A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single-and Multiple Ascending Doses of LY3478045in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
J2M-MC-GZKA(c) Clinical Pharmacology Protocol 
 
 
A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single- and Multiple- 
 
Ascending Doses of LY3478045 in Healthy Subjects 
 
NCT04270370 
 
Approval Date: 11-Aug-2021 
 
 

J2M-MC-GZKA(c) Clinical Pharmacology Protocol 
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LY3478045 
Protocol J2M-MC-GZKA(c) 
A Safety, Tolerability, Pharmacokinetic, and 
Pharmacodynamic Study of Single- and Multiple-
Ascending Doses of LY3478045 in Healthy Subjects 
 
Confidential Information 
The information contained in this protocol 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 
LY3478045, 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.  
 
LY3478045 
Eli Lilly and Company 
Indianapolis, Indiana, USA 46285 
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:   
15 January 2020 
Amendment (a) Electronically Signed and Approved by Lilly: 04 March 2020 
Amendment (b) Electronically Signed and Approved by Lilly: 09 December 2020 
Document ID: VV-CLIN-002394 
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Table of Contents 
A Safety, Tolerability, Pharmacokinetic, and 
Pharmacodynamic Study of Single- and Multiple-Ascending 
Doses of LY3478045 in Healthy Subjects 
Section 
Page 
Protocol J2M-MC-GZKA(c) A Safety, Tolerability, Pharmacokinetic, and 
Pharmacodynamic Study of Single- and Multiple-Ascending Doses 
of LY3478045 in Healthy Subjects .........................................................................................1 
Table of Contents .............................................................................................................................2 
1. 
Protocol Synopsis ....................................................................................................................8 
2. 
Schedule of Activities ............................................................................................................10 
2.1. 
Part A (Single-Ascending Doses) .....................................................................................11 
2.2. 
Part B (Cohorts 1 and 3; Multiple-Ascending Doses) ......................................................13 
2.3. 
Part B (Cohorts 2 and 4; Multiple-Ascending Doses) ......................................................16 
3. 
Introduction ...........................................................................................................................19 
3.1. 
Study Rationale ................................................................................................................19 
3.2. 
Background.......................................................................................................................19 
3.2.1. 
Nonalcoholic Steatohepatitis ....................................................................................19 
3.2.2. 
Ketohexokinase ........................................................................................................20 
3.2.3. 
 .................................................................21 
3.3. 
Benefit/Risk Assessment ..................................................................................................22 
4. 
Objectives and Endpoints ......................................................................................................24 
5. 
Study Design .........................................................................................................................25 
5.1. 
Overall Design ..................................................................................................................25 
5.1.1. 
Part A .......................................................................................................................25 
5.1.2. 
Part B ........................................................................................................................26 
5.2. 
Number of Participants .....................................................................................................27 
5.3. 
End of Study Definition....................................................................................................27 
5.4. 
Scientific Rationale for Study Design ..............................................................................27 
5.5. 
Justification for Dose ........................................................................................................28 
6. 
Study Population ...................................................................................................................32 
6.1. 
Inclusion Criteria ..............................................................................................................32 
6.2. 
Exclusion Criteria .............................................................................................................33 
6.3. 
Lifestyle and/or Dietary Requirements ............................................................................35 
6.3.1. 
Meals and Dietary Restrictions ................................................................................35 
6.3.2. 
Caffeine, Alcohol, and Tobacco ..............................................................................35 
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6.3.3. 
Activity .....................................................................................................................35 
6.3.4. 
Contraception for Males ...........................................................................................35 
6.4. 
Screen Failures .................................................................................................................36 
7. 
Treatment ...............................................................................................................................37 
7.1. 
Treatment Administered ...................................................................................................37 
7.1.1. 
Packaging and Labeling ...........................................................................................37 
7.2. 
Method of Treatment Assignment ....................................................................................37 
7.2.1. 
Selection and Timing of Doses ................................................................................37 
7.3. 
Blinding ............................................................................................................................38 
7.4. 
Dose Modification ............................................................................................................38 
7.4.1. 
Dose Decision/Escalation ........................................................................................38 
7.5. 
Preparation/Handling/Storage/Accountability .................................................................39 
7.6. 
Treatment Compliance .....................................................................................................40 
7.7. 
Concomitant Therapy .......................................................................................................40 
7.8. 
Treatment after the End of the Study ...............................................................................40 
8. 
Discontinuation Criteria ........................................................................................................41 
8.1. 
Discontinuation from Study Treatment ............................................................................41 
8.2. 
Discontinuation from the Study ........................................................................................41 
8.3. 
Subjects Lost to Follow-up ...............................................................................................42 
8.4. 
Discontinuation of the Study ............................................................................................42 
9. 
Study Assessments and Procedures .......................................................................................43 
9.1. 
Efficacy Assessments .......................................................................................................43 
9.2. 
Adverse Events .................................................................................................................43 
9.2.1. 
Serious Adverse Events ...........................................................................................44 
9.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................45 
9.2.2. 
Complaint Handling .................................................................................................45 
9.3. 
Treatment of Overdose .....................................................................................................45 
9.4. 
Safety ................................................................................................................................45 
9.4.1. 
Laboratory Tests ......................................................................................................45 
9.4.2. 
Physical Examination ...............................................................................................46 
9.4.2.1. 
Vital Signs ..........................................................................................................46 
9.4.3. 
Electrocardiograms ..................................................................................................46 
9.4.4. 
Body Temperature ....................................................................................................47 
9.4.5. 
Safety Monitoring ....................................................................................................47 
9.4.5.1. 
Hepatic Safety ....................................................................................................47 
9.4.5.2. 
Testicular safety .................................................................................................48 
9.5. 
Pharmacokinetics ..............................................................................................................48 
9.5.1. 
Bioanalysis ...............................................................................................................49 
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9.6. 
Pharmacodynamics ...........................................................................................................49 
9.7. 
Genetics ............................................................................................................................50 
9.8. 
Biomarkers .......................................................................................................................50 
9.8.1. 
 ......................................................................................................50 
9.8.1.1. 
Bioanalysis .........................................................................................................50 
9.8.2. 
Fasting Insulin and Adiponectin ..............................................................................50 
9.8.3. 
Nonpharmacogenetic Biomarkers ............................................................................51 
9.9. 
Health Economics .............................................................................................................51 
10. Statistical Considerations and Data Analysis ........................................................................52 
10.1. Sample Size Determination ..............................................................................................52 
10.2. Populations for Analyses ..................................................................................................52 
10.2.1. 
Study Participant Disposition ...................................................................................52 
10.2.2. 
Study Participant Characteristics .............................................................................52 
10.3. Statistical Analyses ...........................................................................................................52 
10.3.1. 
Safety Analyses ........................................................................................................52 
10.3.1.1. 
Clinical Evaluation of Safety .............................................................................52 
10.3.1.2. 
Statistical Evaluation of Safety ..........................................................................53 
10.3.2. 
Pharmacokinetic Analyses .......................................................................................53 
10.3.2.1. 
Pharmacokinetic Parameter Estimation .............................................................53 
10.3.2.2. 
Pharmacokinetic Statistical Inference ................................................................53 
10.3.3. 
Pharmacodynamic Analyses ....................................................................................54 
10.3.3.1. 
Pharmacodynamic Parameter Estimation ...........................................................54 
10.3.3.2. 
Pharmacodynamic Statistical Inference .............................................................54 
10.3.4. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................54 
10.3.5. 
Data Review During the Study ................................................................................54 
10.3.6. 
Interim Analyses ......................................................................................................54 
11. References .............................................................................................................................55 
12. Appendices ............................................................................................................................58 
 
 
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List of Tables 
Table 
Page 
Table GZKA.1. 
Objectives and Endpoints ..........................................................................24 
Table GZKA.2. 
 
 ..............................................30 
Table GZKA.3. 
Treatments Administered ...........................................................................37 
 
 
 
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List of Figures 
Figure 
Page 
Figure GZKA.1. 
Illustration of study design for Part A........................................................26 
Figure GZKA.2. 
Illustration of study design for Part B. .......................................................27 
 
 
 
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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...................................................................59 
Appendix 2. 
Clinical Laboratory Tests (Fasting) ...........................................................62 
Appendix 3. 
Study Governance, Regulatory and Ethical Considerations ......................63 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality .............66 
Appendix 5. 
Blood Sampling Summary .........................................................................67 
Appendix 6. 
Excluded Concomitant Medications ..........................................................69 
Appendix 7. 
Protocol Amendment J2M-MC-GZKA(c) Summary - A Safety, 
Tolerability, Pharmacokinetic, and Pharmacodynamic Study of 
Single- and Multiple-Ascending Doses of LY3478045 in Healthy 
Subjects ......................................................................................................71 
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1. Protocol Synopsis 
Title of Study: 
A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single- and Multiple-Ascending Doses of 
LY3478045 in Healthy Subjects. 
Rationale:  
Lilly is developing LY3478045, a ketohexokinase inhibitor, that helps in attenuation of fructose metabolism thus, 
anticipated to result in  
• 
reduction of liver fat, inflammation, and fibrosis 
• 
improvement in glycemic control 
• 
insulin sensitization, and  
• 
reduction in body weight, free fatty acids, and triglycerides.   
Study J2M-MC-GZKA (GZKA) is a first-in-human study, which aims to assess the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of LY3478045 in healthy 
subjects.  The PK, PD, safety, and tolerability data from this study in healthy subjects will assist in identifying an 
appropriate dose range for subsequent clinical studies in patients with nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis. 
Objective(s)/Endpoints: 
Objectives 
Endpoints 
Primary 
To investigate the safety and tolerability of single and 
multiple oral doses of LY3478045 in healthy subjects. 
 
Incidence of TEAE and SAE. 
 
Clinically significant changes in vital signs data, safety 
laboratory parameters, and electrocardiograms. 
Secondary 
To determine the pharmacokinetics of LY3478045 
following single and multiple doses in healthy subjects. 
 
