Clinical trial NCT02714569
Conditions: Dyslipidemias
Sponsor: Eli Lilly and Company
Start date: 2016-03-01; Completion date: 2017-02-15
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this two-part study is to evaluate the safety and tolerability of the study drug known as LY3202328 in healthy overweight participants in Part A, and those with dyslipidemia (abnormal blood fats) in Part B.

Detailed description:

Arms: arm 1: Single ascending doses of 1 milligram (mg), 3 mg, 10 mg, 30 mg, 100 mg, 300mg, 600 mg LY3202328 orally while fasting, or 30 mg LY3202328 orally while fed in 4 periods. arm 2: A single ascending dose of placebo orally, in 1 period while fasting, and up to one period while fed. arm 3: A multiple ascending dose of 5 mg, 20 mg, 100 mg, and 300 mg LY3202328 at up to 4 dose levels, orally, once daily for 29 days, while fasting and with a single dose of 10 mg statin (atorvastatin or simvastatin) one week prior to treatment and on Day 29. arm 4: A multiple ascending dose of placebo at up to 4 dose levels, orally, once daily for 29 days, while fasting and with a single dose of 10 mg statin (atorvastatin or simvastatin) one week prior to treatment and on Day 29.
Interventions: intervention 1: LY3202328 intervention 2: Placebo intervention 3: Atorvastatin intervention 4: Simvastatin
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally intervention 4: Administered orally

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan I8Q-MC-GSEA
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LY3202328
NCT02714569 
Document Approval Date:  31 January 2017  


Statistical Analysis Plan v1_0 FINAL.pdf
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Confidential 
 
Statistical Analysis Plan 
I8Q-MC-GSEA 
A Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Oral Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LY3202328 
 
 
Version 1.0 
 
31 January, 2017 
 
Prepared for 
 
Lilly l CHORUS 
 
Eli Lilly and Company 
Lilly Corporate Center, Indianapolis IN 46285 U.S.A 
 
 
Prepared by 
 
 
 
55 Corporate Woods 
 
9300 West 110th Street, Suite 550 
 
Overland Park, Kansas  66210 
 


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Table of Contents 
Description 
Page 
ABBREVIATIONS/DEFINITIONS .............................................................................. 5 
1 
INTRODUCTION AND OBJECTIVES ............................................................ 7 
1.1 
Introduction .................................................................................................................7 
1.2 
Study Objectives ..........................................................................................................7 
1.2.1 
Primary Objective ..................................................................................................7 
1.2.2 
Secondary Objectives .............................................................................................7 
1.2.3 
Exploratory Objectives ..........................................................................................8 
1.3 
Study Design with Sample Size Justification ............................................................8 
2 
General Statistical Methodology and Conventions ........................................... 8 
2.1 
Randomization Schedule and Unblinding Plan ........................................................9 
2.2 
Analysis Populations and Treatment Groups ........................................................10 
2.2.1 
Analysis Populations ............................................................................................10 
2.2.2 
Treatment Groups ................................................................................................10 
2.3 
Handling of Dropouts and Missing Data ................................................................11 
2.4 
Adjustment for Multiple Centers ............................................................................11 
2.5 
Interim Analysis and Adjustment for Multiplicity ................................................11 
2.6 
Coding of Concomitant Medications and Adverse Events ....................................11 
2.7 
Definition of Study Time Points ...............................................................................12 
2.8 
Reporting Conventions .............................................................................................12 
3 
Subject Accounting and Disposition ................................................................. 12 
3.1 
Subject Accounting ...................................................................................................12 
3.2 
Study Disposition .......................................................................................................13 
4 
Baseline Characteristics ..................................................................................... 13 
4.1 
Demographics ............................................................................................................13 
4.2 
Baseline Anthropometrics ........................................................................................14 
4.3 
Baseline Lipids ...........................................................................................................14 
5 
Concomitant Medications .................................................................................. 14 
6 
Pharmacodynamics Analyses ............................................................................ 14 
6.1 
Fasting Lipid Profile Analyses .................................................................................15 
6.1.1 
Fasting Lipid Profile Analyses in Part A ...........................................................15 


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6.1.2 
Fasting Lipid Profile Analyses in Part B ............................................................16 
6.2 
Post-prandial Lipid Profile Analyses ......................................................................17 
6.2.1 
Post-prandial Lipid Profile Analyses in Part A .................................................17 
6.2.2 
Post-prandial Lipid Profile Analyses in Part B .................................................17 
6.3 
Exploratory Biomarkers ...........................................................................................17 
7 
Safety Analyses ................................................................................................... 18 
7.1 
Study Medication Exposure and Treatment Compliance .....................................18 
7.1.1 
Extent of Exposure ...............................................................................................18 
7.1.2 
Treatment Compliance ........................................................................................19 
7.2 
Adverse Events ..........................................................................................................19 
7.2.1 
Treatment-Emergent Adverse Events ................................................................20 
7.2.2 
Serious Treatment-Emergent Adverse Events ..................................................20 
7.2.3 
TEAE Resulting in Death ....................................................................................20 
7.2.4 
TEAE Leading to Study Discontinuation ...........................................................20 
7.2.5 
Treatment-Related TEAE ...................................................................................21 
7.2.6 
TEAE by Maximal Severity ................................................................................21 
7.2.7 
Treatment-Emergent (not including Serious) Adverse Events ........................21 
7.3 
Clinical Laboratory Analyses ..................................................................................21 
7.3.1 
Clinical Laboratory Analyses in Part A .............................................................21 
7.3.1.1 
Clinical Laboratory over time in Part A ............................................................21 
7.3.1.2 
Clinical Laboratory Shift Tables in Part A ........................................................22 
7.3.2 
Clinical Laboratory Analyses in Part B .............................................................22 
7.3.2.1 
Clinical Laboratory over time in Part B ............................................................22 
7.3.2.2 
Clinical Laboratory Shift Tables in Part b .........................................................22 
7.4 
Vital Signs and Weight .............................................................................................23 
7.4.1 
Vital Signs in Part A .............................................................................................23 
7.4.2 
Vital Signs in Part B .............................................................................................23 
7.4.2.1 
Vital Signs over time in Part B ..........................................................................24 
7.4.2.2 
Post-dose (4-hour) Vital Signs in Part B ...........................................................24 
7.4.2.3 
Clinically Significant Vital Sign Change in Part B ...........................................24 
7.4.3 
Anthropometric variables in Part B ...................................................................25 
7.5 
Electrocardiograms ...................................................................................................25 


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7.5.1 
ECGs in Part A .....................................................................................................25 
7.5.1.1 
Descriptive Summary of ECGs .........................................................................25 
7.5.1.2 
Exposure Response Analysis for QTcf ..............................................................26 
7.5.2 
ECGs in Part B .....................................................................................................26 
7.5.2.1 
ECGs over time in Part B ..................................................................................26 
7.5.2.2 
Clinically Significant ECGs in Part B ...............................................................26 
8 
Pharmacokinetic Analyses ................................................................................. 27 
9 
Exploratory PK/PD and PK/Biomarker Analyses .......................................... 27 
10 
Additional, non-PK, Analyses for the DDI study ............................................ 27 
 


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ABBREVIATIONS/DEFINITIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
ApoB 
apolipoprotein 
AST 
alanine aminotransferase  
AUC 
area under the curve 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
Cmax 
maximum concentration 
CRP 
clinical research physician 
CRU 
clinical research unit 
CSR 
clinical study report 
DDI 
drug-drug interaction 
DGAT2 
Diacylglycerol acyltransferase 2 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
FFA 
free fatty acid 
HDL-c 
high-density lipoprotein cholesterol 
LDL-c 
low-density lipoprotein cholesterol 
Lp(a) 
lipoprotein (a) 
LY 
LY3202328 
MAD 
multiple ascending dose 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
MMRM 
Mixed-effects model repeated measures 
non-HDL-c 
total cholesterol – high-density lipoprotein cholesterol 
PCSK9 
proprotein convertase subtilisin/kexin type 9 


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Abbreviation 
Definition 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
QD 
quaque die (once a day) 
QTcf 
Fridericia corrected QT interval 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical analysis plan 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TC 
total cholesterol 
TG 
triglycerides 
WHODD 
World Health Organization Drug Dictionary 
 


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1 
INTRODUCTION AND OBJECTIVES 
1.1 Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the analysis variables and 
statistical procedures that will be used to analyze and report the results from a Phase 1 study 
evaluating the safety and pharmacodynamics of LY3202328 (LY), a diacylglycerol 
acyltransferase 2 (DGAT2) inhibitor, in overweight, healthy subjects (Part A) and in 
dyslipidemic, statin-free, overweight, healthy subjects (Part B). This SAP addresses only the 
planned analyses based on amended Protocol I8Q-MC-GSEA(a) that was approved on 22 
JUN 2016.  
Changes to the protocol that impact the design, the data collected, or the statistical methods and 
that occur after the finalization of this SAP may require amendment of the approved SAP. 
Similarly, changes to the planned analysis variables and/or statistical methods described in the 
approved SAP may also require amendment of the SAP.  
The formats for the tables, listings, and figures described in this SAP are provided in a 
companion documents. Changes to the formats of these reports that are decided after the 
finalization of the SAP will not require an amendment. In addition, any additional supportive or 
exploratory analyses requested after SAP approval will not require amendment of the SAP. 
These additional analyses will be described in the clinical study report (CSR).  
Please see the study protocol for details about the study design, procedures, and schedule of 
assessments and see the electronic case report form (eCRF) for details about variables collected 
and their possible values. 
1.2 Study Objectives 
1.2.1 Primary Objective 
The primary objective of this study is to explore safety and tolerability of single and multiple 
doses of LY in statin-free, overweight, healthy subjects. 
1.2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To assess the pharmacokinetic (PK) characteristics of LY in statin-free, overweight, healthy 
subjects after single and multiple doses. 
• To evaluate the effect of food on the extent and rate of LY absorption. 
• To determine the effects of LY upon multiple dose administration on: 
− Fasting lipid profiles 
− Simvastatin and atorvastatin exposure 


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1.2.3 Exploratory Objectives 
The exploratory objective of this study is to explore the effects of LY on: 
• Post-prandial lipid profiles. 
• Fasting free fatty acids and β-hydroxybutyrate. 
• Fasting apolipoprotein (Apo) B100, ApoC3, proprotein convertase subtilisin/kexin type 9 
(PCSK9), lipoprotein (Lp [a]), and insulin. 
• Body weight. 
1.3 Study Design with Sample Size Justification 
Study I8Q-MC-GSEA(a) (GSEA) is a first-in-man, Phase 1, randomized, double-blind, placebo-
controlled, 2-part, ascending single- and multiple-oral dose study of LY in overweight, healthy 
subjects (Part A) and in dyslipidemic, statin-free, overweight, healthy subjects with a statin drug-
drug interaction (DDI) assessments (Part B). 
This study will be conducted in 2 parts:  Part A, a single ascending dose (SAD) study design at a 
single site and Part B, a multiple ascending dose (MAD) study design conducted in multiple 
sites. 
Eighteen statin-free, overweight, healthy males and female subjects may be enrolled in one of 
two 9-subject cohorts in Part A. Each subject is scheduled to receive 2 single doses of LY and 1 
dose of placebo in ascending dose levels. This sample size is customary for Phase 1 studies 
evaluating safety, tolerability, and pharmacokinetic parameters, and is not powered on the basis 
of statistical hypothesis testing. 
Forty statin-free, overweight, dyslipidemic subjects may be enrolled in Part B. Subjects will be 
enrolled in one of four dose-ascending 10-subject cohorts (8 subjects will receive LY and 2 
subjects will receive placebo in each cohort).  This sample size is a customary sample size for a 
Phase 1b MAD study evaluating safety, tolerability, and pharmacokinetic parameters. 
2 
General Statistical Methodology and Conventions 
Chorus will designate a provider to generate the statistical analyses detailed in this SAP. All 
computations for statistical analyses will be performed using SAS® software, Version 9.3 or 
later. All SAS programs used in the production of statistical summary outputs will be validated 
with independent programming prior to finalization. In addition, all program outputs will be 
independently reviewed. The validation process will be used to confirm that all data 
manipulations and calculations were accurately done. Once validation is complete, a senior 
statistical reviewer will perform a final review of the documents to ensure the accuracy and 
consistency with this plan and consistency within tables. Upon completion of validation and 
quality review procedures, all documentation will be collected and filed by the project statistician 
or designee. 
For the implementation of parametric methods of analysis, residual plots will be examined to 
determine if model assumptions are satisfied. Transformations or nonparametric methods of 


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analysis may be used if warranted. In some cases, nonparametric analysis may be the initially 
proposed method due to the expected distribution of response. Whenever alternative methods of 
analysis are required, the description of the new method along with the rationale for its use will 
be documented in the CSR. 
The eCRF data for all subjects will be provided in Standard Data Tabulation Model (SDTM) 
datasets, and the production of the tables, figures and listings for the study will be generated 
from the SDTM datasets. Data listings supplied as part of the CSR will be sorted by investigative 
site and subject identification number, and subjects will be identified in the listings by the 
investigator number concatenated with the subject number. 
2.1 Randomization Schedule and Unblinding Plan 
Both Parts A and B are double-blinded so the subjects, investigator, and study site personnel will 
be blinded to treatment assignment – LY or Placebo. Simvastatin and atorvastin dosing in Part B 
will also be determined by random assignment, but the subjects, investigators, and study site 
personnel will be unblinded to the statin assignment since commercially available product will 
be used. PRA Health Sciences International will be responsible for generating the schedules for 
both parts of the study.  
In Part A, the subjects in each of the 9-patient cohorts -- Cohort 1 (1mg, 10mg, 100mg) and 
Cohort 2 (3mg, 30mg, 300mg) – will be randomized in a 1:1:1 ratio to one of the treatment 
sequences (Placebo, LY, LY), (LY, Placebo, LY), or (LY, LY, Placebo). The 30 mg dose level 
treatment assignments for Cohort 2 will be repeated in Period 4 to evaluate food effects on 
exposure.  One of the period’s treatment assignments for Cohort 1 will be repeated in Period 4 to 
evaluate the 600 mg dose level, so a couple subjects in Cohort 1 may receive Placebo twice. 
In Part B, the subjects in each of four planned 10-patient cohorts -- Cohort 3 (5mg QD), Cohort 4 
(20mg QD), Cohort 5 (100mg QD), and Cohort 6 (300mg QD) -- will be randomized to receive 
LY with simvastatin assessment (4 subjects), LY with atorvastatin assessment (4 subjects), 
placebo with simvastatin assessment (1 subject), or placebo with atorvastatin assessment (1 
subject). 
PRA Health Sciences will provide emergency codes to the investigator and pharmacy.  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. The 
investigator has the sole responsibility for determining if unblinding of a subject’s treatment 
assignment is warranted for medical management of an event. However, if the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
Chorus clinical research physician (CRP) prior to unblinding a study subject’s treatment 
assignment unless this could delay emergency treatment of the subject. If a study subject’s 
treatment assignment is unblinded for the investigator, Chorus must be notified immediately and 
the subject must be discontinued from the study, unless the investigator obtains specific approval 
from a Chorus CRP for the study participant to continue in the study. All cases of emergency 
unblinding, including who and why, will be documented in the CSR 


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To preserve the blinding of the study, only a minimum number of Chorus personnel will have 
access to the actual treatment assignments for a cohort before the dosing is completed for all 
patients in the cohort. The Chorus personnel with access to unblinded treatment information 
prior to the completion of dosing for a cohort will be limited to the Clinical Trial Supply Planner 
and potentially personnel monitoring ongoing safety of subjects in the study. All Chorus 
personnel can be unblinded to the actual treatment assignments for a cohort once dosing has been 
completed for the cohort. However, the blind for investigators, subjects and study personnel with 
direct contact with the sites will remain until the completion of the study. 
After the last subject completes the study and all data management data activities have been 
completed – data entered, coding completed, and all queries resolved – the Chorus Asset 
Manager or designee will approve PRA Health Sciences to release the randomization schedule to 
the reporting team. 
Upon completion of the study, all codes must be returned to Chorus or its designee. 
2.2 Analysis Populations and Treatment Groups 
The study population will consist of 18 statin-free, overweight, healthy male and female subjects 
in Part A and 40 statin-free, overweight, healthy male and female subjects with dyslipidemia in 
Part B, aged 18 to 70 years old inclusive for males, or 40 to 70 years old, inclusive for females. 
The number of subjects in the study population may increase if replacement subjects are treated 
in the study. 
2.2.1 Analysis Populations 
Two analysis populations will be used in this study: 
• Safety data and baseline information will be analyzed using the Safety Population. The 
Safety Population is defined as all randomized subjects who received at least one dose of 
study treatment. 
• Pharmacodynamics (PD) data will be analyzed using the PD Population. The PD Population 
is defined as all subjects who received at least one dose of LY and have both a baseline and 
post-baseline assessment of at least one PD parameter.  
2.2.2 Treatment Groups 
During Part A, subjects will be treated in multiple dosing periods with single doses of a subset of 
the treatments -- Placebo, and 1mg, 3mg, 10mg, 30mg, 100mg, 300mg, or 600mg of LY. Dosing 
will be performed in a fasted state, except in the fourth dosing period for Cohort 2 when subjects 
will be dosed with 30mg LY after a standard meal. The treatment groups for Part A will be the 
dose levels of LY, plus the group 30mg LY fed. 
During Part B, subjects will be enrolled in one of four dose-ascending groups (5mg LY, 20mg 
LY, 100mg LY, and 300mg LY) where they will be randomized to receive LY or placebo. The 
treatment groups for Part B will be Placebo, 5mg LY, 20mg LY, 100mg LY, and 300mg LY. 


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2.3 
Handling of Dropouts and Missing Data 
Summaries are primarily based on the Safety population, and safety data will be reported for all 
available subjects. In situations where Subjects in Part A discontinue early from the study, 
replacement subjects may be included for subsequent dosing periods.  
Analyses of the PD endpoints will be performed using mixed-effects model repeated measures 
(MMRM). This methodology mitigates the impact of missing data, which will be assumed to be 
missing at random during the study. 
Imputation of missing or partial dates is not expected, but if a complete date is required for 
calculations, the following algorithms will be applied:  
• For the start date:  
− If year, month, and day are missing then use the minimum of the subject's first visit date 
or the consent date.  
− If either only month or month and day are missing then use January 1.  
− If only day is missing, impute the first day of the month.  
• For the end date:  
− If year, month, and day are missing then use the subject's last visit date.  
− If either only month or month and day are missing then use December 31.  
− If only day is missing then use the last day of the month.  
− Do not expand the record past the subject's last visit.  
The original missing or partial date, the imputed complete date, and the indicator variable 
identifying dates that were imputed will be retained in the database. 
2.4 
Adjustment for Multiple Centers 
Part A will be conducted in a single study center.  
Part B will be conducted in multiple study centers, but PRA will centrally manage the 
randomization. No adjustment of multiple study centers will be incorporated into the statistical 
analyses for this study. This is common for early phase studies with limited enrollment. 
2.5 
Interim Analysis and Adjustment for Multiplicity 
Not applicable. 
2.6 
Coding of Concomitant Medications and Adverse Events 
Adverse events (AEs) will be coded using version 19.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA™), and concomitant medications will be coded using the Mar-2016 version 
of the World Health Organization Drug Dictionary. The version of the dictionary used for 
reporting will be provided in the CSR. 


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2.7 
Definition of Study Time Points 
Study day is explicitly defined in the study protocol.  
2.8 Reporting Conventions 
This section details the general conventions to be used for the statistical analyses. Departures 
from these general conventions will be provided in the specific detailed sections of this analysis 
plan. The following conventions will be applied to all data presentations and analyses:   
• Continuous variables will generally be summarized by the number of subjects, mean, 
standard deviation, median, minimum, and maximum.   
• Categorical variables will be summarized by the number and percentage of subjects within 
each category. 
• All mean and median values will be formatted to one more decimal place than the measured 
value. 
• Standard deviation values will be formatted to two more decimal places than the measured 
value. 
• Minimum and maximum values will be presented with the same number of decimal places as 
the measured value. 
• The number and percent of responses will be presented in the form XX (XX %), where the 
percentage is in parentheses. Percentages will be rounded to the nearest percent. In the case 
of a frequency of zero, the frequency and percentage will be presented as 0 rather than 0 
(0%). 
• All summary tables will include the analysis population sample size (i.e., number of subjects) 
in each treatment group. 
• Date variables will be formatted as ddMMMYY for presentation. 
3 
Subject Accounting and Disposition 
3.1 Subject Accounting 
The number of subjects in the Safety and PD populations will be presented by treatment group. 
For each treatment group the date of the first subject visit and the last subject visit will also be 
provided. These dates and subject totals will also be summarized by study site for Part B. In 
addition, the total number of subjects randomized and the number of subjects added as 
replacements will be presented by cohort for Part A 
A list of protocol violations that could potentially impact the analysis of the study will be 
determined during the conduct of the study by study team members who are blinded to study 
treatment being received. The number and percentage of subjects with each violation will be 
tabulated overall and by randomized treatment assignment for Part B. 


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3.2 Study Disposition 
The disposition of all randomized subjects will be presented. The number of subjects in the 
Safety Population will be presented overall and by treatment group. In addition, the reason for 
study discontinuation will be tabulated for the overall population and by treatment group using 
the list of reasons provided in the eCRF.  
For Part A the disposition of all subjects in the Safety Population will be presented. Since 
subjects receive multiple treatments during the course of the study, the number (percent) of 
subjects who complete a treatment period will be presented. The number (percent) of subjects 
who discontinue from the study will be tabulated according to the most recently received 
treatment. The reason for study discontinuation will also be tabulated using the list of reasons 
provided in the eCRF. Denominators for all percentages in the table will be the number of 
subjects in the Safety Population who received the given treatment. 
For Part B the disposition of all randomized subjects will be presented. Randomization of 
subjects for Part B occurs early, on Day -7, so that subjects can be allocated evenly to treatment 
with simvastatin or atorvastatin for the DDI component of the study. The number of subjects 
randomized, the number of subjects randomized but not treated with LY or placebo, and the 
number of subjects added as replacements will be summarized by treatment assignment and 
overall for each statin and the combined statin assignment. The reason for discontinuation for 
subjects who were randomized but not treated with LY or placebo will only be presented in data 
listings. 
The number (percent) of subjects who complete Part B of the study, and the number (percent) of 
subject who discontinue, along with the reason for discontinuation, will be summarized by 
treatment group and overall. Denominators for all percentages in the table will be the number of 
subjects in the Safety Population. 
4 
Baseline Characteristics 
Demographic data, baseline anthropometric measurements, and fasting lipids will be summarized 
at the subject level using descriptive statistics for the overall study population and by treatment 
group for both Parts A and B. These summaries will be based on the Safety population. Subjects 
who are missing measurements of the baseline variable being analyzed will not be included in 
the summary for that variable. 
4.1 
Demographics 
Demographic variables collected prior to randomization include date of birth, sex, race, and 
Hispanic ethnicity. Age at study entry, age group, sex, and race will be summarized and reported. 
Age at study entry will be based on the age of the subject on the date the informed consent is 
signed. Age group will be defined using the median age group for the Safety population (Age <= 
Median age; Age > Median age). Subject race will be reported using the categories provided in 
the eCRF (i.e., American Indian or Alaskan Native, Asian, Black or African American, Native 
Hawaiian or other Pacific Islander, and White). The responses for Hispanic ethnicity are 
Hispanic or Latino and Non-Hispanic or Latino.  


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4.2 
Baseline Anthropometrics 
Subject height and weight will be collected prior to randomization for both Parts A and B. Both 
variables will be reported in metric units (height in cm and weight in kg) and will be summarized 
as continuous variables along with Body Mass Index (BMI; in kg/m2). Body mass index will also 
be analyzed categorically using the categories overweight (25 ≤ BMI <  30 kg/m2) and Class 1 
Obese (30 ≤ BMI < 35 kg/m2) that are provided by United States Center for Disease Control 
(http://www.cdc.gov/obesity/adult/defining.html). 
In Part B the additional anthropometric variables waist, hip, and neck circumference (all in cm) 
will be collected on Day -1 of the study. These variables will also be summarized as continuous 
variables for each of the treatment groups and overall. 
4.3 Baseline Lipids 
For enrollment in Part B subjects are required to have screening triglyceride (TG) levels between 
150 and 499 mg/dL, inclusive, and screening low-density lipoprotein cholesterol (LDL-c) levels 
between 100 and 200 mg/dL, inclusive. These lipids levels are allowed for enrollment in Part A 
but they are not required. During the Part B screening visit, fasting measurements of TG, total 
cholesterol (TC), and high-density lipoprotein cholesterol (HDL-c) will be obtained from plasma 
samples. LDL-c and non-HDL-c will then be derived as follows: 
LDL-c = TC – (TG/5 + HDL-c), and 
non-HDL-c = TC – LDL-c. 
Descriptive statistics for these five lipid parameters for subjects enrolled in Part B will be 
provided for each of the treatment groups and overall. 
5 
Concomitant Medications 
Concomitant medications will be defined as medications, other than simvastatin and atorvastatin, 
taken on or after the date of first dose of randomly assigned study treatment (LY or placebo). 
This includes all medications initially taken prior to the date of first dose of randomly assigned 
study medication but with a stop date that is either missing or after the date of first dose of 
randomly assigned study medication. Those medications where the stop date is documented as 
prior to the date of first dose of randomly assigned study medication will be classified as prior 
medications. The prior medications will not be included in any summary reports. 
The number (percent) of subjects who receive each concomitant medication, based on the 
WHODD preferred drug name, will be tabulated for Part B, but it is not planned to summarize in 
table format the concomitant medication usage for Part A of the study. However, by-subject 
listings of all concomitant medications that includes WHODD preferred drug name will be 
prepared separately for Parts A and B.  
6 
Pharmacodynamics Analyses 
Pharmacodynamics (PD) analyses for this study will be based on fasting and post-prandial lipid 
profiles, fasting free fatty acids (FFA), β-hydroxybutyrate, apolipoprotein (Apo) B100, ApoC3, 


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proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein (a) [Lp(a)] and insulin, and 
body weight. All of these assessments will be collected longitudinally during the study. 
All PD analyses will be performed using the PD population. Presentations of PD analyses will 
include the number of subjects with data at each time point plus related statistics derived from 
the analysis. Subjects who received Placebo during more than 1 dosing period in Part A will 
have their data from different dosing periods reported separately. The following sections contain 
the planned analyses. If plots of the raw data or residuals suggest alternative analysis techniques, 
such as log-transformation or nonparametric methods, then additional analyses will also be 
performed. The rationale for and results of the alternatives techniques will be described in the 
CSR. 
6.1 Fasting Lipid Profile Analyses 
6.1.1 Fasting Lipid Profile Analyses in Part A 
A fasting lipid profile will be collected from all subjects in each dosing period in Part A, except 
for dosing period 4 for Cohort 2 which prescribes dosing subjects in a fed state. Fasting 
measurements of TG, TC, and HDL-c will be obtained and fasting measurements of LDL-c and 
non-HDL-c will be derived from plasma samples collected just prior to dosing on the day of 
dosing, then at 24, 48 and 96 hours after dosing. 
A last observation measurement will be derived for each subject using the last post-dose 
measurement of a lipid parameter. Change from baseline for each of the lipid parameters will be 
derived for each of the post-dosing time points (Day 1 [24 hours], Day 2 [48 hours], and Day 4 
[96 hours]) and the last observation using the pre-dose measurement from the day of dosing as 
the baseline.  
Descriptive statistics for the measurement at baseline and the measurement and change from 
baseline at each post-dose time point plus the last observation will be tabulated.  
A mixed-effect repeated measures (MMRM) analyses will be conducted for each lipid parameter 
using the change from baseline values from Days 1, 2, and 4. The MMRM model for change 
from baseline will contain fixed effects for treatment, time, and their interaction, a random effect 
for subject, and the baseline measurement as a covariate. The covariance structure among the 
repeated measurements for a subject will be assumed to be common across subjects and modeled 
using an unstructured 3x3 matrix. Satterthwaite’s approximation will be used to estimate 
denominator degrees of freedom. Any missing assessments will be assumed to be missing at 
random, so estimates of treatment effects from the model will be assumed to be unbiased. These 
analyses will be performed using the SAS procedure PROC MIXED. The tabular output for 
these MMRM analyses will present the least squares means, standard errors and 95% confidence 
intervals and Type 3 p-values for each main effect marginal. Pairwise contrasts of the least 
squares means between the LY dose levels and placebo along with the associated 95% 
confidence interval and Type 3 p-values will also be provided at each time point using 
LSMESTIMATE statements. 
Plots of the least squares mean ± standard error estimates for each lipid parameter over time (pre-
dose through Day 4 post-dose) will be provided by treatment group.  


