information about the event on 
initial presentation of this AE, and on subsequent visits until the AE resolves. 
In addition, on first presentation of these events, a detailed neurologic examination by a 
neurologist may be conducted if deemed clinically appropriate, per investigator’s discretion. The 
goal of these activities is to describe the distribution and character of the symptoms, as well as 
their time course and relieving/exacerbating factors. 
8.2.6. 
Glucose Monitoring 
Blood glucose will be monitored for safety according to the SoA (Section 1.3). The study 
participant’s blood glucose concentrations for safety assessment will be monitored during the 
inpatient part of the study and on Day 6, using a validated method (for example, glucose 
analyzer) available at the site. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs, and 
 product complaints 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow up each participant at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.3) will 
be followed up until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). For product complaints, the investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as indicated to 
elucidate the nature and/or causality. Further information on follow-up procedures is provided in 
Appendix 10.2.1.
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8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of the 
ICF 
Participation in study has 
ended 
As soon as 
possible upon 
site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention 
and deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of the 
ICF 
Start of intervention 
Within 24 
hours of 
awareness 
SAE paper 
form 
N/A 
SAE# and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation in study has 
ended 
Within 24 
hours of 
awareness 
SAE paper 
form 
N/A 
SAE* – after 
participant’s 
study 
participation 
has ended and 
the investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper 
form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants 
and female 
partners of 
male 
participants 
After the start 
of study 
intervention 
Approximately 6 weeks after 
last dose. If a pregnancy is 
reported, the investigator 
should inform the sponsor 
and should follow the 
procedures outlined in 
Section 8.3.2 
Within 24 
hours (see 
Section 8.3.2) 
Pregnancy 
paper form 
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study intervention 
Within 24 
hours of 
awareness 
Product 
complaint 
form 
N/A 
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Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for Reporting 
Back-up 
Method of 
Reporting 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study intervention 
Within 1 
business day 
of awareness 
Product 
complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as 
possible upon 
site awareness 
Originally 
completed 
product 
complaint 
form with all 
changes 
signed and 
dated by the 
investigator 
N/A 
PC (if 
investigator 
becomes 
aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product 
complaint 
form 
 
* SAEs should not be reported unless the investigator deems them to be possibly related to study treatment or study 
participation. 
8.3.2. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study.  
● After learning of a pregnancy in the female partner of a study participant, the 
investigator will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed up to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
 