AUC(0-24), AUC(0-inf), Cmax, and tmax. 
Abbreviations:  AUC(0-24) = area under concentration versus time curve from time zero to 24 hours; AUC(0-inf) = 
AUC from time zero to infinity; Cmax = maximum observed drug concentration; SAE = serious adverse event; 
tmax = time of Cmax; TEAE = treatment-emergent adverse event. 
Summary of Study Design: 
Study GZKA is a Phase 1, single site, randomized, double-blind, placebo-controlled, 2-part study of LY3478045 in 
healthy subjects. 
Part A:  single-ascending dose. 
Part B:  multiple-ascending dose design that evaluates the potential for a drug-drug interaction. 
In Part A, single-ascending oral doses of either LY3478045 or placebo will be administered in up to 5 cohorts.  Each 
cohort will consist of at least 8 subjects, 6 subjects will receive LY3478045 and 2 subjects will receive placebo.  
Cohort 5 is an optional cohort that may be assessed based on the available safety and PK data from the previous 4 
cohorts. 
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LY3478045 
Part B will be initiated after assessing safety, tolerability, PK, and PD data through Cohort 3 in Part A.  
Multiple-ascending oral doses of LY3478045 will be administered once daily for 14 days in up to 4 cohorts.  Each 
cohort will consist of at least 8 subjects.  In Cohorts 1 and 3, six subjects will receive LY3478045 and 2 subjects 
will receive placebo.  In Cohorts 2 and 4, six subjects will receive LY3478045 followed by  single dose of 
 and 2 subjects will receive placebo followed by a single dose of atorvastatin 
 later. 
Treatment Arms and Planned Duration for an Individual subject:   
Treatment Name 
LY3478045 
Placebo 
Atorvastatin 
Dosage Formulation 
 
Capsules 
Tablets 
Dose strength 
 
- 
40 mg 
Route of Administration 
Oral 
Oral 
Oral 
The planned duration for each subject is approximately 43 days in Part A and 57 to 59 days in Part B of the study.   
Number of Subjects:  
Up to 50 subjects may be enrolled in Part A to ensure that at least 40 subjects complete the study (depending on 
whether subjects will be enrolled in optional Cohort 5).  Up to 40 subjects may be enrolled in Part B to ensure that 
at least 32 subjects complete the study. 
Statistical Analysis: 
Pharmacokinetic/PD analyses will be conducted on data from all subjects who receive at least 1 dose of the 
investigational product and have evaluable PK and PD data.  Safety analyses will be conducted for all enrolled 
subjects, whether or not they completed all protocol requirements.  Additional exploratory analyses of the data may 
be conducted as deemed appropriate. 
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and electrocardiogram 
parameters.  Analyses may be performed to determine the effects of PK and PD parameters on QT interval corrected 
using Fridericia’s formula.   
The primary parameters for analysis will be maximum observed drug concentration (Cmax), time of Cmax (tmax), 
area under concentration versus time curve (AUC) from time zero to 24 hours (AUC0-24) and AUC from time zero 
to infinity (AUC0-inf) of LY3478045.  The primary PK parameters for analysis of 
will be AUC(0-inf) and Cmax. 
 
 
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2. Schedule of Activities 
Study schedules for Protocol J2M-MC-GZKA are presented for Part A (SAD; Section 2.1) and 
Part B (MAD; Section 2.2 [Cohorts 1 and 3]) and Section 2.3 [Cohorts 2 and 4 with 
atorvastatin]). 
 
 
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2.1. Part A (Single-Ascending Doses) 
 
Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 
4 
5 
7 
14 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
X 
 
 
 
 
Subjects may be discharged 
on Day 5 at the discretion of 
the investigator. 
Non-Residential Visit 
 
 
 
 
 
 
X 
X 
X 
X 
 
LY3478045 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Information regarding 
occasional use of 
vitamin/mineral supplements 
will be taken as a part of the 
medical history evaluation at 
the time of subject screening. 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
X 
X 
Targeted PE may be 
conducted at other visits at 
the discretion of the 
investigator. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
X 
X 
Serum pregnancy test will be 
performed at screening and 
urine pregnancy test will be 
performed at all other 
specified timepoints. 
Blood Pressure and Pulse 
Rate (Supine)c 
X 
X 
P, every 1 h up 
to 12 h postdose 
24, 36 h 
48 h 
72 h 
 
X 
X 
X 
 
Body Temperature 
X 
X 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory Tests 
X 
X 
P 
X 
X 
 
 
X 
X 
 
See Appendix 2 for complete 
list. 
Serum Creatinined 
 
 
P, 4, 12, 24 h 
 
 
 
 
 
 
 
 
Triplicate 12-Lead ECG 
 
 
Predose: 1.5 h, 
1 h, and 30 min. 
Postdose: 0.5, 
1.5, 2.5, 4, 6, 8, 
24 h 
 
 
 
 
 
 
 
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Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 
4 
5 
7 
14 
 
 
10, 12, 16 h 
Single 12-Lead ECG 
X 
 
 
 
X 
 
 
 
X 
X 
 
Adverse Event Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic 
Samplingd 
 
 
P, 0.75, 1.5, 3, 
4, 6, 8, 10, 
12 ,16 h 
24 h 
48 h 
72 h 
96 h 
 
 
 
 
Meal (Low Fructose) 
 
 
20 min, 6, 12 h 
 
 
 
 
 
 
 
 
Fructose Beverage (for 
Fructose Tolerance Test) 
 
 
during meal: 
20 min, 6, 12 h 
 
 
 
 
 
 
 
 
Fructose Tolerance Test 
Assayd 
 
 
 
 
 
 
 
 
 
Genetic Sample 
 
 
X 
 
 
 
 
 
 
 
 
Fasting Biomarker 
Samples 
(Nonpharmacogenetic) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
P, 
0.75, 1.5, 3, 4, 
8, 12, 16 h 
24 h 
48 h 
72 h 
96 h 
 
 
 
 
24-hour Urine Collection 
for LY3478045 and 
Creatinined 
 
 
0-12, 12-24 h 
24-36, 36-
48 h 
48-60, 
60-72 h 
 
 
 
 
 
 
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = hour(s); min = minutes; P = predose; PE = physical 
examination. 
Notes:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECG, vital signs, and venipuncture.  Samples collected for 
clinical laboratory tests including urine analysis may be analyzed at a local laboratory.  All time points specified in the table are approximate and may be adjusted at the 
discretion of the investigator. 
a 
Additional FU visits may occur depending upon emerging pharmacokinetic and/or safety data. 
b 
At the discretion of the investigator, subjects may be requested to return to the CRU for safety monitoring at additional visits following completion of the ED procedures.  At 
the discretion of the investigator, assessments may include, but will not be limited to, those presented for the FU visit with the addition of safety laboratory tests. 
c 
Time points may be added for each study period, if warranted and agreed upon between Lilly and the investigator. 
d 
Sampling times are relative to the time of study treatment administration (0 min). 
 
 
 
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2.2. Part B (Cohorts 1 and 3; Multiple-Ascending Doses) 
 
Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 to 
6 
7 
8 
9 to 
13 
14 
15 to 17 
28 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to CRUe 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
Day 17 
 
 
 
LY3478045 
Administration 
 
 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Information 
regarding 
occasional use 
of 
vitamin/mineral 
supplements 
will be taken as 
a part of the 
medical history 
evaluation 
at 
the 
time 
of 
subject 
screening. 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted PE 
may be 
conducted at 
other visits at 
the discretion 
of the 
investigator. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
Day 15 
X 
X 
 
Pregnancy Test 
X 
X  
 
 
 
 
 
 
 
 
X  
X  
Serum 
pregnancy test 
will be 
performed at 
screening and 
urine 
pregnancy test 
will be 
performed at all 
other specified 
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Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 to 
6 
7 
8 
9 to 
13 
14 
15 to 17 
28 
 
 
timepoints. 
Blood Pressure and Pulse 
Rate (Supine)c 
X 
X 
P, every 
1 h up to 
12 h 
postdose 
24, 36 h 
48, 
72 h 
 
 
 
X 
 
X 
X 
 
Body Temperature 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory Tests 
(See Appendix 2) 
X 
X 
P 
 
Day 
4 
X 
 
 
X 
 
X 
X 
 
Serum Creatinine 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Total Testosterone, 
Follicle-Stimulating 
Hormone, and 
Luteinizing Hormone 
X 
 
P 
P 
 
 
 
 
 
 
X 
X 
Samples will be 
collected early 
in the morning 
on Days 1 and 
2, at the same 
time for both 
days, before or 
immediately 
after breakfast. 
Single 12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Triplicate 12-Lead ECG 
 
 
Predose: 
1.5 h, 1 
h, and 30 
min. 
 
 
 
 
 
P, 0.5, 1.5, 
2.5, 4, 6, 8, 
12, 16 h 
24 h  
 
 
 
Adverse Event Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic 
Samplingd 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24 h 
(predose) 
 
P 
 
 
P, 0.75, 
1.5, 3, 4, 6, 
8, 12, 16 h 
24, 48, 
72 h  
 
 
Sampling times 
may be 
adjusted based 
upon review of 
interim PK 
Fasting Insulin and 
Adiponectin 
 
 
P 
 
 
 
 
 
P 
 
 
 
 
Meal (Low Fructose) 
 
 
20 min, 
6 h, 12 h 
 
 
 
 
 
20 min, 
6 h, 12 h 
 
 
 
 
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Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 to 
6 
7 
8 
9 to 
13 
14 
15 to 17 
28 
 
 
Fructose Beverage (for 
Fructose Tolerance Test) 
 
 
during 
meal: 
20 min, 
6, 12 h 
 
  
 
 
 
during 
meal: 
20 min, 6, 
12 h 
 
 
 
 
Fructose Tolerance Test 
Assayd 
 
 
 
 
 
 
 
 
 
Genetic Sample 
 
P 
 
 
 
 
 
 
 
 
 
 
 
Fasting Biomarker 
Samples 
(Nonpharmacogenetic) 
 
X 
 
X 
 
 
 
 
 
Day 15 
 
 
 
 
 
P, 1.5, 3, 
4, 6, 8, 
12, 16 h 
24 h 
(predose) 
 
P, 1.5, 
3, 4, 6, 
8, 12, 
16 h 
24 h 
(predose) 
 
 
 
 
 
Sampling times 
may be 
adjusted based 
upon review of 
preliminary 
data 
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = hour(s); min = minutes; P = predose; PE = physical 
examination; PK = pharmacokinetics. 
Notes:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECG, vital signs, and venipuncture.  Samples collected for 
clinical laboratory tests including urine analysis may be analyzed at a local laboratory.  All time points specified in the table are approximate and may be adjusted at the 
discretion of the investigator. 
a 
Additional FU visits may occur depending upon emerging pharmacokinetic and/or safety data. 
b 
At the discretion of the investigator, subjects may be requested to return to the CRU for safety monitoring at additional visits following completion of the ED procedures.  At 
the discretion of the investigator, assessments may include, but will not be limited to, those presented for the FU visit with the addition of safety laboratory tests. 
c Where possible, measurements of blood pressure and pulse rate should be performed at approximately the same time of day at each scheduled time point.  
Time points may be added for each study period, if warranted and agreed upon between Lilly and the investigator. 
d Sampling times are relative to the time of study treatment administration (0 min). 
e If the predicted mean exposure for the dose at any cohort is estimated to be higher than 71.7 µg∙hr/mL, only female subjects will be included in the cohort and 
mandated to stay in the CRU until 24 hours after the last dose. 
 