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A last observation analysis will be performed for change from baseline using an analysis of 
covariance (ANCOVA) model with a fixed effect for treatment a random effect for subject and 
the baseline value as a covariate. Tabular output for these ANCOVA analyses will present the 
least squares means, standard errors and 90% confidence intervals and Type 3 p-values for each 
main effect marginal. Pairwise contrasts of the least squares means between each LY dose level 
and placebo along with the associated 95% confidence interval and Type 3 p-values will also be 
provided.  
6.1.2 Fasting Lipid Profile Analyses in Part B 
Fasting lipid profiles will be collected from all subjects in Part B just prior to dosing on the day 
of dosing, Day 7, Day 14, Day 21, and Day 28, and 7 (Day 35) days after stopping dosing of the 
randomized treatment. An additional follow-up assessment will be collected 14 (Day42) or 28 
(Day 56) days after stopping dosing of the randomized treatment for Cohort 3 (5mg QD) and 
Cohorts 4 through 6, respectively. 
A last on-treatment observation measurement will be derived for each subject using the last post-
dose measurement for a lipid parameter taken while the subject is taking study medication during 
the 28-day treatment period. Change from baseline for each of the lipid parameters will be 
derived for each of the post-dosing time points (Days 7, 14, 21, 28, 35, and 42 or 56) and the last 
on-treatment observation using the pre-dose measurement from the first day of dosing as the 
baseline.  
Descriptive statistics for the measurement at baseline and the measurement and change from 
baseline at each post-baseline time point plus the last observation will be tabulated.  
An MMRM analysis will be conducted for each lipid parameter using the change from baseline 
values from Days 7, 14, 21, 28, 35, and 42. The MMRM model for change from baseline will 
contain fixed effects for treatment, time, and their interaction, a random effect for subject, and 
the baseline measurement as a covariate. Since the time points are evenly spaced the covariance 
structure among the repeated measurements for a subject will be assumed to be common across 
subjects and modeled using a autoregressive(1) 7x7 matrix. Satterthwaite’s approximation will 
be used to estimate denominator degrees of freedom. Any missing assessments will be assumed 
to be missing at random, so estimates of treatment effects from the model will be unbiased. 
These analyses will be performed using the SAS procedure PROC MIXED. The tabular output 
for these MMRM analyses will present the least squares means, standard errors and 95% 
confidence intervals and Type 3 p-values for each main effect marginal. Pairwise contrasts of the 
least squares means between the LY dose levels and placebo along with the associated 95% 
confidence interval and Type 3 p-values will also be provided at each time point using 
LSMESTIMATE statements. 
Plots of the least squares mean ± standard error estimates for each lipid parameter over time 
(baseline through Day 56) will be provided by treatment group.  
A last on-treatment observation analysis will be performed for change from baseline using an 
analysis of covariance (ANCOVA) model with a fixed effect for treatment a random effect for 
subject and the baseline value as a covariate. Tabular output for these ANCOVA analyses will 
present the least squares means, standard errors and 95% confidence intervals and Type 3 p-
values for each main effect marginal. Pairwise contrasts of the least squares means between each 


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LY dose level and placebo along with the associated 95% confidence interval and Type 3 p-
values will also be provided.  
6.2 Post-prandial Lipid Profile Analyses 
6.2.1 Post-prandial Lipid Profile Analyses in Part A 
Measurement of the lipids TC, TG, HDL-c, LDL-c, and non-HDL-c will be obtained just prior to 
the midday meal on the day of dosing and again at 0.5, 1, 2, and 4 hours post-meal for all 
subjects in each dosing period in Part A.   
Change from baseline for each of the lipid parameters will be derived for each of the post-meal 
time points using the pre-meal measurement as the baseline, and the level of excursion within the 
4-hour post-meal period will be determined using a post-meal area under the curve (AUC). The 
areas of the trapezoidal region for change from baseline between successive planned collection 
time points will be calculated, and these areas will be summed to obtain the AUC value. 
Descriptive statistics for the post-meal AUC will be tabulated by treatment group.  
An ANOVA will be conducted for each lipid parameter using post-meal AUC values. The 
ANOVA model will have a fixed effect for treatment and a random effect for subject. Subjects 
treated with Placebo for the second time during the fourth dosing period will be handled as ‘new’ 
subjects in the analysis. 
Boxplots of the lipid values at pre-meal and each planned post-meal time point (0.5, 1, 2, and 4 
hours post-meal) will be presented for each treatment group.  
6.2.2 Post-prandial Lipid Profile Analyses in Part B 
Measurement of the lipids TC, TG, HDL-c, LDL-c, and non-HDL-c will be obtained just prior to 
the midday meal on Days -1 and 28 of dosing. Post-meal measurements will be collected on both 
days at 0.5, 1, 2, and 4 hours after the meal for all subjects in Part B.  
Change from baseline for each of the lipid parameters will be derived for each of the post-meal 
time points using the pre-meal measurement as the baseline, and the level of excursion within the 
4-hour post-meal period will be determined using the post-meal AUC, as described in 
Section 6.2.1. 
Descriptive statistics for the post-meal AUC at Days -1 and 28 as well as the difference between 
Days -1 and 28 will be presented by treatment group.  
An ANCOVA will be conducted for each lipid parameter using the difference in post-meal AUC 
values from Day -1 to Day 28. The ANCOVA model will have a fixed effect for treatment, a 
random effect for subject, and the Day -1 post-meal AUC as a covariate.  
Boxplots of the lipid values at pre-meal and each planned post-meal time point (0.5, 1, 2, and 4 
hours post-meal) will be presented for each treatment group for both Day -1 and Day 28.  
6.3 Exploratory Biomarkers 
The exploratory biomarkers FFA, β-hydroxybutyrate, and ApoB100 will be assessed from 
samples collected from all subjects in Part B on Day -1, Day 7, Day 14, Day 21, and Day 28, 


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plus 7 (Day 35) and 14 (Day 42) or 28 (Day 56) days after stopping dosing of the randomized 
treatment, while the biomarkers ApoC3, PCSK9, Lp(a) and insulin will only be collected on Day 
-1, Day 14, Day 28, Day 35, and Day 42 or 56. While the subjects are receiving randomized 
study medication samples will be collected just prior to dosing. 
For each parameter a last on-treatment observation measurement will be derived for each subject 
using the last post-dose measurement for a parameter taken while the subject is taking study 
medication during the 28-day treatment period. Change from baseline for each parameter will be 
derived for each of the post-dosing time points (Days 7, 14, 21, 28, 35, and 42 or 56) and the last 
on-treatment observation using the Day -1 measurement as the baseline.  
Descriptive statistics for the measurement at baseline and the measurement and change from 
baseline at each post-baseline time point plus the last observation will be tabulated.  
An MMRM analysis will be conducted for each parameter using the change from baseline 
values. The MMRM model for change from baseline will contain fixed effects for treatment, 
time, and their interaction, a random effect for subject, and the baseline measurement as a 
covariate. Since the time points are evenly spaced the covariance structure among the repeated 
measurements for a subject will be assumed to be common across subjects and modeled using an 
autoregressive matrix. The analyses will be conducted and tabulated as described in 
Section 6.1.2. 
Plots of the least squares mean ± standard error estimates for each parameter over time (baseline 
through Day 56) will be provided by treatment group.  
A last on-treatment observation analysis will be performed for change from baseline using an 
ANCOVA model with a fixed effect for treatment, a random effect for subject and the baseline 
value as a covariate. The analyses will be conducted and tabulated as described in Section 6.1.2. 
Sufficient biomarker samples will be collected during Part B to allow for the determination of 
ApoB48, lathosterol, lanosterol, demosterol, and potentially other biomarkers of interest. No 
analyses for these biomarkers are currently planned. If analyses for these biomarkers are 
subsequently added, the description of the analysis will be documented in the CSR. 
7 
Safety Analyses 
All analyses of safety including the extent of exposure to study medication will be performed 
using the Safety population. Summaries will be presented at the subject level, and subjects who 
received Placebo for the second time during the fourth dosing period will be presented as 
separate subjects in the summaries. 
7.1 Study Medication Exposure and Treatment Compliance 
7.1.1 Extent of Exposure 
In Part A, the single dose of LY or placebo will be administered at the clinical research unit 
(CRU) under the supervision of the investigator.  As a result, subject compliance will be ensured. 
A by-subject listing of the treatment received by each subject for each dosing period in Part A 
will be provided. 


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In Part B, the daily dose of LY or placebo will be administered at the CRU on Days 1, 2, 7, 14, 
21, 28, and 29, while doses on the intermittent days will be administered by the subject while at 
home. Each subject will document in a daily diary the administration of each daily dose along 
with the time of dosing and the time of the first meal of the day. From the daily diaries and the 
Medication Dosing pages of the CRF, the total number of doses received and date of last dose of 
study medication can be determined. The extent of exposure can be derived as: 
Extent of Exposure = Date of last dose of study drug – Date of 1st dose of study drug + 1. 
Extent of exposure will be reported as a continuous variable by treatment group. In addition, 
extent of exposure will be reported as a categorical variable using the categories: 1 to <7 days, 7 
to <14 days, 14 to <21 days, 21 to <29 days, and 29 days.  
7.1.2 Treatment Compliance 
Compliance for the study will be derived as:   
Compliance = Total number of doses received / Extent of Exposure. 
Each subject in Part B is supposed to take ≥80% of the intended dose to be deemed compliant 
with study drug administration.  Compliance with study medication will be reported by treatment 
group using the categories: < 80% compliance, 80% to < 100% compliances, and 100% or 
greater compliance. 
A by-subject listing of each subject’s daily dose will be provided for the subjects in Part B. 
7.2 Adverse Events 
Investigators will monitor the safety of subjects and will be responsible for their medical care 
during the study. The investigator will interpret and document adverse advents and will indicate 
whether each event is serious and the strength of causality to the study medication. The subject 
will be followed until adverse events are resolved.  
Only those adverse events (AE) that emerge or worsen after the date of first dose of study 
medication, i.e. treatment emergent adverse events (TEAE), will be summarized. Adverse events 
with a missing start date will also be classified as TEAE. 
Summaries of TEAE will include the number of subjects with at least one TEAE for each 
treatment group. When reporting by system organ class (SOC) and preferred term (PT), the 
reports will present the SOC in alphabetical order; while PTs within the SOC will be presented in 
order of overall decreasing frequency of occurrence in the combined LY treatment groups. A 
subject with multiple TEAEs (different PTs) coded to the same SOC will be counted only once 
for that SOC, but will be counted each time for different PTs within that SOC. A subject with 
separate events of the same PT (different start/stop dates) will be counted only once in the 
frequency tables for that PT. 
In Part A, TEAEs will be reported using the treatment that the subject most recently received. 
Adverse events that occur on the first day of a dosing period will be assigned to the treatment 
received on that day.  


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No statistical testing will be performed for comparisons of TEAEs. 
An overview of all TEAEs for both Parts A and B will also be provided by treatment group using 
the types of TEAEs defined in the following subsections. 
7.2.1 Treatment-Emergent Adverse Events 
For both Parts A and B, TEAEs will be summarized by SOC and PT for each treatment group. 
These reports will also present the total number of TEAE for each SOC and PT, since this 
information is needed for reporting on clinicaltrials.gov. In addition, a presentation of TEAE 
preferred terms by decreasing frequency will be provided. The sort order for the table will based 
on the number of subjects in the combined LY treatment groups who had the TEAE.  
7.2.2 Serious Treatment-Emergent Adverse Events 
A serious TEAE (SAE) is a TEAE that met one or more of the following criteria: 
• Is fatal 
• Is life-threatening 
• Requires or prolongs hospitalization 
• Is significantly or permanently disabling or incapacitating 
• Constitutes a congenital anomaly or a birth defect or 
• Jeopardizes the subject and may require medical or surgical intervention to prevent one of the 
above outcomes 
For both Parts A and B, SAEs will be summarized for each treatment arm by SOC and PT for the 
Safety population. These reports will also include the total number of SAE for each SOC and PT. 
A listing of all SAE will also be provided. The listing will include the criteria that a TEAE met to 
be declared an SAE. 
7.2.3 TEAE Resulting in Death 
If there are any TEAE that result in death for either part of the study, then a listing of all deaths 
will be provided for that part of the study.  
7.2.4 TEAE Leading to Study Discontinuation 
For Part A subjects receive only a single dose of study medication which precludes drug 
withdrawal in response to an adverse event. ‘Drug Withdrawn’. The subjects who experience 
adverse events leading to study discontinuation during Part A will be captured in the disposition 
listing. 
For Part B, adverse events for resulting in drug discontinuation (designated as ‘Drug 
Withdrawn’) will be classified as a TEAE leading to study drug discontinuation. TEAEs that 
lead to study drug discontinuation will be summarized for each treatment group by SOC and PT 
for the Safety population. A by-subject listing of the TEAE that lead to study drug 
discontinuation will also be provided. 


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7.2.5 Treatment-Related TEAE 
Every AE will be assessed by the investigator for its relationship to study medication. The 
TEAEs either assessed by the investigator to be possibly, probably, or definitely related to study 
treatment or that are missing the investigator’s assessment will be categorized as treatment-
related TEAEs. 
The tabled results for all TEAE, serious TEAE, and TEAE that lead to study discontinuation will 
be repeated for Parts A and B using the subset of TEAE that are classified as treatment-related.  
7.2.6 TEAE by Maximal Severity 
Every AE will be graded by the investigator as mild, moderate, or severe, so for each subject the 
greatest severity observed can be obtained by comparing the severity of all of a subject’s TEAE 
that share the same SOC or PT. A table of TEAE by maximal severity will be prepared for each 
treatment arm by SOC and PT for the Safety population. This report will be generated for both 
Parts A and B. 
7.2.7 Treatment-Emergent (not including Serious) Adverse Events 
To meet the requirements for reporting on clinicaltrials.gov, the most common non-serious 
TEAE will be reported for both Parts A and B. All PT that occur in at least 5% of the Safety 
Population subjects in any treatment group, when not counting the serious TEAE, will be 
tabulated by SOC and PT for each treatment group. These reports will also present the total 
number of TEAE for each SOC and PT  
7.3 Clinical Laboratory Analyses 
Blood samples for hematology and clinical chemistry and urine samples for urinalysis will be 
collected in both Parts A and B. Profiles for the hematology, clinical chemistry and the numeric 
urinalysis parameters will be summarized for both Parts A and B.  
7.3.1 Clinical Laboratory Analyses in Part A 
For Part A, blood samples will be collected pre-dose on Day 1 and at 24, 48 and 96 hours post-
dose for all subjects in each dosing period in Part A. The measurements from dosing period 4 for 
Cohort 2 will not be included in this analysis since dosing of study medication occurred in a fed 
state.  
7.3.1.1 Clinical Laboratory over time in Part A 
Change from baseline for each of the hematology, clinical chemistry and the numeric urinalysis 
parameters will be derived for each of the post-dose time points using the pre-dose measurement 
as the baseline. Descriptive statistics for the measurement at baseline and the measurement and 
change from baseline at each post-dose time point will be tabulated.  
Plots of the least squares mean ± standard error estimates for each parameter over time (pre-dose 
through 96 hours post-dose) will be provided by treatment group.  


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7.3.1.2 Clinical Laboratory Shift Tables in Part A 
Each laboratory parameter will be classified as low, normal or high relative to the central 
laboratory’s normal range. For each treatment group shift tables will be generated from the pre-
dose category to the category 96 hours post-dose for each laboratory parameter. The shift tables 
will present the number (percent) of subjects who started in a category (low, normal, high) at 
baseline and ended in a category at the end of the study. A missing category will be included for 
both pre-dose and 96-hours post-dose, so that all subjects in the Safety population will be 
represented in the table. The percentages will be calculated using number of subjects in the 
Safety population who have measurements at pre-dose and 96-hours post-dose.  
Shift tables comparing pre-dose to the other time points in the study may be generated if 
warranted after data review. 
Similar shift tables for the categorical urinalysis parameter will also be produced using all 
categories reported for a parameter during the study.  
7.3.2 Clinical Laboratory Analyses in Part B 
For Part B, blood samples will be collected on Day -1 then pre-dose on Days 2, 7, 14, 21, and 29 
and during follow-up on Days 35 and 42 or 56 for all subjects in Part B.  
7.3.2.1 Clinical Laboratory over time in Part B 
Change from baseline for each of the hematology, clinical chemistry and the numeric urinalysis 
parameters will be derived for each of the post-baseline time points using the Day -1 
measurement as the baseline. Descriptive statistics for the measurement at baseline and the 
measurement and change from baseline at each post-baseline time point will be tabulated.  
Plots of the least squares mean ± standard error estimates for each lipid parameter over time 
(baseline through Day 56) will be provided by treatment group.  
7.3.2.2 Clinical Laboratory Shift Tables in Part B 
For each treatment group shift tables will be generated from the baseline category to the category 
at Day 42 or 56 for each laboratory parameter. The shift tables will present the number (percent) 
of subjects who started in a category (low, normal, high) at baseline and ended in a category at 
the end of the study. A missing category will be included for both baseline and Day 42 or 56, so 
that all subjects in the Safety population will be represented in the table. The percentages will be 
calculated using number of subjects in the Safety population who have measurements at baseline 
and at Day 42 or 56.  
Additional shift tables may be generated if warranted after data review. 
Shift tables for the categorical urinalysis parameter will also be produced.  


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7.4 Vital Signs and Weight 
7.4.1 Vital Signs in Part A 
On the Day -1 for each dosing period the blood pressure, pulse rate, and temperature for each 
subject in Part A will be collected. At each collection time point all vital signs are to be collected 
after the subject has been supine for at least 5 minutes. Then, to assess orthostatic hypertension, 
measurements of blood pressure and pulse rate will to be collected in triplicate at 1, 2, and 3 
minutes after rising to a standing position, Vital signs will be similarly assessed at 2, 4, and 8, 
24, 48, and 96 hours after dosing for each subject. At each time point, the maximum value 
among the triplicate standing measurements will be obtained, and the change from the supine 
measurement will be derived for the triplicate maximum. 
Descriptive statistics for the supine measurement and triplicate maximum along with the change 
from supine for the triplicate maximum will be tabulated for each treatment group, except the 
30mg fed treatment group, at each time point. 
Subjects will be determined to have orthostatic hypotension if either of the following occur after 
the subject rises from a supine to standing position. 
• Systolic blood pressure decreases ≥ 20 mmHg, or 
• Diastolic blood pressure decreases ≥ 10 mmHg. 
In addition, subjects with the following increases in the pulse rate after rising from a supine to 
standing position will be tabulated. 
• Pulse rate increases ≥ 20 beats per minute (bpm), 
The number (percent) of subjects having orthostatic hypotension and pulse rate increases will be 
tabulated by treatment group. The percentage will be calculated using the number of subjects in 
the Safety population with data at the time point as the denominator. 
Change from baseline statistics will also be defined for the supine measurements of blood 
pressure, pulse rate and temperature using the pre-dose values as baseline. Descriptive statistics 
for the supine measurement of temperature will also be provided by treatment group. 
Plots of the mean ± standard error for each vital sign, collected while supine, over time (baseline 
through Day 4 [96 hours]) will be provided by treatment group. 
7.4.2 Vital Signs in Part B 
Orthostatic blood pressure and pulse rate along with temperature will be collected pre-dose on 
Days 1, 2, 7, 14, 21, and 29, at 4 hours post-dose on Days 1 and 28, and as follow-up 
assessments on Days 35 and 42. Data summaries will be created using the pre-dose and follow-
up assessments, and a separate summary will examine the 4-hour post-dose measurements.  The 
orthostatic blood pressure and pulse rate measurements collected on Days -6, -2, -1 and 27 along 
with all unscheduled vital sign assessments will be provided in the listings but will not be 
included in the summary tables or figures. 


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7.4.2.1 Vital Signs over time in Part B 
For the pre-dose and follow-up assessments on Days 1, 2, 7, 14, 21, and 29 and Days 35 and 42, 
respectively, the maximum value among the triplicate standing measurement will be obtained, 
and the change from the supine measurement will be derived for the triplicate maximum. 
Descriptive statistics for the supine measurement and triplicate maximum along with the change 
from supine for the triplicate maximum will be tabulated for each treatment group at each time 
point.  
Subjects will be determined to have orthostatic hypotension using the criteria provided in 
Section 7.4.1. The number (percent) of subjects having orthostatic hypotension will be tabulated 
by treatment group. The percentage will be calculated using the number of subjects in the Safety 
population with data at the time point as the denominator. 
Change from baseline statistics will also be defined for the supine measurements of blood 
pressure, pulse rate and temperature using the Day 1 values as baseline. Descriptive statistics for 
the supine measurement of temperature will also be provided by treatment group. 
Plots of the mean ± standard error for each vital sign, collected while supine, over time (baseline 
through Day 4 [96 hours]) will be provided by treatment group. 
7.4.2.2 Post-dose (4-hour) Vital Signs in Part B 
For the 4-hour post-dose assessments on Days 1 and 28 the maximum value among the triplicate 
standing measurement will be obtained, and the change from the supine measurement will be 
derived for the triplicate maximum. 
Descriptive statistics for the supine measurement and triplicate maximum along with the change 
from supine for the triplicate maximum will be tabulated for each treatment group at each time 
point. Subjects will be determined to have orthostatic hypotension using the criteria provided in 
Section 7.4.1. The number (percent) of subjects having orthostatic hypotension will be tabulated 
by treatment group. The percentage will be calculated using the number of subjects in the Safety 
population with data at the time point as the denominator. Descriptive statistics for the supine 
measurement of temperature will also be provided by treatment group. 
7.4.2.3 Clinically Significant Vital Sign Change in Part B 
The number (percent) of subjects who experience either orthostatic hypotension or a clinically 
significant deviation in vital signs while on-treatment will be tabulated by treatment group. Vital 
sign normal are defined as follows:  
• Pulse rate < 50 bpm or > 100 bpm, 
• Systolic blood pressure either ≤ 90 mmHg or ≥ 160 mmHg,  
• Diastolic blood pressure either ≤ 50 mmHg or ≥ 100 mmHg. 
All on-treatment values, including unscheduled assessments, will be considered, and the 
denominator for the percentages will be the number of subjects in the Safety Population. 
All subjects who have a clinically significant change in vital signs or orthostatic hypotension will 
be documented in a by-subject listing. The listing will include all of the vital sign measurements 


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from the study for the subject, and abnormal values will be flagged. A similar listing for the data 
from Part A will also be produced, but no a summary table of the results as are planned for Part 
A. 
7.4.3 Anthropometric variables in Part B 
Weight plus waist, hip and neck circumference will be collected on Days -1, 7, 14, 21, and 29, 
and at the follow-up assessments times on Days 35 and 42 or 56.  
Change from baseline statistics will be defined for each parameter using the Day -1 values as 
baseline; descriptive statistics for each parameter will also be tabulated by treatment group. 
Plots of the mean ± standard error for weight over time (baseline through Day 56) will be 
provided by treatment group. 
7.5 Electrocardiograms 
Subjects must be supine for at least 5 minutes prior to and remain awake during each 12-lead, 
digital, triplicate electrocardiogram (ECG) collection.  ECGs will be read by a qualified 
physician at the site to document parameter measurements and to determine any clinically 
relevant findings. The triplicate numeric measurements will be averaged at each time point to 
obtain the value that will be used for analyses, while the most severe interpretation (Normal; 
Abnormal, not Clinically Significant; Abnormal, Clinically Significant) among the triplicate 
measurements will be used for analyses. However, all abnormalities documented on any of the 
triplicate measurements will be reported in the listings. The investigator, or qualified designee, 
will report any new clinically relevant finding from any of the triplicate measurements as an AE. 
7.5.1 ECGs in Part A 
In Part A, triplicate ECGs will be collected during each dosing period at pre-dose and at 2, 4, 6, 
8, 12, 24, 48, and 96 hours post-dose. The parameters heart rate, PR interval, QRS duration, QT 
interval, RR interval, QTc Bazett, and QTc Fridericia (QTcf ) will be obtained as the mean of the 
triplicate measurements for each ECG collection, plus the investigator will provide an overall 
ECG evaluation.  
7.5.1.1 Descriptive Summary of ECGs 
At each time point, the change from baseline will be derived for each numeric parameter using 
the pre-dose value as baseline. Descriptive statistics for the value of each parameter at each time 
point and the change from baseline for each parameter at each post-dose time point will be 
provided by treatment group. 
Plots of the mean ± standard error for the changes from baseline in each parameter over time will 
be provided by treatment group. 
The single tracing collected at Screening and the triplicate measurements collected on the Day -1 
for each dosing interval will be included in by-subject listings but will not be included in any 
summary tables. 


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DGAT2 inhibitor LY3202328 
Statistical Analysis Plan 
Version 1.0 
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Page 26 of 27 
7.5.1.2 Exposure Response Analysis for QTcf 
To evaluate the effect of LY3202328 on QTc prolongation, QTcf will be assessed across a range 
of concentrations using concentration response modeling. The changes in QTcf at the time points 
2, 4, 6, 8, 12, and 24 post-dose, where PK blood samples are also collected, will be modeled with 
drug concentration as a continuous covariate, treatment (LY3202328 or placebo) and time as 
fixed effects, and a random effect for subject within dosing period. This random effect introduces 
correlation among a subject’s QTcf measurements with a dosing period, but the measurements 
from different dosing intervals will be treated as independent. Estimates of the regression 
coefficient and the treatment effect along with their associated 90% confidence intervals (CIs) 
will be obtained from the model. 
The predicted mean placebo-adjusted change from baseline in QTcf will be obtained by 
multiplying the estimated regression coefficient and the observed geometric mean Cmax and 
adding the estimate of the treatment effect (LY3202328 – Placebo). An estimate of the 90% CI 
for the predicted mean placebo-adjusted change from baseline in QTcf will be bootstrapped using 
5000 resamples with subject within dosing interval as the resampling unit. For each resample the 
model will be fitted and the predicted estimate obtained using the geometric mean Cmax based 
on the resample. The CI will be determined from the distribution of the resampled predicted 
values. 
If the upper bound of the 90% CI does not exceed 10 ms then a clinically relevant QT effect can 
be excluded.  
7.5.2 ECGs in Part B 
In Part B, ECGs will be collected on Day -1, at pre-dose on Days  2, 7, 14, 21, and 29, at post-
dose on Day 1 (4 hours) and Day 28 (1, 4, and 8 hours), during follow-up on Days 35 and 42 or 
56. The same parameters reported in Part A will also be reported for Part B.  
7.5.2.1 ECGs over time in Part B 
At each time point, the change from baseline will be derived for each numeric parameter using 
the Day -1 value as baseline. Descriptive statistics for the value of each parameter at each time 
point and the change from baseline for each parameter at each post-dose time point will be 
provided by treatment group. 
Plots of the mean ± standard error for each vital sign, collected while supine, over time (baseline 
through Day 56) will be provided by treatment group. 
The single tracing collected on the Day -2 will be included in by-subject listings but will not be 
included in any summary tables. 
7.5.2.2 Clinically Significant ECGs in Part B 
The number (percent) of subjects who either had an abnormal ECG (regardless whether 
clinically significant or not) or had a clinically significant change in the QTcf value while on-
treatment will be tabulated by treatment group. Abnormal QTcf values will be determined using 
the following criteria:  


Lilly l CHORUS  
I8Q-MC-GSEA 
DGAT2 inhibitor LY3202328 
Statistical Analysis Plan 
Version 1.0 
Confidential 
Page 27 of 27 
• QTcf  ≥ 480 msec 
• QTcf  ≥ 500 msec 
• QTcf  ≥ 550 msec 
• Change from baseline in QTcf  ≥ 30 msec 
• Change from baseline in QTcf  ≥ 60 msec. 
All on-treatment values, including unscheduled assessments, will be considered, and the 
denominator for the percentages will be the number of subjects in the Safety Population. 
All subjects who have an extreme QTcf value or orthostatic value will be documented in a by-
subject listing. The listing will include all of the ECG measurements from the study for the 
subject, and the noteworthy values will be flagged. A similar listing for the Part A will also be 
produced, but no summary table of the results is planned for Part A. 
8 
Pharmacokinetic Analyses 
The PK analysis for the study will be detailed in a separate PK SAP. 
9 
Exploratory PK/PD and PK/Biomarker Analyses 
The exploratory PK/PD and PK/biomarker analyses for the study will be detailed in a separate 
SAP. 
10 
Additional, non-PK, Analyses for the DDI study 
Any additional non-PK analyses for the DDI study will be detailed in a separate SAP. 
 