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Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy.  
● The participant will be followed up to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of gestational age, 
fetal status (presence or absence of anomalies) or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will be withdrawn from the study. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
8.3.3. Adverse Events of Special Interest  
Nausea, vomiting, and diarrhea events, skin burning sensations and related AEs are considered 
AEs of interest; each occurrence will be recorded as a discrete AE in the CRF. For each event, 
assessment of severity, duration (actual date together with onset and end times) and 
investigator’s opinion of relatedness to IP and protocol procedure will be captured. 
8.4. 
Pharmacokinetics 
Plasma samples will be collected for measurement of plasma concentrations of study 
intervention as specified in the SoA (Section 1.3). 
A maximum of 2 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (for example, to 
obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
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Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Samples will be used to evaluate the PK of study intervention. Samples collected for analyses of 
study intervention plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality will 
be maintained. 
Drug concentration information will not be reported to the site. 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3493269, SNAC, and C10 will be assayed using validated liquid 
chromatography with tandem mass spectrometry methods.  
8.4.1. 
Bioanalysis 
Bioanalytical samples collected to measure study intervention concentrations will be retained for 
a maximum of 1 year following last participant visit for the study. During this time, samples 
remaining after the bioanalyses may be used for exploratory metabolism studies or exploratory 
analyses such as bioanalytical assay validation or cross-validation exercises. 
8.5. 
Pharmacodynamics 
Not applicable. 
8.6. 
Genetics 
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease being 
treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected 
for DNA analysis from consenting participants. 
DNA samples will be used for research related to the drug target and mechanism of action of 
LY3493269 or diabetes, obesity, and diabetic complications including NASH and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
LY3493269 and interventions of this drug class and diabetes, obesity, and diabetic complications 
including NASH. Genetic research may consist of the analysis of 1 or more candidate genes or 
the analysis of genetic markers throughout the genome (as appropriate). 
Additional analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
The samples may be analyzed as part of a multistudy assessment of genetic factors involved in 
the response to LY3493269 or study interventions of this class to understand study disease or 
related conditions. 
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The results of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on LY3493269, similar study interventions of this 
class, or diabetes, obesity, and diabetic complications including NASH continues but no longer 
than 15 years or other period as per local requirements. 
8.7. 
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements. Exploratory biomarker measures may also include potential markers 
of GIP and GLP-1 receptor target engagement. 
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3493269, pathways associated with T2DM, obesity, or diabetes complications including 
NASH, mechanism of action of LY3493269, and/or research method, or for validating diagnostic 
tools or assay(s) related to T2DM, obesity, or diabetes complications including NASH. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the Site personnel. 
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and/or ethical review boards impose shorter time limits, at a 
facility selected by Lilly or its designee. This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of LY3493269 or after LY3493269 or is commercially available. 
8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
and stored for future analysis to determine antibody production against LY3493269. Antibodies 
may be further characterized for cross-reactive binding to native GIP and GLP-1. To interpret the 
results of immunogenicity, a venous blood sample will be collected at the same time points to 
determine the plasma concentrations of LY3493269. 
In the case that ADA samples are tested before end of study and if the immunogenicity sample at 
the last scheduled assessment or discontinuation visit is TE-ADA positive, additional samples 
may be taken every 3 months until the ADA signal returns to baseline (that is, no longer TE-
ADA positive) or for up to 1 year after last dose. 
TE-ADAs are defined in Section 9.3.4. 
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A PK sample will continue to be collected at each time point at the investigator’s discretion. 
Participants followed up for at least 1 year since last dose, whose titer has not returned to within 
2-fold of the baseline, will be assessed for safety concerns. If no clinical sequelae are recognized 
by the clinical team, then no further follow-up will be required. 
Refer to Appendix 10.1.9 for details on sample retention. 
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
The statistical analysis plan will be finalized prior to first participant first visit, and it will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
This study will evaluate and compare PK of LY3493269 administered as multiple once-daily 
oral doses in heathy participants. Descriptive statistics, instead of hypothesis testing, will be used 
for evaluating PK and safety. 
9.1.1. 
Multiplicity Adjustment 
No adjustment or control is needed for multiple testing. 
9.2. 
Analyses Populations 
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the ICF 
Randomized/ 
Enrolled 
All participants assigned to treatment, regardless of whether they take any 
doses of study treatment, or whether they took the correct treatment. 
Participants will be analyzed according to the treatment group to which 
they were assigned. 
Safety 
All enrolled participants who received at least 1 dose of LY3493269. 
Participants will be analyzed according to the intervention they actually 
received. 
Pharmacokinetic 
Analysis 
All enrolled participants who received at least 1 dose of LY3493269 and 
have at least 1 evaluating PK sample. 
9.2.1. 
Study Participant Disposition 
A detailed description of participant disposition will be provided at the end of the study. All 
participants who discontinue from the study will be identified and the extent of their participation 
in the study will be reported. If known, a reason for their discontinuation will be given. 
9.2.2. 
Study Participant Characteristics 
The participant’s age, sex, weight, height, or other demographic characteristics will be recorded 
and may be used in the PK, PD, and safety analyses as quantitative or classification variables. 
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9.2.3. 
Treatment Compliance 
At the inpatient visit, the study intervention will be administered and documented at the clinical 
site.  
9.3. 
Statistical Analyses 
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan and the clinical study report. Additional exploratory analyses of the 
data will be conducted as deemed appropriate. Study results may be pooled with the results of 
other studies for population PK analysis purposes. PK analyses will be conducted on data from 
all participants who receive at least 1 dose of study intervention and have evaluable PK, 
respectively. 
Safety analyses will be conducted for all randomly assigned participants who received at least 1 
dose of study intervention, whether or not they completed all protocol requirements. 
9.3.1. General Considerations 
Data listings will be provided for all data that are databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in the statistical analysis plan. For 
continuous data (for example, the demography data, clinical laboratory data, vital signs data, 
ECG data), summary statistics will include the arithmetic mean, arithmetic standard deviation, 
median, minimum, maximum, and the number of observations; for log-normal data (for example, 
the PK parameters: AUC during 1 dosing interval [AUC{0-τ}] and Cmax), the geometric mean 
and geometric coefficient of variation (%) will also be presented. For categorical data (for 
example, the AE data and hypoglycemic classification data), frequency count and percentages 
will be presented. Data listings will be provided for all participants up to the point of withdrawal, 
with any participants excluded from the relevant population highlighted. Summary statistics and 
statistical analyses will generally be performed only for participants included in the relevant 
analysis population. For the calculation of summary statistics and statistical analysis, unrounded 
data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values. Each individual change from baseline will be calculated by subtracting the individual 
participant’s baseline value from the value at the time point. Baseline is defined to be Day 1 
predose measurements unless otherwise stated. 
Data analysis will be performed using SAS® Version 9.4 or greater. 
9.3.2. 
Pharmacokinetic Analyses 
9.3.2.1. 
Pharmacokinetic Parameter Estimation 
PK parameter estimates for LY3493269, C10, and SNAC will be calculated using standard 
noncompartmental methods of analysis. The primary parameters for analysis will be Cmax, AUC, 
and time of maximum observed concentration (tmax). PK parameters for Cmax and AUC will be 
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computed after the first, second, and third doses. Other parameters, such as half-life, apparent 
clearance, and apparent volume of distribution, may be reported.  
9.3.2.2. 
Pharmacokinetic Statistical Inference 
PK parameters will be evaluated to estimate the relative bioavailability. Log-transformed Cmax 
and AUC of LY3493269 from Treatments A1 to A3 and B1 and B2 will be evaluated in a linear 
mixed-effects model with a fixed effect for formulation and study day, and a random effect for 
subject. The estimated ratios of geometric means of different formulations compared to reference 
(SNAC) and the corresponding 90% CIs will be reported.  
The parameter tmax of LY3493269, C10, and SNAC will be analyzed nonparametrically using a 
Wilcoxon rank sum test. Estimates of the median difference and the corresponding 90% CIs will 
be calculated. 
All PK parameters will be summarized using descriptive statistics. 
Additional analysis may be conducted if deemed necessary. 
9.3.3. 
Safety Analyses 
All safety analyses will be made on the Safety Population. 
All AEs will be listed, and if the frequency of events allows, safety data will be summarized 
using descriptive methodology. 
The incidence of symptoms for each treatment will be presented by severity and by association 
with the study drug as perceived by the investigator. Symptoms reported to occur prior to the 
first study drug dosing will be distinguished from those reported as new or increased in severity 
during the study. Each symptom will be classified by the most suitable term from the Medical 
Dictionary for Regulatory Activities. 
All SAEs will be reported. 
In addition to AEs, safety parameters that will be assessed include laboratory tests, vital signs, 
immunogenicity, hypoglycemic events, injection-site reactions, and ECG parameters. The 
parameters will be listed and summarized using standard descriptive statistics. Additional 
analyses may be performed if warranted based upon review of the data. 
Laboratory measurements will be summarized regarding observed values and change from 
baseline by treatment group, at each time point, using descriptive statistics. In addition, all 
clinical chemistry, hematology, and urinalysis data outside the reference ranges will be tabulated 
by parameter and treatment group. 
Vital signs will be summarized regarding observed values and change from baseline values by 
treatment at each time point using descriptive statistics. For change from baseline values, a 
mixed-model repeated-measure model with treatment, day (of measurement), and treatment-by-
day interaction as fixed effects, participant as random effect, and baseline as covariate will be 
used to determine the effects of LY3493269. Least-squares means as well as 90% CIs will be 
reported. 
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9.3.4. 
Evaluation of Immunogenicity 
Upon full assay validation, TE-ADAs may be assessed. The frequency and percentage of 
participants with preexisting ADA and with TE-ADA+ to LY3493269 may be tabulated.  
TE-ADAs are defined as those with a 
 titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were 
detected at baseline (treatment-induced ADA), or 
 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA). 
The frequency of cross-reactive binding to native GIP, GLP-1, or neutralizing antibodies may 
also be tabulated in TE-ADA+ participants, when available. 
The relationship between the presence of antibodies and PK exposures and PD response 
including safety and efficacy to LY3493269 may be assessed. 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol. 
Interim access to PK and safety data is planned to occur as described in Section 6.5.1. 
9.5. 
Sample Size Determination 
Up to approximately 70 participants may be randomly assigned to study intervention to ensure 
approximately 10 evaluable participants from each of the 5 planned treatment groups complete 
the study.
 
 
  
Participants who are randomly assigned but not administered treatment prior to discontinuation 
may be replaced to ensure that the target number of participants complete the study.   
Participants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ Applicable ICH GCP Guidelines, and 
○ Applicable laws and regulations. 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2. 
Informed Consent Process 
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
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● Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 Code of Federal Regulation 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant and is kept on file. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date. 
10.1.3. 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information that would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent.  
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
10.1.4. 
Dissemination of Clinical Study Data 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, through phone and/or 
email) as soon as possible. It will be a requirement that investigators respond upon receipt to 
confirm that they understand the communication and have taken the appropriate action prior to 
further dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.  
 
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Reports  
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.   
The summary of results will be posted within the time frame specified by local law or regulation.  
Data   
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.5. 
Data Quality Assurance 
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  Source data may include laboratory 
tests, medical records, and clinical notes. 
 Source data may include laboratory tests, medical records, and clinical notes.  
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
● Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
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● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
clinical trial agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
● In addition, the sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the study site. The study 
may be audited by the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and relevant reports (if any) will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.6. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in Section 10.1.5.
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10.1.7. 
Study and Site Start and Closure 
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
● 
Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, and 
● Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.8. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
10.1.9. 
Sample Retention 
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of LY3493269 or after LY3493269 becomes commercially available T2DM.  
 
 
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Sample Type  
Custodian  
Retention Period After Last Patient Visit*  
Long-term storage samples  Sponsor or designee  
15 years  
Pharmacokinetic  
Sponsor or designee  
1 year   
Genetics 
Sponsor or designee  
15 years  
Immunogenicity  
Sponsor or designee  
15 years  
*Retention periods may differ locally.   
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in the following table will be performed by the local laboratory. Results of 
these assays will be validated by the local laboratory at the time of testing. Additional tests may 
be performed or auto-calculated by the laboratory as part of its standard panel that cannot be 
removed. Some of the above parameters are calculated from measured values. Omission of 
calculated values will not be considered as a protocol violation. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. Investigators must document their 
review of the laboratory safety results.  
 