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2.3. Part B (Cohorts 2 and 4; Multiple-Ascending Doses) 
Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before  
Day -3 
-3 
-2 
-1 
1 
2 
3 to 6 
7 
8 
9 to 13 
14 
15, 16, 17 
28 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to CRUe 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
 
 
 
 
 
Day 17 
 
 
 
LY3478045 
Administration 
 
 
 
 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Information regarding 
occasional use of 
vitamin/mineral 
supplements will be 
taken as a part of the 
medical history 
evaluation at the time 
of subject screening. 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted PE may be 
conducted at other 
visits at the discretion 
of the investigator. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
Day 15 
X 
X 
 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
X  
X  
Serum pregnancy test 
will be performed at 
screening and urine 
pregnancy test will be 
performed at all other 
specified timepoints. 
Blood Pressure and 
Pulse Rate (Supine)c 
X 
 
 
X 
P, every 1 h 
up to 12 h 
postdose 
24, 36 h 
48, 
72 h 
 
 
 
X 
 
X 
X 
 
Body Temperature 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory 
Tests (See 
Appendix 2) 
X 
X 
 
 
P 
 
Day 4 
X 
 
 
X 
 
X 
X 
 
Total Testosterone, 
Follicle-Stimulating 
Hormone, and 
Luteinizing Hormone 
X 
 
 
 
P 
P 
 
 
 
 
 
 
X 
X 
Samples will be 
collected early in the 
morning on Days 1 
and 2, at the same 
time for both days, 
before or immediately 
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Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before  
Day -3 
-3 
-2 
-1 
1 
2 
3 to 6 
7 
8 
9 to 13 
14 
15, 16, 17 
28 
 
 
after breakfast. 
Serum Creatinine 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Single 12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Triplicate 12-Lead 
ECG 
 
 
 
 
Predose: 1.5 
h, 1 h, and 
30 min. 
 
 
 
 
 
P, 0.5, 
1.5, 2.5, 
4, 6, 8, 
12, 16 h 
24 h 
 
 
 
Adverse Event 
Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetic 
Samplingd 
 
 
 
 
P, 0.75, 1.5, 
3, 4, 6, 8, 
12, 16 h 
24 h 
(predose) 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24 h 
(predose) 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24, 48, 
72 h  
 
 
Sampling times may 
be adjusted based 
upon review of 
interim PK 
Fasting insulin and 
Adiponectin 
 
 
 
 
P 
 
 
 
 
 
P 
 
 
 
 
Meal (Low Fructose) 
 
 
breakfast 
 
20 min, 6, 
12 h 
 
 
20 min 
 
 
20 min, 
6, 12 h 
 
 
 
 
Fructose Beverage (for 
Fructose Tolerance 
Test) 
 
 
 
 
during 
meal: 
20 min, 6, 
12 h 
 
 
 
 
 
during 
meal: 
20 min, 
6, 12 h 
 
 
 
 
Fructose Tolerance 
Test Assayd 
 
 
 
 
 24 h 
(predose 
and 
premeal)  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Atorvastatin will be 
administered 4 hours 
after LY3478045 
administration on Day 
7 or 4 hours after 
breakfast on Day -2. 
Pharmacokinetics 
 
 
P, 0.5, 1, 
2, 3, 4, 6, 20, 32 h 
48 h 
 
 
P, 0.5, 1, 
2, 3, 4,  20, 32 h 48 h 
 
 
 
 
Sampling times are 
relative to the time of 
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Screening 
Days 
FUa 
EDb 
Comments 
Procedure 
≤28 days 
before  
Day -3 
-3 
-2 
-1 
1 
2 
3 to 6 
7 
8 
9 to 13 
14 
15, 16, 17 
28 
 
 
8, 12 h 
6, 8, 
12 h 
atorvastatin 
administration 
Genetic Sample 
 
 
 
P 
 
 
 
 
 
 
 
 
 
 
 
Fasting Biomarker 
Samples 
(Nonpharmacogenetic) 
 
 
 
X 
 
X 
 
 
 
 
 
Day 15 
 
 
 
 
 
P, 1.5, 3, 
4, 6, 8, 
12, 16 h 
24 h 
(predose
) 
P, 1.5, 3, 4, 
6, 8, 12, 16 
h 
24 h  
(predose) 
 
P, 1.5, 3, 
4, 6, 8, 
12, 16 h 
24 h  
(predose) 
 
 
 
 
 
Sampling times may 
be adjusted based 
upon review of 
preliminary data 
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = hour(s); min = minutes; P = predose; PE = physical 
examination; PK = pharmacokinetics. 
Notes:  if multiple procedures take place at the same time point, the following order of the procedures should be used:  ECG, vital signs, and venipuncture.  Samples collected for 
clinical laboratory tests including urine analysis may be analyzed at a local laboratory.  All time points specified in the table are approximate and may be adjusted at the 
discretion of the investigator. 
a 
Additional FU visits may occur depending upon emerging pharmacokinetic and/or safety data. 
b 
At the discretion of the investigator, subjects may be requested to return to the CRU for safety monitoring at additional visits following completion of the ED procedures.  At 
the discretion of the investigator, assessments may include, but will not be limited to, those presented for the FU visit with the addition of safety laboratory tests. 
c 
Where possible, measurements of blood pressure and pulse rate should be performed at approximately the same time of day at each scheduled time point.  Time points may be 
added for each study period, if warranted and agreed upon between Lilly and the investigator. 
d 
Sampling times are relative to the time of study treatment administration (0 min). Time of breakfast represents 0 min on study Day -2. 
e If the predicted mean exposure for the dose at any cohort is estimated to be higher than 71.7 µg∙hr/mL, only female subjects will be included in the cohort and mandated to stay 
in the CRU until 24 hours after the last dose.
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3. Introduction 
3.1. Study Rationale 
Lilly is developing LY3478045, a ketohexokinase (KHK) inhibitor, that helps in attenuation of 
fructose metabolism thus, anticipated to result in  
• reduction of liver fat, inflammation, and fibrosis 
• improvement in glycemic control 
• insulin sensitization, and  
• reduction in body weight, free fatty acids, and triglycerides.   
Study J2M-MC-GZKA (GZKA) is a first-in-human study, which aims to assess the safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral 
doses of LY3478045 in healthy subjects.  The PK, PD, safety, and tolerability data from this 
study in healthy subjects will assist in identifying an appropriate dose range for subsequent 
clinical studies in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic 
steatohepatitis (NASH).  
3.2. Background 
3.2.1. Nonalcoholic Steatohepatitis 
Sugar consumption has significantly increased over the several decades; the per capita 
consumption of dietary fructose has increased 100-fold and fructose now accounts for 
approximately 10% of calorie intake in the United States (Bray et al. 2004; Tappy and 
Mittendorfer 2012).  Furthermore, the polyol pathway, which converts glucose into fructose, is 
active in tissues including the liver, heart, and kidney.  Activity of the polyol pathway is 
increased in metabolic disease conditions resulting in higher levels of endogenous fructose 
generated from glucose (Lanaspa et al. 2013; Andres-Hernando et al. 2019). 
While modest amount of fructose found in fruits and vegetables is not of concern, the increased 
intake of sucrose (50% glucose/50% fructose) and high fructose corn syrup (55% to 90% 
fructose) is considered to be a cause for metabolic disease and complications including 
NAFLD/NASH. 
Nonalcoholic steatohepatitis is the progressive stage of NAFLD, characterized histologically by 
the presence of steatosis, lobular inflammation, and hepatocyte injury (ballooning), with or 
without fibrosis (Chalasani et al. 2018).   
Nonalcoholic steatohepatitis is currently the third most common cause of hepatocellular 
carcinoma (Chalasani et al. 2018) and NASH is expected to become the leading cause of liver 
transplantation in the future (Charlton et al. 2011). 
Patients with NASH with fibrosis are at a higher risk of adverse outcomes, including liver 
cirrhosis, liver-related mortality, and cardiovascular (CV) mortality (Angulo et al. 2015).  There 
is a high unmet medical need for safe and effective pharmacological treatments for NASH, as no 
approved therapies are currently available (Younossi et al. 2018). 
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3.2.2. Ketohexokinase 
Ketohexokinase (also known as fructokinase) is the enzyme responsible for the first step in 
fructose metabolism (phosphorylation of fructose to fructose 1-phosphate).   
As fructose (exogenous or endogenous), per se, is biologically inactive, metabolism by KHK is 
required to elicit negative metabolic phenotype(s) associated with fructose intake, including 
NAFLD/NASH and insulin resistance.  Excessive fructose flux through KHK causes 
pro-lipogenic and inflammatory profiles in the liver where KHK is abundantly expressed and is 
the primary site of fructose metabolism (Hannou et al. 2018). 
Various epidemiological and human intervention studies revealed the association of fructose 
consumption with insulin resistance (Basciano et al. 2005), NAFLD/NASH (Vos and McClain 
2009; Weber et al. 2018), CV disease (Fung et al. 2009; de Koning et al. 2012), and 
accompanying mortality (Collin et al. 2019).  Conversely, significant metabolic benefits from 
isocaloric fructose restriction in human intervention trials that may be anticipated by reducing 
fructose metabolism (via KHK inhibition) include 
• reduced liver steatosis 
• suppressed hepatic de novo lipogenesis 
• decreased inflammation, and  
• improved insulin sensitivity.   
As KHK acts as the gatekeeper to fructose metabolism and associated adverse phenotypes, 
reducing fructose metabolism via KHK inhibition is anticipated to mimic the isocaloric fructose 
restriction profiles. 
Ketohexokinase as a Therapeutic Target 
KHK inhibition (via mouse knockout, siRNA, small molecule) in nonclinical animal models 
support efficacy in NAFLD/NASH (Ishimoto et al. 2012, 2013; Lanaspa et al. 2013, 2018; Softic 
et al. 2017). 
Human genetic validation of KHK as a therapeutic target exists based on loss of function 
mutations which results in essential fructosuria, an autosomal recessive disorder (Laron 1961; 
Froesch 1969; Bonthron et al. 1994).  Individuals with this benign condition have inactive 
isoforms of KHK, limiting the liver’s ability to metabolize and clear fructose upon fructose 
ingestion, increased fructose excursion into the serum, and ultimately excretion of fructose into 
urine.  Due to the low prevalence of condition (approximately 1/100,000) and/or its benign 
nature, individuals with essential fructosuria have not been characterized well enough to define 
potential metabolic phenotype improvements.  However, characterization of these individuals 
supports the notion that a KHK inhibitor is anticipated to eliminate excess carbohydrates without 
a mechanism-based safety issue. 
A clinical trial (Calle et al. 2019) in patients with NAFLD treated for 6 weeks with a KHK 
inhibitor revealed 
• statistically greater reduction from baseline in the whole liver fat 
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• dose-dependent decrease in fasting insulin and insulin resistance 
• dose-dependent percent changes in high-sensitivity C-reactive protein (reduction) and 
adiponectin (increase), and 
• six weeks of KHK inhibition was demonstrated to be safe and well tolerated. 
3.2.3. Preclinical Development of LY3478045 
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3.3. Benefit/Risk Assessment 
LY3478045 has not been administered to humans previously. 
Given that there are no significant adverse events (AEs) in subjects who have a genetic 
deficiency for KHK (essential fructosuria), there are no anticipated risks based on target 
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inhibition.  Further, the nonclinical pharmacology does not predict mechanism of action-based 
risk for this compound. 
Study GZKA will be conducted in accordance with principles outlined in the Guideline on 
Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational 
Medicinal Products (EMA 2017).  Based on the nonclinical data, LY3478045 is not considered 
to be a high uncertainty compound. 
There is no anticipated therapeutic benefit for the healthy subjects participating in this study. 
The available nonclinical safety information for LY3478045 supports its evaluation in healthy 
subjects. 
In recognition of the apparent steep dose-response curve in rats between the repeat-dose NOAEL 
in the 1-month GLP study and a nontolerated dose in a 14-day non-GLP study that was 
associated with mortality, sentinel dosing will be performed in Cohorts 3, 4, and 5 of Part A, as 
drug exposures in these dose cohorts are projected to approach 10-fold below the exposure 
observed at the NOAEL (
 in dogs).  
Overall, the nonclinical safety assessment risks identified for the planned doses in the current 
study are considered low. 
More details about the known and expected benefits, risks, serious adverse events (SAEs), and 
reasonably anticipated AEs of LY3478045 is available in the Investigator’s Brochure (IB). 
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4. Objectives and Endpoints 
Table GZKA.1 shows the objectives and endpoints of the study. 
Table GZKA.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To investigate the safety and tolerability of single and 
multiple oral doses of LY3478045 in healthy subjects. 
 