Prot_001.pdf: 
Protocol I8Q-MC-GSEA(a)
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LY3202328
NCT02714569 
Document Approval Date:  22 June 2016  


I8Q-MC-GSEA(a) Clinical Pharmacology Protocol 
Page 1 
LY3202328 
1. Protocol I8Q-MC-GSEA(a)
A Randomized, Double-Blind, Placebo-Controlled, Single 
and Multiple Oral Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of LY3202328 
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 
LY3202328, 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. 
LY3202328 
Chorus, a division of Lilly Research Laboratories 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Clinical Pharmacology Protocol Electronically Signed and Approved by Chorus on date 
provided below. 
22 June 2016 


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LY3202328 
2. Table of Contents 
A Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Oral Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LY3202328 
Section 
Page 
1. 
Protocol I8Q-MC-GSEA A Randomized, Double-Blind, Placebo-
Controlled, Single and Multiple Oral Ascending Dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
LY3202328 ..............................................................................................................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Protocol Synopsis ....................................................................................................................8 
4. 
Introduction ...........................................................................................................................11 
4.1. 
Study Rationale ................................................................................................................11 
4.2. 
Background.......................................................................................................................12 
4.3. 
Benefit/Risk Assessment ..................................................................................................13 
5. 
Objectives ..............................................................................................................................14 
5.1. 
Primary Objective .............................................................................................................14 
5.2. 
Secondary Objectives .......................................................................................................14 
5.3. 
Exploratory Objectives .....................................................................................................14 
6. 
Study Design .........................................................................................................................15 
6.1. 
Overall Design ..................................................................................................................15 
6.1.1. 
Part A: Single Ascending Dose with Food Effect Design .......................................16 
6.1.2. 
Part B:  Multiple Ascending Dose – Drug-Drug Interaction 
Design ......................................................................................................................18 
6.2. 
Number of Participants .....................................................................................................19 
6.3. 
End of Study Definition....................................................................................................19 
6.4. 
Scientific Rationale for Study Design ..............................................................................19 
6.5. 
Justification for Dose ........................................................................................................20 
7. 
Study Population ...................................................................................................................22 
7.1. 
Inclusion Criteria ..............................................................................................................22 
7.2. 
Exclusion Criteria .............................................................................................................23 
7.3. 
Lifestyle and Dietary Requirements .................................................................................25 
7.3.1. 
Meals and Dietary Restrictions ................................................................................25 
7.3.2. 
Caffeine, Alcohol, and Tobacco ..............................................................................26 
7.3.3. 
Activity .....................................................................................................................26 
7.4. 
Screen Failures .................................................................................................................26 


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LY3202328 
8. 
Treatment ...............................................................................................................................27 
8.1. 
Treatment Administered ...................................................................................................27 
8.1.1. 
Packaging and Labeling ...........................................................................................28 
8.2. 
Method of Treatment Assignment ....................................................................................28 
8.2.1. 
Selection and Timing of Doses ................................................................................28 
8.3. 
Blinding ............................................................................................................................29 
8.3.1. 
Dose Decision/Escalation ........................................................................................29 
8.4. 
Preparation/Handling/Storage/Accountability .................................................................30 
8.5. 
Treatment Compliance .....................................................................................................30 
8.6. 
Concomitant Therapy .......................................................................................................30 
8.7. 
Treatment after the End of the Study ...............................................................................31 
8.7.1. 
Continued Access to Investigational Product ..........................................................31 
9. 
Discontinuation Criteria ........................................................................................................32 
9.1. 
Discontinuation from Study Treatment ............................................................................32 
9.1.1. 
Discontinuation of Inadvertently Enrolled Subjects ................................................32 
9.2. 
Discontinuation from the Study ........................................................................................32 
9.3. 
Subjects Lost to Follow-up ...............................................................................................33 
10. Study Assessments and Procedures .......................................................................................34 
10.1. Efficacy Assessments .......................................................................................................34 
10.2. Adverse Events .................................................................................................................34 
10.2.1. 
Serious Adverse Events ...........................................................................................35 
10.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................35 
10.2.2. 
Complaint Handling .................................................................................................36 
10.3. Treatment of Overdose .....................................................................................................36 
10.4. Safety ................................................................................................................................36 
10.4.1. 
Laboratory Tests ......................................................................................................36 
10.4.2. 
Vital Signs ................................................................................................................36 
10.4.3. 
Electrocardiograms ..................................................................................................36 
10.4.4. 
Safety Monitoring ....................................................................................................37 
10.5. Pharmacokinetics ..............................................................................................................38 
10.5.1. 
Bioanalysis ...............................................................................................................39 
10.6. Pharmacodynamics ...........................................................................................................39 
10.6.1. 
Exploratory Biomarker Analyses .............................................................................39 
10.7. Pharmacogenomic/Stored Samples ..................................................................................40 
11. Statistical Considerations and Data Analysis ........................................................................41 
11.1. Sample Size Determination ..............................................................................................41 
11.2. Populations for Analyses ..................................................................................................41 
11.2.1. 
Study Participant Disposition ...................................................................................41 


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LY3202328 
11.2.2. 
Study Participant Characteristics .............................................................................41 
11.2.3. 
Treatment Compliance .............................................................................................42 
11.3. Statistical Analyses ...........................................................................................................42 
11.3.1. 
Safety Analyses ........................................................................................................42 
11.3.1.1. 
Clinical Evaluation of Safety .............................................................................42 
11.3.1.2. 
Statistical Evaluation of Safety ..........................................................................42 
11.3.2. 
Pharmacokinetic Analyses .......................................................................................43 
11.3.3. 
Pharmacodynamic and Biomarker Analyses ...........................................................43 
11.3.4. 
Interim Analyses ......................................................................................................44 
12. References .............................................................................................................................45 
 
 


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LY3202328 
List of Tables 
Table 
Page 
Table GSEA.1. 
Margin of Safety for Oral Administration of LY3202328 Based on 
Administered Dose and Predicted Exposure ..............................................21 
Table GSEA.2. 
Treatments Administered ...........................................................................27 
 
 
 


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List of Figures 
Figure 
Page 
Figure GSEA.1. 
Study design for Protocol I8Q-MC-GSEA. ...............................................16 
 
 
 


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LY3202328 
List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...................................................................46 
Appendix 2. 
Schedule of Events for Protocol I8Q-MC-GSEA ......................................50 
Appendix 3. 
Clinical Laboratory Tests ...........................................................................59 
Appendix 4. 
Study Governance, Regulatory, and Ethical Considerations .....................60 
Appendix 5. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality .............63 


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3. Protocol Synopsis 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of LY3202328. 
Rationale:  
Cardiovascular (CV) disease remains one of the largest causes of morbidity worldwide and new treatments are 
needed.  The principle aim of this single and multiple ascending dose study is to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of LY3202328 when administered orally as single doses to overweight, healthy subjects 
(Part A, single ascending dose [SAD] design) and as multiple doses to overweight, dyslipidemic subjects (Part B, 
multiple ascending dose [MAD] design).  The data obtained in this study will help establish the doses and dosage 
regimen suitable for administration to dyslipidemic patient populations in future efficacy studies.  In vitro testing 
showed some potential for LY3202328 to have mechanism-based inhibition of cytochrome P450 (CYP) 3A4; thus a 
drug-drug interaction (DDI) comparison arm has been included in Part B to investigate the effect of LY3202328 on 
the exposure of commonly used statins that are metabolized, at least in part, by CYP3A4.  Additionally, the 
exploration of the degree of target inhibition (pharmacodynamic [PD] assessments) in dyslipidemic subjects will be 
assessed in Part B. 
Objectives/Endpoints: 
Objectives 
Endpoints 
Primary 
To explore safety and tolerability of single and multiple doses of LY3202328 
in statin-free, overweight, healthy subjects, or subjects with dyslipidemia. 
Secondary 
• 
To assess the PK characteristics of LY3202328 in statin-free, 
overweight, healthy subjects after single doses and in dyslipidemic 
subjects after multiple doses. 
• 
To evaluate the effect of food on the extent and rate of LY3202328 
absorption. 
• 
To determine the effects of LY3202328 upon multiple dose 
administration on: 
o 
Fasting lipid profiles 
o 
Simvastatin and atorvastatin exposure. 
Exploratory 
• 
To explore the effects of LY3202328 on: 
o 
Post-prandial lipid profiles. 
o 
Fasting free fatty acids and β-hydroxybutyrate. 
o 
Fasting apolipoprotein (Apo) B100, ApoC3, proprotein convertase 
subtilisin/kexin type 9, lipoprotein (a), and insulin. 
o 
Body weight. 
Summary of Study Design: 
Study I8Q-MC-GSEA (GSEA) is a first-in-man, Phase 1, randomized, double-blind, placebo-controlled, ascending 
single- and multiple-oral dose study of LY3202328 in statin-free, overweight, healthy male and female subjects.  
This study will be conducted in 2 parts. 


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LY3202328 
Part A, will comprise a SAD crossover design in statin-free, overweight, healthy male and female subjects, 
investigating the safety, tolerability, and PK of single doses of LY3202328 administered in the fasted state.  In 
addition, one dose level will also be administered in the fed state to evaluate effects of food on the rate and extent of 
absorption. 
Part B will comprise a MAD staggered parallel design in statin-free, overweight, dyslipidemic male and female 
subjects, investigating the safety, tolerability, and PK of multiple doses of LY3202328 and its effect on simvastatin 
and atorvastatin exposure. 
Treatment Arms: 
Part A:  A total of 18 subjects will be enrolled in 2 cohorts.  Cohort 1 will consist of 3 periods at dose levels 1, 10, 
and 100 mg, and Cohort 2 will consist of 3 periods at dose levels 3, 30, and 300 mg.  A fourth dosing period will be 
added to either Cohort 1 or Cohort 2 to assess exposure differences when LY3202328 is administered in a fed state.  
Each cohort will consist of 9 subjects where subjects will receive either a single LY3202328 dose or a 
corresponding placebo in alternating ascending order. 
In each cohort, 6 subjects will receive LY3202328 and 3 subjects will receive placebo.  Subjects will be dosed in the 
fasted state in all periods except for subjects in the cohort that will return to repeat 1 dose level (planned 30 mg dose 
level) in the fed state to evaluate food effects on LY3202328 exposure.  An additional potential cohort (not 
evaluated for food effect) will be reserved for the fourth dosing period at a higher dose level (600 mg).  Escalation to 
this higher dose will only be made if exposure continues to increase between 100 and 300 mg dose levels and the 
safety profile supports dosing to a higher level. 
Part B:  A total of 40 subjects will be enrolled and divided evenly into 4 study periods (n=10 subjects per study 
period) to evaluate 4 dose levels of LY3202328 (Periods 5, 6, 7, and 8 at 5, 20, 100, and 300 mg, respectively, are 
planned). 
Within each study period, 5 subjects will be stratified to the simvastatin DDI assessment and 5 subjects will be 
stratified to the atorvastatin DDI assessment.  Within each stratum subjects will be randomly assigned 4:1 to receive 
LY3202328 or placebo so that 8 subjects will receive LY3202328 and 2 subjects receive placebo in each cohort.  
Subjects will receive a once daily (QD) dose of LY3202328 or placebo, to be administered in the morning in the 
fasted state for 29 total days.  For DDI assessment, subjects will also receive a single atorvastatin or simvastatin 
dose a week prior to LY3202328 treatment initiation, and on Day 29 after initiation of LY3202328 dosing 
(coadministered with LY3202328).  See Figure GSEA.1 for details. 
The dose levels intended for study in Part B will be within the range of those tested in Part A.  Specific dose levels 
will be selected after review of Part A data.  Doses may range up to 300 mg or the maximum tolerated dose 
established in SAD Part A. 
Number of Subjects: 
Part A:  It is planned that a total of 18 subjects will be enrolled in 2 cohorts with 9 statin-free, overweight, healthy 
subjects in each cohort. 
Part B:  It is planned that a total of 40 subjects will be enrolled in 4 cohorts with 10 statin-free, overweight, 
dyslipidemic subjects in each cohort. 


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LY3202328 
Additional subjects may be enrolled to replace drop-outs or discontinued subjects, but are not required. Replacement 
subjects may complete any portion of the study as needed, i.e. any portion not completed by the discontinued 
subject. 
Data Analysis: 
Safety 
The primary endpoint of this study is the number and severity of treatment-emergent adverse events, clinical 
laboratory abnormalities, changes in vital sign measurements, and other safety endpoints after administration of 
LY3202328 or placebo.  Summary statistics will be provided by dose group and for all study subjects combined 
wherever appropriate.  For continuous variables, summary statistics will include number of subjects, mean, median, 
standard deviation, minimum, and maximum.  Categorical endpoints will be summarized using number of subjects, 
frequency, and percentages.  Additional analysis will be performed if warranted upon review of the data. 
Pharmacokinetics 
The primary PK parameters for analysis will be maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) for LY3202328.  The primary AUC metric will be calculated AUC from time zero 
to infinity (AUC0-∞) after single dose administration and AUC during one dosing interval (AUC0-τ) on day 28 after 
multiple dose administration.  Pharmacokinetic parameter estimates (Cmax and AUC) for LY3202328 will be 
evaluated to delineate effects of dose proportionality using a power model approach. 
Drug-drug interaction assessment of the effect of LY3202328 coadministration on simvastatin and atorvastatin 
exposure will be conducted using ANOVA.  Pharmacokinetic parameter estimates (Cmax and AUC) for simvastatin 
and atorvastatin, administered alone or coadministered with LY3202328, will be compared.  The ratios of statin 
exposure with and without LY3202328 coadministration at different dose levels of LY3202328 will be estimated, 
along with their confidence intervals. 
The impact of food on the rate and extent of LY3202328 absorption will be assessed by calculating and 
summarizing the ratios of Cmax and AUC0-∞, as well as the difference in the time to reach Cmax (Tmax), with and 
without food at the same dose level. 
Review of PK may occur during the conduct of Part A and B to confirm exposure trends. 
Pharmacodynamics 
The PD assessments conducted in this study are typical and appropriate for  Phase I single and multiple ascending 
dose evaluations of a novel therapeutic agent.  The triglycerides concentrations will be analyzed to evaluate 
evidence of target engagement and intended pharmacological benefits. 
Visual and tabular summarization of all PD measurements will be done.  For the endpoints in the primary or 
secondary objectives, a statistical analysis will also be conducted. 
Mixed effect model repeated measure would be the default method of analysis for PD endpoints with time-course 
data.  For endpoints with only baseline and end-of-therapy measurements, ANCOVA will be the default, with 
baseline as a covariate.  Other covariates may be a priori defined and included in the model. 
Normality assumption will be tested using an appropriate visual or statistical method and, if it is violated, log 
transformation may also be performed on these data.  The most sensitive analysis will be selected to test the effect of 
LY3202328 on the change from baseline in these PD data. 


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4. Introduction 
Diacylglycerol acyltransferase 2 (DGAT2) plays a key role in processing fatty acids and 
secreting triglycerides (TG) from the liver.  DGAT2 is responsible for catalyzing the formation 
of triacylglycerol from diacylglycerol and fatty acyl-coenzyme A.  Despite the significant 
advancements made by statins in the treatment of dyslipidemia and cardiovascular (CV) disease, 
unmet need exists in a market projected to remain one of the largest causes of morbidity and 
mortality worldwide.  DGAT2 inhibitor LY3202328 has the potential to offer value to patients, 
physicians, and providers through its expected diverse pharmacological profile to decrease TG, 
total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), body weight, liver fat 
content, and improve glucose utilization.  This broad pharmacological profile is expected to 
result in a reduction in CV events when added to or compared with statins or other standard-of-
care therapies for these indications.  A DGAT2 inhibitor also has the potential to treat other 
important metabolic diseases beyond dyslipidemia, including nonalcoholic fatty liver disease, 
and possibly Type-2 diabetes mellitus.  Antisense oligonucleotide reduction of DGAT2 in liver 
and white adipose tissues for 18 weeks in LDL receptor (LDLr) knockout (KO) mice fed high-
fat, cholesterol-enriched diets, reduced body weight (10%), total body fat (48%), plasma TG 
(70%), TC (52%), LDL-c (31%), and free fatty acids (FFA; 46%); and increased the glucose 
infusion rate needed to maintain glucose concentrations in a hyperinsulinemic-euglycemic clamp 
study by 70% (Manchem, 2010). 
LY3202328 is a potent inhibitor of human DGAT2 with a half maximal inhibitory concentration 
(IC50) of 124 nM in the primary enzyme assay and IC50 values of 197 nM and 47 nM in the 
HepG2 cell-based assay, with TG and apolipoprotein (Apo) B100 readouts, respectively.  
LY3202328 is highly selective compared to other acyl transferases in the TG synthesis pathway 
(IC50 >50 µM for DGAT-1, glycerophosphate acyltransferases-1 and -4, monoacylglycerol 
O-acyltransferases-2 and -3, as well as a general panel of enzymes and receptors), and it inhibits 
carbonic anhydrase with IC50 of 5 µM.  LY3202328 demonstrated dose dependent inhibition of 
hepatic TG secretion in mice, with a median effective dose (ED50) of 0.3 mpk when 
administered orally and a half maximal effective concentration (EC50) of 142 ng/mL. 
4.1. Study Rationale 
There are many opportunities to address unmet need in the CV market. These include:  
1) reducing residual CV event risk in patients already taking maximally-tolerated doses of 
statins; 2) providing predictable, robust lowering of both LDL-c and TG; 3) addressing common 
dyslipidemia co-morbidities such as obesity and diabetes; and 4) improving CV patient 
experience through decreased polypharmacy and a more acceptable mode of administration (oral 
versus injectable). 
LY3202328 has the potential to offer a broad clinical profile that may result in a reduction in CV 
events when added to or compared to the standard of care.  Further preclinical and Phase 1 
studies will contribute to our understanding of the magnitudes of each clinical effect of 
LY3202328. 


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LY3202328 
The principle aim of these dose-escalation  studies is to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of LY3202328 when administered orally as single doses to healthy 
subjects (Part A, single ascending dose [SAD] design) and as multiple doses to dyslipidemic 
subjects (Part B, multiple ascending dose [MAD] design).  A food effect period will be 
performed in Part A to compare the exposure profile when LY3202328 is dosed in the fed or 
fasted state.  The data obtained in this study will help establish the doses and dose regimen 
suitable for administration to dyslipidemic patient populations. 
A drug-drug interaction (DDI) comparison arm will be included in Part B to investigate the 
effect of LY3202328 on the exposure of statins (i.e., simvastatin and atorvastatin).  Additionally, 
the exploration of the degree of target inhibition (pharmacodynamic [PD] assessments) in 
dyslipidemic subjects will be assessed in Part B. 
4.2. Background 
LY3202328 is a low solubility, highly permeable molecule with high oral exposure in preclinical 
species.  Oral bioavailability at the predicted human 80% maximal effective dose (ED80) 
efficacious dose (13 mg once daily [QD]) is greater than 30% in preclinical species and is 
predicted to be 89% in humans.  As the dose increases, exposures are expected to increase until 
reaching a plateau as absorption limitations are expected in humans for doses above 190 mg due 
to the solubility characteristics of the compound.  In vivo, LY3202328 exhibits near linear 
increases in area under the plasma concentration-time curve (AUC) at doses up to 100 mg/kg 
with much lower than dose proportional increases in exposure above 100 mg/kg.  The maximum 
plasma concentration (Cmax) also increases with dose in a less than proportional manner.  The 
time to reach Cmax (Tmax) is reached between 1 to 3 hours in most preclinical species.  
LY3202328 is eliminated predominantly by cytochrome P450 (CYP) 3A4 microsomal oxidation 
with <5% of dose excreted as parent by renal elimination.  Based on in vitro data, LY3202328 is 
also a time-dependent inhibitor of CYP3A4 at high concentrations.  However, lack of 
accumulation upon multiple dosing in vivo suggests that LY3202328 does not inhibit its own 
metabolism.  These properties suggest a potential for DDIs with concomitantly administered 
CYP3A4 substrates (particularly those with a narrow therapeutic margin) or CYP3A4 inhibitors.  
Half-life in animal preclinical toxicology studies ranged from 3 to 12 hours, yet exposures in rat 
and dog toxicology studies showed no accumulation of LY3202328 after 28 days of repeat 
dosing.  In humans, LY3202328 is projected to have a half-live of 6 to 8 hours.  Human clinical 
dose projections based on Simcyp modeling of animal PK data predict a dose of 13 mg to 
achieve an average steady state concentration of 325 ng/mL (equivalent to a 24 hour AUC of 
7.8 µg x h/mL) which is associated with 80% efficacy based on preclinical pharmacology studies 
(after correction for species difference in protein binding and receptor affinity). 
In 28-day repeat dose Good Laboratory Practice (GLP) toxicology studies conducted at doses up 
to 500 mg/kg in rat and 250 mg/kg in dog (maximum feasible dose levels), no dose-limiting 
toxicities and no observable adverse effects were observed in either species.  In rats administered 
500 mg/kg, animals had minimal decreases in body weight gain (4%).  Slight hypertrophy 
observed in liver centrilobular hepatocytes, adrenal zona fasciculata cells, and thyroid follicular 
cells correlated with minimal organ weight increases.  These findings were consistent with 


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LY3202328 
physiological adaptations to stress or minimal metabolic induction commonly observed in 
rodents.  In dogs administered 250 mg/kg, there were infrequent emesis, liquid feces, and minor 
body weight loss (1%) with reduced food consumption.  Rats and dogs administered 500 mg/kg 
and 250 mg/kg, respectively, had slight decreases in red blood cell mass (red blood cell count, 
hemoglobin concentration, and hematocrit) with evidence of regeneration based on higher 
absolute reticulocyte count.  These effects observed in rats and dogs were not observed at the end 
of the 1-month reversibility phase of either study.  The effects observed in rats and dogs were 
monitorable and there were adequate margins to the proposed clinical doses. 
4.3. Benefit/Risk Assessment 
The nonclinical safety information for LY3202328 adequately supports the transition from 
preclinical to clinical study.  On the basis of the nonclinical data, LY3202328 is not considered 
to be a high-risk compound.  This protocol reflects the fact that LY3202328 has not been 
administered to humans previously and, to mitigate this risk, the study has been designed to be 
conducted in accordance with principles outlined in the Guideline on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products 
(2007).  Any identified risks are considered to be monitorable and manageable at the planned 
dose range of 1 to 300 mg for LY3202328 in healthy subjects. 
More information about the known and expected benefits and risks of LY3202328 can be found 
in Section 3.2 of the Investigator’s Brochure (IB). 
The sponsor, monitor, and investigator will perform this study in compliance with the protocol, 
good clinical practice (GCP), International Conference on Harmonisation (ICH) guidelines, and 
applicable regulatory requirements. 


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LY3202328 
5. Objectives 
5.1. Primary Objective 
The primary objective of this study is to explore safety and tolerability of single and multiple 
doses of LY3202328 in statin-free, overweight, healthy subjects. 
5.2. Secondary Objectives 
The secondary objectives of this study are: 
• 
To assess the PK characteristics of LY3202328 in statin-free, overweight, healthy 
subjects after single and multiple doses. 
• 
To evaluate the effect of food on the extent and rate of LY3202328 absorption. 
• 
To determine the effects of LY3202328 upon multiple dose administration on: 
o Fasting lipid profiles 
o Simvastatin and atorvastatin exposure 
5.3. Exploratory Objectives 
The exploratory objective of this study is to explore the effects of LY3202328 on: 
• 
Post-prandial lipid profiles. 
• 
Fasting free fatty acids and β-hydroxybutyrate. 
• 
Fasting ApoB100, ApoC3, proprotein convertase subtilisin/kexin type 9 (PCSK9), 
lipoprotein (a) (Lp[a]), and insulin. 
• 
Body weight. 


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LY3202328 
6. Study Design 
6.1. Overall Design 
Study I8Q-MC-GSEA (GSEA) is a first-in-man, Phase 1, randomized, double-blind, placebo-
controlled, 2-part, ascending single- and multiple-oral dose study of LY3202328 in statin-free, 
overweight, healthy subjects (Part A) and in statin-free, overweight, dyslipidemic subjects with a 
statin DDI assessments (Part B). 
This study will be conducted in 2 parts:  Part A, a SAD study design at a single site and Part B, a 
MAD study design conducted in multiple sites. 
Figure GSEA.1 illustrates the study design. 
 
 


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LY3202328 
 
Abbreviations:  AS = atorvastatin; CRU = clinical research unit; D/C = discharge (from 
the CRU); LY = LY3202328; N = number of subjects; SS = simvastatin. 
a 
Discharge from the CRU will occur on Day 2 with Follow-up visits to occur on 
Days 3 and 5. 
b 
LY3202328 or placebo will be administered with food. 
c 
A single dose of simvastatin or atorvastatin will be administered on Day –7. 
d 
Multiple doses of LY3202328 or placebo will be administered daily on Days 1 
through 28. 
e 
LY3202328 or placebo will be coadministered with simvastatin or atorvastatin on 
Day 29. 
f 
Discharge from the CRU will occur on Day 30 with Follow-up visits to occur on 
Days 35 and 56. 
Note:  The doses for Part B are subject to change and will not exceed the maximum 
tolerated dose from Part A (starting as low as 5 mg and not to exceed 300 mg). 
Figure GSEA.1. 
Study design for Protocol I8Q-MC-GSEA. 
6.1.1. Part A: Single Ascending Dose with Food Effect Design 
Part A will comprise a double-blinded, 2-staggered, alternating, 3- or 4-period sequence design 
of single ascending doses in statin-free, overweight (body mass index [BMI] 25.0 to 35.0 kg/m2), 


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LY3202328 
healthy male and female subjects, investigating the safety, tolerability, and PK of single doses of 
LY3202328 administered in the fasted state.  One dose level will be repeated in the fed state 
using the same randomization as conducted in the fasted state to assess the effect of food on 
LY3202328 exposure. 
A total of 18 subjects will be enrolled in 2 cohorts.  Cohort 1 will consist of 3 periods at dose 
levels 1, 10, and 100 mg, and Cohort 2 will consist of 3 periods at dose levels 3, 30, and 300 mg.  
A fourth dosing period will be added to either Cohort 1 or Cohort 2 to assess exposure 
differences when LY3202328 is administered in a fed state.  Each cohort will consist of 
9 subjects where subjects will receive either a single LY3202328 dose or a corresponding 
placebo in alternating ascending order. 
In each cohort, 6 subjects will receive LY3202328 and 3 subjects will receive placebo.  Subjects 
will be dosed in the fasted state in all periods except for subjects in the cohort that will return for 
the fourth dosing period to repeat 1 dose level (planned 30 mg dose level) in the fed state to 
evaluate food effects on LY3202328 exposure.  An additional potential cohort (not evaluated for 
food effect) will be reserved for the fourth dosing period at a higher dose level (600 mg).  
Escalation to this higher dose will only be made if exposure continues to increase between 
100 and 300 mg dose levels and the safety profile supports dosing to a higher level. 
Potential subjects will be screened to assess their eligibility to enter the study within 42 days 
prior to study entry (i.e., prior to Check in for Part A).  Subjects will be confined at the clinical 
research unit (CRU) from Day –1 (the day before dosing) to Day 2 (24 hours postdose), and 
return on Days 3 and 5 (48 and 96 hours postdose, respectively) for follow-up assessments.  
Dosing in subsequent periods will be approximately 2 weeks after dosing in the prior period, 
with subjects dosed on Day 1 of Week 1, 3, or 5 (Cohort 1); Week 2, 4, or 6 (Cohort 2); and 
Week 8 (food effect period, Cohort 2). 
Treatment of the cohorts in Part A will be staggered so that the appropriateness of escalation to 
the next dose level can be determined from the current dose level. 
Safety assessments in Part A and Part B will include monitoring of adverse events (AEs), clinical 
laboratory test results, vital sign measurements, physical examination findings, and 12-lead 
electrocardiogram (ECG) results.  Escalation to the next dose period will be decided by the 
investigator in consultation with the sponsor’s clinical research physician (CRP) at the dose 
escalation Data Review Meeting (DRM) as outlined in Section 7.3.1.  The decision will be made 
based on safety data from each dosing period (Appendix 2).  Pharmacokinetic and PD data are 
not required for the dose escalation decision; however, any drug concentration or PD data that 
becomes available prior to the DRM may be reviewed at the DRM.  Interim analysis of PK will 
take place after collecting the 300 mg dose level samples to determine if a 600 mg dose level will 
be conducted.  No interim analysis for PD is planned for the DRM. 


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6.1.2. Part B:  Multiple Ascending Dose – Drug-Drug Interaction 
Design 
Part B will comprise a double-blinded, MAD, staggered parallel design in dyslipidemic (TG: 
150 to 499 mg/dL; LDL-c: 100 to 200 mg/dL), statin-free, overweight (BMI 27.0 to 40.0 kg/m2), 
male and female subjects investigating the safety, tolerability, and PK of multiple doses of 
LY3202328 and the effect of LY3202328 on simvastatin and atorvastatin exposure. 
A total of 40 subjects will be enrolled and divided evenly into 4 study periods (n=10 subjects per 
study period) to evaluate 4 dose levels of LY3202328 (Periods 5, 6, 7, and 8 at 5, 20, 100, and 
300 mg, respectively, are planned). 
Within each cohort, 5 subjects will be stratified to the simvastatin DDI assessment and 5 subjects 
will be stratified to the atorvastatin DDI assessment.  Within each stratum subjects will be 
randomly assigned 4:1 to receive LY3202328 or placebo so that 8 subjects will receive 
LY3202328 and 2 subjects receive placebo in each cohort.  Subjects will receive QD dose of 
LY3202328 or placebo in the morning in the fasted state for 29 total days.  For DDI assessment, 
subjects will also receive a single atorvastatin or simvastatin dose a week prior to LY3202328 
treatment initiation, and on Day 29 after initiation of LY3202328 daily dosing (coadministered 
with LY3202328). 
The dose levels intended for study in Part B may change based upon data from Part A, but will 
range from as low as 1 mg and are not to exceed the highest dose evaluated in Part A.  Any dose 
level used in Part B will not start until the safety data from the same or higher dose level in Part 
A has been reviewed by the safety committee responsible for dose escalation decisions. 
Potential subjects will be screened to assess their eligibility to enter the study within 42 days 
prior to study entry (i.e., prior to Check in for Part B).  For each cohort, subjects will be admitted 
to the CRU on Day –8 (the day before administration of a single dose of simvastatin or 
atorvastatin) and will be discharged 24 hours postdose (Day –6). 
Subjects will be confined to the CRU from Day –2 to Day 2 (48 hours postdose) for initial 
dosing with LY3202328 and are required to return to the CRU for dosing and PK sampling the 
mornings of Days 7, 14, and 21.  Prior to discharge from the CRU on Day 2, subjects will 
receive a labeled container with doses of LY3202328 that subjects will self‑administer daily at 
home until the next morning visit at the CRU.  Subjects will be instructed to take the drug QD in 
the morning in the fasted state and wait at least 60 minutes after the completion of dosing prior to 
commencing their breakfast.  Subjects will be given diaries to record the time of their self‑
administered doses, whether the dose was administered with food or fasted, and the time of 
commencing the breakfast meal.  Subjects must return the container (empty or not) and their 
diary at the next morning visit.  Home dosing will be monitored via attempted phone calls when 
subjects will be reminded to take their medication and queried about the occurrence of AEs.  
Subjects should be instructed to take their dose at approximately the same time they received 
their first dose.  Subjects will again be confined to the CRU on Day 27 (2 days before 
coadministration of LY3202328 or placebo with simvastatin or atorvastatin on Day 29) to 
Day 30 (24 hours post-coadministration of LY3202328 or placebo with simvastatin or 


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LY3202328 
atorvastatin).  Subjects will return to the CRU on Days 35 and 56 (168 and 672 hours postdose, 
respectively) for follow-up assessments. 
The dose levels intended for study in Part B will be within the range of those tested in Part A.  
Specific dose levels will be selected after review of Part A data.  Doses may range up to 300 mg 
or the maximum tolerated dose established in SAD Part A. 
6.2. Number of Participants 
Eighteen healthy males and female subjects may be enrolled in Part A where each subject is 
scheduled to receive 2 single doses of LY3202328 and 1 dose of placebo in ascending dose 
levels.  Forty subjects may be enrolled in Part B (8 subjects will receive LY3202328 and 2 
subjects will receive placebo in each of 4 dose level cohorts).  Additional subjects may be 
enrolled to replace drop-outs or discontinued subjects, but are not required.  Replacement 
subjects may complete any portion of the study as needed, i.e. any portion not completed by the 
discontinued subject with the goal to complete up to 18 subjects in Part A and up to 40 subjects 
in Part B.  The decision to replace subjects will be discussed with the Sponsor prior to adding 
subjects. 
6.3. End of Study Definition 
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Events (Appendix 2) for the last subject. 
6.4. Scientific Rationale for Study Design 
The purpose of this study is to evaluate the safety, tolerability, PK, and degree of target 
inhibition (PD) of LY3202328 when administered orally as single doses to statin-free, 
overweight, healthy subjects (Part A) and as multiple doses (with a statin DDI assessment) to 
statin-free, overweight, dyslipidemic subjects (Part B). 
For Part A, a standard single-dose, double-blind, randomized, placebo–controlled, SAD 
crossover design will be used.  A randomization schedule for treatment sequence assignment will 
be used to reduce the potential for selection bias.  For Part B, a double-blind, randomized, 
placebo–controlled, sequential MAD design will be used.  The data obtained from this study will 
help establish the doses suitable for administration to patients with dyslipidemia and the possible 
existence of a DDI between LY3202328 and simvastatin and/or atorvastatin prior to studies in 
patient populations on stable treatment. 
The selection of healthy subjects is appropriate and consistent with standard practices for an 
early phase clinical pharmacology study.  The inclusion and exclusion criteria are chosen to 
select subjects who are known to be free from any significant illness.  A placebo is included to 
enable characterization of AEs by serving as a negative control.  LY3202328 is not anticipated to 
provide any benefit to the study subjects, and therefore the use of placebo will not deprive 
subjects of any benefit. 