 
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Hematology 
Clinical Chemistry (fasting) 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium, total 
Mean cell hemoglobin concentration 
Phosphate 
Leukocytes (WBC) 
Magnesium 
Absolute counts of 
Creatinine 
Neutrophils 
Glucose (fasting) 
Lymphocytes 
Urea 
Monocytes 
Total protein 
Eosinophils 
Albumin 
Basophils 
Total bilirubin 
Platelets 
Alkaline phosphatase (ALP) 
  
Aspartate aminotransferase (AST) 
Urinalysis 
Alanine aminotransferase (ALT) 
Specific gravity 
Lipase 
pH 
Amylase 
Protein 
Triglyceride 
Glucose 
Total cholesterol 
Ketones 
High-density lipoprotein  
Bilirubin 
Low-density lipoprotein 
Urobilinogen 
HbA1ca 
Nitrite 
Creatine kinase 
Blood 
 
Leukocytes 
 
Microscopyb  
 
 
Serology (at Screening only) 
 
Hepatitis B surface antigenc 
Follicle-stimulating hormone (FSH)d 
Hepatitis B core antibody, totalc 
 
Hepatitis C virus serology (anti-HCV)c 
 
Human immunodeficiency virus (HIV)c 
Abbreviations: HbA1c = glycated hemoglobin; RBC = red blood cell; WBC = white blood cell. 
a 
Predose at Day 1 only. 
b Test only if dipstick result is abnormal and are further definable by microscopy. Microscopy to be performed at 
the local safety laboratory, if clinically indicated, per investigator’s discretion. 
c Tests may be waived if they have been performed within 6 months before screening with reports available for 
review. 
d Performed for females at screening, if needed to confirm postmenopausal status. 
 
 
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10.2.1. 
Blood Sampling Summary 
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Purpose 
Blood Volume 
per Sample 
(mL) 
Approximate 
Number of 
Blood Samples 
Approximate 
Blood Volume 
(mL) 
Screening testsa (local laboratory) 
20 
1 
20 
Clinical laboratory testsa (local 
laboratory) 
 
 
 
 
Study visit: Day 1 
13 
1 
13 
 
Study visits: Days 5, 8, and 15 
10 
3 
30 
 
Follow-up visit: Days 29, 43 
10 
2 
20 
LY3493269 and SNAC/C10 
pharmacokinetics 
(1 blood sample for both analytes) 
3 
44 
132 
Potential additional LY3493269 and 
SNAC/C10 pharmacokinetic 
samples 
3 
2 
6 
Blood discard for cannula patency 
0.3 
55 
16.5 
Point-of-care safety glucose (on-site) 
0.3 
18 
5.4 
Pharmacogenetic sample (stored) 
10 
1 
10 
Nonpharmacogenetic sample 
(stored) 
 
 
 
 
Plasma 
2 
6 
12 
 
Serum 
2.5 
6 
15 
 
P800 
2 
6 
12 
Immunogenicity 
10 
4 
40 
Total 
  
  
331.9 
Total for clinical purposes (rounded up to the nearest 10 mL) 
340 
 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
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 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
 
10.3.3. 
Definition of Product Complaints 
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate CRF page and 
product complaint information is reported on the Product Complaint Form. 
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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the CRF page for AE/SAE 
and the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship/ 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
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 The investigator will also consult the IB in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor or designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings including histopathology. 
10.3.5. 
Reporting of SAEs 
SAE Reporting via SAE Report 
 Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SAE Report. 
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
● Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
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● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/ IECs, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Females of childbearing potential 
Adult females are considered women of childbearing potential unless they are WNOCBP. 
Females less than 18 years of age are considered women of childbearing potential if they have  
 had at least 1 cycle of menses, or  
 Tanner Stage 4 breast development.  
Any amount of spotting should be considered menarche. 
Females NOT of childbearing potential 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Müllerian agenesis  
 are infertile due to surgical sterilization, or  
 are postmenopausal.  
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-oophorectomy, 
bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman 
 at any age at least 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note; or 
 aged at least 40 years and up to 55 years with an intact uterus, not on hormone therapya, 
who has had cessation of menses for at least 12 consecutive months without an 
alternative medical cause, AND with a follicle-stimulating hormone >40 mIU/mL; or  
 55 years or older not on hormone therapy, who has had at least 12 months of spontaneous 
amenorrhea, or ·  
 aged at least 55 years with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
a Women should not be taking medications during amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor modulators, or chemotherapy that 
could induce transient amenorrhea. 
10.4.2. 
Contraception Guidance 
10.4.2.1. Female Participants 
Female participants of childbearing potential are excluded from this study. 
Female participants who are not of childbearing potential may participate in this study. 
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10.4.2.2. Male Participants  
Male participants with partners of childbearing potential, must agree to either 
1. remain abstinent (if this is their preferred and usual lifestyle), or 
2. use condoms during intercourse  
a. for the duration of the study, and 
b. for approximately 5 months. 
Contraception for men in exclusively same-sex relationships, as their preferred and usual 
lifestyle are not required. 
Male participants should refrain from sperm donation for the duration of the study plus 105 days, 
which corresponds to approximately 5 months or until their plasma concentrations are below the 
level that could result in a relevant potential exposure to a possible fetus. 
10.4.2.3. Contraception Methods 
Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below.  
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed 
through hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
 
Note:  The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone  
 
immunocontraceptives 
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 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post-coital douche 
 
lactational amenorrhea 
Abstinence 
Participants who are abstinent (if this is complete abstinence, as their preferred and usual 
lifestyle) must agree to either remain abstinent without sexual relationships with the opposite 
sex. 
 
 
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10.5. 
Appendix 5: Genetics 
Use/analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to LY3493269 or T2DM and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to LY3493269 and/or interventions of this drug class and 
T2DM. Genetic research may consist of the analysis of 1 or more candidate genes 
or the analysis of genetic markers throughout the genome or analysis of the entire 
genome (as appropriate). 
● The samples may be analyzed as part of a multistudy assessment of genetic 
factors involved in the response to study intervention or study interventions of this 
class to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on LY3493269 or study interventions 
of this class or T2DM continues but no longer than 15 years or other period as per 
local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
See Section 8.2.5.1 for guidance on appropriate test selection. 
The sponsor-designated central laboratory must complete the analysis of all selected testing 
except for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
  Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
  Lymphocytes 
Creatine kinase (CK) 
  Monocytes 
Other Chemistry 
  Basophils 
Acetaminophen 
  Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Prothrombin time, INR (PT-INR) 
Ethyl alcohol (EtOH) 
Serology 
Haptoglobin 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgA (quantitative) 
  HAV total antibody 
Immunoglobulin IgG (quantitative) 
  HAV IgM antibody 
Immunoglobulin IgM (quantitative) 
Hepatis B virus (HBV) testing: 
Phosphatidylethanol (PEth) 
  Hepatitis B surface antigen (HBsAg) 
Urine Chemistry 
  Hepatitis B surface antibody (anti-HBs) 
Drug screen 
  Hepatitis B core total antibody (anti-HBc) 
Ethyl glucuronide (EtG) 
  Hepatitis B core IgM antibody 
Other Serology 
  Hepatitis B core IgG antibody 
Anti-nuclear antibody (ANA) 
  HBV DNAb 
Anti-smooth muscle antibody (ASMA)a 
Hepatis C virus (HCV) testing: 
Anti-actin antibodyc 
  HCV antibody 
Epstein-Barr virus (EBV) testing: 
  HCV RNAb 
  EBV antibody 
Hepatitis D virus (HDV) testing: 
  EBV DNAb 
  HDV antibody 
Cytomegalovirus (CMV) testing: 
Hepatitis E virus (HEV) testing: 
  CMV antibody 
  HEV IgG antibody 
  CMV DNAb 
  HEV IgM antibody 
Herpes simplex virus (HSV) testing: 
  HEV RNAb 
  HSV (Type 1 and 2) antibody 
Microbiologyd 
  HSV (Type 1 and 2) DNAb 
Culture: 
Liver kidney microsomal type 1 (LKM-1) antibody 
  Blood 
  