Incidence of TEAE and SAE. 
 
Clinically significant changes in vital signs data, safety 
laboratory parameters, and electrocardiograms. 
Secondary 
To determine the pharmacokinetics of LY3478045 
following single and multiple doses in healthy subjects. 
 
AUC(0-24), AUC(0-inf), Cmax, and tmax. 
 
Exploratory 
 
To determine the pharmacodynamic effects of 
LY3478045 following single and multiple doses in 
healthy subjects. 
AUC(0-24) of fructose concentration over time 
following fructose tolerance test. 
 
 
 
 
 
Abbreviations:  AUC(0-24) = area under concentration curve from time zero to 24 hours; AUC(0-inf) = area under 
concentration curve from time zero to infinite hours; Cmax = maximum observed drug concentration; OATP = 
organic-anion-transporting polypeptide; SAE = serious adverse event; tmax = time of Cmax; TEAE = treatment-
emergent adverse event. 
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5. Study Design 
5.1. Overall Design 
Study GZKA is a Phase 1, single site, randomized, double-blind, placebo-controlled, 2-part study 
of LY3478045 in healthy subjects. 
Part A:  single-ascending doses (SAD) (Section 5.1.1). 
Part B:  multiple-ascending dose (MAD) design that evaluates the potential for a drug-drug 
interaction (Section 5.1.2). 
During the study, replacement of subjects who do not have any safety concerns due to the study 
drug administration may be allowed at the discretion of investigator.  Replaced subject will 
assume the randomization schedule of the discontinued subject for treatment assignment. 
Safety, PD, PK, and other assessments and activities will be performed as specified in Section 2.  
Section 7.4.1 describes the criteria for dose escalation. 
Study governance considerations are described in Appendix 3. 
5.1.1. Part A 
Single-ascending oral doses of either LY3478045 or placebo will be administered in up to 
5 cohorts.  Each cohort will consist of 8 subjects.  Cohort 5 is an optional cohort that may be 
assessed based on the available safety and PK data from the previous cohorts.
 
A sentinel dosing strategy will be utilized for Cohorts 3, 4, and 5.  Two subjects (1 LY3478045 
and 1 placebo) in each cohort will receive a sentinel dose on the same day.  After at least 
48 hours after dose, the remaining subjects in each cohort may be dosed based on the available 
safety data. 
Figure GZKA.1 illustrates the study design. 
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Abbreviations:  LY = LY3478045; PL = placebo. 
Figure GZKA.1. 
Illustration of study design for Part A. 
5.1.2. Part B 
Part B will be initiated after assessing safety, tolerability, PK, and PD data through Cohort 3 in 
Part A. 
Multiple-ascending oral doses of LY3478045 will be administered once daily for 14 days in up 
to 4 cohorts.  Each cohort will consist of 8 subjects.  In Cohorts 1 and 3, six subjects will receive 
LY3478045 and 2 subjects will receive placebo.  In Cohorts 2 and 4, six subjects will receive 
LY3478045 followed by a single dose of atorvastatin 4 hours later and 2 subjects will receive 
placebo followed by a single dose of atorvastatin 4 hours later.  
The maximum dose in males and females in the MAD will be determined based on the PK 
analyses from previous cohorts, to ensure that the predicted mean exposure at steady state 
(AUC0-24) at the maximum dose in males does not exceed
A sentinel dosing strategy will be utilized in the cohorts for which the mean AUC0-24 is 
predicted to exceed 
 Two subjects (1 LY3478045 and 1 placebo) in the cohorts 
for which the mean AUC0-24 is predicted to exceed
will receive a sentinel dose 
on the same day.  At least 48 hours after dose, the remaining subjects in each cohort may be 
dosed based on the available safety data. 
Figure GZKA.2 illustrates the study design. 
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Abbreviations:  AT = atorvastatin; LY = LY3478045; PL = placebo. 
Figure GZKA.2. 
Illustration of study design for Part B. 
5.2. Number of Participants 
Up to 50 subjects may be enrolled in Part A to ensure that at least 40 subjects complete the study 
(depending on whether subjects will be enrolled in optional Cohort 5).  Up to 40 subjects may be 
enrolled in Part B to ensure that at least 32 subjects complete the study.  For purposes of this 
study, a subject completes the study when all scheduled procedures shown in the Schedule of 
Activities (Section 2) have been completed. 
5.3. End of Study Definition 
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject. 
5.4. Scientific Rationale for Study Design 
Healthy Subjects 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients, and therefore provides the most unbiased 
assessment of the safety and tolerability in this first-in-human study. 
Sentinel Dosing 
Consistent with the concept of sentinel dosing (EMA 2017), sentinel dosing will be performed 
in:  
Part A: Cohorts 3, 4, and 5 as the exposures of LY3478045 in these cohorts may approach 1/10th 
the exposure at the NOAEL (
).  Sentinel dosing will not be performed in 
Cohorts 1 and 2 as LY3478045 exposures in these cohorts are anticipated to be substantially 
below 1/10th the exposure at the NOAEL. 
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Part B: Sentinel dosing will be included for the cohort(s) of female subjects tested at dose(s) 
predicted to result in mean exposure(s) between
Blinding 
A subject- and investigator-blinded, randomized, placebo-controlled design has been chosen to 
minimize bias during the conduct of the study. 
Clinical Data 
Safety, tolerability, PK, and PD data in healthy subjects will assist in identifying an appropriate 
dose range for subsequent clinical studies. 
Periodic Reviews 
Periodic trial-level safety data reviews will ensure that any subject can be discontinued early, or 
the dose escalation can be terminated, or the study can be terminated, in case of any AE 
requiring such a decision. 
5.5. Justification for Dose 
A planned dose range of 20 to 320 mg was selected to assess safety, tolerability, PK, and PD of 
LY3478045 following SAD and MAD in healthy subjects: 
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The planned starting dose in Part A (SAD) is 20 mg in both male and female subjects.  The 
planned top dose in Part A (SAD) is a dose that is predicted to not exceed the mean exposure 
(it is currently anticipated that this dose is 320 mg; however, the 
exact dose will be determined once PK data are analyzed from the previous cohorts in Part A). 
The human PK in healthy subjects was projected with physiologically based pharmacokinetic 
(PBPK) modeling using data from in vitro studies in human systems. 
 
 
 The predicted 
efficacious dose is 100 to 200 mg once daily based on maintaining plasma exposure over the 
total cell-based KHK half maximal inhibitory concentration for 24 hours.  The PD measurement 
of serum fructose in Part A (SAD) will define the level of target engagement at each dose, which 
will further allow refinement of predicted efficacious dose. 
The starting dose of
 
 
 
  
The dose levels in MAD (Part B) will be selected based on available PK/PD data from Part A.  
The maximum dose in males in the MAD will be determined based on the PK analyses from 
previous cohorts to ensure that the predicted mean exposure AUC0-24 at the maximum dose in 
males does not 
  This is 1/10th of the mean exposure level observed at 75 
mg/kg in dogs, which is the lowest dose tested in dogs with no testicular findings.  The 
maximum dose in females in the MAD will be determined based on the PK analyses from 
previous cohorts to ensure that the predicted mean exposure AUC0-24 at the maximum dose in 
females does not exceed
  This is 1/12th of NOAEL exposure at 
 dose 
in dogs. 
 
 
 
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Table GZKA.2. 
 