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6.5. Justification for Dose 
Human PK/PD modeling and preclinical absorption, disposition, metabolism, and excretion 
(ADME) profiles in rat, dog, and primate were used to predict that LY3202328 should achieve a 
sustained average ED80 concentration in man with an oral dose of 13 mg QD.  This projected 
human dose compares favorably with the projected maximum absorbable dose of 190 mg 
determined using GastroPlus modelling of rat, dog, and monkey ADME profiles.  In chronic 
lipid lowering studies, LY3202328 produced dose-dependent inhibition of LDL-c (61%), ApoB 
(53%), ApoC3 (43%), and PCSK9 (55%) in plasma, as well as liver TG (37%) in LDLr KO 
mice, and reduced liver TG (56%) in C57Bl/6 mice on a high fat diet.  Finally, body surface area 
dose and predicted AUC exposure multiples are greater than 195x in GLP rat and dog toxicology 
studies relative to the predicted efficacy dose/exposure, and greater than 13x relative to the 
highest planned human dose of 300 mg.  The proposed dose range for this first-in man-study of 
1 to 300 mg of LY3202328 administered orally QD for up to 28 days was selected based on 
toxicology studies and modeling of PK/PD data from nonclinical studies of LY3202328, and the 
established margin of safety. 
The nonclinical no-observed-adverse-effect level (NOAEL) doses and AUC values for 
LY3202328 following daily administration compared with planned human doses and projected 
human exposures are presented in Table GSEA.1.  


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LY3202328 
Table GSEA.1. 
Margin of Safety for Oral Administration of LY3202328 Based on 
Administered Dose and Predicted Exposure 
 
Dose 
(mg) 
Dose 
(mg/kg) 
HED 
(mg/kg) 
Dose 
Multiplea 
AUC 
(µg•h/mL)b 
Exposure 
Multiplea 
Humanc 
 
 
 
– 
 
– 
Starting dose 
1 
0.0143 
0.0143 
 
0.6 
 
Efficacy dose 
13 
0.186 
0.186 
 
7.8 
 
Highest dose 
300 
4.29 
4.29 
 
114 
 
Rat NOAELd 
 
500 
80.6 
 
1710 
 
Starting dose 
 
 
 
5600x 
 
2850x 
Efficacy dose 
 
 
 
433x 
 
219x 
Highest dose 
 
 
 
19x 
 
15x 
Dog NOAELe 
 
250 
139 
 
1520 
 
Starting dose 
 
 
 
9700x 
 
2533x 
Efficacy dose 
 
 
 
747x 
 
195x 
Highest dose 
 
 
 
32x 
 
13x 
Abbreviations:  AUC = area under the plasma concentration x time curve; HED = human equivalent dose based on 
body surface area; NOAEL = no-observed-adverse-effect level. 
a Dose multiple is the dose in animal HED/human dose based on  mg/kg2 using Guidance for Industry, Estimating 
the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, 
FDA/CDER, July 2005.  Exposure multiple is the calculated as AUC in animals/predicted AUC in humans. 
b Predicted human AUC over 24 hours upon repeat once daily dosing, based on predicted human pharmacokinetics 
mentioned in Section 5.1.8 of the Investigators Brochure.  Note:  human predicted AUC listed at a dose of 
300 mg accounts for the expected absorption limitation, resulting in a maximum absorbable dose of 190 mg. 
c Clinical dose based on 70-kg human. 
d NOAEL determined in a 28-day repeat dose rat toxicity study.  AUC is mean of male and female data at the end 
of the study (Study 8327-151). 
e NOAEL determined in a 28-day repeat dose dog toxicity study.  AUC is mean of male and female data at the end 
of the study (Study 8327-163). 


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7. Study Population 
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG results. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. Inclusion Criteria 
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment: 
[1] 
are healthy males or females, as determined by medical history and physical 
examination   
• male subjects: 
o agree to use a reliable method of birth control during the study and 3 months 
following the last dose of the investigational product. Acceptable methods of 
birth control may include: 1) condom with spermicide; 2) Diaphragm with 
spermicide; or 3) female condom with spermicide. 
• female subjects: 
o postmenopausal women include women with either: 
 spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications that induced 
amenorrhea (for example:  oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-estrogens, selective estrogen receptor modulators, or 
chemotherapy; or 
 spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level greater than 40 mIU/mL; or 
 women with a prior history of hysterectomy or bilateral oopherectomy have 
to be at least 40 year of age and FSH >40 mIU/mL. 
[2] 
are at least 18 to 70 years old inclusive (for males), or 40 to 70 years old, 
inclusive (for females), at the time of study entry. 
[3] 
are on a stable diet and exercise regimen for >3 months prior to screening. 
[4] 
have a BMI of 25.0 – 35.0 (Part A) or 27.0 – 40.0 kg/m2 (Part B) , inclusive, at 
screening. 
[5] 
have a fasting TG between 150 and 499 mg/dL, inclusive, at screening (allowed 
but not required in Part A; required for Part B only). 
[6] 
have a fasting LDL-c between 100 and 200 mg/dL inclusive, at screening 
(allowed but not required in Part A; required for Part B only). 


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LY3202328 
[7] 
have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.  However, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transpeptidase (GGT), and alkaline phosphatase (ALP) have to be ≤1.5 × upper 
limit of normal (ULN); total bilirubin has to be within normal limit, unless in 
subjects with Gilbert’s Syndrome; thyroid stimulating hormone (TSH) <ULN. 
[8] 
estimated glomerular filtration rate ≥60 mL/minute/1.73m2 with no proteinuria 
(defined as 1+ or greater on urine dipstick). 
[9] 
are normotensive (defined as supine systolic blood pressure [BP] <150 mm Hg 
and diastolic BP <100 mm Hg).  Subjects with controlled hypertension who are 
taking ACE-I (Lisinopril or captopril) or other antihypertensive agents not 
metabolized through the CYP3A4 may be considered.   Blood pressure may be 
retested up to 2 additional times, under well-rested conditions. 
[10] have venous access sufficient to allow for blood sampling as per the protocol. 
[11] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures. 
[12] have given written informed consent approved by Chorus and the Ethical 
Review Board (ERB) governing the site. 
7.2. Exclusion Criteria 
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment: 
[1] 
are taking a statin, any PCSK9 medications, or have started taking other TG 
lowering agents (e.g., niacin, fish oils) within the last 3 months.  Subjects on 
stable background (>3 months) of non-statin TG lowering agents may be 
included in the study. 
[2] 
are investigator site personnel directly affiliated with this study or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted. 
[3] 
are Chorus (Lilly) or  CRO-site employees. 
[4] 
are currently enrolled in a clinical trial involving an investigational product or 
off-label use of a drug or device, or are concurrently enrolled in any other type 
of medical research judged not to be scientifically or medically compatible with 
this study. 
[5] 
have participated (defined as last dose of study drug) in a clinical trial involving 
an investigational product or non-approved use of a drug within the last 30 days 
or within 5 half-lives, whichever is longer. 


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LY3202328 
[6] 
have an abnormality in the 12-lead ECG, including corrected QT (QTc) interval 
with Bazett’s correction >450 msec for men and >470 msec for women or an 
abnormality that, in the opinion of the investigator, increases the risks 
associated with participating in the study.  ECGs may be repeated after 
5 minutes resting quietly if the subject’s heart rate is >75 bpm. 
[7] 
have uncontrolled hypertension, or at screening a resting supine systolic BP of 
>150 mmHg or diastolic BP of >100 mmHg, confirmed after 5 minutes in the 
supine and resting state. 
[8] 
have any current or prior history of significant cardiovascular disease, including 
acute myocardial infarction, unstable angina, congestive heart failure, 
cardiomyopathy or cardiomyositis.  Subjects with clinically significant 
arrhythmia, including but not limited to atrial fibrillation, 
supraventricular/ventricular tachycardia, atrial-ventricular block, or sick sinus 
syndrome should also be excluded.  Subjects with asymptomatic sinus 
arrhythmia, sinus bradycardia, or mild sinus tachycardia may be enrolled. 
[9] 
show evidence of hepatitis C virus (HCV) and/or positive HCV antibody. 
[10] show evidence of hepatitis B virus and/or positive hepatitis B surface antigen. 
[11] have evidence of other chronic liver disease, including but not limited to chronic 
alcoholic disease, cirrhosis of any cause, or recent history (within 3 months of 
screening) of acute viral hepatitis or chronic autoimmune hepatitis.  Subjects 
with history of biliary disease, including primary sclerosing cholangitis, must be 
excluded.  Subjects with history of cholecystectomy longer than 6 months prior 
to visit 1 could be enrolled. 
[12] have an alcohol intake that exceeds 7 units per week with no more than 3 units 
per day, or are unwilling to stop alcohol consumption for the duration of the 
study (1 unit = 12 ounces or 360 mL of beer; 5 ounces or 150 mL of wine; 
1.5 ounces or 45 mL of distilled spirits). 
[13] have a history of untreated endocrine illness such as diabetes mellitus, growth 
hormone insufficiency / acromegaly, adrenal gland, or thyroid illness. 
[14] have been on medications or supplements for weight loss within 3 months of 
screening. 
[15] have a history of active neuropsychiatric disease or are on pharmacological 
therapy for such conditions within 1 year of screening or have taken any 
antidepressants or antipsychotics within 3 months of screening for non-
psychological indications. 
[16] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies. 
[17] have had any major surgery within 30 days prior to screening or have planned 
elective surgeries to occur during the study. 


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LY3202328 
[18] have a history or current presence of other cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, autoimmune, hematological (including any 
coagulopathy), neoplastic, or neurological disorders (Part B only) capable of 
significantly altering the absorption, metabolism, or elimination of drugs; or 
constituting a risk when taking the study medication; or of interfering with the 
interpretation of data.  Basal cell or squamous epithelial carcinomas of the skin 
that have been resected with no evidence of metastatic disease may be allowed. 
[19] have been on medications that are known to inhibit CYP3A4 or P-glycoprotein 
(P-gp), or regularly consume grapefruit or grapefruit juice within 2 weeks of 
screening. 
[20] are regular users of known drugs of abuse and/or show positive findings on 
urinary drug screening. 
[21] are women who are pregnant or lactating. 
[22] have donated blood of more than 500 mL within the last month, or have 
intention for blood donation during the study period. 
[23] smoke >10 cigarettes per day or are unwilling to follow the CRU smoking rules. 
[24] are unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor. 
[25] have proteinuria (defined as 1+ or greater on urine dipstick) at screening. 
7.3. Lifestyle and Dietary Requirements 
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.   
7.3.1. Meals and Dietary Restrictions 
While confined at the CRU, subjects will receive a standardized diet at scheduled times that do 
not conflict with other study-related activities.  When not at the study site, subjects will be asked 
to take regular meals and avoid major deviations from their usual regimen and habits.  Subjects 
are prohibited from consuming grapefruit or grapefruit juice during the entire duration of the 
study. 
At required time points, subjects will be served  high-fat/high-calorie lunch which must be 
consumed within 20-25 minutes.  For subjects participating in the food effect period, a high-fat 
lunch will not be given.  However, subjects will be required to consume a high-fat/high-calorie 
breakfast 30 minutes before study drug dosing.  Both meals should be fully consumed by the 
subject. 
A high-fat/high-calorie meal must contain approximately 60% fat, 20% carbohydrate, and 20% 
protein. 


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LY3202328 
7.3.2. Caffeine, Alcohol, and Tobacco 
Subjects will abstain from consuming alcohol-containing products for the duration of the study.  
Subjects are required to maintain their regular intake of caffeine- or xanthine-related beverages 
for the duration of the study. 
While confined at the CRU, subjects are required to adhere to the CRU smoking and caffeine 
policy during the inpatient treatment days.  Subjects should otherwise not intentionally change 
their consumption of tobacco- or caffeine-containing products during the study.  
7.3.3. Activity 
Subjects will refrain from strenuous exercise during the period of confinement at the CRU and 
will otherwise maintain their normal level of physical activity throughout the entire study (i.e., 
will not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
7.4. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  Subjects who do not meet clinical laboratories inclusion/exclusion criteria may be 
reevaluated once. Screening of fasting triglycerides may be repeated for subjects with initial 
screening triglycerides of 140 to 150 mg/dl. The mean of the two values must be ≥ 150 mg/dl 
(following usual rounding rules) for inclusion. 


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LY3202328 
8. Treatment 
8.1. Treatment Administered 
This study involves a comparison of LY3202328 to placebo when administered orally as a single 
dose in Part A and when administered in multiple doses both with and without a statin 
(simvastatin or atorvastatin) in Part B.  Table GSEA.2 shows the treatment regimens. 
In Part A, LY3202328 or placebo will be administered orally in the morning of Day 1 with 
approximately 240 mL of room temperature water in a sitting position.  Subjects will not be 
allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study procedures. 
In Part B, all study drugs will be administered orally in the morning with approximately 240 mL 
of room temperature water.  Simvastatin or atorvastatin will be administered on Day –7.  
LY3202328 or placebo will be administered QD on Days 1 to 29 while confined to the CRU (on 
Days 1 to 3, 7, 14, and 21) or at home.  Simvastatin or atorvastatin will be coadministered with 
LY3202328 or placebo on Day 29 while subjects are confined to the CRU.  Investigators should 
instruct subjects to store the LY3202328 or placebo capsules at home in the original container 
out of the reach of children at room temperature.  Capsules should not be opened, crushed, or 
dissolved. 
Table GSEA.2. 
Treatments Administered 
 
Treatment Name 
LY3202328 
Placebo 
Simvastatin 
Atorvastatin 
Dosage 
Formulation 
HPMC capsule 
HPMC capsule 
Commercial 
Commercial 
Unit dose 
strength(s)/ 
Dosage Level(s) 
1, 5, or 50 mg LY 
Part A:  1, 3, 10, 30, 100, 
or 300 mg 
Part B:  5, 20, 100 or 
300 mg  
Inactive 
10 mg 
10 mg 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Abbreviations:  LY = LY3202328; HPMC = hydroxypropyl methylcellulose. 
The investigator or designee is responsible for: 
• explaining the correct use of the investigational product(s) to the subject,  
• verifying that instructions are followed properly, 
• maintaining accurate records of investigational product dispensing and collection, 
• and returning all unused medication to Chorus or its designee at the end of the study. 


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Note:  In some cases, study sites may destroy the material if, during the investigative site 
selection, the evaluator has verified and documented that the site has appropriate facilities and 
written procedures to dispose of clinical trial materials.  
8.1.1. Packaging and Labeling 
The drug product LY3202328 is supplied for clinical trial use as capsules and is composed of 
LY3202328 drug substance filled directly into hydroxypropyl methylcellulose capsules without 
additional ingredients.  Each capsule is manufactured to contain LY3202328 equivalent to either 
1, 5, or 50 mg of the free basic compound. 
Placebo capsules look identical but contain no active ingredient and will be provided in similar 
packaging. 
Simvastatin (Zocor®) and Atorvastatin (Lipitor®) will be obtained by the CRU as commercially 
available. 
Clinical trial materials will be labeled according to the country’s regulatory requirements and 
stored under ambient temperature conditions of 15°C to 30°C. 
8.2. Method of Treatment Assignment 
Subjects who meet all criteria for enrollment during Part A will be assigned to a randomization 
sequence number by the CRU on Day –1 within Cohort 1 (1, 10, and 100 mg) or Cohort 2 (3, 30, 
and 300 mg) that corresponds to 1 of the 3 treatment sequences in a 1:1:1 ratio so that 6 subjects 
receive LY3202328 and 3 subjects receive placebo, per dose level if all subjects are retained on 
study.  The 30 mg dose level in Cohort 2 will be repeated in Period 4 to evaluate food effects on 
exposure. 
Subjects who meet all criteria for enrollment during Part B will be stratified evenly to the 
simvastatin DDI assessment and the atorvastatin DDI assessment and assigned a randomization 
number on Day –7 of Part B for each cohort (Cohorts 3, 4, 5, and 6 at 5, 20, 100, and 300 mg, 
respectively, planned) in the order in which they were enrolled into the study.  For each cohort, 
subjects will be randomly assigned 4:1 to receive LY3202328 or placebo within each stratum. 
Randomization for Parts A and B will be performed in accordance with the randomization 
schedule generated by Chorus (or designee). 
8.2.1. Selection and Timing of Doses 
Study treatment will be administered as shown in the Schedule of Events (Appendix 2). 
All doses in Parts A and B should be administered in the morning under fasted conditions 
(12 hours), except for food effect Period 4 in Part A, which will be administered in the fed state.  
All doses should be administered at approximately the same time on each day for Part B (on 
Days 2 to 29, within ±1 hour of dosing time of Day 1).  In Part B, subjects will receive standard 
meals at appropriate times when confined to the CRU or during return visits for dosing.  At least 
60 minutes should separate the ingestion of the dose and the beginning of the breakfast meal 
while confined to the CRU and at home.  Additionally, subjects will be asked to document time 


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of dosing and time of first meal in a diary and keep their standard diet when at home.  A high-fat 
lunch meal will be administered 4 hours postdose in each period of Part A (with exception of 
Period 4) and on Days –1 and 28 in Part B to measure the post-prandial lipid profiles. 
The actual time of all dose and initial meal administrations in the CRU will be recorded in the 
subject’s case report form (CRF) and from the diary entries for the at-home dosings. 
8.3. Blinding 
Blinding will be maintained throughout the conduct of the study until all data are cleaned and the 
databased has been locked.  Chorus may review interim unblinded data, the details of which will 
be included in the Blinding/Unblinding Plan.  The simvastatin and atorvastatin dosing in Part B 
is planned to be an unblinded element of this study. 
Emergency codes will be available to the investigator and pharmacy.  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 Chorus 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.  A 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the Chorus CRP prior to unblinding a study subject’s treatment assignment unless this 
could delay emergency treatment of the subject.  If a study subject’s treatment assignment is 
unblinded, Chorus must be notified immediately. 
Upon completion of the study, all codes must be returned to Chorus or its designee. 
8.3.1. Dose Decision/Escalation 
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
maximum tolerated dose (MTD) is determined.  The highest dose level that is tolerated will be 
designated as the MTD.  Doses in Part B will not exceed the MTD dose determined in Part A. 
Safety data will be the primary criteria for the dose escalation.  Dose escalation cannot occur 
without prior discussion and agreement between the investigator and the Chorus CRP. 
Safety data, in particular AEs, serious adverse events (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. 
After review of these data, an agreement on the appropriate dose escalation will be made by the 
investigator and sponsor for the next cohort.  The magnitude of the dose escalation may be 


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reduced following DRM, but subsequent escalations cannot be increased by more than 
approximately 3 fold (a half-log increment). 
For dose escalation decisions safety data from at least 6 subjects completing Day 5 procedures 
from each dosing period in Part A will be reviewed prior to escalating to the next dosing level.  
For Part B, safety data from at least 8 subjects completing Day 14 safety procedures will be 
reviewed prior to escalating to the next dosing level. 
8.4. Preparation/Handling/Storage/Accountability 
Only participants enrolled in the study may receive investigational product and only authorized 
site staff may supply or administer study treatment.  All study treatments should be stored at the 
site in an environmentally controlled and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation and final disposition records). 
Subjects will be given instructions and take home diary’s to record dosing times and initiation of 
the first meal after dosing as described in Section 8.2.1. 
8.5. Treatment Compliance 
In Part A, LY3202328 or placebo will be administered at the CRU under the supervision of the 
investigator.  As a result, subject compliance will be ensured. 
In Part B, simvastatin and atorvastatin will be administered at the CRU under the supervision of 
the investigator.  As a result, subject compliance will be ensured.  LY3202328 or placebo will be 
administered at the CRU (on days of confinement) and subjects will also self-administer 
LY3202328 at home between study visits.  Compliance will be assessed by subject diary entries, 
direct questioning, and enumeration of returned capsules. 
Subjects who are significantly noncompliant in Part B will be discontinued from the study.  The 
subject must take ≥80% of the intended dose to be deemed compliant with study drug 
administration.  Similarly, a subject will be considered significantly noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication (≥120% of the intended dose taken in a visit interval). 
Study medication administration data and deviation(s) from the prescribed dosage regimen 
should be recorded in the subject’s CRF. 
8.6. Concomitant Therapy 
Subjects on stable concomitant medication allowed by inclusion/exclusion criteria and/or 
through prior consultation with the Chorus Medical Monitor at the time of study entry should 
continue their regular, unchanged dose throughout the study.  Subjects on oral or injectable 
diabetic medications are excluded from the study. 


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Drugs that are known inhibitors of CYP3A4 (e.g. Alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or P-gp are specifically 
excluded.  Additional drugs are to be avoided during the study unless required to treat an AE or 
for the treatment of an ongoing medical problem. 
If the need for concomitant medication arises for the treatment of minor AEs, the following 
medication may be administered by the investigator without consultation of Chorus CRP. 
• Paracetamol as needed: <2000 mg/day. 
• Topical medication for minor dermatological conditions. 
• Stool softeners. 
All additional medication used during the course of the study must be documented on the 
subject’s CRF. 
8.7. Treatment after the End of the Study 
8.7.1. Continued Access to Investigational Product 
LY3202328 will not be made available after conclusion of the study to subjects who participate 
in this study. 


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9. Discontinuation Criteria 
9.1. Discontinuation from Study Treatment 
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets one of the following conditions after consultation with the 
Chorus designated medical monitor: 
• ALT or AST >8 × ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN along with one of the following criteria 
o total bilirubin level >2 × ULN or 
o prothrombin time >1.5 × ULN or 
o the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
• ALP >3 × ULN 
• ALP >2.5 × ULN and total bilirubin >2 × ULN 
• ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%). 
Subjects who discontinue the investigational product early for any reason will have the end-of-
study procedures (Day 5 for SAD; Day 56 for MAD) performed as shown in the Schedule of 
Events (Appendix 2). 
9.1.1. Discontinuation of Inadvertently Enrolled Subjects 
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Chorus CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Chorus CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product. 
9.2. Discontinuation from the Study 
Subjects will be discontinued in the following circumstances: 
• Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
• Significant noncompliance with study drug administration. 
• Investigator Decision 
o the investigator decides that the subject should be discontinued from the study. 


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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 requests to be withdrawn from the study. 
• Sponsor Decision 
o the sponsor decides study participation should be stopped for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP. 
Subjects who discontinue the study early will have end-of-study procedures (Day 5 for SAD; 
Day 56 for MAD) performed as shown in the Schedule of Events (Appendix 2). 
9.3. Subjects Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 


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10. Study Assessments and Procedures 
Appendix 2 lists the Schedule of events, detailing the study procedures and their timing. 
Appendix 3 lists the laboratory tests that will be performed for this study. 
Appendix 6 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study. 
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
Investigators must document their review of each laboratory safety report. 
10.1. Efficacy Assessments 
Efficacy will not be assessed in this study.  Pharmacodynamics will be assessed as described in 
Section 10.6. 
10.2. Adverse Events 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Chorus 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. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
After the informed consent form (ICF) is signed, study site personnel will record, via CRF, 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, taking into account the disease, concomitant 
treatment, or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE. 
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study. 


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If a subject’s investigational product administration is discontinued as a result of an AE, study 
site personnel must report this to Chorus or its designee via CRF or designated data transmission 
methods. 
10.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in one of the following: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• events considered significant by the investigator based upon appropriate medical 
judgment 
Study site personnel must alert Chorus, or its designee, of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method.  If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific SAE 
forms.  This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.   
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting begins 
after the subject has signed informed consent and has received investigational product.  
However, if an SAE occurs after signing informed consent, but prior to receiving investigational 
product, AND is considered “reasonably possibly related” to a study procedure then it MUST be 
reported. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF 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 Chorus. 
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. 
10.2.1.1. 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 identifies as related to investigational product or procedure.  
United States 21 CFR 312.32, European Union Clinical Trial Directive 2001/20/EC, and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  The sponsor/designee has procedures that will be followed for 


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the recording and expedited reporting of SUSARs that are consistent with global regulations and 
the associated detailed guidances. 
10.2.2. Complaint Handling 
Chorus/designee collects product complaints on investigational products and drug delivery 
systems used in clinical trials in order to ensure the safety of study participants, monitor quality, 
and to facilitate process and product improvements. 
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product (or drug delivery system) so that the 
situation can be assessed. 
10.3. Treatment of Overdose 
Refer to the IB (Section 7.3.9) and/or Product Label (LY and/or comparator) for details 
regarding an overdose of investigational product. 
10.4. Safety 
10.4.1. Laboratory Tests 
For each subject, laboratory tests detailed in Appendix 3 should be conducted according to the 
Schedule of Events (Appendix 2).  When collections for clinical laboratory tests are scheduled at 
the same time point as ECG collections, ECGs must be recorded prior to any blood sampling. 
10.4.2. Vital Signs 
For each subject, vital signs measurements should be conducted according to the Schedule of 
Events (Appendix 2) and following the study specific recommendations included in an Appendix 
or the Manual of Operations for the study. 
Respiratory rate (collected at Screening and, for Part B only, Day -1, Hour -1), BP, pulse, and 
temperature should be measured after at least 5 minutes supine. 
Orthostatic BP and pulse rate will be obtained from each subjects at all specified vital sign 
collection time points in Part A and on Day –1 through study discharge at specified vital sign 
collection time points in Part B.  Supine BP and pulse rate will be measured after the subject has 
been supine for at least 5 minutes; standing BP and pulse rate will be measured in triplicate at 1, 
2, and 3 minutes after the subject has been standing. 
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 and agreed upon between the sponsor and investigator. 
10.4.3. Electrocardiograms 
For each subject, ECGs should be collected according to the Schedule of Events (Appendix 2) 
and the study specific recommendations included in a Manual of Operations for the study that 
will be maintained that the CRU. 


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When ECG collections are scheduled at the same time point as any other tests the order of 
collection will be as follows: 
1) ECGs. 
2) vital signs. 
3) any clinical laboratory, PK, PD, or biomarker blood sampling. 
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 Chorus, or its 
designee, as an AE via CRF or designated data transmission methods. 
In Part A, a 12-lead digital ECG will be collected from each subject as a single tracing during 
Screening and in triplicate (spaced approximately 1 minute apart) at all other specified ECG 
collection time points.  In Part B, ECGs will be collected as a single tracing during Screening 
and Day -2.  Twelve-lead ECGs will be collected in triplicate on Day –1 through study discharge 
at specified ECG collection time points. 
Subjects must be supine for at least 5 minutes prior to ECG collection and remain supine but 
awake during ECG collection.  Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
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 finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE. 
10.4.4. Safety Monitoring 
The Chorus CRP/scientist, or designee, will monitor safety data throughout the course of the 
study. 
Chorus will review SAEs within time frames mandated by company procedures to meet local 
regulatory requirements.  The Chorus CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist when appropriate, and 
periodically review: 
• trends in safety data 
• AEs of special interest here. 


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If a study subject experiences elevated ALT or AST ≥3 × ULN or ALP/GGT/elevated total 
bilirubin ≥2 × ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities (see Appendix 5).  To ensure subject safety and compliance with regulatory 
guidance, the investigator is to consult with the Chorus designated CRP regarding collection of 
specific recommended clinical information and follow-up laboratory tests (Appendix 4). 
If anemia (defined as a hemoglobin or hematocrit below normal reference range in the 
laboratory) develops during dosing, additional evaluation with a peripheral blood film, 
reticulocyte count, haptoglobin, indirect bilirubin, and LDH will be implemented. 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Unblinding/Blinding Plan. 
10.5. Pharmacokinetics 
At the visits and times specified in the Schedule of Events (Appendix 2), serial venous blood 
samples of approximately 4 mL each will be collected to determine the plasma concentrations of 
LY3202328, simvastatin (Part B only), and atorvastatin (Part B only).  Blood samples for PK 
characterization will be collected after single- and multiple-dose administration and follow-up 
visits in Parts A and B.  Trough concentrations over multiple days during Part B will also be 
assessed. 
Sample timing may be adjusted based on information gained during the study, while the total 
number of samples described in the Schedule of Events (Appendix 2) will be planned.  Up to 
2 additional PK samples may be collected per period if needed and with appropriate 
documentation of rationale for the additional samples. 
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. 
Urine samples will be collected and pooled over the 24 hour dosing period to determine the urine 
concentrations and for the characterization of renal clearance of LY3202328 in Part A.  Total 
urine output for the appropriate period post investigational product administration will be 
collected, pooled, and refrigerated.  A predose urine sample will be collected to serve as a blank.  
The final urine sample will be collected at a time that coincides with a PK sample.  At the end of 
the collection period (24 hours), the total urine volume will be recorded.  Urine samples will be 
used to determine creatinine, quantification of LY3202328, and urine creatinine measurements.  
Approximately 20 mL of urine from the 24-hour urine collection will be stored for potential 
LY3202328 metabolite identification and other exploratory testing (10 mL each).  Although not 
currently planned, urine sample collection may be added to Part B depending on results obtained 
from Part A. 