  Urine 
  
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Abbreviations: Ig = immunoglobulin; INR = international normalized ratio. 
a 
Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if ASMA is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
10.7. 
Appendix 7: Pancreatic Monitoring 
GLP-1 agonists have been associated with a possible risk of acute pancreatitis. In 2006, the 
United States prescribing information for exenatide was revised to include the event of 
pancreatitis. In 2007, the US prescribing information for this medication was amended to include 
pancreatitis under “Precautions.” Epidemiologic studies have indicated that there is an increased 
incidence and prevalence of pancreatitis in persons with T2DM. 
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, to assess for any potential effects of LY3493269 on the exocrine pancreas, 
amylase and lipase values will be monitored in all current and future clinical trials with 
LY3493269. 
Additional monitoring will be requested for amylase or lipase values ≥3x the ULN at any visit 
after randomization. Lipase and amylase values may also be obtained at any time during the 
clinical trials for any participant suspected of having symptoms suggestive of pancreatitis (such 
as severe GI signs and/or symptoms), at the investigator’s discretion. 
Acute pancreatitis is an AE defined as an acute inflammatory process of the pancreas that may 
also involve peripancreatic tissues and/or remote organ systems. The diagnosis of acute 
pancreatitis requires 2 of the following 3 features: 
 abdominal pain characteristic of acute pancreatitis 
 serum amylase and/or lipase >3x ULN, and 
 characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging. 
Most participants with acute pancreatitis experience abdominal pain that is located generally in 
the epigastrium and radiates to the back in approximately one-half of the cases. The pain is often 
associated with nausea and vomiting.  
Participants diagnosed with pancreatitis will be discontinued from the study. Investigators will 
be responsible for following, through an appropriate health care option, these pancreatitis AEs 
until the events resolve or are explained. AEs that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs. For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to IP. 
10.8. Appendix 8: Hypersensitivity Event Tests 
This table lists the recommended tests that should be obtained in case of a clinically significant 
hypersensitivity/allergy event. Selected tests may be obtained in the event of anaphylaxis or 
generalized urticaria. 
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Anti-LY antibodies (immunogenicity) 
Tryptase 
LY concentration (PK) 
N-methylhistamine 
  
Drug-specific IgEa 
  
Basophil activation testa 
  
Complements 
  
Cytokine panel 
Abbreviations: Ig = immunoglobulin; LY = LY3493269; PK = pharmacokinetics. 
a 
Basophil activation test will be performed if a drug-specific IgE assay is unavailable. 
 
 
 
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10.9. 
Appendix 9: Provisions for Changes in Study Conduct during 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ethical review boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits,” 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
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Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Telephone- or technology-assisted virtual visits, or both, are acceptable to complete appropriate 
assessments. Assessments to be completed in this manner include, but are not limited to, review 
of AEs and concomitant medications. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at the screening visit are valid for a maximum of 28 days. The following rules will be applied for 
active, non-enrolled participants whose participation in the study must be paused due to 
exceptional circumstances: 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. Allowable visit interval tolerance limits are included in the SoA 
(Section 1.3). To maximize the possibility that these visits can be conducted as on-site visits, the 
windows for visits may be adjusted, upon further guidance from the sponsor. This minimizes 
missing data and preserves the intended conduct of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances.  
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Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
 
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10.10. 
Appendix 10: Abbreviations and Definitions 
Term 
Definition 
ADA 
Antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
BP 
Blood pressure 
C10 
sodium caprate 
CI 
confidence interval 
Cmax 
maximum observed drug concentration 
companion diagnostic  An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant. 
CRP 
clinical research physician:  Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer. 
CRU 
clinical research unit 
CT 
computed tomography 
CV 
cardiovascular 
ECG 
Electrocardiogram 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
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J1X-MC-GZHI 
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GCP 
good clinical practice 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide  
GLP 
glucagon-like peptide 
GZHA 
Study J1X-MC-GZHA 
GZHB 
Study J1X-MC-GZHB 
GZHC 
Study J1X-MC-GZHC 
GZHF 
Study J1X-MC-GZHF 
GZHI 
Study J1X-MC-GZHI 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IP 
investigational product 
IRB 
institutional review board 
NASH 
nonalcoholic steatohepatitis 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PK/PD 
pharmacokinetics/pharmacodynamics 
QTcF 
QT interval corrected using Fridericia’s formula 
RA 
receptor agonist 
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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.  
SNAC 
salcaprozate sodium 
SoA 
Schedule of activities 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin level 
TE 
treatment emergent 
treatment-emergent 
adverse event 
An untoward medical occurrence that emerges during a defined treatment period, 
having been absent pretreatment, or worsens relative to the pretreatment state, and 
does not necessarily have to have a causal relationship with this treatment. 
ULN 
upper limit of normal 
WNOCBP 
Women not of childbearing potential 
 
 
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11. 
References 
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400. https://doi.org/10.1111/j.1572-0241.2006.00856.x 
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone 
action. Cell Metab. 2013;17(6):819-837.  
Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor 
agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of 
concept. Mol Metab. 2018;18:314.  
Danne T, Philotheou A, Goldman D, et al. A randomized trial comparing the rate of 
hypoglycemia—assessed using continuous glucose monitoring—in 125 preschool children 
with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). 
Pediatr Diabetes. 2013;14(8):593-601.  
Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and 
GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and 
active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.  
Granhall C, Donsmark M, Blicher TM, et al. Safety and pharmacokinetics of single and multiple 
ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy 
subjects and subjects with type 2 diabetes. Clin Pharmacokin. 2019; 58:781-791. 
Halberg IB, Lyby K, Wassermann K, et al. the effect of food intake on the pharmacokinetics of 
oral basal insulin: a randomised crossover trial in healthy male subjects. Clin Pharmacokinet. 
2019;58:1497-1504. 
Koizumi M, Takada T, Kawarada Y, et al. JPN guidelines for the management of acute 
pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32. https://doi.org/10.1007/s00534-005-1048-2 
Nauck M. Incretin therapies: highlighting common features and differences in the modes of 
action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 
Diabetes Obes Metab. 2016;18(3):203-216. https://doi.org/10.1111/dom.12591 
Steinberg WM, Buse JB, Ghorbani MLM, et al.; LEADER Steering Committee; LEADER Trial 
Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated 
with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017a;40(7):966-
972 [Erratum in: Diabetes Care. 2018;41(7):1538]. https://doi.org/10.2337/dc16-2747 
Steinberg WM, Rosenstock J, Wadden TA, et al. Impact of liraglutide on amylase, lipase, and 
acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or 
type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development 
program. Diabetes Care. 2017b;40(7):830-848. https://doi.org/10.2337/dc16-2684 
Twarog C, Fattah S, Heade J, et al. Intestinal permeation enhancers for oral delivery of 
macromolecules: a comparison between salcaprozate sodium (SNAC) and sodium caprate 
(C10). Pharmaceutics. 2019;11(2):78. 
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Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582. https://doi.org/10.1177/193229681000400311 
 