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6. Study Population 
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Screening may occur up to 28 days prior to day of clinical research unit (CRU) admission.  
Subjects who are not enrolled within 28 days of screening may be subjected to an additional 
medical assessment and/or clinical measurements to confirm their eligibility. 
Subjects will continue the study procedures despite clinical laboratory abnormalities on Day -1 
of Part A and Part B (Cohorts 1 and 3) and on Day -3 of Part B (Cohorts 2 and 4) unless 
otherwise specified by the investigator or sponsor. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Subjects enrolled in Part A will not be allowed to participate in Part B of the study. 
6.1. Inclusion Criteria 
Subjects are eligible for inclusion in the study only if they meet all the following criteria at 
screening: 
[1] are overtly healthy subjects as determined through medical history and 
physical examination. 
[1a] male subjects agree to use a highly effective method of contraception for the 
duration of the study and for 90 days thereafter, which corresponds to 
4 months after the last investigational product dose.  See Sections 6.3.4 and 
7.4.1. 
[1b] female subjects not of child-bearing potential may participate and include 
those who are 
i. 
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis; or 
ii. 
postmenopausal – defined as either 
a. a woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has 
i. cessation of menses for at least 1 year without an 
alternative medical cause, AND 
ii. a follicle-stimulating hormone >40 mIU/mL; or 
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LY3478045 
b. A woman 55 years or older not on hormone therapy, who has 
had at least 12 months of spontaneous amenorrhea; or 
c. A woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy. 
[2] are aged between 18 and 60 years, inclusive.  
[3] have a body mass index of ≥18.5 and ≤40 kg/m2. 
[4] have had a stable weight for the 3 months prior to screening and enrollment 
(<5% body weight change) and have not received dietary intervention in the 
3 months prior to screening and enrollment. 
[5] have safety laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator. 
[6] have venous access enough to allow for blood sampling as per the protocol. 
[7] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures including dietary 
requirements. 
[8] are able and willing to give signed informed consent. 
6.2. Exclusion Criteria 
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening: 
[9] 
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling. 
[10] are Lilly employees. 
[11] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
[12] have participated, within 30 days of screening, in a clinical study involving an 
investigational product.  At least 5 half-lives or 30 days (whichever is longer) 
should have passed. 
[13] have known allergies to LY3478045, related compounds, or any components 
of the formulation, or history of significant atopy. 
[14] 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.  
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[15] have blood pressure of >160/90 mmHg and pulse rate <50 or >100 bpm, 
supine (at screening), or with minor deviations judged to be acceptable by the 
investigator (see Section 6.4). 
[16] have a significant history of or current CV (e.g. myocardial infarction, 
congestive heart failure, cerebrovascular accident, venous thromboembolism), 
respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk while taking the 
investigational product; or of interfering with the interpretation of data. 
[17] have a history of fructosuria. 
[18] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies. 
[19] show evidence of hepatitis B and positive hepatitis B surface antigen. 
[20] show evidence of hepatitis C and/or positive hepatitis C antibody. 
[21] have obvious clinical signs or symptoms of liver disease, acute or chronic 
hepatitis. 
[22] have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), creatine phosphokinase >1.5x upper limit 
of normal (ULN), or total bilirubin level (TBL) ≥1.5x ULN.  Participants with 
Gilbert’s syndrome can be enrolled with TBL of <2x ULN. 
[23] intend to use over-the-counter or prescription medication including herbal 
medications such as St. John’s wort and/or vitamin/mineral supplements 
within 14 days prior to dosing. 
[24]   
[25]
[26] have consumed or intend to consume herbal supplements, grapefruits or 
 grapefruit-containing products, Seville oranges or Seville orange-containing 
products, star fruits or star fruit-containing products, pomelo, or commercial 
 apple juice or orange juice within 14 days prior to the first dose of any study 
drug until discharge from the study 
[27] have donated blood of more than 450 mL or have participated in a clinical 
study that required similar blood volume drawn within the past 3 calendar 
months. 
[28] regularly use known drugs of abuse and/or positive urine drug screen at 
screening or check-in. 
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[29] smoke >10 cigarettes per day or the equivalent or are unable or unwilling to 
refrain from nicotine during CRU admission. 
[30] have either moderate or severe alcohol consumption.  Moderate alcohol 
consumption is defined as 1 standard drink per day for women and 2 standard 
drinks per day for men, whereby, 1 standard drink is equivalent to 12 ounces 
of beer (5% alcohol) or 5 ounces of wine (12% alcohol) or 1.5 ounces of 
distilled spirits (40% alcohol).  
[31] have estimated glomerular filtration rate <60 mL/min/1.73 m2. 
[32] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study. 
6.3. Lifestyle and/or Dietary Requirements 
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study. 
6.3.1. Meals and Dietary Restrictions 
Subjects should be fasted for 8 hours prior to predose blood sampling, performing ECGs, and 
LY3478045 dose administration. On days of
assessment 
(Cohorts 2 and 4), subjects should fast overnight, eat breakfast, and be given 
 