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Remaining plasma and urine PK samples may also be stored for LY3202328 metabolite 
identification. 
At the visits and times specified in the Schedule of Events (Appendix 2) venous blood samples 
of approximately 4 mL each will be collected to determine serum creatinine measurements.  
10.5.1. Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3202328, simvastatin, and atorvastatin will be assayed using validated 
analytical methods.  Samples collected from placebo-treated subjects in each period are not 
planned for analyses.  Simvastatin and atorvastatin analyses will only occur on samples collected 
during the 24 hour post dosing periods starting on Day –7 and Day 29. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses (such as 
metabolism and/or protein binding work). 
10.6. Pharmacodynamics 
Pharmacodynamic blood samples of approximately 10 mL will be collected in Parts A and B as 
specified in the Schedule of Events (Appendix 2). 
Plasma TG, TC, and high-density lipoprotein cholesterol (HDL-c)  (to calculate LDL-c and non-
HDL-c) will be assessed in the fasted state for the first 4 hours postdose and then again during 
the post-prandial period following a high-fat meal administration at 4 hours postdose in Part B.  
Changes in these PD markers from baseline (Day –1) and Day 28 will be assessed at each dose 
level to find at least 1 dose level that shows evidence of target engagement by a decrease in 
fasting or post-prandial lipids. 
The lipid lowering ability of LY3202328 in subjects with a statin-free background will be 
quantified by TG, TC, and HDL-c (to calculate LDL-c and non-HDL-c) in Parts A and B, and by 
LDL-c ultracentrifugation methods in Part B only. 
10.6.1. Exploratory Biomarker Analyses 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, 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. 
Plasma samples for exploratory biomarker research will be collected at the times specified in the 
Schedule of Events (Appendix 2).  Fasting LDL-c, FFA, β-hydroxybutyrate, ApoB100, ApoC3, 
PCSK9, and Lp(a) measured at baseline (Day –1), Day 28, and Follow-up will be evaluated in 
Part B. 


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Samples will be retained for a maximum of 1 year after the last subject visit, or until testing is 
complete after the last subject visit for the study at a facility selected by Chorus or its designee. 
10.7. Pharmacogenomic/Stored Samples 
A blood sample will be collected for pharmacogenetic analysis in Part A and Part B as specified 
in the Schedule of Events (Appendix 2) where local regulations allow. 
DNA will be isolated from the pharmacogenetic sample to test genetic polymorphisms that may 
affect: 
• the absorption, disposition, metabolism, or excretion of LY3202328; 
• response to LY3202328; 
• adverse reactions to LY3202328; 
• unusual response to LY3202328 (either safety or PD response; genome-wide association 
studies may be used); and/or 
• dyslipidemia-related gene polymorphisms. 
Additionally, the samples obtained from the biomarker collections in Parts A and/or B will be 
stored and may be used as follows: 
• plasma and serum for biomarker analysis to help explore and understand the mechanism 
of action of LY3202328 and/or dyslipidemia; and  
• residue plasma samples from lipid collections may be stored for exploratory testing of 
other lipid pathways. 
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 response to LY3202328 and to 
investigate genetic variants thought to play a role in dyslipidemia.  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 (DNA) or 5 years (plasma and serum) after 
the last subject visit, or for a shorter period if local regulations and/or ERBs impose shorter time 
limits, for the study at a facility selected by Chorus 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 LY3202328 or after LY3202328 is 
commercially available. 


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11. Statistical Considerations and Data Analysis 
11.1. Sample Size Determination 
Part A (SAD):  9 statin-free, overweight, healthy subjects for Cohort 1 and 2 (each subject to 
receive investigational product at 2 active dose levels and placebo) and a possible additional 
cohort (each subject to receive investigational product at 1 active dose level [600 mg] or 
placebo).  This sample size is customary for Phase 1 studies evaluating safety, tolerability, and 
PK parameters, and is not powered on the basis of statistical hypothesis testing. 
Part B (MAD):  10 statin-free, overweight, dyslipidemic subjects per cohort (8 subjects to 
receive active investigational product: 2 subjects to receive placebo) is a customary sample size 
for a Phase 1b MAD study evaluating safety, tolerability, and PK parameters, and is not powered 
on the basis of statistical hypothesis testing. 
Additional subjects may be enrolled at any time if agreed to by the Sponsor to replace drop-outs 
or discontinued subjects with the goal to complete up to 18 subjects in Part A and 40 subjects in 
Part B. Replacements are not required. Replacement subjects for Part A may not be required to 
complete all periods.   
11.2. Populations for Analyses 
The study population will consist of up to 18 statin-free, overweight, healthy male and female 
subjects in Part A and up to 40 statin-free, overweight, healthy male and female subjects with 
dyslipidemia in Part B, aged 18 to 70 years old, inclusive, for males, or 40 to 70 years old, 
inclusive, for females.  Two analysis populations will be used in this study: 
• The Safety population will include all subjects who receive at least 1 dose of LY3202328. 
• The PK population will include all subjects who receive LY3202328 (and simvastatin or 
atorvastatin in Part B) and have sufficient concentration data to obtain reliable estimates 
of the key PK parameters (Cmax and AUC). 
11.2.1. Study Participant Disposition 
A subject disposition flow diagram will be prepared that will summarize the disposition of all 
subjects entered into the study, including the number of subjects entered and enrolled into the 
study, and the number who received at least 1 dose of study treatment.  Subjects who 
discontinued from the study will be summarized by their reasons. 
11.2.2. Study Participant Characteristics 
Demographic and baseline information will be summarized using descriptive statistics.  For 
continuous variables, the mean, standard deviation (SD), median, minimum, and maximum will 
be presented.  For categorical variables, the number of subjects, frequency, and percentages will 
be presented.  Individual subject demographics and baseline information will be presented in 
data listings. 
Concomitant therapy used during the study period will be listed and summarized by dose group. 


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11.2.3. Treatment Compliance 
Compliance will be ensured for administration of LY3202328 in Part A and administration of 
LY3202328, simvastatin and atorvastatin in Part B, as study drug will be administered at the 
CRU under the supervision of the investigator. 
Treatment compliance for LY3202328 in Part B will be ensured on days of subject confinement 
to the CRU and study visits, but will be assessed by comparing returned pills with dispensed pills 
(the percentage of the actual number of capsules taken versus the number of capsules expected to 
be taken) for dosing days while not confined to the CRU. 
Subjects who demonstrated significant noncompliance (<80% or >120% of the intended dose 
taken in a visit interval) will also be summarized. 
Study medication administration data and deviation(s) from the prescribed dosage regimen 
should be recorded in the subject’s CRF. 
11.3. Statistical Analyses 
Statistical analysis of this study will be the responsibility of Chorus or its designee. 
Pharmacokinetic/PD and safety analyses will be conducted on the PK and Safety populations, 
respectively. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses. 
11.3.1. Safety Analyses 
11.3.1.1. Clinical Evaluation of Safety 
All LY3202328 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 study entry 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 current medical 
regulatory dictionary.  Severity of the AE will be assessed according to the “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials 2007”. 
The number of investigational product-related SAEs will be reported. 
11.3.1.2. Statistical Evaluation of Safety 
The primary endpoint of this study is the number and severity of treatment-emergent adverse 
events (TEAEs), clinical laboratory abnormalities, changes in vital sign measurements, and other 
safety endpoints after administration of LY3202328 or placebo.  Summary statistics will be 
provided by dose group and for all study subjects combined wherever appropriate.  For 


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continuous variables, summary statistics will include number of subjects, mean, median, SD, 
minimum, and maximum.  Categorical endpoints will be summarized using number of subjects, 
frequency, and percentages.  Additional analysis will be performed if warranted upon review of 
the data. 
11.3.2. Pharmacokinetic Analyses 
Pharmacokinetic parameter estimates for LY3202328, simvastatin (Part B only), and atorvastatin 
(Part B only) in plasma will be calculated by standard noncompartmental methods of analysis. 
The primary PK parameters for analysis will be Cmax and AUC.  The primary AUC metric will 
be calculated AUC from time zero to infinity (AUC0-∞) on Day 1 (Parts A and B) and AUC 
during one dosing interval (AUC0-τ) on Day 28 of Part B of LY3202328 after single- and 
multiple-dose administrations (Parts A and B, respectively).  If the half-life (t1/2) was relatively 
long, AUC0-∞ may not be calculable for Day 1 of Part B, and would thus not be reported. 
Other noncompartmental parameters, such as Tmax, t1/2, trough concentration (Ctrough), apparent 
clearance (CL/F), and apparent volume of distribution (V/F) may be reported.  Descriptive 
statistics of PK parameters will be presented with each dose. 
Renal clearance of LY3202328 will be calculated as the ratio of amount excreted in urine/AUC.  
This will be compared to the unbound glomerular filtration rate, which is estimated using 
creatinine. 
Pharmacokinetic parameter estimates (Cmax and AUC) for LY3202328 will be evaluated to 
delineate effects of dose proportionality using a power model approach (Smith et al. 2000). 
Drug-drug interaction assessment of the effect of LY3202328 coadministration on simvastatin 
and atorvastatin exposure will be conducted using ANOVA.  Pharmacokinetic parameter 
estimates (Cmax and AUC)  for simvastatin and atorvastatin administered alone or 
coadministered with LY3202328 will be compared.  The ratios of statin exposure with and 
without LY3202328 coadministration at different dose levels of LY3202328 will be estimated, 
along with their confidence intervals. 
The impact of food on the rate and extent of absorption of LY3202328 will be assessed by 
estimating the ratio of Cmax and AUC0-∞ in the fed and fasted state of at the same dose level.  
The ratio will be calculated within each subject, and then summarized for the group.  Similarly, 
the difference in Tmax between the fed and fasted will be calculated and summarized. 
Other analyses, including PK modeling, may be conducted on the PK data. 
11.3.3. Pharmacodynamic and Biomarker Analyses 
The PD assessments conducted in this study are typical and appropriate for a Phase I single and 
multiple ascending dose evaluations of a novel therapeutic agent.  The TG concentrations will be 
analyzed to evaluate evidence of target engagement and intended pharmacological benefits. 
Visual and tabular summarization of all PD measurements will be done.  For the endpoints in the 
primary or secondary objectives, a statistical analysis will also be conducted. 


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Mixed effect model repeated measure will be the default method of analysis for PD endpoints 
with time-course data.  For endpoints with only baseline and end-of-therapy measurements, 
ANCOVA will be the default, with baseline as a covariate.  Other covariates may be a priori 
defined and included in the model. 
Normality assumption will be tested using an appropriate visual or statistical method, and, if it is 
violated, log transformation may also be performed on these data.  The most sensitive analysis 
will be selected to test the effect of LY3202328 on the change from baseline in these PD data. 
11.3.4. Interim Analyses 
In Part A, interim analysis of PK will take place after collecting the 300 mg dosing group to 
determine if a 600 mg dose level will be conducted. In Part B, lipid assessments (triglycerides, 
LDLc, non-HDLc, and ApoB100) will be evaluated after completion of 20, 100, and 300 mg 
dose levels and reviewed by Chorus unblinded staff. No other interim analyses are planned for 
this study, however pharmacokinetic data may be reviewed at anytime it becomes available. 
Select individuals may gain access to unblinded data, prior to the interim or final database lock, 
in order to initiate some analysis activities.  In such a case, the individuals and unblinded data 
will be specified in the unblinding plan.  Information that may unblind the study during the 
analyses will not be reported to study sites or blinded study team until the study has been 
unblinded. 


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12. References 
1. Chorus. DGAT2 inhibitor LY3202328 investigator’s brochure, 1st ed. Indianapolis, (IN); 
2016. 
2. European Medicines Agency. Committee For Medicinal Products For Human Use. 
Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with 
investigational medicinal products. September 2007. [Accessed 20 December 2015]. 
Available from:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002988.pdf. 
3. Manchem P, Yu XX, Mullick A, Booten S, Murray S, Watts LM, Monia BP, Bhanot S.  
Antisense reduction of DGAT2 reduces body weight and improves dyslipidemia in high-
fat high-cholesterol diet fed LDLr knockout mice. American Diabetes Association 
Annual Meeting 2010;448-PP. 
4. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue 
ST. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283. 


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Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
ADME 
absorption, disposition, metabolism, and excretion 
AE 
adverse event:  Any untoward medical occurrence in a 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 
Apo 
apolipoprotein 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
AUC from time zero to infinity 
AUC0-τ 
AUC during one dosing interval 
blinding 
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock. 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received 
BMI 
body mass index 
BP 
blood pressure 
CL/F 
apparent clearance 
Cmax 
maximum plasma concentration 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements. 


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confirmation 
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Chorus is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results. 
CRF 
case report form 
CRP 
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer. 
CRU 
clinical research unit 
Ctrough 
trough concentration 
CV 
cardiovascular 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DGAT2 
diacylglycerol acyltransferase 2 
DRM 
Data Review Meeting 
ECG 
electrocardiogram 
ED80 
80% maximal effective dose 
enroll 
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment. 
enter 
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
Ethical Review Board 
FFA 
free fatty acids 
FSH 
follicle-stimulating hormone 
GCP 
GLP 
Good Clinical Practice 
Good Laboratory Practice  
HCV 
hepatitis C virus 
HDL-c 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 


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ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial 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.  
Investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator. 
KO 
knockout 
LDL-c 
low-density lipoprotein cholesterol 
LDLr 
low-density lipoprotein receptor 
Lp(a) 
Lipoprotein (a) 
MAD 
multiple ascending dose(s) 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect level 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
QD 
once daily 
QTc 
corrected QT 
SAE 
serious adverse event 
SAD 
single ascending dose(s) 
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 trial. 
SD 
standard deviation 


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SUSAR 
 
suspected unexpected serious adverse reaction 
 
t1/2 
half-life 
TC 
total cholesterol 
TEAE 
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment  
Tmax 
time to reach maximum plasma concentration 
TG 
TSH 
triglyceride(s) 
thyroid stimulating hormone 
ULN 
upper limit of normal 
V/F 
apparent volume of distribution 
 


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Appendix 2. 
Schedule of Events for Protocol 
I8Q-MC-GSEA 
 


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Appendix Table GSEA.1 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part A (SAD) 
Study Proceduresa 
 
Study Days 
Day 
Screeningb 
C–1c 
1 
2 
3 
5 
Hour 
 
-0.5s 
0 
0.5 
1 
2 
3 
4 
4.5 
5 
6 
8 
12 
24 
48 
96 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
Full physical examinationd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Height & weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
Xe 
X 
 
Xf 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
Clinical laboratory testsh 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Serum pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol/drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine & serum creatinine 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
X 
Conmed monitoring 
X 
X 
Dosing/PK/PD/Pharmacogenomics 
Serum TG, TC, HDL-cj,k 
 
 
Xf,l 
 
 
 
Xm 
X 
X 
X 
X 
Xl,m 
Xl,m 
Xl,m 
Urine PK collection 
 
 
X 
X 
X 
 
 
LY/placebo dosing 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samplek 
 
 
 
Xf 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Pharmacogenomic sampleo 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker samplep 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Other 
Confined at the CRU 
 
Xq 
 
 
Meal at the CRU 
 
X 
 
 
 
 
 
 
Xr 
 
 
 
X 
 
X 
X 
X 
CRU Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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LY3202328 
Abbreviations:  AE = adverse events; C–1 = Check‑in; CRU = clinical research unit; Conmed = concomitant medication; ECG = electrocardiogram; 
FSH = follicle stimulating hormone; HDL-c = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL-c = low-density lipoprotein 
cholesterol; LY = LY3202328; PD = pharmacodynamic; PK = pharmacokinetics; TC = total cholesterol; TG = triglycerides. 
a Refer to Section 10 of the protocol for details on study procedures. 
b Screening to occur within 42 days of first study drug administration. 
c Subjects will be admitted on Day –1 prior to dinner to control fasting times for Day 1 dosing. 
d A full physical examination will be performed on the scheduled days.  Symptom‑driven physical examination may be performed at other times, at the 
investigator’s discretion. 
e Single 12-lead ECGs to be collected during Screening, triplicate ECGs (spaced approximately 1 minute apart) to be collected at all other time points.  Subjects 
must be supine for at least 5 minutes prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed 
by vital signs, must be recorded prior to any clinical laboratory, PK, PD, or biomarker blood sampling. 
f 
Collection to occur prior to dosing. 
g Vital signs to be measured include respiratory rate (Screening only), blood pressure, pulse rate, and temperature.  Orthostatic blood pressure and pulse rate to 
be measured at all specified time points. 
h Refer to Appendix 3 for the serum chemistry, hematology, and urinalysis clinical laboratory tests. 
i 
Serum pregnancy tests to be performed on female subjects only; serum FSH tests to be performed on postmenopausal female subjects only. 
j 
Serum TC, TG, and HDL-c will be measured; HDL-c will be used to calculate LDL-c and non-HDL-c. 
k Any leftover plasma will be stored for residual or LY3202328 metabolite assessment, after all study related needs are met. 
l 
Samples for serum chemistry will be obtained following a fast of at least 12 hours when a fasting lipid assessment is being performed at the same time.  In 
case of dropouts or rechecks, subjects may not have fasted for 8 hours or 12 hours, as applicable, before the serum chemistry sample is taken. 
m Sample collection to occur just prior to meal. 
n LY3202328/placebo dosing will occur in the fasted state in all periods except the food effect period.  Subjects being assessed for food effects on exposure will 
be given a high-fat/high-calorie meal prior to dosing during the food effect arm in Period 4.   
o A blood sample from all randomized/enrolled subjects will be collected prior to Day 1 dosing. 
p Biomarker plasma and serum collection (10 mL) should be sufficient for determination of ApoB48, lathosterol, lanosterol, desmosterol, among other 
biomarkers of interest. 
q Subjects will be discharged following Hour 24 procedures (i.e., Day 2). 
r 
A high-fat/high-calorie meal (containing approximately 60% fat, 20% carbohydrate, and 20% protein ) will be given to subjects to 4 hours postdose for the 
post-prandial lipid assessment in all periods except for subjects in the food effect arm of Period 4. 
s  Assessments can be performed any time predose  
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) 
Study Proceduresa 
 
Study Days 
Day 
Screeningb 
C–8c 
–7 
Hourd 
 
 
0d 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
Administrative Procedures 
Informed consent 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
Medical history 
X 
 
Safety Evaluations 
Full physical examinatione 
X 
 
 
 
 
 
 
 
 
 
 
 
Height & weight 
X 
 
 
Waist, neck, and hip 
circumference  
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
 
 
 
X 
Clinical laboratory testsh,i 
X 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid paneli 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol/drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
X 
Conmed monitoring 
X 
X 
Dosing/PK/PD 
Simvastatin/atorvastatin 
dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
Simvastatin/atorvastatin 
PK blood sample 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other 
Confined at the CRU 
 
Xk 
Meal at CRU 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Visit 
X 
 
 
 
 
 
 
 
 
 
 
 


I8Q-MC-GSEA(a) Clinical Pharmacology Protocol 
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LY3202328 
Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Day 
C–2c 
–1 
Hourd 
 
-1y 
0d 
1 
2 
4 
4.5 
5 
6 
8 
Administrative Procedures 
Informed consent 
 
 
Inclusion/exclusion criteria 
X 
 
Medical history 
 
Safety Evaluations 
Full physical examinatione 
X 
 
 
 
 
 
 
 
Height & weight 
 
X 
 
 
 
 
 
 
 
Waist, neck, and hip 
circumference  
 
X 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
 
 
 
 
 
 
Clinical laboratory testsh,i 
 
X 
 
 
 
 
 
 
 
 
Fasting lipid paneli 
 
X 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
Serum FSHj 
X 
 
 
 
 
 
 
 
 
 
alcohol/drug screen 
X 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD 
Serum TG, TC, HDL-cl 
 
X 
Xm,n 
X 
X 
Xm 
X 
X 
X 
Xm 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, 
ApoB100o 
 
X 
 
 
 
 
 
 
 
 
ApoC3, Lp(a), PCSK9, 
fasting insulin 
 
X 
 
 
 
 
 
 
 
 
Pharmacogenomic samplep 
 
X 
 
 
 
 
 
 
 
 
Biomarker sampleq 
 
X 
 
 
 
 
 
 
 
 
Other 
Confined at the CRU 
Xk 
Meal at CRUr 
X 
 
 
 
 
Xr 
 
 
 
X 
 


I8Q-MC-GSEA(a) Clinical Pharmacology Protocol 
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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Day 
1 
2 
3 to 6 
7 
8 to 13 
14 
15 to 20 
21 
22 to 27 
Hourd 
0 
0.5 
1 
2 
4 
8 
12 
24/0 
0 
0 
0 
0 
0 
0 
0 
Safety Evaluations 
Full physical examinatione,h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Waist, neck, and hip 
circumference  
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
12-lead ECGf 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vital signsg 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Clinical laboratory testsh,i 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD/Pharmacogenomics 
LY/placebo dosing at CRU 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
LY/placebo dosing at homet 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
LY/placebo PK blood samples 
Xn 
X 
Xm 
X 
Xm 
X 
X 
Xm 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
Serum TG, TC, HDL-cl 
 
 
 
 
 
 
 
 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, ApoB100o 
 
 
 
 
 
 
 
 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
ApoC3, Lp(a), PCSK9, fasting 
insulin 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
 
 
 
Biomarker sampleq 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
 
 
 
Other 
Confined at the CRU 
X 
 
 
 
 
 
 
 
Meal at CRUu 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Visit 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Follow-up 
Day 
27 
28 
29 
30 
35v 
56v 
Hourd 
0 
–1y 
0 
0.5 
1 
2 
4 
4.5 
5 
6 
8 
12 
24/0 
48/0 
168/0 
336/0 
Safety Evaluations 
Full physical examinationse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Waist, neck, and hip 
circumference  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
12-lead ECGf 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Vital signsg 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
Clinical laboratory testsh,i 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
alcohol/drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD/Pharmacogenomics 
LY/placebo dosing at CRU 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Simvastatin/atorvastatin 
dosing at CRU 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
LY/placebo PK blood sample 
 
 
Xn 
X 
Xm 
X 
Xm 
 
 
X 
Xm 
X 
Xm,n 
Xm 
Xm 
Xm 
Simvastatin/atorvastatin PK 
blood sample 
 
 
 
 
 
 
 
 
 
 
 
 
Xw 
 
 
 
Serum TG, TC, HDL-cl 
 
X 
Xi,m
,n 
 
X 
X 
Xm 
X 
X 
X 
Xm 
 
 
 
Xm 
Xm 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, ApoB100o 
 
 
Xi,m
,n 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Xm 
ApoC3, Lp(a), PCSK9, fasting 
insulin 
 
 
Xi,m
,n 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Xm 
Biomarker sampleq 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
Other 
Confined at the CRU 
Xx 
 
 
Standardized meal at CRUr 
X 
 
 
 
 
 
Xr 
 
 
 
X 
 
X 
X 
X 
X 
Within the CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Abbreviations:  AE = adverse events; Apo = apolipoprotein; C –2, C –8 = Check‑in; CRU = clinical research unit; Conmed = concomitant medication; ECG = 
electrocardiogram; FFA = free fatty acid; FSH = follicle stimulating hormone;   HDL-c = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; LDL-c = low-density lipoprotein cholesterol; Lp = lipoprotein; LY = LY3202328; PCSK9 = proprotein convertase subtilisin/kexin 
type 9; PD = pharmacodynamic; PK = pharmacokinetics; TC = total cholesterol; TG = triglycerides. 
a Refer to Section 10 of the protocol for details on study procedures. 
b Screening to occur within 42 days of first study drug administration. 
c Subjects will be admitted on Day –8 (for simvastatin/atorvastatin dosing and PK), Day –2, and prior to dinner on Day 27, at the time indicated by the CRU. 
d On Day –7 and –1, Hour 0 is defined as relative to Day 1 dosing time.  On Days 1 to 28, Hour 0 is defined as the actual dosing time (for Days 2 to 28, within 
±1 hour of dosing time of Day 1). 
e A full physical examination with neurological assessments will be performed (predose) on the scheduled days.  Symptom‑driven physical or neurological 
examination may be performed at other times, at the investigator’s discretion. 
f 
Single 12-lead ECGs to be collected during Screening and on Day –2.  Triplicate ECGs (spaced approximately 1 minute apart) to be collected on Day–1.  The 
decision to collect triplicate or single ECGs at all remaining time points will be made based on ECG data from Part A (triplicate ECGs are planned).  Subjects 
must be supine for at least 5 minutes prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed 
by vital signs, must be recorded prior to any clinical laboratory, PK, PD, or biomarker blood sampling. 
g Vital signs to be measured include respiratory rate (Screening and Day –1, Hour –1 only) blood pressure, pulse rate, and temperature.  Orthostatic blood 
pressure and pulse rate to be measured at all specified time points on from Day –1 to study discharge. 
h Refer to Appendix 3 for the serum chemistry, hematology, and urinalysis clinical laboratory tests. 
i 
Samples for serum chemistry will be obtained following a fast of at least 8 hours or 12 hours when a fasting simple lipid assessment (i.e., TC, TG and HDL-c) 
is will be performed at the same time.  In case of dropouts or rechecks, subjects may not have fasted for 8 hours or 12 hours, as applicable, before the serum 
chemistry sample is taken.  Lipid panel will also be assessed during the post-prandial lunch period on Days –1 and 28. 
j 
Serum pregnancy tests to be performed on female subjects only; serum FSH tests to be performed on postmenopausal female subjects only. 
k Subjects will be discharged following Hour 24 procedures (i.e., Days –6 and 2). 
l 
Serum TC, TG, and HDL-c will be measured; HDL-c will be used to calculate LDL-c and non-HDL-c. 
m Collection to occur just prior to meal. 
n Collection to occur prior to the relative dosing time/prior to dosing. 
o Low-density lipoprotein cholesterol for PD analysis will be evaluated by ultracentrifuge. 
p A blood sample from all randomized/enrolled subjects will be collected prior to Day 1 dosing. 
q Biomarker plasma and serum collection (10 mL) should be sufficient for determination of ApoB48, lathosterol, lanosterol, desmosterol, among other 
biomarkers of interest. 
r 
A high-fat/high-calorie meal (approximately 60% fat, 20% carbohydrate, 20% protein) will be given to subjects to 4 hours postdose for the post-prandial lipid 
assessment. 
s Any leftover plasma will be stored for residual or LY3202328 metabolite assessment, after all study related needs are met. 


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t 
Prior to release from the CRU, subjects will receive a properly labeled container with LY3202328 or placebo doses which will be self‑administered by 
subjects at home until the next morning visit at the CRU.  Subjects will be instructed to take the drug once daily in the morning in the fasted state and wait at 
least 60 minutes after the completion of dosing prior to commencing their breakfast.  Subjects will be given diaries to record the time of their self‑
administered doses whether the dose was administered with food or fasted, and the time of commencing the breakfast meal.  Subjects must return the 
container (empty or not) and their diary at the next morning visit.  Home dosing will be monitored via attempted phone calls where subjects will be reminded 
to take their medication and queried about the occurrence of AEs.  Subjects should be instructed to take their dose at approximately the same time they 
received their first dose. 
u When confined in the CRU or during return visits for dosing, subjects will receive standard or high-fat meals at appropriate times.  At least 60 minutes should 
separate the completion of ingestion of the dose and the beginning of the breakfast meal.  While at home, subjects will be asked to keep their standard diet. 
v Procedures to be performed at end of study or prior to early termination from the study.  Subjects will be contacted for follow-up if the investigator deems 
necessary. 
w Day 29 simvastatin/atorvastatin PK blood sample collection will follow the same schedule as Day –7 (predose [0], 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours 
postdose). 
x Subjects will be discharged on Day 30 after all assessments are completed. 
y  Assessments can be performed anytime predose. 


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Appendix 3. 
Clinical Laboratory Tests 
Laboratory Tests 
Hematologya 
Clinical Chemistrya 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration  
Phosphorus 
Leukocytes (WBC) 
Magnesium 
Cell Morphology 
Glucose (fasting) 
Absolute/relative/% counts of: 
Blood urea nitrogen (BUN) 
Neutrophils 
Total cholesterol 
Lymphocytes 
Total protein 
Monocytes 
Albumin 
Eosinophils 
Total bilirubin 
Basophils 
Alkaline phosphatase (ALP) 
Platelets 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysisa 
Creatinine 
Specific gravity 
Gamma-glutamyl transferase (GGT) 
pH 
 
Protein 
Additional tests (lipid panel, biomarker analyses) 
Glucose 
Apoliproprotein B100 
Ketones 
Apoliproprotein C3 
Bilirubin 
β hydroxybutyrate, 
Urobilinogen 
Free fatty acids (FFA) 
Blood 
Low-density lipoprotein cholesterol (LDL-c) 
Nitrite 
Lipoprotein (a) 
 
High-density lipoprotein cholesterol (HDL-c) 
Ethanol testingbc 
Insulin 
Urine drug screenbc 
Triglycerides (TG) 
Hepatitis B surface antigenb 
Proprotein convertase subtilisin/kexin type 9 
(PCSK9) 
Hepatitis C antibodyb 
 
HIVb 
 
Pregnancy test (serum, in females only) 
 
Serum FSH (in postmenopausal females only) 
 
TSH (screening and Day 29 only) 
 
 
Serum and Urine Creatinine (Part A, Day -1 only) 
 
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells, TSH = Thyroid stimulating hormone. 
a Results will be reported and/or validated by the Central Laboratory at the time of initial testing. 
b Performed at screening only 
c Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit. 