Approved on 18 Sep 2022 GMT


Signature Page for VV-CLIN-023691 v2.0
Signature Page for VV-CLIN-023691 v2.0
Approval
Medical Director
14-Sep-2022 21:46:30 GMT+0000
Approval
Statistician
18-Sep-2022 03:13:05 GMT+0000
Approved on 18 Sep 2022 GMT
PPD
PPD

SAP_001.pdf: 
 
Statistical Analysis Plan: J1X-MC-GZHI (Final Version 2.0) 
 
 
An Open-Label, Multiple-Dose Study to Investigate the Pharmacokinetics of LY3493269 
Oral Formulations Administered in a Fed or Fasted State in Healthy Participants 
 
 
NCT05794243 
 
 
Approval Date: 05-Jul-2023 


 
Final Version 2.0, 30JUN2023 
 
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STATISTICAL ANALYSIS PLAN 
An Open-Label, Multiple-Dose Study to Investigate the Pharmacokinetics of LY3493269 
Oral Formulations Administered in a Fed or Fasted State in Healthy Participants  
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Version: 2.0 
Statistical Analysis Plan Date: 30JUN2023 
Investigational Medicinal Product: LY3493269 
Protocol Reference: J1X-MC-GZHI 
Fortrea Study: 8498974 
Clinical Phase I 
 
 
 
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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................... 2 
2. 
ABBREVIATIONS ............................................................................................................ 4 
3. 
INTRODUCTION .............................................................................................................. 6 
4. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 6 
5. 
STUDY DESIGN ............................................................................................................... 7 
6. 
BLINDING ......................................................................................................................... 8 
7. 
TREATMENTS .................................................................................................................. 8 
8. 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 9 
9. 
DEFINITION OF ANALYSIS POPULATIONS .............................................................. 9 
10. STATISTICAL METHODOLOGY ................................................................................. 10 
10.1 General ....................................................................................................................... 10 
10.2 Demographics and Participant Disposition ............................................................... 10 
10.3 Pharmacokinetic Assessment ..................................................................................... 10 
10.3.1 Pharmacokinetic Analysis ................................................................................ 10 
10.3.2 Pharmacokinetic Statistical Methodology ........................................................ 16 
10.4 Safety and Tolerability Assessments ......................................................................... 16 
10.4.1 Adverse events ................................................................................................. 16 
10.4.2 Skin Burning Sensations and Related AEs ....................................................... 17 
10.4.3 Glucose Monitoring and Hypoglycemia .......................................................... 17 
10.4.4 Concomitant medication ................................................................................... 18 
10.4.5 Clinical laboratory parameters ......................................................................... 18 
10.4.6 Vital signs ......................................................................................................... 18 
10.4.7 Electrocardiogram (ECG) ................................................................................. 19 
10.4.8 Hepatic Monitoring .......................................................................................... 19 
10.4.9 Immunogenicity Assessments .......................................................................... 19 
10.4.10 Hypersensitivity reactions ................................................................................ 20 
10.4.11 Elevated Lipase or Amylase ............................................................................. 20 
10.4.12 Other assessments ............................................................................................. 20 
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11. INTERIM ANALYSES .................................................................................................... 20 
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 21 
13. REFERENCES ................................................................................................................. 21 
14. DATA PRESENTATION ................................................................................................ 21 
14.1 Derived Parameters .................................................................................................... 21 
14.2 Missing Data .............................................................................................................. 21 
14.3 Insufficient Data for Presentation .............................................................................. 21 
15. APPENDICES .................................................................................................................. 22 
Appendix 1: Document History .......................................................................................... 22 
 
 
 
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2. ABBREVIATIONS  
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]). 
%AUC(tlast-∞) 
Percentage of AUC(0-∞) extrapolated 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AUC 
Area under the concentration versus time curve 
AUC(0-∞) 
area under the concentration versus time curve from time zero to 
infinity 
AUC(0-tlast) 
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration 
AUCτ 
Area under the concentration versus time curve during one dosing 
interval 
BQL 
Below the quantifiable lower limit of the assay 
C10 
Sodium caprate 
CI 
Confidence interval 
CL/F 
Apparent total body clearance of drug calculated after extra vascular 
administration 
Clast 
Last quantifiable drug concentration 
Cmax 
Maximum observed drug concentration 
Cmin 
Minimum observed drug concentration 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
DMP 
Data Management Plan 
EC 
Early Clinical  
ECG 
Electrocardiogram 
FAbs 
 
Absolute bioavailability of each oral treatment compared to an 
intravenous formulation 
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FRel 
Relative bioavailability of the test formulation compared to reference 
formulation 
ICH 
International Conference on Harmonisation 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRE 
Magnetic resonance elastography 
PK 
Pharmacokinetic 
RA 
Accumulation ratio 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation  
SNAC 
Salcaprozate sodium 
SOP 
Standard Operating Procedure 
t1/2 
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis 
TBL 
Total bilirubin 
TEADAs 
Treatment-emergent anti-drug antibody 
TEAEs 
Treatment-emergent adverse event 
TFLs 
Tables, Figures, and Listings 
tlast 
Time of the last quantifiable concentration 
tmax 
Time of maximum observed drug concentration 
ULN 
Upper limit of normal 
Vss/F 
Apparent volume of distribution at steady state after extra-vascular 
administration 
Vz/F 
Apparent volume of distribution during the terminal phase after 
extra-vascular administration 
WHO 
World Health Organization 
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3. INTRODUCTION  
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
18 September 2022). 
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. This SAP must 
be finalized prior to first participant visit. When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2. 
4. STUDY OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
 
 To evaluate and compare the PK of up to 3 test capsule 
formulations with a reference tablet formulation of 
LY3493269 following 3 consecutive once-daily oral doses 
in healthy participants  
 Area under the 
concentration versus 
time curve (AUC) and 
maximum observed 
drug concentration 
(Cmax)  
Secondary 
 
 To evaluate the PK of up to 2 LY3493269 formulations 
when administered in a fed condition following 3 
consecutive once-daily oral doses in healthy participants 
 AUC and Cmax  
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 To assess the safety and tolerability of up to 3 test capsule 
formulations of LY3493269 with that of a reference tablet 
formulation following 3 once-daily oral doses in healthy 
participants 
 Treatment-emergent 
adverse events 
(TEAEs) 
Exploratory 
 