after breakfast (Day -2) or 4 hours after LY3478045 (Day 7). Subjects should not eat again until 
2 hours after 
 administration on Days -2 and Day 7. 
6.3.2. Caffeine, Alcohol, and Tobacco 
Subjects will be encouraged to maintain their regular caffeine consumption. 
Nicotine use is not permitted at the CRU. 
Alcohol consumption is not permitted from 48 hours prior to admission and while resident at the 
CRU. 
6.3.3. Activity 
Subjects should avoid strenuous exercise immediately prior to the screening visit and should 
avoid strenuous exercise 3 days prior to each admission and while at the CRU.  Subjects should 
maintain their normal levels of activity at other times. 
6.3.4. Contraception for Males 
Male subjects (regardless of their fertility status) with nonpregnant female partners of 
childbearing potential must agree to either remain abstinent (if this is their preferred and usual 
lifestyle), or to use condoms as well as 1 additional highly effective (<1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted contraceptives, or intrauterine 
devices) or 2 effective methods of contraception (such as diaphragms with spermicide or cervical 
sponges) from the entirety of the study, plus 90 days thereafter, which corresponds to 4 months 
after the last investigational product dose. 
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Men and their partners may choose to use a double-barrier method of contraception; however, 
barrier protection methods without concomitant use of a spermicide are not considered an 
effective or acceptable method of contraception (each barrier method must include use of a 
spermicide).  The use of male and female condoms as a double-barrier method is not considered 
acceptable due to the high failure rate when these barrier methods are combined. 
Male subjects with pregnant partners should use condoms during intercourse from the entirety of 
the study, plus 90 days thereafter, which corresponds to 4 months after the last investigational 
product dose. 
Male subjects should refrain from sperm donation from the entirety of the study, plus 90 days 
thereafter, which corresponds to 4 months after the last investigational product dose.  
Male subjects who chose to remain abstinent (if this is their preferred and usual lifestyle) must 
adhere to the contraception requirements indicated above should their circumstances change. 
Male subjects who are in exclusively same-sex relationships (as their preferred and usual 
lifestyle) are not required to use contraception. 
6.4. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened with the exception of vital signs and laboratory values slightly outside the normal 
range, in the opinion of the investigator.  These participants may be re-screened.  However, 
participants who were eligible for inclusion in previous cohorts, but who were not randomized 
for nonmedical reasons, may be re-assessed for inclusion in subsequent cohorts. 
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7. Treatment 
7.1. Treatment Administered 
LY3478045 or placebo will be administered orally with approximately 240 mL of room 
temperature water in the morning of each dosing day (Day 1 in SAD; Days 1 to 14 in MAD) in a 
sitting position.  Subjects will not be allowed to lie supine for 2 hours after dosing, unless 
clinically indicated or for study procedures. 
Table GZKA.3. 
Treatments Administered 
Treatment Name 
LY3478045 
Placebo 
Atorvastatin 
Dosage Formulation 
Capsules 
Tablets 
Dose strength 
- 
40 mg 
Route of Administration 
Oral 
Oral 
Oral 
The investigator or designee is responsible for 
• explaining the correct use of the investigational product(s) to the site personnel 
• verifying that instructions are followed properly 
• maintaining accurate records of investigational product dispensing and collection, and 
• returning all unused medications to Lilly or its designee at the end of the study 
Note:  In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose off the clinical materials.  
7.1.1. Packaging and Labeling 
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Each capsule of LY3478045 will contain 
 active ingredient.  Placebo capsules will 
match LY3478045 capsules in appearance. 
LY3478045 and matching placebo capsules will be supplied to the investigator by Lilly for 
dispensing by unblinded pharmacy staff.  
Atorvastatin will be sourced locally by the site. 
7.2. Method of Treatment Assignment 
Subjects will be randomized to a treatment using a computer-generated randomization schedule. 
7.2.1. Selection and Timing of Doses 
The doses will be administered at the visits and times specified in Section 2 of this protocol.  The 
actual time of all dose administrations will be recorded in the subject’s case report form (CRF). 
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7.3. Blinding 
Blinding will be maintained throughout the conduct of the study as described in the separate 
blinding plan. 
The unblinded pharmacist or designee will prepare the study drug. 
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study subject, may be opened during the study only if the subject’s well-being requires 
knowledge of the subject’s treatment assignment. 
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist (CP) 
or clinical research physician (CRP) for the study participant to continue in the study.  During 
the study, emergency unblinding should occur only by accessing the study subject’s emergency 
code. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible. 
Upon completion of the study, all codes must be returned to Lilly or its designee. 
7.4. Dose Modification 
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
highest planned dose has been administered, or the maximum tolerated dose (MTD) is 
determined.  If the highest planned dose is not reached, the highest dose level that is tolerated 
will be designated as the MTD. 
Safety and tolerability data will be the primary criteria for the dose escalation.  No dose decision 
can occur without prior discussion and agreement between the investigator and the Lilly 
CP/CRP/study team. 
Any available PK data may be used to guide dose selection or to determine if the number of 
doses to be studied may be reduced. 
After review of these data, an agreement on the appropriate dose will be made by the investigator 
and sponsor for the next cohort/dose level.  A lower dose may be administered; dose levels may 
be repeated provided that it is not the result of a safety finding; or the magnitude of dose 
escalations may be reduced following data review, provided that subsequent escalations do not 
increase by more than approximately 3-fold (a half-log increment). 
7.4.1. Dose Decision/Escalation 
For dose escalation decisions in Part A and Part B, the following must occur: 
• All planned subjects in current cohort must have been dosed. 
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• Clinical assessment through Day 7 for at least 6 of 8 subjects. 
• Safety laboratory tests are obtained from Day 7 for at least 6 of 8 subjects. 
For Cohorts 3, 4, and 5 in Part A, the PK results (Cmax, AUC0-inf, AUC0-tlast, and apparent 
clearance of drug [CL/F]) estimated from the previous cohorts will also be used as supporting 
data for dose escalation.  For Cohort 2 in Part A, PK results may be used if available at the time 
of dose escalation decision.  
In Part A, male and female subjects will only be dosed up to the dose with predicted mean 
exposure not exceeding 
 For Part B, the PK results (Cmax, AUC0-24, and 
apparent clearance of drug [CL/F]) estimated from the previous cohorts will also be used as 
supporting data for dose escalation. 
Male subjects are allowed in Part B in the cohorts for which the predicted mean exposure AUC0-
24 levels for the dose will not exceed
 1/10th exposure level observed at
in dogs, which is the lowest dose tested in dogs with no testicular findings, as determined from 
PK data in Parts A and B.   
Female subjects are allowed in Part B in every cohort. The predicted mean exposure AUC0-24 
levels for the doses investigated in Part B will not exceed 
, 1/12th exposure level 
observed at
 in dogs, as determined from PK data in Parts A and B.  
More details about the planned dose levels in Parts A and B are available in Section 5.5. 
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be interrupted until a further sponsor decision: 
1) One or more subjects on active drug experience an SAE considered to be related to 
LY3478045. 
2) One or more subjects on active drug experience 2 clinically significant events 
defined as moderate to severe symptoms, clinical signs, and clinical laboratory 
findings that could cause harm to health.  The clinically significant events will 
be determined by the investigator or Lilly CP and may include findings that do 
not fulfill the criteria for SAEs. 
7.5. Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational products 
received and any discrepancies are reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational products.  All 
investigational products should be stored in an environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records). 
7.6. Treatment Compliance 
The investigational products will be administered at the clinical site, and documentation of 
treatment administration will occur at the site. 
7.7. Concomitant Therapy 
Subjects on stable concomitant medications at the time of study entry should continue their 
regular, unchanged dose throughout the study. 
In general, concomitants medication should be avoided; however, acetaminophen (1 g, maximum 
4 g/24 hours) may be administered at the discretion of the investigator for treatment of headache, 
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP or CRP.  Any medication used during the study must be documented. 
Vitamin/mineral supplements are not allowed during the study. 
Drugs that are known strong inducers or inhibitors of CYP3A or OATPs and known substrates of 
OATPs or BCRP are specifically excluded.  For more information, refer to Appendix 6. 
7.8. Treatment after the End of the Study 
Not applicable. 
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8. Discontinuation Criteria 
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol. 
Subjects discontinuing from the treatment or from the study prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 of this protocol. 
8.1. Discontinuation from Study Treatment 
In Part B, discontinuation of the investigational product for abnormal liver test results should be 
considered by the investigator when a subject meets 1 of the following conditions, after 
consultation with the Lilly-designated medical monitor: 
• ALT or AST >8X ULN 
• ALT or AST >5X ULN sustained for more than 2 weeks or 
• ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio >1.5 or 
• ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• ALP >3X ULN 
• ALP >2.5X ULN and TBL >2X ULN 
• ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
• creatine kinase >5x ULN. 
8.2. Discontinuation from the Study 
Subjects will be discontinued under the following circumstances: 
• Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study 
• Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP) 
o Any TEAE or SAE considered possibly or probably related to study drug that is 
severe or medically significant but not immediately life threatening; or where 
hospitalization or prolongation of hospitalization is indicated; or is disabling; or 
limits self-care activities of daily living. 
o Any TEAE or SAE regardless of attribution to study drug that has life-threatening 
consequences or urgent intervention is indicated. 
• Investigator Decision 
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o the investigator decides that the subject should be discontinued from the study 
o if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent 
• Subject Decision 
o the subject, or legal representative, requests to be withdrawn from the study. 
The replacement strategy for discontinued participants is described in Section 10.1.  If deemed 
appropriate by the investigator, early discontinuation procedures will be performed as shown in 
the Schedule of Activities (Section 2). 
8.3. Subjects Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 
8.4. Discontinuation of the Study 
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
A safety investigation will be triggered to determine if the study should be terminated early 
based on the following criteria: 
o Three study participants develop the same TEAE or SAE considered possibly or 
probably related to study drug that is severe or medically significant, but not 
immediately life threatening; or where hospitalization or prolongation of 
hospitalization is indicated; or is disabling; or limits self-care activities of daily 
living OR 
o Two study participants develop any TEAE or SAE regardless of attribution to 
study drug that has life-threatening consequences or requires urgent intervention 
OR 
o Death of any study participant at any time related to AE. 
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9. Study Assessments and Procedures 
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing). 
Appendix 2 lists the laboratory tests that will be performed for this study. 
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study. 
Unless otherwise stated in the subsequent subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards. 
The specifications in this protocol for the timings of safety, PK, and PD sampling are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon the safety and PK information obtained.  The scheduled time points may be subject 
to minor alterations; however, the actual time must be correctly recorded in the electronic case 
report form (eCRF).  Failure to obtain samples due to clinical issues, such as problems with 
venous access, technical difficulty with obtaining samples, or if the subject does not show up for 
planned procedural visits will not be considered a protocol deviation.  However, the CRU will 
still be required to notify the sponsor in writing to account for missing samples to facilitate data 
reconciliation. 
If the predicted mean exposure for the dose at any cohort is estimated to be higher than 71.7 
µg∙hr/mL, only female subjects will be included in the cohort and mandated to stay in the CRU 
until 24 hours after the last dose. 
9.1. Efficacy Assessments 
This section is not applicable for this study. 
9.2. Adverse Events 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. 
The investigator is responsible for the appropriate medical care of subjects during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed up until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
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The investigator will record all relevant AE and SAE information in the eCRF.  After the 
informed consent form (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.   
The investigator will interpret and document whether an AE has a reasonable possibility of being 
related to study treatment, or a study procedure, considering the disease, concomitant treatment 
or pathologies. 
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the investigational 
product unless there is clear evidence that the event is not related. 
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the study. 
If a subject’s investigational product is discontinued because of an AE, study site personnel must 
report this to Lilly or its designee via eCRF. 
9.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in 1 of the following: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (i.e., immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• important medical events that may not be immediately life threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 1 
of the other outcomes listed in the definition earlier. 
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible. 
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed up with official notification 
on study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information. 
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
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investigational product, AND is considered reasonably possibly related to a study procedure then 
it MUST be reported. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus. 
9.2.1.1. Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidance. 
9.2.2. Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials to ensure the safety of study participants, monitor quality, and to facilitate process 
and product improvements. 
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product [or drug delivery system] so that the 
situation can be assessed. 
9.3. Treatment of Overdose 
For the purposes of this study, an overdose of LY3478045 is considered any dose higher than the 
dose assigned through randomization. 
Refer to the LY3478045 IB for more details. 
9.4. Safety 
9.4.1. Laboratory Tests 
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2) locally. 
Except for safety laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the study. 
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9.4.2. Physical Examination 
Physical examinations and routine medical assessments including body temperature will be 
conducted as specified in the Schedule of Activities (Section 2) and as clinically indicated.  
Subjects will be advised to wear sunglasses, hats, and sunscreen during sun exposure. During 
physical examination, treatment-emergent ocular and dermal photosensitivity events will also be 
assessed by asking the subject for any abnormal eye or skin irritation, redness, itching, burning 
sensation in daylight or on exposure to sunlight.  The subject will be examined for abnormal skin 
erythema and hyperemia in exposed areas, hyperemia, scleritis, and conjunctivitis.   
9.4.2.1. Vital Signs 
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2). 
Blood pressure and pulse rate should be measured after at least 5 minutes supine. 
If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 2 minutes. 
If the subject feels unable to stand, supine vital signs only will be recorded.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted. 
9.4.3. Electrocardiograms 
For each subject, single and triplicate ECGs should be collected according to the Schedule of 
Activities (Section 2). 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational product should be reported to Lilly, or its 
designee, as an AE via eCRF.  
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  Consecutive replicate ECGs will be obtained at approximately 1-minute 
intervals.  Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary. 
Electrocardiograms will be interpreted by a qualified investigator (physician or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management should any clinically relevant findings be 
identified. 
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (e.g., palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
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or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point. 
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (e.g., demographics and 
study details) then store the ECGs in a database.  At a future time, the stored ECG data may be 
overread at the central ECG laboratory for further evaluation of machine-read measurements or 
to meet regulatory requirements. 
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used). 
9.4.4. Body Temperature 
Body temperature will be measured as specified in the Schedule of Activities (Section 2) and as 
clinically indicated. 
9.4.5. Safety Monitoring 
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study. 
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data: 
• trends in safety data 
• laboratory analytes, and 
• adverse events. 
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist. 
If the safety monitoring procedure uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the unblinding/blinding plan.  
9.4.5.1. Hepatic Safety 
If a study participant experiences elevated ALT ≥3x ULN, AST ≥3x ULN, ALP ≥2x ULN, or 
TBL ≥2x, tests specified in Appendix 4 should be repeated within 48 to 72 hours to confirm the 
abnormality and to determine if the abnormality is increasing or decreasing.  
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (e.g., heart 
failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
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medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
consumption 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. 
Additional hepatic safety data collection (hepatic safety CRF) should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
• 
Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests  
• 
Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
• 
Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests  
• 
Hepatic event considered to be an SAE 
• 
Discontinuation of study drug due to a hepatic event 
Note:  The interval between the 2 consecutive blood tests should be at least 2 days. 
9.4.5.2. Testicular safety 
Male subjects will be enrolled in this trial only if they agree to comply with the contraception 
requirements specified in this protocol.   
In Part B (MAD), blood samples for evaluating hormonal biomarkers of testicular injury (serum 
concentrations of total testosterone, follicle-stimulating hormone, and luteinizing hormone) will 
be collected at the visits and times specified in the Schedule of Activities (Section 2). 
To mitigate risks of testicular injury, in Part B of the study (MAD), male participants’ dose will 
be restricted to the dose with predicted mean exposure not exceeding
which is the lowest dose tested in dogs 
with no testicular findings. 
9.5. Pharmacokinetics 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3478045.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
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Urine samples will be collected for the characterization of renal clearance.  Total urine output for 
the appropriate period after investigational product administration will be collected, pooled, and 
refrigerated.  The final urine sample will be collected at a time that coincides with a PK sample.  
At the end of the collection period, the total urine volume will be recorded.  Urine samples will 
be used to determine creatinine, quantification of LY3478045, and exploratory metabolite 
identification. 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood 
samples will be collected to determine serum creatinine measurements.  
Atorvastatin will be administered in Part B as indicated in the Schedule of Activities (Section 2).  
Blood samples of approximately 2 mL each will be collected to determine the plasma 
concentrations of atorvastatin and metabolites. 
9.5.1. Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3478045 will be assayed using a validated liquid chromatography-tandem 
mass spectrometry method.  Analyses of samples collected from placebo-treated subjects are not 
planned. 
Plasma concentrations of
 
 will be analyzed using validated liquid 
chromatography/tandem mass assay.  Analyses of samples collected from LY- and placebo-
treated subjects are planned. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses. 
9.6. Pharmacodynamics 
Fructose Tolerance Test:  Three meals (breakfast, lunch, and dinner) will be served at 
approximately 20 minutes, 6 hours, and 12 hours after dose with low fructose content.  A 
beverage containing mixture of fructose and glucose  
 
 in approximately 300 to 500 mL  of non-caloric solution) will be served with 
each of the 3 meals on Day 1 in Part A (SAD) and Days 1 and 14 in Part B (MAD).  The 
beverage should be served after a portion of the meal has been consumed.  The meals should 
start at the defined time (20 minutes, 6 hours, and 12 hours postdose) Blood samples for the 
analysis of fructose will be collected into appropriately labeled tubes containing ethylene 
diamine tetra acetic acid at the time points specified in the Schedule of Activities (Section 2).  
Sample handling and shipment to the central laboratory will occur per instructions given to the 
study site.  
The samples will be stored for up to a maximum of 1 year after the last subject visit for the study 
at a facility selected by the sponsor. 
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9.7. Genetics 
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3478045 and to investigate genetic variants thought to play a role in NASH.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.   
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or institutional review boards (IRBs) impose shorter time limits, 
for the study at a facility selected by Lilly or its designee.  This retention period enables use of 
new technologies, response to regulatory questions, and investigation of variable response that 
may not be observed until later in the development of LY3478045 or after LY3478045 is 
commercially available.   
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8. Biomarkers 
9.8.1. 
 