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Appendix 4. 
Study Governance, Regulatory, and 
Ethical Considerations 
Informed Consent 
The investigator is responsible for: 
• ensuring that the subject understands the potential risks and benefits of participating in 
the study. 
• 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 trial. 
Ethical Review 
The investigator must provide assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to Chorus before 
the study may begin at the investigative site(s).  Chorus 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 
• ICFs 
• relevant curricula vitae 
Regulatory Considerations 
This study will be conducted in accordance with: 
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines  
2) applicable ICH GCP Guidelines  
3) applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party organization. 


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Protocol Signatures 
The sponsor’s responsible medical officer, (
, Chief Medical officer, 
Chorus) will approve the protocol, confirming that, to the best of his or her knowledge, the 
protocol accurately describes the planned design and conduct of the study.  
After reading the protocol, the investigator will sign the protocol signature page and send a copy 
of the signed page to a Chorus representative. 
Final Report Signature 
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, Chorus or its representatives will do the 
following: 
• provide instructional material to the study sites, as appropriate. 
• provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures. 
• make periodic visits to the study site. 
• be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
• review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection. 
• conduct a quality review of the database. 
In addition, Chorus 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, Chorus, 
and/or regulatory agencies at any time.  Investigators will be given notice before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable 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. 
PPD


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Study and Site Closure 
Discontinuation of Study Site 
Study site participation may be discontinued if Chorus, 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 Chorus judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 


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Appendix 5. 
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Chorus or its designee CRP. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologyab 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Conjugated bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibodya 
AST 
 
GGT 
CPK  
Anti-smooth muscle antibody (or anti-actin 
antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by Chorus-designated local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability 
 
 

Prot_000.pdf: 
Protocol I8Q-MC-GSEA
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LY3202328
NCT02714569 
Document Approval Date:  28 January 2016  


DGAT2_Clinical Pharmacology Protocol Final-final with links.pdf
Electronic Signature Page
  Workflow History
The following individuals have electronically signed this document.
Assigned To
Purpose 
Date Signed
Status
Outcome
Approve 
28 Jan 2016 03:26:34 PM 
Completed 
Approved
PPD


I8Q-MC-GSEA Clinical Pharmacology Protocol 
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LY3202328 
1. Protocol I8Q-MC-GSEA 
A Randomized, Double-Blind, Placebo-Controlled, Single 
and Multiple Oral Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of LY3202328 
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 
LY3202328, 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. 
LY3202328 
Chorus, a division of Lilly Research Laboratories 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Clinical Pharmacology Protocol Electronically Signed and Approved by Chorus on date 
provided below. 


I8Q-MC-GSEA Clinical Pharmacology Protocol 
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LY3202328 
2. Table of Contents 
A Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Oral Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LY3202328 
Section 
Page 
1. 
Protocol I8Q-MC-GSEA A Randomized, Double-Blind, Placebo-
Controlled, Single and Multiple Oral Ascending Dose Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of 
LY3202328 ..............................................................................................................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Protocol Synopsis ....................................................................................................................8 
4. 
Introduction ...........................................................................................................................11 
4.1. 
Study Rationale ................................................................................................................11 
4.2. 
Background.......................................................................................................................12 
4.3. 
Benefit/Risk Assessment ..................................................................................................13 
5. 
Objectives ..............................................................................................................................14 
5.1. 
Primary Objective .............................................................................................................14 
5.2. 
Secondary Objectives .......................................................................................................14 
5.3. 
Exploratory Objectives .....................................................................................................14 
6. 
Study Design .........................................................................................................................15 
6.1. 
Overall Design ..................................................................................................................15 
6.1.1. 
Part A: Single Ascending Dose with Food Effect Design .......................................16 
6.1.2. 
Part B:  Multiple Ascending Dose – Drug-Drug Interaction 
Design ......................................................................................................................17 
6.2. 
Number of Participants .....................................................................................................19 
6.3. 
End of Study Definition....................................................................................................19 
6.4. 
Scientific Rationale for Study Design ..............................................................................19 
6.5. 
Justification for Dose ........................................................................................................19 
7. 
Study Population ...................................................................................................................21 
7.1. 
Inclusion Criteria ..............................................................................................................21 
7.2. 
Exclusion Criteria .............................................................................................................22 
7.3. 
Lifestyle and Dietary Requirements .................................................................................24 
7.3.1. 
Meals and Dietary Restrictions ................................................................................24 
7.3.2. 
Caffeine, Alcohol, and Tobacco ..............................................................................24 
7.3.3. 
Activity .....................................................................................................................24 
7.4. 
Screen Failures .................................................................................................................24 


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8. 
Treatment ...............................................................................................................................25 
8.1. 
Treatment Administered ...................................................................................................25 
8.1.1. 
Packaging and Labeling ...........................................................................................26 
8.2. 
Method of Treatment Assignment ....................................................................................26 
8.2.1. 
Selection and Timing of Doses ................................................................................26 
8.3. 
Blinding ............................................................................................................................27 
8.3.1. 
Dose Decision/Escalation ........................................................................................27 
8.4. 
Preparation/Handling/Storage/Accountability .................................................................28 
8.5. 
Treatment Compliance .....................................................................................................28 
8.6. 
Concomitant Therapy .......................................................................................................28 
8.7. 
Treatment after the End of the Study ...............................................................................29 
8.7.1. 
Continued Access to Investigational Product ..........................................................29 
9. 
Discontinuation Criteria ........................................................................................................30 
9.1. 
Discontinuation from Study Treatment ............................................................................30 
9.1.1. 
Discontinuation of Inadvertently Enrolled Subjects ................................................30 
9.2. 
Discontinuation from the Study ........................................................................................30 
9.3. 
Subjects Lost to Follow-up ...............................................................................................31 
10. Study Assessments and Procedures .......................................................................................32 
10.1. Efficacy Assessments .......................................................................................................32 
10.2. Adverse Events .................................................................................................................32 
10.2.1. 
Serious Adverse Events ...........................................................................................33 
10.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................33 
10.2.2. 
Complaint Handling .................................................................................................34 
10.3. Treatment of Overdose .....................................................................................................34 
10.4. Safety ................................................................................................................................34 
10.4.1. 
Laboratory Tests ......................................................................................................34 
10.4.2. 
Vital Signs ................................................................................................................34 
10.4.3. 
Electrocardiograms ..................................................................................................34 
10.4.4. 
Safety Monitoring ....................................................................................................35 
10.5. Pharmacokinetics ..............................................................................................................36 
10.5.1. 
Bioanalysis ...............................................................................................................37 
10.6. Pharmacodynamics ...........................................................................................................37 
10.6.1. 
Exploratory Biomarker Analyses .............................................................................37 
10.7. Pharmacogenomic/Stored Samples ..................................................................................38 
11. Statistical Considerations and Data Analysis ........................................................................39 
11.1. Sample Size Determination ..............................................................................................39 
11.2. Populations for Analyses ..................................................................................................39 
11.2.1. 
Study Participant Disposition ...................................................................................39 


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LY3202328 
11.2.2. 
Study Participant Characteristics .............................................................................39 
11.2.3. 
Treatment Compliance .............................................................................................40 
11.3. Statistical Analyses ...........................................................................................................40 
11.3.1. 
Safety Analyses ........................................................................................................40 
11.3.1.1. 
Clinical Evaluation of Safety .............................................................................40 
11.3.1.2. 
Statistical Evaluation of Safety ..........................................................................40 
11.3.2. 
Pharmacokinetic Analyses .......................................................................................41 
11.3.3. 
Pharmacodynamic and Biomarker Analyses ...........................................................41 
11.3.4. 
Interim Analyses ......................................................................................................42 
12. References .............................................................................................................................43 
 
 


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List of Tables 
Table 
Page 
Table GSEA.1. 
Margin of Safety for Oral Administration of LY3202328 Based on 
Administered Dose and Predicted Exposure ..............................................20 
Table GSEA.2. 
Treatments Administered ...........................................................................25 
 
 
 


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List of Figures 
Figure 
Page 
Figure GSEA.1. 
Study design for Protocol I8Q-MC-GSEA. ...............................................16 
 
 
 


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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...................................................................44 
Appendix 2. 
Schedule of Events for Protocol I8Q-MC-GSEA ......................................48 
Appendix 3. 
Clinical Laboratory Tests ...........................................................................57 
Appendix 4. 
Study Governance, Regulatory and Ethical Considerations ......................58 
Appendix 5. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality .............61 
Appendix 6. 
Blood Sampling Summary .........................................................................62 


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3. Protocol Synopsis 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of LY3202328. 
Rationale:  
Cardiovascular (CV) disease remains one of the largest causes of morbidity worldwide and new treatments are 
needed.  The principle aim of this single and multiple-ascending dose study is to evaluate the safety, tolerability, and 
PK of LY3202328 when administered orally as single doses to healthy subjects (Part A, single ascending dose 
[SAD] design) and as multiple doses to dyslipidemic subjects (Part B, multiple ascending dose [MAD] design).  The 
data obtained in this study will help establish the doses and dosage regimen suitable for administration to 
dyslipidemic patient populations in future efficacy studies.  In vitro testing showed some potential for LY3202328 to 
have mechanism-based inhibition of cytochrome P450 (CYP) 3A4; thus a drug-drug interaction (DDI) comparison 
arm has been included in Part B to investigate the effect of LY3202328 on the exposure of commonly used statins 
that are metabolized, at least in part, by CYP3A4.  Additionally, the exploration of the degree of target inhibition 
(pharmacodynamic [PD] assessments) in dyslipidemic subjects will be assessed in Part B. 
Objectives/Endpoints: 
Objectives 
Endpoints 
Primary 
To explore safety and tolerability of single and multiple doses of LY3202328 
in statin-free, overweight, healthy subjects. 
Secondary 
• 
To assess the pharmacokinetic (PK) characteristics of LY3202328 in 
statin-free, overweight, healthy subjects after single and multiple doses. 
• 
To evaluate the effect of food on the extent and rate of LY3202328 
absorption 
• 
To determine the effects of LY3202328 upon multiple dose 
administration on: 
o 
Fasting lipid profiles 
o 
Simvastatin and atorvastatin exposure. 
Exploratory 
• 
To explore the effects of LY3202328 on: 
o 
Post-prandial lipid profiles 
o 
Fasting free fatty acids and β-hydroxybutyrate. 
o 
Fasting apolipoprotein (Apo) B100, ApoC3, proprotein convertase 
subtilisin/kexin type 9, lipoprotein (a), and insulin. 
o 
body weight. 
Summary of Study Design: 
Study I8Q-MC-GSEA (GSEA) is a first-in-man, Phase 1, randomized, double-blind, placebo-controlled, ascending 
single- and multiple-oral dose study of LY3202328 in statin-free male and female overweight healthy subjects.  This 
study will be conducted in 2 parts. 
Part A, will comprise a SAD crossover design in statin-free, overweight healthy male and female subjects, 
investigating the safety, tolerability, and PK of single doses of LY3202328 administered in the fasted state.  In 


I8Q-MC-GSEA Clinical Pharmacology Protocol 
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LY3202328 
addition, one dose level will also be administered in the fed state to evaluate effects of food on the rate and extent of 
absorption. 
Part B will comprise a MAD staggered parallel design in, statin-free, overweight healthy male and female subjects, 
investigating the safety, tolerability, and PK of multiple doses of LY3202328 and its effect on simvastatin and 
atorvastatin exposure. 
Treatment Arms: 
Part A:  A total of 18 subjects will be enrolled in 2 cohorts.  Cohort 1 will consist of 3 periods at dose levels 1, 10, 
and 100 mg, and Cohort 2 will consist of 3 periods at dose levels 3, 30, and 300 mg.  A fourth dosing period will be 
added to either Cohort 1 or Cohort 2 to assess exposure differences when LY3202328 is administered in a fed state.  
Each cohort will consist of 9 subjects where subjects will receive either a single LY3202328 dose or a 
corresponding placebo at each of the 3 assigned dose levels in alternating ascending order. 
In each cohort, 6 subjects will receive LY3202328 and 3 subjects will receive placebo during each dosing period.  
Subjects will be dosed in the fasted state in all periods except for subjects in the cohort that will return to repeat 
1 dose level (planned 30 mg dose level) in the fed state to evaluate food effects on LY3202328 exposure.  An 
additional cohort (not evaluated for food effect) will be reserved for a potential fifth dosing period at a higher dose 
level (600 mg).  Escalation to this higher dose will only be made if exposure continues to increase between 100 and 
300 mg dose levels and the safety profile supports dosing to a higher level. 
Part B:  A total of 40 subjects will be enrolled and divided evenly into 4 study periods (n=10 subjects per study 
period) to evaluate 4 dose levels of LY3202328 (Periods 5, 6, 7 and 8 at 5, 20, 100, and 300 mg, respectively, are 
planned). 
Within each study period, 5 subjects will be stratified to the simvastatin DDI assessment and 5 subjects will be 
stratified to the atorvastatin DDI assessment.  Within each stratum subjects will be randomly assigned 4:1 to receive 
LY3202328 or placebo so that 8 subjects will receive LY3202328 and 2 subjects receive placebo in each cohort.  
Subjects will receive a once daily (QD) dose of LY3202328 or placebo, to be administered in the morning in the 
fasted state for 29 total days.  For DDI assessment, subjects will also receive a single atorvastatin or simvastatin 
dose a week prior to LY3202328 treatment initiation, and on Day 29 after initiation of LY3202328 dosing 
(coadministered with LY3202328).  See Figure GSEA.1 for details. 
The dose levels intended for study in Part B will be within the range of those tested in Part A.  Specific dose levels 
will be selected after review of Part A data.  Doses may range up to 300 mg or the maximum tolerated dose 
established in SAD Part A. 
Number of Subjects: 
Part A:  It is planned that a total of 18 subjects will be enrolled in 2 cohorts with 9 statin-free, overweight, healthy 
subjects in each cohort. 
Part B:  It is planned that a total of 40 subjects will be enrolled in 4 cohorts with 10 dyslipidemic, statin-free, 
overweight, healthy subjects in each cohort. 
Additional subjects may be enrolled to replace drop-outs or discontinued subjects. 


I8Q-MC-GSEA Clinical Pharmacology Protocol 
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LY3202328 
Data Analysis: 
Safety 
The primary endpoint of this study is the number and severity of treatment-emergent adverse events, clinical 
laboratory abnormalities, changes in vital sign measurements, and other safety endpoints after administration of 
LY3202328 or placebo.  Summary statistics will be provided by dose group and for all study subjects combined 
wherever appropriate.  For continuous variables, summary statistics will include number of subjects, mean, median, 
SD, minimum, and maximum.  Categorical endpoints will be summarized using number of subjects, frequency, and 
percentages.  Additional analysis will be performed if warranted upon review of the data. 
Pharmacokinetics 
The primary PK parameters for analysis will be maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUC) for LY3202328.  The primary AUC metric will be AUC0-∞ after single dose 
administration and AUC0-τ, day 28 after multiple dose administration.  Pharmacokinetic parameter estimates (Cmax 
and AUC) for LY3202328 will be evaluated to delineate effects of dose proportionality using a power model 
approach. 
Drug-drug interaction assessment of the effect of LY3202328 coadministration on simvastatin and atorvastatin 
exposure will be conducted using ANOVA.  Pharmacokinetic parameter estimates (Cmax and AUC) will be 
compared for simvastatin and atorvastatin administered alone or coadministered with LY3202328.  The ratios of 
exposure with and without LY3202328 coadministration at different dose levels of LY3202328 will be estimated, 
along with their confidence intervals. 
The impact of food on the rate and extent of LY3202328 absorption will be assessed by calculating and 
summarizing the ratios of Cmax and AUC0-∞, as well as the difference in Tmax, with and without food. 
Review of PK may occur during the conduct of Part A and B to confirm exposure trends. 
Pharmacodynamics 
The PD assessments conducted in this study are typical and appropriate for  Phase I single and multiple ascending 
dose evaluations of a novel therapeutic agent.  The TG concentrations will be analyzed to evaluate evidence of target 
engagement and intended pharmacological response. 
Visual and tabular summarization of all PD measurements will be done.  For the endpoints in the primary or 
secondary objectives, a statistical analysis will also be conducted. 
Mixed effect model repeated measure would be the default method of analysis for PD endpoints with time-course 
data.  For endpoints with only baseline and end of treatment measurements, ANCOVA will be the default, with 
baseline as a covariate.  Other covariates may be apriori defined and included in the model. 
Normality assumption will be tested using an appropriate visual or statistical method and, if it is violated, log 
transformation of data may also be performed on these data.  The most sensitive analysis will be selected to test the 
effect of LY3202328 on the change from baseline in these PD data. 


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LY3202328 
4. Introduction 
Diacylglycerol acyltransferase 2 (DGAT2) plays a key role in processing fatty acids and 
secreting triglycerides (TG) from the liver.  DGAT2 is responsible for catalyzing the formation 
of triacylglycerol from diacylglycerol and fatty acyl-coenzyme A.  Despite the significant 
advancements made by statins in the treatment of dyslipidemia and cardiovascular disease, 
unmet need exists in a market projected to remain one of the largest causes of morbidity and 
mortality worldwide.  DGAT2 inhibitor LY3202328 has the potential to offer value to patients, 
physicians, and providers through its’ expected diverse pharmacological profile to decrease TG, 
total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), body weight, liver fat 
content, and improve glucose utilization.  This broad pharmacological profile is expected to 
result in a reduction in cardiovascular (CV) events when added to or compared with statins or 
other standard of care therapies for these indications.  A DGAT2 inhibitor also has the potential 
to treat other important metabolic diseases beyond dyslipidemia, including nonalcoholic fatty 
liver disease, and possibly Type-2 diabetes mellitus (T2DM).  Antisense oligonucleotide 
reduction of DGAT2 in liver and white adipose tissues for 18 weeks in high fat, cholesterol-
enriched, diet-fed, LDL receptor (LDLr) knockout (KO) mice, reduced body weight (10%), total 
body fat (48%), plasma TG (70%), TC (52%), LDL-c (31%), and free fatty acids (FFA; 46%); 
and increased the glucose infusion rate needed to maintain glucose concentrations in a 
hyperinsulinemic-euglycemic clamp study by 70% (Manchem, 2010). 
LY3202328 is a potent inhibitor of human DGAT2 with a half maximal inhibitory concentration 
(IC50) of 124 nM in the primary enzyme assay and IC50 values of 197 nM and 47 nM in the 
HepG2 cell-based assay, with TG and apolipoprotein (Apo) B100 readouts, respectively.  
LY3202328 is highly selective compared to other acyl transferases in the TG synthesis pathway 
(IC50 >50 µM for DGAT-1, glycerophosphate acyltransferases-1 and -4, monoacylglycerol 
O-acyltransferases-2 and -3, as well as a general panel of enzymes and receptors), and it inhibits 
carbonic anhydrase with IC50 of 5 µM.  LY3202328 demonstrated dose dependent inhibition of 
hepatic TG secretion in mice, with a median effective dose (ED50) of 0.3 mpk when 
administered orally and a half maximal effective concentration (EC50) of 142 ng/mL. 
4.1. Study Rationale 
Despite the significant advancement made by statins in the treatment of CV disease, unmet need 
exists in a market projected to remain one of the largest causes of morbidity and mortality 
worldwide.  Some of the opportunities to address unmet need in the CV market include:  
1) reducing residual CV event risk in patients already taking maximally-tolerated doses of 
statins; 2) providing predictable, robust lowering of both LDL-c and TG; 3) addressing common 
dyslipidemia co-morbidities such as obesity and diabetes; and 4) improving CV patient 
experience through decreased polypharmacy and a more acceptable mode of administration (oral 
versus injectable). 
LY3202328 has the potential to offer a broad clinical profile that is may result in a reduction in 
CV events when added to or compared to the standard of care.  Further preclinical and Phase 1 


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LY3202328 
studies will contribute to our understanding of the magnitude of effect across the clinical 
attributes of LY3202328. 
The principle aim of these dose-escalation  studies is to evaluate the safety, tolerability, and PK 
of LY3202328 when administered orally as single doses to healthy subjects (Part A, single 
ascending dose [SAD] design) and as multiple doses to dyslipidemic subjects (Part B, multiple 
ascending dose [MAD] design).  A food effect period will be evaluated in Part A to compare the 
exposure profile when LY3202328 is dosed in the fed or fasted state.  The data obtained in this 
study will help establish the doses and dose regimen suitable for administration to dyslipidemic 
patient populations. 
A drug-drug interaction (DDI) comparison arm will be included in Part B to investigate the 
effect of LY3202328 on the exposure of statins (i.e., simvastatin and atorvastatin).  Additionally, 
the exploration of the degree of target inhibition (pharmacodynamic [PD] assessments) in 
dyslipidemic subjects will be assessed in Part B. 
4.2. Background 
LY3202328 is a low solubility, highly permeable molecule with high oral exposure in preclinical 
species.  Oral bioavailability at the predicted human 80% maximal effective dose (ED80) 
efficacious dose (13 mg once daily [QD]) is greater than 30% in preclinical species and is 
predicted to be 89% in humans.  As the dose increases, exposures are expected to increase until 
reaching a plateau as absorption limitations are expected in humans for doses above 190 mg due 
to the solubility characteristics of the compound.  In vivo, LY3202328 exhibits near linear 
increases in area under the concentration-time curve (AUC) at doses up to 100 mg/kg with much 
lower than dose proportional increases in exposure above 100 mg/kg.  The maximum plasma 
concentration (Cmax) also increases with dose in a less than proportional manner.  The time to 
reach Cmax (Tmax) is reached between 1 to 3 hours in most preclinical species.  LY3202328 is 
eliminated predominantly by cytochrome P450 (CYP) 3A microsomal oxidation with < 5% of 
dose excreted as parent by renal elimination.  Based on in vitro data, LY3202328 is also a time-
dependent inhibitor of CYP3A at high concentrations.  However, lack of accumulation upon 
multiple dosing in vivo suggests that LY3202328 does not inhibit its own metabolism.  These 
properties suggest a potential for drug-drug interactions with concomitantly administered 
CYP3A4 substrates (particularly those with a narrow therapeutic margin) or CYP3A inhibitors.  
Half-life in animal preclinical toxicology studies ranged from 3 to 12 hours, yet exposures in rat 
and dog toxicology studies showed no accumulation of LY3202328 after 28 days of repeat 
dosing.  In humans, LY3202328 is projected to have a half-live of 6 to 8 hours.  Human clinical 
dose projections based on Simcyp modeling of animal PK data predict a dose of 13 mg to 
achieve an average steady state concentration of 325 ng/mL (equivalent to a 24 hour AUC of 
7.8 µg x h/mL) which is associated with 80% efficacy based on preclinical pharmacology studies 
(after correction for species difference in protein binding and receptor affinity). 
In 28-day repeat dose GLP toxicology studies conducted at doses up to 500 mg/kg in rat and 
250 mg/kg in dog (maximum feasible dose levels), no dose-limiting toxicities and no observable 
adverse effects were observed in either species.  In rats administered 500 mg/kg, animals had 


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LY3202328 
minimal decreases in body weight gain (4%).  Minimal to slight hypertrophy observed in liver 
centrilobular hepatocytes, adrenal zona fasciculata cells, and thyroid follicular cells correlated 
with minimal organ weight increases.  These findings were consistent with physiological 
adaptations to stress or minimal metabolic induction commonly observed in rodents.  In dogs 
administered 250 mg/kg, there were infrequent emesis, liquid feces, and minor body weight loss 
(1%) with reduced food consumption.  Rats and dogs administered 500 mg/kg and 250 mg/kg, 
respectively, had slight decreases in red cell mass (red blood cell count, hemoglobin 
concentration, and hematocrit) with evidence of regeneration based on higher absolute 
reticulocyte count.  These effects observed in rats and dogs were not observed at the end of the 
1-month reversibility phase of either study.  The effects observed in rats and dogs were 
monitorable and there were adequate margins to the proposed clinical doses. 
4.3. Benefit/Risk Assessment 
The nonclinical safety information for LY3202328 adequately supports the transition from 
preclinical to clinical study.  On the basis of the nonclinical data, LY3202328 is not considered 
to be a high-risk compound.  This protocol reflects the fact that LY3202328 has not been 
administered to humans previously and, to mitigate this risk, the study has been designed to be 
conducted in accordance with principles outlined in the Guideline on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products 
(2007).  Any identified risks are considered to be monitorable and manageable at the planned 
dose range of 1 to 300 mg for LY3202328 in healthy subjects. 
More information about the known and expected benefits and risks of LY3202328 can be found 
in Section 3.2 of the Investigator’s Brochure (IB). 
The sponsor, monitor, and investigator will perform this study in compliance with the protocol, 
good clinical practice (GCP), and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements. 


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LY3202328 
5. Objectives 
5.1. Primary Objective 
The primary objective of this study is to explore safety and tolerability of single and multiple 
doses of LY3202328 in statin-free, overweight, healthy subjects. 
5.2. Secondary Objectives 
The secondary objectives of this study are: 
• 
To assess the pharmacokinetic (PK) characteristics of LY3202328 in statin-free, 
overweight, healthy subjects after single and multiple doses. 
• 
To evaluate the effect of food on the extent and rate of LY3202328 absorption. 
• 
To determine the effects of LY3202328 upon multiple dose administration on: 
o Fasting lipid profiles 
o Simvastatin and atorvastatin exposure 
5.3. Exploratory Objectives 
The exploratory objective of this study is to explore the effects of LY3202328 on: 
• 
Post-prandial lipid profiles. 
• 
Fasting free fatty acids and β-hydroxybutyrate. 
• 
Fasting ApoB100, ApoC3, proprotein convertase subtilisin/kexin type 9 (PCSK9), 
lipoprotein (Lp [a]), and insulin. 
• 
body weight. 


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LY3202328 
6. Study Design 
6.1. Overall Design 
Study I8Q-MC-GSEA (GSEA) is a first-in-man, Phase 1, randomized, double-blind, placebo-
controlled, 2-part, ascending single- and multiple-oral dose study of LY3202328 in overweight, 
healthy subjects (Part A) and in dyslipidemic, statin-free, overweight, healthy subjects with a 
statin DDI assessments (Part B). 
This study will be conducted in 2 parts:  Part A, a SAD study design at a single site and Part B, a 
MAD study design conducted in multiple sites. 
Figure GSEA.1 illustrates the study design. 
 