 To assess PK of salcaprozate sodium (SNAC) and sodium 
caprate (C10) following oral administration in healthy 
participants  
 AUC and Cmax 
5. STUDY DESIGN  
This is a 2-part, open-label study with a parallel design to be conducted in healthy participants.  
The purpose of this study is to evaluate and compare the PK of up to 3 test capsule formulations 
with a reference tablet formulation of LY3493269 following 3 consecutive once-daily oral doses 
in healthy participants. 
Study details include: 
 The study duration will be up to 71 days. 
 The treatment duration involves consecutive once-daily dosing up to 3 days. 
 The visit frequency will be one inpatient stay (Day -1 through Day 5) and 5 outpatient 
visits. 
In Parts A and B, eligible participants will receive 3 once-daily doses of study intervention. 
The maximum total duration of study participation for each participant may be up to 71 days, 
across the following study intervals: 
 Screening, approximately 28 days 
 Study period, approximately 15 days, and 
 Follow up, approximately 28 days after the last dose of study intervention. 
The study shall target 10 participants completing each treatment – that is, these participants must 
complete Day 8 PK assessments after receiving all 3 consecutive daily doses of the study 
treatment. 
Part A 
Part A of the study is an initial characterization of 2 test capsule formulations, compared with a 
reference tablet formulation. Participants will be randomly assigned to receive 1 of the 3 possible 
treatments as follows: 
 Treatment A1: Test capsule formulation 1 
 Treatment A2: Test capsule formulation 2 
 Treatment A3: Reference tablet formulation 
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Test formulations 1 and 2 and the reference formulation will be administered in the fasted state.  
Part B 
Part B of the study will investigate the test capsule formulations 1, 2, or 3 or the reference tablet 
formulation.  
An initial review of safety and PK data from Part A will be conducted to determine the test or 
reference formulation(s) to be evaluated in Part B. Participants will be assigned to 1 of the 2 
possible treatments as follows: 
 Treatment B1: Test formulations 1, 2, or 3 (referred to as “X” from this point forward) 
 Treatment B2: Test formulations 1, 2, or 3 or reference formulation (referred to as “Y” 
from this point forward). 
The 3 test formulations will be administered in either the fasted or fed state depending on the 
review of safety and PK data from Part A. If the reference formulation is selected as Treatment 
B2, it will be administered in the fasted state.   
Depending on the review results, the selected formulation(s) will be administered in either the 
fed or fasted state.   
Treatments B1 and B2 may be initiated concurrently if the formulations “X” and “Y” and 
administration conditions are determined for both treatment groups after the first review. 
Otherwise, a second review of available PK data from Treatment B1 may be conducted prior to 
the initiation of Treatment B2. 
Changes from the Planned Study Design 
At the time of writing this SAP amendment, the Sponsor has decided not to proceed with Part B 
of the study. All further references to Part B are no longer applicable. 
6. BLINDING  
This is a randomized, open-label study. 
The Fortrea biometrics and Eli Lilly study teams will be unblinded throughout the study. 
7. TREATMENTS  
The following is a list of the study treatment labels that will be used in the TFLs. Where the 
abbreviation is used, the TFLs will include a footnote. 
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Protocol Reference: J1X-MC-GZHI 
Part 
Study Treatment Name 
Abbreviation 
Treatment 
order in 
TFLs 
A 
Test capsule 1: 4 mg LY3493269 + 280 mg C10 (fasted) 
A1 
1 
Test capsule 2: 4 mg LY3493269 + 280 mg C10 (fasted) 
A2{Insert brief 
description of 
indication} 
2 
Reference tablet: 4 mg LY3493269 + 300 mg SNAC (fasted) 
A3 
3 
B 
Test capsule X: 4 mg LY3493269 + 280 mg C10 (TBC) 
B1 
4 
TBC Y: 4 mg LY3493269 + TBC (TBC) 
B2 
5 
Abbreviations: C10 = sodium caprate; SNAC = salcaprozate sodium; TBC = to be confirmed. 
“X” can be test formulations 1, 2 or 3; “Y” can be test formulations 1, 2, 3 or reference 
formulation; The 3 test formulations will be administered in either the fasted or fed state 
depending on the review of safety and PK data from Part A. If the reference formulation is 
selected as Treatment B2, it will be administered in the fasted state. All TFLs will be based on 
actual treatments. 
8. SAMPLE SIZE JUSTIFICATION  
Up to approximately 70 participants may be randomly assigned to study intervention to ensure 
approximately 10 evaluable participants from each of the 5 planned treatment groups complete 
the study.
 
 
  