9.8.1.1. Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
 will be assayed using a validated liquid 
chromatography tandem mass spectrometry method.  It is planned that samples collected from 
both LY3478045- and placebo-treated subjects will be analyzed. 
9.8.2. Fasting Insulin and Adiponectin 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine the plasma concentrations of fasting insulin and adiponectin. 
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9.8.3. Nonpharmacogenetic Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of subject response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.  
Blood samples for nonpharmacogenetic biomarker research will be collected at the times 
specified in the Schedule of Activities (Section 2), where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3478045, pathways associated with type 2 diabetes mellitus (T2DM), diabetic complications, 
obesity, or the potential mechanism of action of LY3478045 and/or research method, or for 
validating diagnostic tools or assay related to T2DM, diabetic complications, obesity, or the 
potential mechanism of action of LY3478045. 
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, at a facility selected by Lilly 
or its designee.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of LY3478045 or after LY3478045 is commercially available.   
9.9. Health Economics 
This section is not applicable for this study. 
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10. Statistical Considerations and Data Analysis 
10.1. Sample Size Determination 
The sample size for Parts A and B of the study was chosen to provide sufficient data for 
evaluating safety, PK, and/or PD parameters, as well as primary objectives of this study.  For 
details regarding the number of subjects planned for each part, refer to Section 5.2. 
Subjects who are randomized but not administered treatment, and who are discontinued from the 
study (providing that discontinuation was not as a result of a safety finding) may be replaced to 
ensure that enough subjects may complete the study. 
10.2. Populations for Analyses 
10.2.1. Study Participant Disposition 
A detailed description of subject disposition will be provided at the end of the study.  
10.2.2. Study Participant Characteristics 
The subject’s age, sex, race, weight, height, and other demographic characteristics will be 
summarized. 
10.3. Statistical Analyses 
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. 
Pharmacokinetic/PD analyses will be conducted on data from all subjects who receive at least 1 
dose of the investigational product and have evaluable PK and PD data. 
Safety analyses will be conducted for all enrolled subjects, whether they completed all protocol 
requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.   
10.3.1. Safety Analyses 
10.3.1.1. Clinical Evaluation of Safety 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the Medical Dictionary 
for Regulatory Activities. 
The number of investigational product-related SAEs will be reported. 
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10.3.1.2. Statistical Evaluation of Safety 
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 
ECG parameters.  All laboratory values will be reported in both absolute values and changes 
from baseline in units acceptable to the FDA. The parameters will be listed and summarized 
using standard descriptive statistics. 
Analyses may be performed to determine the effects of PK parameters on QT interval corrected.  
A concentration-response analysis will be performed according to International Council for 
Harmonisation (ICH)-E14 (the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs) guidelines. 
Additional analysis will be performed if warranted upon review of the data. 
10.3.2. Pharmacokinetic Analyses 
10.3.2.1. Pharmacokinetic Parameter Estimation 
Pharmacokinetic parameter estimates for LY3478045 will be calculated using standard 
noncompartmental methods of analysis in Parts A and B. 
Parts A and B: 
The primary parameters for analysis will be Cmax, time of Cmax (tmax), AUC from time zero to 
24 hours (AUC0-24), and AUC from time zero to infinity (AUC0-inf) of LY3478045.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported. 
Part A only: 
Renal clearance of LY3478045 will be calculated as the ratio of amount excreted/AUC in Part A 
only.  This will be compared to the unbound glomerular filtration rate, which is estimated using 
creatinine. 
Part B only: 
Accumulation ratio for LY3478045 based on AUC0-24 and Cmax may be reported. 
The primary parameters for analysis for
 will be 
AUC(0-inf) and Cmax.  Other parameters, including tmax, t1/2, CL/F, apparent volume of 
distribution during the terminal elimination phase (Vz/F), metabolite ratios based on AUC0-inf, 
and AUC from time zero to time t, where t is the last time point with a measurable concentration 
(AUC0-tlast) 
 will be calculated as appropriate. 
10.3.2.2. Pharmacokinetic Statistical Inference 
The descriptive statistics for the PK parameters will be provided for each dose level.  Where 
appropriate, geometric mean and coefficient of variation will be reported.  The dose 
proportionality for LY3478045 will be assessed for AUC and Cmax using a power model.  The 
power parameter will be evaluated to determine the dose proportionality. 
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Comparisons of PK parameters between different treatments on the PK sampling days will be 
performed with appropriate statistical models.  Test significance (unadjusted p values) and 90% 
confidence intervals will be reported.  The analyses will be detailed in a separate statistical 
analysis plan.  
10.3.3. Pharmacodynamic Analyses 
10.3.3.1. Pharmacodynamic Parameter Estimation 
The primary PD effect will be evaluated using fructose tolerance test (FTT).  Area under the 
curve over times sampled for FTT will be calculated using trapezoid methods.  Other biomarkers 
including low- and high-density lipoproteins, cholesterol, and triglycerides will be determined if 
appropriate. 
10.3.3.2. Pharmacodynamic Statistical Inference 
Pharmacodynamic data will be summarized using descriptive statistics.  Where appropriate, 
geometric mean and coefficient of variation will be reported.  Comparison of FTT and biomarker 
measurements between different treatments over time will be performed with appropriate 
statistical models.  Test significance (unadjusted p-values) and 90% confidence intervals will be 
reported.  The analyses will be detailed in a separate statistical analysis plan. 
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses 
Pharmacokinetic/PD modeling may be employed to characterize the exposure-response 
relationships between LY3478045 concentrations and various PD endpoints, provided enough 
data are available. 
10.3.5. Data Review During the Study 
Interim access to safety and tolerability data is scheduled to occur after every dosing session.  
Pharmacokinetic/PD data may be included in these reviews, when available.  The purpose of 
these reviews is to guide dose selection for the next dosing session, and/or to inform the design 
of subsequent studies.  The investigator and the Lilly sponsor team will make the determination 
regarding dose escalation, based upon their review of the data.  The investigator will remain 
blinded, and the Lilly sponsor team will be unblinded during these reviews. 
10.3.6. Interim Analyses 
No interim analyses are planned for this study except the interim access to safety, tolerability, 
and other PK/PD data to guide dose selection for the next dosing session as described in 
Section 10.3.5. 
If an unplanned interim analysis is deemed necessary, the Lilly CP, CRP/investigator, or 
designee will consult with the appropriate medical director or designee to determine if it is 
necessary to amend the protocol. 
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11. References 
Andres-Hernando A, Johnson RJ, Lanaspa MA. Endogenous fructose production: what do we 
know and how relevant is it? Curr Opin Clin Nutr Metab Care. 2019;22(4):289-294. 
Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, 
Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver fibrosis, but 
no other histologic features, is associated with long-term outcomes of patients with 
nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389-397. 
Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr 
Metab (Lond). 2005;2(1):5. 
Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: 
molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol 
Genet. 1994;3(9):1627-1631.  
Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may 
play a role in the epidemic of obesity. Am J Clin Nutr. 2004;79:537-543. 
Calle R, Bergman A, Somayaji V, Chidsey K, Kazierad D. PS-110-ketohexokinase inhibitor 
PF-06835919 administered for 6 weeks reduces whole liver fat as measured by magnetic 
resonance imaging-proton density fat fraction in subjects with non-alcoholic fatty liver disease. 
J Hepatol. 70(1)(Suppl);2019:e69-e70. 
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, 
Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice 
guidance from the American Association for the Study of Liver Diseases. Hepatology. 
2018;67(1):328-357. 
Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and 
outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. 
Gastroenterology. 2011;141(4):1249-1253. 
Collin LJ, Judd S, Safford M, Vaccarino V, Welsh JA. Association of sugary beverage 
consumption with mortality risk in us adults: a secondary analysis of data from the REGARDS 
study. JAMA Netw Open. 2019;2(5):e193121. 
de Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage 
consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 
2012;125(14):1735-1741. 
[EMA] European Medicines Agency. Guideline on strategies to identify and mitigate risks for 
first-in-human and early clinical trials with investigational medicinal products. 20 July 2017. 
Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf.  
Accessed on 14 November 2019. 
[FDA] Food and Drug Administration. Guidance for industry on estimating the maximum safe 
starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 2005. 
Available at: https://www.fda.gov/media/72309/download. Accessed 23 December 2019. 
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Froesch ER. Disorders of fructose metabolism. J Clin Pathol Suppl (Assoc Clin Pathol). 
1969;2:7–12. 
Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage 
consumption and risk of coronary heart disease in women. Am J Clin Nutr. 
2009;89(4):1037-1042. 
Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic 
disease. J Clin Invest. 2018;128(2):545-555. 
Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, Jackman MR, Asipu A, 
Roncal-Jimenez CA, Kosugi T, Rivard CJ, Maruyama S, Rodriguez-Iturbe B, Sánchez-Lozada 
LG, Bonthron DT, Sautin YY, Johnson RJ. Opposing effects of fructokinase C and A isoforms 
on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci U S A. 
2012;109(11):4320-4325. 
Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, McMahan 
RH, Abdelmalek MF, Rosen HR, Jackman MR, MacLean PS, Diggle CP, Asipu A, Inaba S, 
Kosugi T, Sato W, Maruyama S, Sánchez-Lozada LG, Sautin YY, Hill JO, Bonthron DT, 
Johnson RJ. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent 
on fructokinase. Hepatology. 2013;58(5):1632-1643. 
Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, Murugesan S, Gaud N, 
Selvam S, Date O, Cheng Y, Shipkova P, Dai J, Humphreys WG, Marathe P. Coproporphyrins 
in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug 
Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition. J Pharmacol 
Exp Ther. 2016;358(3):397-404. 
Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzycki P, Rivard C, Inaba S, Roncal-
Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-
Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ. Endogenous fructose 
production and metabolism in the liver contributes to the development of metabolic syndrome. 
Nat Commun. 2013;4:2434. 
Lanaspa MA, Andres-Hernando A, Orlicky DJ, Cicerchi C, Jang C, Li N, Milagres T, Kuwabara 
M, Wempe MF, Rabinowitz JD, Johnson RJ, Tolan DR. Ketohexokinase C blockade 
ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest. 
2018;128(6):2226-2238. 
Laron Z. Essential benign fructosuria. Arch Dis Child. 1961;36:273-277. 
Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the 
pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81(2):194-
204. 
Softic S, Gupta MK, Wang GX, Fujisaka S, O’Neill BT, Rao TN, Willoughby J, Harbison C, 
Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR. Divergent effects of glucose 
and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017;127(11):4059-
4074. 
Tappy L, Mittendorfer B. Fructose toxicity: is the science ready for public health actions? Curr 
Opin Clin Nutr Metab Care. 2012;15(4):357–361. 
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Vos MB, McClain CJ. Fructose takes a toll. Hepatology. 2009;50(4):1004-1006. 
Weber KS, Simon MC, Strassburger K, Markgraf DF, Buyken AE, Szendroedi J, Müssig K, 
Roden M; GDS Group. Habitual fructose intake relates to insulin sensitivity and fatty liver 
index in recent-onset type 2 diabetes patients and individuals without diabetes. Nutrients. 
2018;10(6).pii:E774. 
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. 
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev 
Gastroenterol Hepatol. 2018;15(1):11-20. 
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12. Appendices 
 