 


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LY3202328 
 
Abbreviations:  AS = atorvastatin; D/C = discharge (from the clinical research unit); 
LY = LY3202328; N = number of subjects; SS = simvastatin. 
a 
Discharge from the CRU will occur on Day 2 with Follow-up visits to occur on 
Days 3 and 5. 
b 
LY3202328 or placebo will be administered with food. 
c 
A single dose of simvastatin or atorvastatin will be administered on Day –7. 
d 
Multiple doses of LY3202328 or placebo will be administered daily on Days 1 
through 28. 
e 
LY3202328 or placebo will be coadministered with simvastatin or atorvastatin on 
Day 29. 
f 
Discharge from the CRU will occur on Day 30 with Follow-up visits to occur on 
Days 35 and 42 
Note:  The doses for Part B are subject to change and will not exceed the maximum 
tolerated dose from Part A (starting as low as 5 mg and not to exceed 300 mg). 
Figure GSEA.1. 
Study design for Protocol I8Q-MC-GSEA. 
6.1.1. Part A: Single Ascending Dose with Food Effect Design 
Part A will comprise a double-blinded, 2-staggered, alternating, 3- or 4-period sequence design 
of single ascending doses in statin-free, overweight (BMI 25.0 to 35.0 kg/m2), healthy male and 


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LY3202328 
female subjects, investigating the safety, tolerability, and PK of single doses of LY3202328 
administered in the fasted state.  One dose level will be repeated in the fed state using the same 
randomization as conducted in the fasted state to assess the effect of food on LY3202328 
exposure. 
A total of 18 subjects will be enrolled in 2 cohorts.  Cohort 1 will consist of 3 periods at dose 
levels 1, 10, and 100 mg, and Cohort 2 will consist of 3 periods at dose levels 3, 30, and 300 mg.  
A fourth dosing period will be added to either Cohort 1 or Cohort 2 to assess exposure 
differences when LY3202328 is administered in a fed state.  Each cohort will consist of 
9 subjects where subjects will receive either a single LY3202328 dose or a corresponding 
placebo at each of the 3 assigned dose levels in alternating ascending order. 
In each cohort, 6 subjects will receive LY3202328 and 3 subjects will receive placebo during 
each dosing period.  Subjects will be dosed in the fasted state in all periods except for subjects in 
the cohort that will return to repeat 1 dose level (planned 30 mg dose level) in the fed state to 
evaluate food effects on LY3202328 exposure.  An additional cohort (not evaluated for food 
effect) will be reserved for a potential fifth dosing period at a higher dose level (600 mg).  
Escalation to this higher dose will only be made if exposure continues to increase between 
100 and 300 mg dose levels and the safety profile supports dosing to a higher level. 
Potential subjects will be screened to assess their eligibility to enter the study within 42 days 
prior to study entry (i.e., prior to Check in for Part A).  Subjects will be confined at the CRU 
from Day –1 (the day before dosing) to Day 2 (24 hours postdose), and return on Days 3 and 5 
(48 and 96 hours postdose, respectively) for follow-up assessments.  Dosing in subsequent 
periods will be approximately 2 weeks after dosing in the prior period, with subjects dosed on 
Day 1 of Week 1, 3, or 5 (Cohort 1); Week 2, 4, or 6 (Cohort 2); and Week 8 (food effect period, 
Cohort 2). 
Treatment of the cohorts in Part A will be staggered so that the appropriateness of escalation to 
the next dose level can be determined from the current dose level. 
Safety assessments in Part A and Part B will include monitoring of adverse events (AEs), clinical 
laboratory test results, vital sign measurements, physical examination findings, and 12-lead 
electrocardiogram (ECG) results.  Escalation to the next dose period will be decided by the 
investigator in consultation with the sponsor’s clinical research physician (CRP) at the dose 
escalation Data Review Meeting (DRM) as outlined in Section 7.3.1.  The decision will be made 
based on safety data from each dosing period (Appendix 2).  Pharmacokinetic and PD data are 
not required for the dose escalation decision; however, any drug concentration or PD data that 
become available prior to the DRM may be reviewed at the DRM.  No interim analysis for PK or 
PD is planned for the DRM. 
6.1.2. Part B:  Multiple Ascending Dose – Drug-Drug Interaction 
Design 
Part B will comprise a double-blinded, MAD, staggered parallel design in dyslipidemic (TG: 
150 to 499 mg/dL; LDL-c: 100 to 200 mg/dL), statin-free, overweight (BMI 27.0 to 35.0 kg/m2), 


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LY3202328 
healthy male and female subjects investigating the safety, tolerability, and PK of multiple doses 
of LY3202328 and the effect of LY3202328 on simvastatin and atorvastatin exposure. 
A total of 40 subjects will be enrolled and divided evenly into 4 study periods (n=10 subjects per 
study period) to evaluate 4 dose levels of LY3202328 (Periods 5, 6, 7, and 8 at 5, 20, 100, and 
300 mg, respectively, are planned). 
Within each cohort, 5 subjects will be stratified to the simvastatin DDI assessment and 5 subjects 
will be stratified to the atorvastatin DDI assessment.  Within each stratum subjects will be 
randomly assigned 4:1 to receive LY3202328 or placebo so that 8 subjects will receive 
LY3202328 and 2 subjects receive placebo in each cohort.  Subjects will receive QD dose of 
LY3202328 or placebo in the morning in the fasted state for 29 total days.  For DDI assessment, 
subjects will also receive a single atorvastatin or simvastatin dose a week prior to LY3202328 
treatment initiation, and on Day 29 after initiation of LY3202328 daily dosing (coadministered 
with LY3202328). 
The dose levels intended for study in Part B may change based upon data from Part A, but will 
range from as low as 1 mg and are not to exceed the highest dose evaluated in Part A.  Any dose 
level used in Part B will not start until the safety data from the same or higher dose level in Part 
A has been reviewed by the safety committee responsible for dose escalation decisions. 
Potential subjects will be screened to assess their eligibility to enter the study within 42 days 
prior to study entry (i.e., prior to Check in for Part B).  For each cohort, subjects will be admitted 
to the CRU on Day –8 (the day before administration of a single dose of simvastatin or 
atorvastatin) and will be discharged 24 hours postdose (Day –6). 
Subjects will be confined to the CRU from Day –2 to Day 2 (48 hours postdose) for initial 
dosing with LY3202328 and are required to return to the CRU for dosing and PK sampling the 
mornings of Days 7, 14, and 21.  Prior to discharge from the CRU on Day 2, subjects will 
receive a labeled container with doses of LY3202328 that subjects will self‑administer daily at 
home until the next morning visit at the CRU.  Subjects will be instructed to take the drug once 
daily in the morning in the fasted state and wait at least 30 minutes after the completion of 
dosing prior to commencing their breakfast.  Subjects will be given diaries to record the time of 
their self‑administered doses, whether the dose was administered with food or fasted, and the 
time of commencing the breakfast meal.  Subjects must return the container (empty or not) and 
their diary at the next morning visit.  Home dosing will be monitored via attempted phone calls 
when subjects will be reminded to take their medication and queried about the occurrence of 
AEs.  Subjects should be instructed to take their dose at approximately the same time they 
received their first dose.  Subjects will again be confined to the CRU from late afternoon on 
Day 27 (2 days before coadministration of LY3202328 or placebo with simvastatin or 
atorvastatin on Day 29) to Day 30 (24 hours post-coadministration of LY3202328 or placebo 
with simvastatin or atorvastatin).  Subjects will return to the CRU on Days 35 and 42 (168 and 
336 hours postdose, respectively) for follow-up assessments. 


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LY3202328 
The dose levels intended for study in Part B will be within the range of those tested in Part A.  
Specific dose levels will be selected after review of Part A data.  Doses may range up to 300 mg 
or the maximum tolerated dose established in SAD Part A. 
6.2. Number of Participants 
Eighteen healthy males and female subjects may be enrolled in Part A where each subject is 
scheduled to receive 2 single doses of LY3202328 and 1 dose of placebo in ascending dose 
levels.  Forty subjects may be enrolled in Part B (8 subjects will receive LY3202328 and 2 
subjects will receive placebo in each of 4 dose level cohorts).  Additional subjects may be 
enrolled to replace drop-outs or discontinued subjects with the goal to complete up to 18 subjects 
in Part A and 40 subjects in Part B. 
6.3. End of Study Definition 
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Events (Appendix 2) for the last subject. 
6.4. Scientific Rationale for Study Design 
The purpose of this study is to evaluate the safety, tolerability, PK, and degree of target 
inhibition (PD) of LY3202328 when administered orally as single doses to statin-free, 
overweight, healthy subjects (Part A) and as multiple doses (with a statin DDI assessment) to 
dyslipidemic, statin-free, overweight subjects (Part B). 
For Part A, a standard single-dose, double-blind, randomized, placebo–controlled, crossover 
design will be used.  A randomization schedule for treatment sequence assignment will be used 
to reduce the potential for selection bias.  For Part B, a double-blind, randomized, placebo–
controlled, sequential, ascending MAD design will be used.  The data obtained from this study 
will help establish the doses suitable for administration to patients with dyslipidemia and the 
possible existence of a DDI between LY3202328 and simvastatin and/or atorvastatin prior to 
studies in patient populations on stable treatment. 
The selection of healthy subjects is appropriate and consistent with standard practices for an 
early phase clinical pharmacology study.  The inclusion and exclusion criteria are chosen to 
select subjects who are known to be free from any significant illness.  A placebo is included to 
enable characterization of AEs by serving as a negative control.  LY3202328 is not anticipated to 
provide any benefit to the study subjects, and therefore the use of placebo will not deprive 
subjects of any benefit. 
6.5. Justification for Dose 
Human PK/PD modeling and preclinical absorption, disposition, metabolism, and excretion 
(ADME) profiles in rat, dog, and primate were used to predict that LY3202328 should achieve a 
sustained average ED80 concentration in man with an oral dose of 13 mg QD.  This projected 
human dose compares favorably with the projected maximum absorbable dose of 190 mg 
determined using GastroPlus modelling of rat, dog and monkey ADME profiles.  In chronic lipid 
lowering studies, LY3202328 produced dose-dependent inhibition of LDL-c (61%), ApoB 


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LY3202328 
(53%), ApoC3 (43%), and PCSK9 (55%) in plasma, as well as liver TG (37%) in LDLr KO 
mice, and reduced liver TG (56%) in C57Bl/6 mice on a high fat diet.  Finally, body surface area 
dose and predicted AUC exposure multiples are greater than 195x in GLP rat and dog toxicology 
studies relative to the predicted efficacy dose/exposure, and greater than 13x relative to the 
highest planned human dose of 300 mg.  The proposed dose range for this first-in man-study of 
1 to 300 mg of LY3202328 administered orally QD for up to 28 days was selected based on 
toxicology studies and modeling of PK/PD data from nonclinical studies of LY3202328, and the 
established margin of safety. 
The nonclinical no-observed-adverse-effect level (NOAEL) doses and AUC values for 
LY3202328 following daily administration compared with planned human doses and projected 
human exposures are presented in Table GSEA.1.  
Table GSEA.1. 
Margin of Safety for Oral Administration of LY3202328 Based on 
Administered Dose and Predicted Exposure 
 
Dose 
(mg) 
Dose 
(mg/kg) 
HED 
(mg/kg) 
Dose 
Multiplea 
AUC 
(µg•h/mL)b 
Exposure 
Multiplea 
Humanc 
 
 
 
– 
 
– 
Starting dose 
1 
0.0143 
0.0143 
 
0.6 
 
Efficacy dose 
13 
0.186 
0.186 
 
7.8 
 
Highest dose 
300 
4.29 
4.29 
 
114 
 
Rat NOAELd 
 
500 
80.6 
 
1710 
 
Starting dose 
 
 
 
5600x 
 
2850x 
Efficacy dose 
 
 
 
433x 
 
219x 
Highest dose 
 
 
 
19x 
 
15x 
Dog NOAELe 
 
250 
139 
 
1520 
 
Starting dose 
 
 
 
9700x 
 
2533x 
Efficacy dose 
 
 
 
747x 
 
195x 
Highest dose 
 
 
 
32x 
 
13x 
Abbreviations:  AUC = area under the plasma concentration x time curve; HED = human equivalent dose based on 
body surface area; NOAEL = no-observed-adverse-effect level. 
a Dose multiple is the dose in animal HED / human dose based on  mg/kg2 using Guidance for Industry, Estimating 
the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, 
FDA/CDER, July 2005.  Exposure multiple is the calculated as AUC in animals / predicted AUC in humans. 
b Predicted human AUC over 24 hours upon repeat once daily dosing, based on predicted human pharmacokinetics 
mentioned in Section 5.1.8 of the Investigators Brochure.  Note:  human predicted AUC listed at a dose of 
300 mg accounts for the expected absorption limitation, resulting in a maximum absorbable dose of 190 mg. 
c Clinical dose based on 70-kg human. 
d NOAEL determined in a 28-day repeat dose rat toxicity study.  AUC is mean of male and female data at the end 
of the study (Study 8327-151). 
e NOAEL determined in a 28-day repeat dose dog toxicity study.  AUC is mean of male and female data at the end 
of the study (Study 8327-163). 


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LY3202328 
7. Study Population 
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG results. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. Inclusion Criteria 
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment: 
[1] 
are healthy males or females, as determined by medical history and physical 
examination   
• male subjects: 
o agree to use a reliable method of birth control during the study and 3 months 
following the last dose of the investigational product. 
• female subjects: 
o postmenopausal women include women with either: 
 spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications that induced 
amenorrhea (for example:  oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-estrogens, selective estrogen receptor modulators, or 
chemotherapy; or 
 spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level greater than 40 mIU/mL; or 
 women with a prior history of hysterectomy have to be at least 40 year of 
age and FSH >40 mIU/mL. 
[2] 
are at least 18 to 70 years old inclusive (for males), or 40 to 70 years old, 
inclusive (for females), at the time of study entry. 
[3] 
are on a stable diet and exercise regimen for >3 months prior to screening. 
[4] 
have a BMI of 25.0 (Part A) or 27.0 (Part B) to 35.0 kg/m2, inclusive, at 
screening. 
[5] 
have a fasting TG between 150 and 499 mg/dL, inclusive, at screening (allowed 
but not required in Part A; required for Part B only). 
[6] 
have a fasting LDL-c between 100 and 200 mg/dL inclusive, at screening 
(allowed but not required in Part A; required for Part B only). 


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LY3202328 
[7] 
have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.  However, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl 
transpeptidase (GGT), and alkaline phosphatase (ALP) have to be ≤ 1.5 × upper 
limit of normal (ULN); total bilirubin has to be within normal limit, unless in 
subjects with Gilbert’s Syndrome. 
[8] 
estimated glomerular filtration rate ≥60 mL/minute/1.73m2 with no proteinuria. 
[9] 
are normotensive (defined as supine systolic blood pressure (BP) <150 mm Hg 
and diastolic BP <100 mm Hg) without the use of any antihypertensives.  Blood 
pressure may be retested up to 2 additional times, under well-rested conditions. 
[10] have venous access sufficient to allow for blood sampling as per the protocol. 
[11] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures 
[12] have given written informed consent approved by Chorus and the ethical review 
board (ERB) governing the site 
7.2. Exclusion Criteria 
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment: 
[1] 
are taking a statin, any PCSK9 medications, or have started taking other TG 
lowering agents (e.g., niacin, fish oils) within the last 3 months.  Subjects on 
stable background (>3 months) of non-statin TG lowering agents may be 
included in the study. 
[2] 
are investigator site personnel directly affiliated with this study or their 
immediate families.  Immediate family is defined as a spouse, parent, child or 
sibling, whether biological or legally adopted. 
[3] 
are Chorus (Lilly) or PRA employees. 
[4] 
are currently enrolled in a clinical trial involving an investigational product or 
off-label use of a drug or device, or are concurrently enrolled in any other type 
of medical research judged not to be scientifically or medically compatible with 
this study. 
[5] 
have participated (defined as last dose of study drug) in a clinical trial involving 
an investigational product or non-approved use of a drug within the last 30 days 
or within 5 half-lives, whichever is longer. 
[6] 
have an abnormality in the 12-lead ECG, including corrected QT (QTc) interval 
with Bazett’s correction >450 msec for men and >470 msec for women or an 
abnormality that, in the opinion of the investigator, increases the risks 
associated with participating in the study.  ECGs may be repeated after 
5 minutes resting quietly if the subject’s heart rate is >75 bpm. 


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LY3202328 
[7] 
have a history of hypertension, or on treatment with any antihypertensives. 
[8] 
have any current or prior history of significant cardiovascular disease, including 
acute myocardial infarction, unstable angina, congestive heart failure, 
cardiomyopathy or cardiomyositis.  Subjects with clinically significant 
arrhythmia, including but not limited to atrial fibrillation, 
supraventricular/ventricular tachycardia, atrial-ventricular block, and sick sinus 
syndrome should also be excluded.  Subjects with asymptomatic sinus 
arrhythmia, sinus bradycardia or mild sinus tachycardia may be enrolled. 
[9] 
show evidence of hepatitis C virus (HCV) and/or positive HCV antibody. 
[10] show evidence of hepatitis B virus and/or positive hepatitis B surface antigen. 
[11] have evidence of other chronic liver disease, including but not limited to chronic 
alcoholic disease, cirrhosis of any cause, recent history (within 3 months of 
screening) of acute viral hepatitis or chronic autoimmune hepatitis.  Subjects 
with history of biliary disease, including primary sclerosing cholangitis, must be 
excluded.  Subjects with history of cholecystectomy longer than 6 months prior 
to visit 1 could be enrolled. 
[12] have an alcohol intake that exceeds 7 units per week with no more than 3 units 
per day, or are unwilling to stop alcohol consumption for the duration of the 
study (1 unit = 12 ounces or 360 mL of beer; 5 ounces or 150 mL of wine; 
1.5 ounces or 45 mL of distilled spirits). 
[13] have a history of untreated endocrine illness such as diabetes mellitus, growth 
hormone insufficiency / acromegaly, adrenal gland or thyroid illness. 
[14] have been on medications or supplements for weight loss within 3 months of 
screening. 
[15] have a history of active neuropsychiatric disease or on pharmacological therapy 
for such conditions within 1 year of screening or have taken any antidepressants 
or antipsychotics within 3 months of screening for non-psychological 
indications. 
[16] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies. 
[17] have had any major surgery within 30 days prior to screening or have planned 
elective surgeries to occur during the study. 
[18] have a history or presence of or current other cardiovascular, respiratory, 
hepatic, renal, gastrointestinal, endocrine, autoimmune, hematological 
(including any coagulopathy), neoplastic or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; or 
constituting a risk when taking the study medication; or of interfering with the 
interpretation of data.  Basal cell or squamous epithelial carcinomas of the skin 
that have been resected with no evidence of metastatic disease may be allowed. 


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[19] have been on medications that are known to inhibit CYP3A or P-glycoprotein 
(P-gp), or regularly consume grapefruit or grapefruit juice within 2 weeks of 
screening. 
[20] are regular users of known drugs of abuse and/or show positive findings on 
urinary drug screening. 
[21] are women who are lactating. 
[22] have donated blood of more than 500 mL within the last month, or have 
intention for blood donation during the study period. 
[23] smoke >10 cigarettes per day or are unwilling to follow the CRU smoking rules. 
[24] are unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor. 
7.3. Lifestyle and Dietary Requirements 
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.   
7.3.1. Meals and Dietary Restrictions 
While confined at the CRU, subjects will receive a standardized diet at scheduled times that do 
not conflict with other study-related activities.  When not at the study site, subjects will be asked 
to take regular meals and avoid major deviations from their usual regimen and habits.  Subjects 
are prohibited from consuming grapefruit or grapefruit juice during the entire duration of the 
study. 
7.3.2. Caffeine, Alcohol, and Tobacco 
Subjects will abstain from consuming alcohol-containing products for the duration of the study.  
Subjects are required to maintain their regular intake of caffeine- or xanthine-related beverages 
for the duration of the study. 
While confined at the CRU, subjects are required to adhere to the CRU smoking policy during 
the inpatient treatment days.  Subjects should otherwise not intentionally change their 
consumption of tobacco-containing products during the study.  
7.3.3. Activity 
Subjects will refrain from strenuous exercise during the period of confinement at the CRU and 
will otherwise maintain their normal level of physical activity throughout the entire study (i.e., 
will not begin a new exercise program nor participate in any unusually strenuous physical 
exertion). 
7.4. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  Subjects who do not meet clinical laboratories inclusion/exclusion criteria may be 
reevaluated once. 


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8. Treatment 
8.1. Treatment Administered 
This study involves a comparison of LY3202328 to placebo when administered orally as a single 
dose in Part A and when administered in multiple doses both with and without a statin 
(simvastatin or atorvastatin) in Part B.  Table GSEA.2 shows the treatment regimens. 
In Part A, LY3202328 or placebo will be administered orally in the morning of Day 1 with 
approximately 240 mL of room temperature water in a sitting position.  Subjects will not be 
allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study procedures. 
In Part B, all study drugs will be administered orally in the morning with approximately 240 mL 
of room temperature water.  Simvastatin or atorvastatin will be administered on Day –7.  
LY3202328 or placebo will be administered QD on Days 1 to 29 while confined to the CRU (on 
Days 1 to 3, 7, 14, and 21) or at home.  Simvastatin or atorvastatin will be coadministered with 
LY3202328 or placebo on Day 29 while subjects are confined to the CRU.  Investigators should 
instruct subjects to store the LY3202328 or placebo capsules at home in the original container 
out of the reach of children at room temperature.  Capsules should not be opened, crushed, or 
dissolved. 
Table GSEA.2. 
Treatments Administered 
 
Treatment Name 
LY3202328 
Placebo 
Simvastatin 
Atorvastatin 
Dosage 
Formulation 
HPMC capsule 
HPMC capsule 
Commercial 
Commercial 
Unit dose 
strength(s)/ 
Dosage Level(s) 
1, 5, or 50 mg LY 
Part A:  1, 3, 10, 30, 100, 
or 300 mg 
Part B:  5, 20, 100 or 
300 mg  
Inactive 
10 mg 
10 mg 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Abbreviations:  LY = LY3202328; HPMC = hydroxypropyl methylcellulose. 
The investigator or designee is responsible for: 
• explaining the correct use of the investigational product(s) to the subject,  
• verifying that instructions are followed properly, 
• maintaining accurate records of investigational product dispensing and collection, 
• and returning all unused medication to Chorus or its designee at the end of the study. 


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Note:  In some cases, study sites may destroy the material if, during the investigative site 
selection, the evaluator has verified and documented that the site has appropriate facilities and 
written procedures to dispose of clinical trial materials.  
8.1.1. Packaging and Labeling 
The drug product LY3202328 is supplied for clinical trial use as capsules and is composed of 
LY3202328 drug substance filled directly into hydroxypropyl methylcellulose capsules without 
additional ingredients.  Each capsule is manufactured to contain LY3202328 equivalent to either 
1, 5, or 50 mg of the free basic compound. 
Placebo capsules look identical but contain no active ingredient and will be provided in similar 
packaging. 
Simvastatin (Zocor®) and Atorvastatin (Lipitor®) will be obtained by the CRU as commercially 
available. 
Clinical trial materials will be labeled according to the country’s regulatory requirements and 
stored under ambient temperature conditions of 15°C to 30°C. 
8.2. Method of Treatment Assignment 
Subjects who meet all criteria for enrollment during Part A will be assigned to a randomization 
sequence number by the CRU on Day –1 within Cohort 1 (1, 10, and 100 mg) or Cohort 2 (3, 30, 
and 300 mg) that corresponds to 1 of the 3 treatment sequences in a 1:1:1 ratio so that 6 subjects 
receive LY3202328 and 3 subjects receive placebo, per dose level.  The 30 mg dose level in 
Cohort 2 will be repeated in Period 4 to evaluate food effects on exposure. 
Subjects who meet all criteria for enrollment during Part B will be stratified evenly to the 
simvastatin DDI assessment and the atorvastatin DDI assessment and assigned a randomization 
number on Day –7 of Part B for each cohort (Cohorts 3, 4, 5, and 6 at 5, 20, 100, and 300 mg, 
respectively, planned) in the order in which they were enrolled into the study.  For each cohort, 
subjects will be randomly assigned 4:1 to receive LY3202328 or placebo within each stratum. 
Randomization for Parts A and B will be performed in accordance with the randomization 
schedule generated by Chorus (or designee). 
8.2.1. Selection and Timing of Doses 
Study treatment will be administered as shown in the Schedule of Events (Appendix 2). 
All doses in Parts A and B should be administered in the morning under fasted conditions 
(12 hours), except for Period 4 in Part A, which will be administered in the fed state.  All doses 
should be administered at approximately the same time on each day for Part B (on Days 2 to 29, 
within ±1 hour of dosing time of Day 1).  In Part B, subjects will receive standard meals at 
appropriate times when confined to the CRU or during return visits for dosing.  At least 
60 minutes should separate the ingestion of the dose and the beginning of the breakfast meal 
while confined to the CRU and at home.  Additionally, subjects will be asked to document time 
of dosing and time of first meal in a diary and keep their standard diet when at home.  A high fat 


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lunch meal will be administered 4 hours post dose in each period of Part A (with exception of 
Period 4) and on Days –1 and 28 in Part B to measure the post-prandial lipid profiles. 
The actual time of all dose and initial meal administrations in the CRU will be recorded in the 
subject’s case report form (CRF) and from the diary entries for the at-home dosings. 
8.3. Blinding 
Blinding will be maintained throughout the conduct of the study until all data are cleaned and the 
databased has been locked.  Chorus may review unblinded data, the details of which will be 
included in the Blinding/Unblinding Plan.  The simvastatin and atorvastatin dosing in Part B is 
planned to be an unblinded element of this study. 
Emergency codes will be available to the investigator and pharmacy.  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 Chorus 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.  A 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the Chorus CRP prior to unblinding a study subject’s treatment assignment unless this 
could delay emergency treatment of the subject.  If a study subject’s treatment assignment is 
unblinded, Chorus must be notified immediately. 
Upon completion of the study, all codes must be returned to Chorus or its designee. 
8.3.1. Dose Decision/Escalation 
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
maximum tolerated dose (MTD) is determined.  The highest dose level that is tolerated will be 
designated as the MTD.  Doses in Part B will not exceed the MTD dose determined in Part A. 
Safety data will be the primary criteria for the dose escalation.  Dose escalation cannot occur 
without prior discussion and agreement between the investigator and the Chorus CRP. 
Safety data, in particular AEs, serious adverse event (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. 
After review of these data, an agreement on the appropriate dose escalation will be made by the 
investigator and sponsor for the next cohort.  The magnitude of the dose escalation may be 
reduced following DRM, but subsequent escalations cannot be increased by more than 
approximately 3 fold (a half-log increment). 


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For dose escalation decisions safety data from at least 6 subjects completing Day 5 procedures 
from each dosing period in Part A will be reviewed prior to escalating to the next dosing level.  
For Part B, safety data from at least 8 subjects completing Day 14 safety procedures will be 
reviewed prior to escalating to the next dosing level. 
8.4. Preparation/Handling/Storage/Accountability 
Only participants enrolled in the study may receive investigational product and only authorized 
site staff may supply or administer study treatment.  All study treatments should be stored at the 
site in an environmentally controlled and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation and final disposition records). 
Subjects will be given instructions and take home diary’s to record dosing times and initiation of 
the first meal after dosing as described in Section 8.2.1. 
8.5. Treatment Compliance 
In Part A, LY3202328 or placebo will be administered at the CRU under the supervision of the 
investigator.  As a result subject compliance will be ensured. 
In Part B, simvastatin and atorvastatin will be administered at the CRU under the supervision of 
the investigator.  As a result subject compliance will be ensured.  LY3202328 or placebo will be 
administered at the CRU (on days of confinement) and subjects will also self-administer 
LY3202328 at home between study visits.  Compliance will be assessed by subject diary entries, 
direct questioning, and enumeration of returned capsules. 
Subjects who are significantly noncompliant in Part B will be discontinued from the study.  The 
subject must take ≥80% of the intended dose to be deemed compliant with study drug 
administration.  Similarly, a subject will be considered significantly noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication (≥120% of the intended dose taken in a visit interval). 
Study medication administration data and deviation(s) from the prescribed dosage regimen 
should be recorded in the subject’s CRF. 
8.6. Concomitant Therapy 
Subjects on stable concomitant medication allowed by inclusion/exclusion criteria at the time of 
study entry should continue their regular, unchanged dose throughout the study. 
Drugs that are known inhibitors of CYP3A or P-gp are specifically excluded.  Additional drugs 
are to be avoided during the study unless required to treat an AE or for the treatment of an 
ongoing medical problem. 


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If the need for concomitant medication arises for the treatment of minor AEs, the following 
medication may be administered by the investigator without consultation of Chorus CRP. 
• Paracetamol as needed: <2000 mg/day. 
• Topical medication for minor dermatological conditions. 
• Stool softeners. 
All additional medication used during the course of the study must be documented on the 
subject’s CRF. 
8.7. Treatment after the End of the Study 
8.7.1. Continued Access to Investigational Product 
LY3202328 will not be made available after conclusion of the study to subjects who participate 
in this study. 


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9. Discontinuation Criteria 
9.1. Discontinuation from Study Treatment 
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets one of the following conditions after consultation with the 
Chorus designated medical monitor: 
• ALT or AST >8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN along with one of the following criteria 
o total bilirubin level >2 × ULN or 
o prothrombin time >1.5 × ULN or 
o the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
• ALP (alkaline phosphatase) >3 × ULN 
• ALP >2.5 × ULN and total bilirubin >2 × ULN 
• ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%). 
Subjects who discontinue the investigational product early for any reason will have procedures 
performed as shown in the Schedule of Events (Appendix 2). 
9.1.1. Discontinuation of Inadvertently Enrolled Subjects 
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Chorus CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Chorus CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product. 
9.2. Discontinuation from the Study 
Subjects will be discontinued in the following circumstances: 
• Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
• Significant noncompliance with study drug administration. 
• Investigator Decision 
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. 


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• Subject Decision 
o the subject requests to be withdrawn from the study. 
• Sponsor Decision 
o the sponsor decides study participation should be stopped for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP. 
Subjects who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Events (Appendix 2). 
9.3. Subjects Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 


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10. Study Assessments and Procedures 
Appendix 2 lists the Schedule of events, detailing the study procedures and their timing. 
Appendix 3 lists the laboratory tests that will be performed for this study. 
Appendix 6 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study. 
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
Investigators must document their review of each laboratory safety report. 
10.1. Efficacy Assessments 
Efficacy will not be assessed in this study.  Pharmacodynamics will be assessed as described in 
Section 10.6. 
10.2. Adverse Events 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Chorus 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. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
After the ICF is signed, study site personnel will record, via CRF, the occurrence and nature of 
each subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE. 
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study. 


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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Chorus or its designee via CRF or designated data transmission methods. 
10.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in one of the following: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• events considered significant by the investigator based upon appropriate medical 
judgment 
Study site personnel must alert Chorus, or its designee, of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method.  If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific SAE 
forms.  This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.   
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting begins 
after the subject has signed informed consent and has received investigational product.  
However, if an SAE occurs after signing informed consent, but prior to receiving investigational 
product, AND is considered “reasonably possibly related” to a study procedure then it MUST be 
reported. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF 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 Chorus. 
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. 
10.2.1.1. 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 identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  The sponsor/designee has procedures that will be followed for 


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the recording and expedited reporting of SUSARs that are consistent with global regulations and 
the associated detailed guidances. 
10.2.2. Complaint Handling 
Chorus/designee collects product complaints on investigational products and drug delivery 
systems used in clinical trials in order to ensure the safety of study participants, monitor quality, 
and to facilitate process and product improvements. 
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product [or drug delivery system] so that the 
situation can be assessed. 
10.3. Treatment of Overdose 
Refer to the IB (Section 7.3.9) and/or Product Label (LY and/or comparator) for details 
regarding an overdose of investigational product. 
10.4. Safety 
10.4.1. Laboratory Tests 
For each subject, laboratory tests detailed in Appendix 3 should be conducted according to the 
Schedule of Events (Appendix 2).  When collections for clinical laboratory tests are scheduled at 
the same time point as ECG collections, ECGs must be recorded prior to any blood sampling. 
10.4.2. Vital Signs 
For each subject, vital signs measurements should be conducted according to the Schedule of 
Events (Appendix 2) and following the study specific recommendations included in an Appendix 
or the Manual of Operations for the study. 
Respiratory rate (Screening only), BP, pulse, and temperature should be measured after at least 
5 minutes supine. 
Orthostatic BP and pulse rate will be obtained from each subjects at all specified vital sign 
collection time points in Part A and on Day –1 only in Part B.  Supine BP and pulse rate will be 
measured after the subject has been supine for at least 5 minutes; standing BP and pulse rate will 
be measured in triplicate at 1, 2, and 3 minutes after the subject has been standing. 
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 and agreed upon between the sponsor and investigator. 
10.4.3. Electrocardiograms 
For each subject, ECGs should be collected according to the Schedule of Events (Appendix 2) 
and the study specific recommendations included in a Manual of Operations for the study that 
will be maintained that the CRU. 