Participants who are randomly assigned but not administered treatment prior to discontinuation 
may be replaced to ensure that the target number of participants complete the study.   
Participants who discontinue early may be replaced after consultation with the investigator and 
sponsor. The replacement participant will be assigned to the same treatment as the discontinued 
participant. 
9. DEFINITION OF ANALYSIS POPULATIONS  
The “Entered” population will consist of all participants sign the informed consent form. 
The “Randomized/Enrolled” population will consist of all participants assigned to treatment, 
regardless of whether they take any doses of study treatment, or whether they took the correct 
treatment. Participants will be analyzed according to the treatment group to which they were 
assigned. 
The “Safety” population will consist of all enrolled participants who received at least one dose of 
LY3493269. Participants will be analyzed according to the intervention they actually received. 
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The “Pharmacokinetic” population will consist of all enrolled participants who received at least 
one dose of LY3493269 and have at least 1 evaluable PK sample. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations. 
10. 
STATISTICAL METHODOLOGY  
10.1 
General  
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum, maximum and number of observations; for log-normal data (e.g. the PK parameters: 
AUC and Cmax) the geometric mean and geometric coefficient of variation (CV%) will also be 
presented. For categorical data, frequency count and percentages will be presented. Data listings 
will be provided for all participants up to the point of withdrawal, with any participants excluded 
from the relevant population highlighted. Summary statistics and statistical analyses will 
generally only be performed for participants included in the relevant analysis population. For the 
calculation of summary statistics and statistical analysis, unrounded data will be used.  
For change from baseline summary statistics, each individual change from baseline will be 
calculated by subtracting the individual participant’s baseline value from the value at that time 
point. The individual participants’ change from baseline values will be used to calculate the 
summary statistics (arithmetic mean, arithmetic SD, median, minimum, maximum and number 
of observations) using a SAS procedure such as Proc Univariate. 
Data analysis will be performed using SAS® Version 9.4 or greater. 
10.2 
Demographics and Participant Disposition  
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, country of enrolment, site ID, body weight, height and body mass index will be 
summarized and listed. All other demographic variables will be listed only. 
10.3 
Pharmacokinetic Assessment  
10.3.1 Pharmacokinetic Analysis  
Noncompartmental methods applied with a validated software program (Phoenix WinNonlin 
v8.3.5) to the plasma concentrations of LY3493269, SNAC, and C10 will be used to determine 
the following PK parameters in Parts A and B, when possible:   
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Profile Day 1 
Parameter 
Units 
Definition 
AUC(0-tlast) 
ng.h/mL 
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration 
AUCτ 
ng.h/mL 
area under the concentration versus time curve during one dosing 
interval 
Cmax 
ng/mL 
maximum observed drug concentration 
tmax 
h 
time of maximum observed drug concentration 
tlast 
h 
time of the last quantifiable concentration 
 Profile Day 2 
Parameter 
Units 
Definition 
AUC(0-tlast) 
ng.h/mL 
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration 
AUCτ,day 2 
ng.h/mL 
area under the concentration versus time curve during one dosing 
interval at day 2 
Cmax,day 2 
ng/mL 
maximum observed drug concentration 
tmax,day 2 
h 
time of maximum observed drug concentration 
tlast 
h 
time of the last quantifiable concentration 
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 Profile Day 3 
Parameter 
Units 
Definition 
AUC(0-tlast) 
ng.h/mL 
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration 
AUCτ,day 3 
ng.h/mL 
area under the concentration versus time curve during one dosing 
interval at day 3 
AUC(0-) 
ng.h/mL 
area under the concentration versus time curve from time zero to 
infinity 
%AUC(tlast-) 
% 
percentage of AUC(0-∞) extrapolated 
Cmax,day 3 
ng/mL 
maximum observed drug concentration 
tmax,day 3 
h 
time of maximum observed drug concentration 
tlast 
h 
time of the last quantifiable concentration 
t½ 
h 
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis 
CL/F 
L/h 
apparent total body clearance of drug calculated after 
extra-vascular administration 
Vz/F 
L 
apparent volume of distribution during the terminal phase after 
extra-vascular administration 
Vss/F 
L 
apparent volume of distribution at steady state after extra-vascular 
administration 
RA 
none 
accumulation ratio (based on AUCτ on Profile Days 1 and 3) 
FRel 
% 
relative bioavailability of the test formulation compared to 
reference formulation (based on AUC[0-]) 
FAbs 
% 
absolute bioavailability of each oral treatment compared to an 
intravenous formulation (based on dose-normalized [DN] 
AUC[0-]): 
FAbs = Oral DNa AUC(0 −∞)
IVb DN AUC(0 −∞) × 100 
a derived by dividing by the total oral dose administered (12) 
b obtained from study J1X-MC-GZHA, using the geometric mean 
AUC(0-) of 
 LY3493269 IV 
Additional PK parameters may be calculated, as appropriate. The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report. 
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool 
effective at the time of PK analysis will be followed. 
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General PK Parameter Rules 
 Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation. 
 Cmax, Cmax,day 2, Cmax,day 3, tmax, tmax,day 2, tmax,day 3, and tlast will be reported from observed 
values.  On a given profile day, if Cmax occurs at more than one time point, tmax will be 
assigned to the first occurrence of Cmax.  
 AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table. 
 Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each participant will be defined by visual inspection and generally will be the 
first point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table.  
 A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve. 
 The parameters based on observed last quantifiable drug concentration (Clast) will be 
reported. 
Individual PK Parameter Rules 
 Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met:  
o The compound is non-endogenous. 
o The samples are from the initial dose period for a participant or from a subsequent 
dose period following a suitable wash-out period. 
o The time points occur before the first quantifiable concentration. 
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 All other BQL concentrations that do not meet the above criteria will be set to missing.  
 Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug. 
 For multiple-dosing data, when pre-dose concentrations are missing, the value to be 
substituted will be minimum observed drug concentration (Cmin) for the dosing interval.  
 For C10 and SNAC: 
o Predose concentrations that are BLQ will be set to half the LLOQ. 
o If quantifiable predose concentrations are observed for any of the PK profile days, 
the postdose concentrations of the impacted PK profile day(s) will be 
baseline-adjusted prior to calculation of PK parameters. Baseline-adjustment will 
be performed by subtracting the PK profile day’s quantifiable predose 
concentration from each postdose concentration belonging to that same PK profile 
day. 
Individual Concentration vs. Time Profiles 
 Individual concentrations will be plotted utilizing actual sampling times. 
 The terminal point selections will be indicated on a semi-logarithmic plot. 
 Observed (unadjusted) concentrations will be plotted for C10 and SNAC. 
Average Concentration vs. Time Profiles 
 The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.  
 The average concentration profiles will be graphed using arithmetic average 
concentrations. 
 The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations. 
 Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles. 
 Concentrations excluded from the mean calculation will be documented in the final study 
report. 
 A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report. 
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 Observed (unadjusted) concentrations will be plotted for C10 and SNAC. 
Treatment of Outliers during Pharmacokinetic Analysis 
Application of this procedure to all pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for 
potential exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis. 
Data within an Individual Profile 
A value within an individual profile may be excluded from analysis if any of the following criteria 
are met: 
 For pharmacokinetic profiles during multiple dosing, the concentration of the pre-dose 
sample exceeds all measured concentrations for that individual in the subsequent 
post-dose samples. 
 For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable. 
 For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.  
Data between Individual Profiles 
1.  If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.   
2.  If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation: 
a. Transform all values in the calculation to the logarithmic domain. 
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset. 
c. Calculate the lower and upper bounds of the range defined by the arithmetic mean 
±3*SD of the remaining log-transformed values. 
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset. 
e. If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis. 
If the remaining dataset contains another atypical datum suspected to be an outlier and n≥6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values. 
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Reporting of Excluded Values 
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion. 
10.3.2 Pharmacokinetic Statistical Methodology  
The PK parameters of LY3493269 will be evaluated to estimate the relative bioavailability. 
Log-transformed AUCτ, AUC(0-tlast), AUC(0-∞) (profile day 3 only) and Cmax of LY3493269 will 
be evaluated in a mixed model for repeated measures with fixed effects for treatment, profile day 
and the treatment-by-day interaction, and a random effect for participant. An unstructured 
covariance structure will be used to model the covariance between a participant’s multiple 
observations, with an alternative structure to be used if the model fails to converge. The 
geometric least squares means, ratio of geometric least squares means and corresponding 90% CI 
will be reported. 
One model including all treatments (A1, A2, A3, B1 and B2) will be used to present the 
following comparisons for each profile day: 
 Test capsule X versus Reference tablet, where X=1, 2 or 3. 
 Fed versus fasted, for matching formulation. 
 240 mL versus 120 mL water administration, for matching formulation and dietary status. 
Example SAS code: 
proc mixed data=xxx; 
 