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Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
AE 
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
serum aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC0-inf 
AUC from time zero to infinity 
BCRP 
breast cancer resistance protein 
Blinding 
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final database 
lock. 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the subjects are aware of the treatment received 
CL/F 
apparent clearance of drug 
Complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
Compliance 
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements. 
Confirmation 
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be re-tested at some defined time point, depending on the steps required to obtain 
confirmed results. 
CP 
clinical pharmacologist 
CRF 
case report form 
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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 
CV 
cardiovascular 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Enroll 
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment. 
Enter 
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
ethical review board 
FTT 
fructose tolerance test 
GCP 
good clinical practice 
GLP 
Good Laboratory Practice 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to the 
subject’s decision to participate.  Informed consent is documented by means of a written, 
signed, and dated informed consent form.   
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
Investigator 
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator. 
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KHK 
ketohexokinase 
legal 
representative 
An individual or judicial or other body authorized under applicable law to consent, on behalf 
of a prospective subject, to the subject’s participation in the clinical study. 
MTD 
maximum tolerated dose 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect level 
non-investigational 
product 
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response. 
open-label 
A study in which there are no restrictions on knowledge of treatment allocation, therefore the 
investigator and the study participant are aware of the drug therapy received during the 
study. 
PBPK 
physiologically based pharmacokinetics 
PK/PD 
pharmacokinetic(s)/pharmacodynamic(s) 
QTc 
corrected QT 
Randomize 
the process of assigning subjects to an experimental group on a random basis 
SAE 
serious adverse event 
Screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.   
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin level 
TEAE 
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment  
ULN 
upper limit of normal 
 
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Appendix 2. 
Clinical Laboratory Tests (Fasting) 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration  
Phosphorus 
Leukocytes (WBC)  
Platelets 
Magnesium 
Glucose 
Creatinine 
 
 
Differential WBC (absolute counts of): 
Blood urea nitrogen (BUN) 
Neutrophils 
Uric acid 
Lymphocytes 
Total cholesterol 
Monocytes 
Total protein 
Eosinophils 
Albumin 
Basophils 
Total bilirubind 
 
Alkaline phosphatase (ALP) 
Urinalysise 
Aspartate aminotransferase (AST) 
Specific gravity 
Alanine aminotransferase (ALT) 
pH 
Creatine Phosphokinase 
Protein 
Gamma-glutamyl transferase (GGT) 
Glucose 
 
Ketones 
Ethanol testinga,b 
Bilirubin 
Urine drug screena,b 
Urobilinogen 
Hepatitis B surface antigena 
Blood 
Hepatitis C antibodya 
Nitrite 
HIVa 
 
Pregnancy test 
 
FSHa,c  
 
Thyroid-stimulating hormonea 
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell. 
a Performed at screening only. 
b Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities. 
c Performed in 40- to 55-year old females to confirm their post-menopausal status.  In males, FSH will be collected 
at screening and at other times indicated in the Schedule of Activities, as part of testicular hormonal function 
assessment. 
d Reflex test will be done if abnormalities are noted. 
e Reflex microscopy  will be done if abnormalities are noted. 
 
 
 
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Appendix 3. 
Study Governance, Regulatory and Ethical 
Considerations 
Informed Consent 
The investigator is responsible for 
• ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary. 
• ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product. 
• answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study. 
• providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file. 
Recruitment 
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly. 
Ethical Review 
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by ICH guidelines and other 
applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP. 
The study site’s ERB(s) should be provided with the following: 
• the current IB and updates during the course of the study 
• ICF 
• relevant curricula vitae 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with 
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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines  
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third-party organization. 
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.   
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative. 
Final Report Signature 
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report. 
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
• provide instructional materials to the study sites, as appropriate. 
• provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures. 
• make periodic visits to the study site. 
• be available for consultation and stay in contact with the study site personnel through 
mail, telephone, and/or fax. 
• review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection. 
• conduct a quality review of the database. 
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
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LY3478045 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents. 
Data Collection Tools/Source Data 
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system. 
Data Protection 
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.   
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor. 
Study and Site Closure 
Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
Discontinuation of the Study 
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
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Appendix 4. 
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin time 
WBC 
Prothrombin time, INR 
Neutrophils 
 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
TBL 
Hepatitis E antibody, IgG 
Conjugated bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear Antibodya 
AST 
Alkaline Phosphatase Isoenzymesa 
GGT 
CPK  
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cell; TBL = total bilirubin level; WBC = white blood cell. 
a Assayed by Lilly-designated or local laboratory. 
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Appendix 5. 
Blood Sampling Summary 
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.   
Protocol J2M-MC-GZKA Sampling Summary for Part A 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
6 
72 
Serum creatinine 
2.5 
3 
7.5 
Pharmacokinetics  
2 
14 
28 
Pharmacodynamics, including 
fructose tolerance test 
2 
13 
26 
Pharmacogenetics 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
2 
23 
 
3 
12 
36 
Total 
 
 
251 
Total for clinical purposes (rounded up to the nearest 10 mL) 
260 
a Additional samples may be drawn if needed for safety purposes. 
 
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Protocol J2M-MC-GZKA Sampling Summary for Part B (Cohorts 1 and 3) 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
7 
84 
Serum creatinine 
2.5 
3 
7.5 
Testosterone, follicle-stimulating 
hormone, and luteinizing hormone 
3.5 
4 
14 
LY3478045 pharmacokinetics  
2 
23 
46 
Fasting insulin and adiponectin 
2.5 
2 
5 
Pharmacodynamics, including 
fructose tolerance test 
2 
26 
52 
Pharmacogenetics 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
3 
34.5 
 
3 
18 
54 
Total 
 
 
355.5 
Total for clinical purposes (rounded up to the nearest 10 mL) 
360 
a Additional samples may be drawn if needed for safety purposes. 
 
Protocol J2M-MC-GZKA Sampling Summary for Part B (Cohorts 2 and 4) 
 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
7 
84 
Serum creatinine 
2.5 
3 
7.5 
Testosterone, follicle-stimulating 
hormone, and luteinizing hormone 
3.5 
4 
14 
LY3478045 pharmacokinetics  
2 
32 
64 
Fasting insulin and adiponectin 
2.5 
2 
5 
Pharmacodynamics, including 
fructose tolerance test 
2 
26 
52 
 
2 
24 
48 
Pharmacogenetics 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
3 
34.5 
 
3 
27 
81 
Total 
 
 
448.5 
Total for clinical purposes (rounded up to the nearest 10 mL) 
450 
a Additional samples may be drawn if needed for safety purposes. 
 
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Appendix 6. 
Excluded Concomitant Medications 
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Appendix 7. 
Protocol Amendment J2M-MC-GZKA(c) 
Summary - A Safety, Tolerability, Pharmacokinetic, and 
Pharmacodynamic Study of Single- and Multiple-
Ascending Doses of LY3478045 in Healthy Subjects 
Overview 
Protocol J2M-MC-GZKA, A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic 
Study of Single- and Multiple-Ascending Doses of LY3478045 in Healthy Subjects, has been 
amended.  The new protocol is indicated by Amendment (c) and will be used to conduct the 
study in place of any preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• Protocol was amended to remove sorbitol analysis from pharmacodynamic analysis 
section as it is an indirect biomarker. The fructose level is a direct biomarker, and its 
analysis was confirmed to provide robust and sufficient pharmacodynamic information. 
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Revised Protocol Sections 
Note: 
All deletions have been identified by strikethroughs. 
All additions have been identified by the use of underscore. 
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9.6 
Pharmacodynamics 
Fructose Tolerance Test:  Three meals (breakfast, lunch, and dinner) will be served at 
approximately 20 minutes, 6 hours, and 12 hours after dose with low fructose content. A 
beverage containing mixture of fructose and glucose (
 
 in approximately 300 to 500 mL of non-caloric solution) will be served with 
each of the 3 meals on Day 1 in Part A (SAD) and Days 1 and 14 in Part B (MAD). The 
beverage should be served after a portion of the meal has been consumed.  The meals should 
start at the defined time (20 minutes, 6 hours, and 12 hours postdose). Blood samples for the 
analysis of fructose and sorbitol will be collected into appropriately labeled tubes containing 
ethylene diamine tetra acetic acid at the time points specified in the Schedule of Activities 
(Section 2). Sample handling and shipment to the central laboratory will occur per instructions 
given to the study site.  
 
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CCI

Signature Page for VV-CLIN-002394 v1.0
Signature Page for VV-CLIN-002394 v1.0
Approval
10-Aug-2021 20:27:10 GMT+0000
Approval
11-Aug-2021 05:07:33 GMT+0000
Approved on 11 Aug 2021 GMT
PPD
PPD