by param; 
class treat day subjid; 
model lpk = treat day treat*day / residual ddfm=kr2; 
repeated day / subject=subjid type=un; 
lsmeans treat*day / cl pdiff alpha=0.1; 
ods output lsmeans=lsm diffs=dif; 
run; 
The parameter tmax of LY3493269 will be analyzed non-parametrically. Estimates of the median 
difference, approximate 90% CI and p-value from the Wilcoxon rank sum test will be calculated. 
All PK parameters will be summarized using descriptive statistics. 
Additional analysis may be conducted if deemed necessary.  
10.4 
Safety and Tolerability Assessments  
10.4.1 Adverse events  
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as a condition that starts before the 
participant has provided written informed consent and is ongoing at consent. A non-treatment 
emergent AE is defined as an AE which starts after informed consent but prior to the first dose. 
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A treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose.  
All AEs will be listed. TEAEs will be summarized by treatment, severity and relationship to the 
study drug. The frequency (the number of AEs, the number of participants experiencing an AE 
and the percentage of participants experiencing an AE) of TEAEs will be summarized by 
treatment, Medical Dictionary for Regulatory Activities (MedDRA) (version is documented in 
the Data Management Plan [DMP]) system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug by the investigator. Any serious AEs will be listed. AEs by day of onset will be presented.  
Discontinuations due to AEs will be listed. 
Adverse events of special interest (AESI) are nausea, vomiting, diarrhea, skin burning sensations 
and related AEs. AESIs will be listed. 
10.4.2 Skin Burning Sensations and Related AEs  
Healthy participants in this short-exposure study may experience AEs of skin burning sensation 
and related AEs. If this AE does occur, dedicated CRF will be used by site personnel to collect 
detailed information about the event on initial presentation of this AE, and on subsequent visits 
until the AE resolves. 
The data will be summarized by treatment and listed. 
10.4.3 Glucose Monitoring and Hypoglycemia  
During the study, plasma glucose concentrations will be monitored for safety assessments. 
Glucose data will be listed and summarized by treatment together with changes from baseline, 
where baseline is defined as Day 1 pre-breakfast. 
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:  
 Level 1 hypoglycemia: 
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L):  Level 1 hypoglycemia 
can alert a person to take action such as treatment with fast-acting carbohydrates. Providers 
should continue to counsel participants to treat hypoglycemia at this glucose alert value. 
 Level 2 hypoglycemia: 
Glucose <54 mg/dL (3.0 mmol/L):  This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence of absence of symptoms of hypoglycemia.  
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 Level 3 hypoglycemia: 
Severe hypoglycemia (in adults):  A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia.  For example, participants 
had altered mental status, and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person was needed to actively administer carbohydrate, glucagon, or other resuscitative 
actions. Glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low glucose concentration. 
 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the participant to 
have required assistance and is not predicated on the report of a participant simply having 
received assistance. 
 Other hypoglycemia categories: 
 Nocturnal hypoglycemia is defined as a hypoglycemia event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.   
10.4.4 Concomitant medication  
Concomitant medication will be coded using the WHO drug dictionary (version is documented 
in the DMP). Concomitant medication will be listed. 
10.4.5 Clinical laboratory parameters  
All clinical chemistry and hematology data will be summarized by treatment and time point 
together with change from baseline, where baseline is defined as Day 1 predose, and listed. 
Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed and flagged on individual participant data listings. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
calculation of summary statistics, <x and ≤x values will be set to 0.5 × x, whereas >x and ≥x 
values will be set to 1.1 × x. 
10.4.6 Vital signs  
Vital signs data will be summarized by treatment and time point together with changes from 
baseline, where baseline is defined as the Day 1 predose assessment. Figures of mean vital signs 
and mean changes from baseline profiles will be presented by treatment.  
Values for individual participants will be listed. 
Change from baseline in supine blood pressure and pulse rate will be analyzed using a mixed 
model for repeated measures. The model will include baseline (Day 1 predose) as a covariate, 
treatment, timepoint and the treatment-by-timepoint interaction as fixed effects, and participant 
as a random effect. An unstructured covariance structure will be used to model the covariance 
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between a participant’s multiple observations, with an alternative structure to be used if the 
model fails to converge. Follow-up data will not be included in the model. 
One model including all treatments (A1, A2, A3, B1 and B2) will be used to present 
comparisons of each test formulation versus the reference formation at each post-dose timepoint. 
The difference in least squares means, along with the 90% confidence interval, will be reported.  
Example SAS code: 
proc mixed data=xxx; 
 
by param; 
class treat time subjid; 
model chg = base treat time treat*time / residual ddfm=kr2; 
repeated time / subject=subjid type=un; 
lsmeans treat*time / cl pdiff alpha=0.1; 
ods output lsmeans=lsm diffs=dif; 
run; 
10.4.7 Electrocardiogram (ECG)  
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE. 
10.4.8 Hepatic Monitoring  
If a participant experiences elevated laboratory parameters, as detailed in Section 8.2.5.1 of the 
protocol, additional tests will be performed to confirm the abnormality. Additional safety data 
may be collected if required, as defined in the protocol. Where applicable, the following will be 
presented. 
The participants’ liver disease history and associated person liver disease history data will be 
listed. Use of acetaminophen during the study, which has potential for hepatotoxicity, will be 
listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) scan, and biopsy assessments will be listed, if performed. 
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment, if there are sufficient data available, and listed. Alcohol and 
recreational drug use data will also be listed. 
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings. 
10.4.9 Immunogenicity Assessments  
Immunogenicity data may be listed and frequency tables may be presented if analysed. The 
frequency and percentage of participants with pre-existing antidrug antibody (ADA) and with 
treatment-emergent ADAs (TE ADAs) may be presented. TE ADAs are those that are boosted or 
induced by exposure to study drug, with a 4-fold increase in titer compared to baseline if ADAs 
were detected at baseline or a titer 2-fold greater than the minimum required dilution (1:10) if no 
ADAs were detected at baseline, where baseline is defined as Day 1 predose. 
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Venus blood samples will be stored for future analysis to determine antibody production against 
LY3493269. Any analysis, whether performed at a later date or during this study, will be 
performed by Eli Lilly. If applicable, the frequency and percentage of participants with 
cross-reactive binding to native GIP, GLP-1 or neutralizing antibodies, if measured, may also be 
tabulated for participants with TE ADA.  
The relationship between the presence of antibodies and PK parameters of LY3493269 may be 
assessed if deemed appropriate. 
10.4.10 Hypersensitivity reactions  
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to 
assess the participant’s medical history, alternative causes, and symptoms. 
These data will be listed. 
10.4.11 Elevated Lipase or Amylase  
If a patient experiences elevated serum amylase or lipase values ≥3× ULN, additional monitoring 
and tests may be performed to confirm the abnormality. 
The frequency of serum amylase or lipase values ≥3× ULN will be summarized by treatment and 
listed. 
10.4.12 Other assessments  
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
11. 
INTERIM ANALYSES  
No formal interim statistical analyses are planned. 
Data Review during the Study 
The following reviews will be the responsibility of Eli Lilly. 
Part A 
A review of available safety and PK data will be conducted to determine the test formulation(s) 
to be evaluated in Part B. 
This review will include data from at least 8 participants who have completed 3 consecutive 
doses of the study intervention in each of the 3 planned treatment groups, and who have 
completed protocol assessments up to Day 8. 
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Part B 
Emerging PK data from Part A will determine the formulations to be tested as Treatments B1 
and B2, as well as the conditions (fed or fasted) under which the test or reference formulations 
are administered. If deemed appropriate, an interim review of PK data from Treatment B1 may 
be conducted prior to the initiation of Treatment B2. This review will include data from at least 8 
participants who have completed 3 consecutive doses of the study intervention, and who have 
completed protocol assessments up to Day 8. 
12. 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES  
Part B of this study has been cancelled. 
13. 
REFERENCES  
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
14. 
DATA PRESENTATION  
14.1 
Derived Parameters  
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. Number of 
observations and percentage values should be reported as whole numbers. Median values should 
be treated as an observed parameter and reported to the same number of decimal places as 
minimum and maximum values. 
14.2 
Missing Data  
Missing data will not be displayed in listings. 
14.3 
Insufficient Data for Presentation  
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.” 
 
 
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15. 
APPENDICES  
Appendix 1: Document History  
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
Final Version 2.0 
30JUN2023 
Added additional PK parameter, FAbs, following request 
from Sponsor. 
AUC(0-∞) on profile day 3 added to statistical analysis 
following request from Sponsor. 
Part B of the study has been cancelled – text added to 
Sections 5 and 12 to clarify. 
“Labcorp Drug Development” amended to “Fortrea” 
throughout. 
NA = not applicable 
Approved on 05 Jul 2023 GMT


Signature Page for VV-CLIN-123648 v1.0
Signature Page for VV-CLIN-123648 v1.0
Approval
PKPDPMx
04-Jul-2023 13:18:29 GMT+0000
Approval
Statistician
04-Jul-2023 13:26:07 GMT+0000
Approval
PKPDPMx
05-Jul-2023 06:48:24 GMT+0000
Approval
Statistician
05-Jul-2023 17:10:22 GMT+0000
Approved on 05 Jul 2023 GMT
PPD
PPD
PPD
PPD