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When ECG collections are scheduled at the same time point as any other tests the order of 
collection will be as follows: 
1) ECGs. 
2) vital signs. 
3) any clinical laboratory, PK, PD, or biomarker blood sampling. 
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 Chorus, or its 
designee, as an AE via CRF or designated data transmission methods. 
In Part A, a 12-lead digital ECG will be collected from each subject as a single tracing during 
Screening and in triplicate (spaced approximately 1 minute apart) at all other specified ECG 
collection time points.  In Part B, ECGs will be collected as a single tracing during Screening.  
Twelve-lead ECGs will be collected in triplicate on Day –1; the decision to collect triplicate or 
single ECGs at all remaining time points will be made based on ECG data from Part A (triplicate 
ECGs are planned). 
Subjects must be supine for at least 5 minutes prior to ECG collection and remain supine but 
awake during ECG collection.  Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
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 finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE. 
10.4.4. Safety Monitoring 
The Chorus CRP/scientist, or designee, will monitor safety data throughout the course of the 
study. 
Chorus will review SAEs within time frames mandated by company procedures to meet local 
regulatory requirements.  The Chorus CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist when appropriate, and 
periodically review: 
• trends in safety data 


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• AEs of special interest here. 
If a study subject experiences elevated ALT or AST ≥3 × ULN or ALP/GGT/elevated total 
bilirubin ≥2 × ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities (see Appendix 5).  To ensure subject safety and compliance with regulatory 
guidance, the investigator is to consult with the Chorus designated CRP regarding collection of 
specific recommended clinical information and follow-up laboratory tests (Appendix 4). 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Unblinding/Blinding Plan. 
10.5. Pharmacokinetics 
At the visits and times specified in the Schedule of Events (Appendix 2) serial venous blood 
samples of approximately 4 mL each will be collected to determine the plasma concentrations of 
LY3202328, simvastatin (Part B only), and atorvastatin (Part B only).  Blood samples for PK 
characterization will be collected after single- and multiple-dose administration and follow-up 
visits in Parts A and B.  Trough concentrations over multiple days during Part B will also be 
assessed. 
Sample timing may be adjusted based on information gained during the study, while the total 
number of samples described in the Schedule of Events (Appendix 2) will be planned.  Up to 
2 additional PK samples may be collected per period if needed and with appropriate 
documentation of rationale for the additional samples. 
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. 
Urine samples will be collected and pooled over the 24 hour dosing period to determine the urine 
concentrations and for the characterization of renal clearance of LY3202328 in Part A.  Total 
urine output for the appropriate period post investigational product administration will be 
collected, pooled, and refrigerated.  A predose urine sample will be collected to serve as a blank.  
The final urine sample will be collected at a time that coincides with a PK sample.  At the end of 
the collection period (24 hours), the total urine volume will be recorded.  Urine samples will be 
used to determine creatinine, quantification of LY3202328 and urine creatinine measurements.  
Approximately 20 mL of urine from the 24-hour urine collection will be stored for potential 
LY3202328 metabolite identification and other exploratory testing (10 mL each).  Although not 
currently planned, urine sample collection may be added to Part B depending on results obtained 
from Part A. 
Remaining plasma PK samples may also be stored for LY3202328 metabolite identification. 


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At the visits and times specified in the Schedule of Events (Appendix 2) venous blood samples 
of approximately 4 mL each will be collected to determine serum creatinine measurements.  
10.5.1. Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3202328, simvastatin, and atorvastatin will be assayed using validated 
analytical methods.  Samples collected from placebo-treated subjects in each period are not 
planned for analyses.  Simvastatin and atorvastatin analyses will only occur on samples collected 
during the 24 hour post dosing periods starting on Day –7 and Day 29. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses (such as 
metabolism and/or protein binding work). 
10.6. Pharmacodynamics 
Pharmacodynamic blood samples of approximately 10 mL will be collected in Parts A and B as 
specified in the Schedule of Events (Appendix 2). 
Plasma TG, TC, and HDLc (to calculate LDLc and non-HDLc) will be assessed in the fasted 
state for the first 4 hours postdose and then again during the post-prandial period following a 
high fat meal administration at 4 hours post dose in Part B.  Changes in these PD markers from 
baseline (Day –1) and Day 28 will be assessed at each dose level to find at least 1 dose level that 
shows evidence of target engagement by a decrease in fasting or post-prandial lipids. 
The lipid lowering ability of LY3202328 in subjects with a statin-free background will be 
quantified by TG, TC, and HDL-c (to calculate LDL-c and non-HDL-c) in Parts A and B, and by 
LDL-c ultracentrifugation methods in Part B only. 
10.6.1. Exploratory Biomarker Analyses 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, 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. 
Plasma samples for exploratory biomarker research will be collected at the times specified in the 
Schedule of Events (Appendix 2).  Fasting LDL-c, FFA, β-hydroxybutyrate, ApoB100, ApoC3, 
PCSK9, and Lp(a) measured at baseline (Day –1) and Day 28 will be evaluated in Part B. 
Samples will be retained for a maximum of 1 year after the last subject visit, or until testing is 
complete after the last subject visit for the study at a facility selected by Chorus or its designee. 


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10.7. Pharmacogenomic/Stored Samples 
A blood sample will be collected for pharmacogenetic analysis in Part A and Part B as specified 
in the Schedule of Events (Appendix 2) where local regulations allow. 
DNA will be isolated from the pharmacogenetic sample to test genetic polymorphisms that may 
affect: 
• the absorption, disposition, metabolism, or excretion of LY3202328; 
• response to LY3202328; 
• adverse reactions to LY3202328; 
• unusual response to LY3202328 (either safety or PD response; genome-wide association 
studies may be used); and/or 
• dyslipidemia-related gene polymorphisms. 
Additionally, the samples obtained from the biomarker collections in Parts A and/or B will be 
stored and may be used as follows: 
• plasma and serum for biomarker analysis to help explore and understand the mechanism 
of action of LY3202328 and/or dyslipidemia; and  
• residue plasma samples from lipid collections may be stored for exploratory testing of 
other lipid pathways. 
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 response to LY3202328 and to 
investigate genetic variants thought to play a role in dyslipidemia.  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 (DNA) or 5 years (plasma and serum) after 
the last subject visit, or for a shorter period if local regulations and/or ERBs impose shorter time 
limits, for the study at a facility selected by Chorus 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 LY3202328 or after LY3202328 is 
commercially available. 


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11. Statistical Considerations and Data Analysis 
11.1. Sample Size Determination 
Part A (SAD):  9 statin-free, overweight, healthy subjects for each cohort (each subject to receive 
investigational product at 2 active dose levels and placebo).  This sample size is customary for 
Phase 1 studies evaluating safety, tolerability, and pharmacokinetic parameters, and is not 
powered on the basis of statistical hypothesis testing. 
Part B (MAD):  10 statin-free, overweight, dyslipidemic subjects per cohort (8 subjects to 
receive active investigational product: 2 subjects to receive placebo) is a customary sample size 
for a Phase 1b MAD study evaluating safety, tolerability, and pharmacokinetic parameters, and is 
not powered on the basis of statistical hypothesis testing. 
Additional subjects may be enrolled to replace drop-outs or discontinued subjects with the goal 
to complete up to 18 subjects in Part A and 40 subjects in Part B. 
11.2. Populations for Analyses 
The study population will consist of 18 statin-free, overweight, healthy male and female subjects 
in Part A and 40 statin-free, overweight, healthy male and female subjects with dyslipidemia in 
Part B, aged 18 to 70 years old inclusive for males, or 40 to 70 years old, inclusive for females.  
Two analysis populations will be used in this study: 
• The Safety population will include all subjects who receive at least 1 dose of LY3202328. 
• The PK population will include all subjects who receive LY3202328 (and simvastatin or 
atorvastatin in Part B) and have sufficient concentration data to obtain reliable estimates 
of the key PK parameters. 
11.2.1. Study Participant Disposition 
A subject disposition flow diagram will be prepared that will summarize the disposition of all 
subjects entered into the study, including the number of subjects entered and enrolled into the 
study, and the number who received at least 1 dose of study treatment.  Subjects who 
discontinued from the study will be summarized by their reasons. 
11.2.2. Study Participant Characteristics 
Demographic and baseline information will be summarized using descriptive statistics.  For 
continuous variables, the mean, standard deviation (SD), median, minimum, and maximum will 
be presented.  For categorical variables, the number of subjects, frequency, and percentages will 
be presented.  Individual subject demographics and baseline information will be presented in 
data listings. 
Concomitant therapy used during the study period will be listed and summarized by dose group. 


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11.2.3. Treatment Compliance 
Compliance will be ensured for administration of LY3202328 in Part A and administration of 
LY3202328, simvastatin and atorvastatin in Part B, as study drug will be administered at the 
CRU under the supervision of the investigator. 
Treatment compliance for LY3202328 in Part B will be ensured on days of subject confinement 
to the CRU and study visits, but will be assessed by comparing returned pills with dispensed pills 
(the percentage of the actual number of capsules taken versus the number of capsules expected to 
be taken) for dosing days while not confined to the CRU. 
Subjects who demonstrated significant noncompliance (<80% or >120% of the intended dose 
taken in a visit interval) will also be summarized. 
Study medication administration data and deviation(s) from the prescribed dosage regimen 
should be recorded in the subject’s CRF. 
11.3. Statistical Analyses 
Statistical analysis of this study will be the responsibility of Chorus or its designee. 
Pharmacokinetic/PD and safety analyses will be conducted on the PK and Safety populations, 
respectively. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses. 
11.3.1. Safety Analyses 
11.3.1.1. Clinical Evaluation of Safety 
All LY3202328 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 study entry 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 current medical 
regulatory dictionary.  Severity of the AE will be assessed according to the “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials 2007”. 
The number of investigational product-related SAEs will be reported. 
11.3.1.2. Statistical Evaluation of Safety 
The primary endpoint of this study is the number and severity of treatment-emergent adverse 
events (TEAEs), clinical laboratory abnormalities, changes in vital sign measurements, and other 
safety endpoints after administration of LY3202328 or placebo.  Summary statistics will be 
provided by dose group and for all study subjects combined wherever appropriate.  For 


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continuous variables, summary statistics will include number of subjects, mean, median, SD, 
minimum, and maximum.  Categorical endpoints will be summarized using number of subjects, 
frequency, and percentages.  Additional analysis will be performed if warranted upon review of 
the data. 
11.3.2. Pharmacokinetic Analyses 
Pharmacokinetic parameter estimates for LY3202328, simvastatin (Part B only), and atorvastatin 
(Part B only) in plasma will be calculated by standard noncompartmental methods of analysis. 
The primary PK parameters for analysis will be Cmax and AUC.  The primary AUC metric will 
be AUC0-∞ on Day 1 (Parts A and B), AUC during one dosing interval [AUC0-τ] on Day 28 of 
Part B) of LY3202328 after single- and multiple-dose administrations (Parts A and B, 
respectively).  If the half-life (t1/2) was relatively long, AUC0-∞ may not be calculable for Day 1 
of Part B, and would thus not be reported. 
Other noncompartmental parameters, such as time to peak concentration (Tmax), t1/2, trough 
concentration (Ctrough), apparent clearance (CL/F), and apparent volume of distribution (V/F) 
may be reported.  Descriptive statistics of PK parameters will be presented with each dose. 
Renal clearance of LY3202328 will be calculated as the ratio of amount excreted in urine/AUC.  
This will be compared to the unbound glomerular filtration rate, which is estimated using 
creatinine. 
Pharmacokinetic parameter estimates (Cmax and AUC) for LY3202328 will be evaluated to 
delineate effects of dose proportionality using a power model approach (Smith et al. 2000). 
Drug-drug interaction assessment of the effect of LY3202328 coadministration on simvastatin 
and atorvastatin exposure will be conducted using ANOVA.  Pharmacokinetic parameter 
estimates (Cmax and AUC) will be compared for simvastatin and atorvastatin administered alone 
or coadministered with LY3202328.  The ratios of exposure with and without LY3202328 
coadministration at different dose levels of LY3202328 will be estimated, along with their 
confidence intervals. 
The impact of food on the rate and extent of absorption of LY3202328 will be assessed by 
estimating the ratio of Cmax and AUC0-∞ in the fed and fasted state of at the same dose level.  
The ratio will be calculated within each subject, and then summarized for the group.  Similarly, 
the difference in Tmax between the fed and fasted will be calculated and summarized. 
Other analyses, including PK modeling, may be conducted on the PK data. 
11.3.3. Pharmacodynamic and Biomarker Analyses 
The PD assessments conducted in this study are typical and appropriate for a Phase I single and 
multiple ascending dose evaluations of a novel therapeutic agent.  The TG concentrations will be 
analyzed to evaluate evidence of target engagement and intended pharmacological benefits. 
Visual and tabular summarization of all PD measurements will be done.  For the endpoints in the 
primary or secondary objectives, a statistical analysis will also be conducted. 


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Mixed effect model repeated measure would be the default method of analysis for PD endpoints 
with time-course data.  For endpoints with only baseline and end of therapy measurements, 
ANCOVA will be the default, with baseline as a covariate.  Other covariates may be apriori 
defined and included in the model. 
Normality assumption will be tested using an appropriate visual or statistical method, and if it is 
violated, log transformation of data may also be performed on these data.  Most sensitive 
analysis will be selected to test the effect of LY3202328 on the change from baseline in these PD 
data. 
11.3.4. Interim Analyses 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Chorus CRP, investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol. 
Select individuals may gain access to unblinded data, prior to the interim or final database lock, 
in order to initiate some analysis activities.  In such a case, the individuals and unblinded data 
will be specified in the unblinding plan.  Information that may unblind the study during the 
analyses will not be reported to study sites or blinded study team until the study has been 
unblinded. 


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12. References 
1. Chorus. DGAT2 inhibitor LY3202328 investigator’s brochure, 1st ed. Indianapolis, (IN); 
2016. 
2. European Medicines Agency. Committee For Medicinal Products For Human Use. 
Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with 
investigational medicinal products. September 2007. [Accessed 20 December 2015]. 
Available from:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002988.pdf. 
3. Manchem P, Yu XX, Mullick A, Booten S, Murray S, Watts LM, Monia BP, Bhanot S.  
Antisense reduction of DGAT2 reduces body weight and improves dyslipidemia in high-
fat high-cholesterol diet fed LDLr knockout mice. American Diabetes Association 
Annual Meeting 2010;448-PP. 
4. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue 
ST. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283. 


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Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
ADME 
absorption, disposition, metabolism, and excretion 
AE 
adverse event:  Any untoward medical occurrence in a 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 
Apo 
apolipoprotein 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCR 
area under the curve ratio 
blinding 
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock. 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CoA 
coenzyme A 
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 trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements. 


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confirmation 
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Chorus is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results. 
CRF 
case report form 
CRP 
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer. 
CRU 
clinical research unit 
CV 
cardiovascular 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DGAT2 
diacylglycerol acyltransferase 2 
DRM 
Data Review Meeting 
ECG 
electrocardiogram 
ED80 
80% maximal effective dose 
enroll 
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment. 
enter 
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
Ethical Review Board 
FFA 
free fatty acids 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HDL-c 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 


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informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial 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.  
Investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator. 
KO 
knockout 
LDL-c 
low-density lipoprotein cholesterol 
LDLr 
low-density lipoprotein receptor 
Lp (a) 
Lipoprotein (a) 
MAD 
multiple ascending dose(s) 
MTD 
maximum tolerated dose 
NOAEL 
no-observed-adverse-effect level 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
QD 
once daily 
QTc 
corrected QT 
SAE 
serious adverse event 
SAD 
single ascending dose(s) 
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 trial. 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
T2DM 
Type-2 diabetes mellitus 


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TC 
total cholesterol 
TEAE 
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment  
Tmax 
time to maximum plasma concentration 
TG 
triglyceride(s) 
ULN 
upper limit of normal 
 


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Appendix 2. 
Schedule of Events for Protocol 
I8Q-MC-GSEA 
 


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Appendix Table GSEA.1 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part A (SAD) 
Study Proceduresa 
 
Study Days 
Day 
Screeningb 
C–1c 
1 
2 
3 
5 
Hour 
 
–0.5 
0 
0.5 
1 
2 
3 
4 
4.5 
5 
6 
8 
12 
24 
48 
96 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
Full physical examinationd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Height & weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
Xe 
X 
 
Xf 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
Clinical laboratory testsh 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Serum pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine alcohol/drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine & serum creatinine 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
X 
Conmed monitoring 
X 
X 
Dosing/PK/PD/Pharmacogenomics 
Serum TG, TC, HDL-cj,k 
 
 
Xf,l 
 
 
 
Xm 
X 
X 
X 
X 
Xl,m 
Xl,m 
Xl,m 
Urine PK collectionk 
 
 
X 
X 
X 
 
 
LY/placebo dosing 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samplek 
 
 
 
Xf 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Pharmacogenomic sampleo 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker samplep 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Other 
Confined at the CRU 
 
Xq 
 
 
Meal at the CRU 
 
X 
 
 
 
 
 
 
Xr 
 
 
 
X 
 
X 
X 
X 
CRU Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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Abbreviations:  AE = adverse events; C –1 = Check‑in; CRU = clinical research unit; Conmed = concomitant medication; ECG = electrocardiogram; 
FSH = follicle stimulating hormone; HDL-c = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL-c = low-density lipoprotein 
cholesterol; LY = LY3202328; PD = pharmacodynamic; PK = pharmacokinetics; TC = total cholesterol; TG = triglycerides. 
a Refer to Section 10 of the protocol for details on study procedures. 
b Screening to occur within 42 days of first study drug administration. 
c Subjects will be admitted on Day –1 prior to dinner to control fasting times for Day 1 dosing. 
d A full physical examination will be performed on the scheduled days.  Symptom‑driven physical examination may be performed at other times, at the 
investigator’s discretion. 
e Single 12-lead ECGs to be collected during Screening, triplicate ECGs (spaced approximately 1 minute apart) to be collected at all other time points.  Subjects 
must be supine for at least 5 minutes prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed 
by vital signs, must be recorded prior to any clinical laboratory, PK, PD, or biomarker blood sampling. 
f 
Collection to occur prior to dosing. 
g Vital signs to be measured include respiratory rate (Screening only), blood pressure, pulse rate, and temperature.  Orthostatic blood pressure and pulse rate to 
be measured at all specified time points. 
h Refer to Appendix 3 for the serum chemistry, hematology, and urinalysis clinical laboratory tests. 
i 
Serum pregnancy tests to be performed on female subjects only; serum FSH tests to be performed on postmenopausal female subjects only. 
j 
Serum TC, TG, and HDL-c will be measured; HDL-c will be used to calculate LDL-c and non-HDLc. 
k Any leftover plasma will be stored for residual or LY3202328 metabolite assessment, after all study related needs are met. 
l 
Samples for serum chemistry will be obtained following a fast of at least 12 hours when a fasting lipid assessment is being performed at the same time.  In 
case of dropouts or rechecks, subjects may not have fasted for 8 hours or 12 hours, as applicable, before the serum chemistry sample is taken. 
m Sample collection to occur just prior to meal. 
n LY3202328/placebo dosing will occur in the fasted state during Period 1 to 3.  Subjects will be given a meal prior to dosing during Period 4. 
o A blood sample from all randomized/enrolled subjects will be collected prior to Day 1 dosing. 
p Biomarker plasma and serum collection (10 mL) should be sufficient for determination of ApoB48, lathosterol, lanosterol, desmosterol, among other 
biomarkers of interest. 
q Subjects will be discharged following Hour 24 procedures (i.e., Day 2). 
r 
A high-fat meal (containing approximately 60% Fat, 20% Carbohydrate and 20% Protein ) will be given to subjects to 4 hours postdose for the post-prandial 
lipid assessment. 
 
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) 
Study Proceduresa 
 
Study Days 
Day 
Screeningb 
C–7c 
–7 
Hourd 
 
 
0d 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
Administrative Procedures 
Informed consent 
X 
 
Inclusion/exclusion criteria 
X 
X 
 
Medical history 
X 
 
Safety Evaluations 
Full physical examinatione 
X 
 
 
 
 
 
 
 
 
 
 
 
Height & weight 
X 
 
 
Waist, neck, and hip 
circumference  
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
 
 
 
X 
Clinical laboratory testsh,i 
X 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid paneli 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine alcohol/drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
HIV/hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
X 
Conmed monitoring 
X 
X 
Dosing/PK/PD 
Simvastatin/atorvastatin 
dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
Simvastatin/atorvastatin 
PK blood sample 
 
 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other 
Confined at the CRU 
 
Xk 
Meal at CRU 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Visit 
X 
 
 
 
 
 
 
 
 
 
 
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Day 
C–2c 
–1 
Hourd 
 
–1 
0d 
1 
2 
4 
4.5 
5 
6 
8 
Administrative Procedures 
Informed consent 
 
 
Inclusion/exclusion criteria 
X 
 
Medical history 
 
Safety Evaluations 
Full physical examinatione 
X 
 
 
 
 
 
 
 
Height & weight 
 
X 
 
 
 
 
 
 
 
Waist, neck, and hip 
circumference  
 
X 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
 
 
 
 
 
 
 
Clinical laboratory testsh,i 
 
X 
 
 
 
 
 
 
 
 
Fasting lipid paneli 
 
X 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
Serum FSHj 
X 
 
 
 
 
 
 
 
 
 
Urine alcohol/drug screen 
X 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD 
Serum TG, TC, HDL-cl 
 
X 
Xm,n 
X 
X 
Xm,n 
X 
X 
X 
Xm,n 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, 
ApoB100o 
 
X 
 
 
 
 
 
 
 
 
ApoC3, Lp(a), PCSK9, 
fasting insulin 
 
X 
 
 
 
 
 
 
 
 
Pharmacogenomic samplep 
 
X 
 
 
 
 
 
 
 
 
Biomarker sampleq 
 
X 
 
 
 
 
 
 
 
 
Other 
Confined at the CRU 
X 
Meal at CRU 
X 
 
 
 
 
Xr 
 
 
 
X 
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Day 
1 
2 
3 to 6 
7 
8 to 13 
14 
15 to 20 
21 
22 to 27 
Hourd 
0 
0.5 
1 
2 
4 
8 
12 
24/0 
0 
0 
0 
0 
0 
0 
0 
Safety Evaluations 
Full physical examinatione,h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Waist, neck, and hip 
circumference  
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
12-lead ECGf 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vital signsg 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Clinical laboratory testsh,i 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD/Pharmacogenomics 
LY/placebo dosing at CRU 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
LY/placebo dosing at homes 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
LY/placebo PK blood samplet 
Xm 
X 
X 
X 
Xl 
X 
X 
Xm 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
Serum TG, TC, HDL-cl 
 
 
 
 
 
 
 
 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, ApoB100o 
 
 
 
 
 
 
 
 
 
Xm,n 
 
Xm,n 
 
Xm,n 
 
ApoC3, Lp(a), PCSK9, fasting 
insulin 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
 
 
 
Biomarker sampleq 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
 
 
 
Other 
Confined at the CRU 
Xi 
 
 
 
 
 
 
 
Meal at CRUu 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Visit 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 


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Appendix Table GSEA.2 
Schedule of Events for Protocol I8Q-MC-GSEA:  Part B (MAD) (continued) 
Study Proceduresa 
Study Days 
Follow-up 
Day 
27 
28 
29 
30 
35v 
42v 
Hourd 
0 
–1 
0 
0.5 
1 
2 
4 
4.5 
5 
6 
8 
12 
24/0 
48/0 
168/0 
336/0 
Safety Evaluations 
Full physical examinationse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Waist, neck, and hip 
circumference  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
12-lead ECGf 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Vital signsg 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
Clinical laboratory testsh,i 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine alcohol/drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
X 
Conmed monitoring 
X 
Dosing/PK/PD/Pharmacogenomics 
LY/placebo dosing at CRU 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Simvastatin/atorvastatin 
dosing at CRU 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
LY/placebo PK blood samplet 
 
 
Xm 
X 
X 
X 
Xm 
 
 
X 
Xm 
X 
Xm,n 
Xm,n 
Xm,n 
Xm,n 
Simvastatin/atorvastatin PK 
blood sample 
 
 
 
 
 
 
 
 
 
 
 
 
Xw 
 
 
 
Serum TG, TC, HDL-cl 
 
X 
Xi,m 
 
X 
X 
Xm 
X 
X 
X 
Xm 
 
 
 
Xm,n 
Xm,n 
Fasting LDL-c, FFA, 
β-hydroxybutyrate, ApoB100o 
 
 
Xi,m 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
Xm,n 
ApoC3, Lp(a), PCSK9, fasting 
insulin 
 
 
Xi,m 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
Xm,n 
Biomarker sampleq 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
Xm,n 
Other 
Confined at the CRU 
 
Xx 
 
 
Standardized meal at CRUp 
X 
 
 
 
 
 
Xr 
 
 
 
X 
 
X 
X 
X 
X 
Within the CRU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations:  AE = adverse events; Apo = apolipoprotein; BP = blood pressure; C –1 = Check‑in; CRU = clinical research unit; Conmed = concomitant 
medication; ECG = electrocardiogram; FFA = free fatty acid; FSH = follicle stimulating hormone;   HDL-c = high-density lipoprotein cholesterol; 
HIV = human immunodeficiency virus; HR = heart rate; LDL-c = low-density lipoprotein cholesterol; Lp = lipoprotein; LY = LY3202328; PCSK9 = 
proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamic; PK = pharmacokinetics; TC = total cholesterol; TG = triglycerides. 


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a Refer to Section 10 of the protocol for details on study procedures. 
b Screening to occur within 42 days of first study drug administration. 
c Subjects will be admitted on Day –7 (for simvastatin/atorvastatin dosing and PK), Day –2, and prior to dinner on Day 27, at the time indicated by the CRU. 
d On Day –7 and –1, Hour 0 is defined as relative to Day 1 dosing time.  On Days 1 to 28, Hour 0 is defined as the actual dosing time (for Days 2 to 28, within 
±1 hour of dosing time of Day 1). 
e A full physical examination will be performed (predose) on the scheduled days.  Symptom‑driven physical examination may be performed at other times, at 
the investigator’s discretion. 
f 
Single 12-lead ECGs to be collected during Screening and on Day –7.  Triplicate ECGs (spaced approximately 1 minute apart) to be collected on Day–1.  The 
decision to collect triplicate or single ECGs at all remaining time points will be made based on ECG data from Part A (triplicate ECGs are planned).  Subjects 
must be supine for at least 5 minutes prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed 
by vital signs, must be recorded prior to any clinical laboratory, PK, PD, or biomarker blood sampling. 
g Vital signs to be measured include respiratory rate (Screening and Day –1 Hour –1 only) blood pressure, pulse rate, and temperature.  Orthostatic blood 
pressure and pulse rate to be measured at all specified time points on from Day –1 to study discharge. 
h Refer to Appendix 3 for the serum chemistry, hematology, and urinalysis clinical laboratory tests. 
i 
Samples for serum chemistry will be obtained following a fast of at least 8 hours or 12 hours when a fasting simple lipid assessment (i.e., TC, TG and HDL-c) 
is will be performed at the same time.  In case of dropouts or rechecks, subjects may not have fasted for 8 hours or 12 hours, as applicable, before the serum 
chemistry sample is taken.  Lipid panel will also be assessed during the post-prandial lunch period on Days –1 and 28. 
j 
Serum pregnancy tests to be performed on female subjects only; serum FSH tests to be performed on postmenopausal female subjects only. 
k Subjects will be discharged following Hour 24 procedures (i.e., Days –6 and 2). 
l 
Serum TC, TG, and HDL-c will be measured; HDL-c will be used to calculate LDL-c and non-HDLc. 
m Collection to occur just prior to meal. 
n Collection to occur prior to the relative dosing time/prior to dosing. 
o Low-density lipoprotein cholesterol for PD analysis will be evaluated by ultracentrifuge. 
p A blood sample from all randomized/enrolled subjects will be collected prior to Day 1 dosing. 
q Biomarker plasma and serum collection (10 mL) should be sufficient for determination of ApoB48, lathosterol, lanosterol, desmosterol, among other 
biomarkers of interest. 
r 
A high-fat meal (approximately 60% Fat, 20% carbohydrate, 20% protein) will be given to subjects to 4 hours postdose for the post-prandial lipid assessment. 
s Any leftover plasma will be stored for residual or LY3202328 metabolite assessment, after all study related needs are met. 
t 
Prior to release from the CRU, subjects will receive a properly labeled container with LY3202328 or placebo doses which will be self‑administered by 
subjects at home until the next morning visit at the CRU.  Subjects will be instructed to take the drug once daily in the morning in the fasted state and wait at 
least 30 minutes after the completion of dosing prior to commencing their breakfast.  Subjects will be given diaries to record the time of their self‑
administered doses whether the dose was administered with food or fasted, and the time of commencing the breakfast meal.  Subjects must return the 
container (empty or not) and their diary at the next morning visit.  Home dosing will be monitored via attempted phone calls where subjects will be reminded 
to take their medication and queried about the occurrence of AEs.  Subjects should be instructed to take their dose at approximately the same time they 
received their first dose. 


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u When confined in the CRU or during return visits for dosing, subjects will receive standard or high-fat meals at appropriate times.  At least 30 minutes should 
separate the completion of ingestion of the dose and the beginning of the breakfast meal.  While at home, subjects will be asked to keep their standard diet. 
v Procedures to be performed at end of study or prior to early termination from the study.  Subjects will be contacted for follow-up if the investigator deems 
necessary. 
w Day 29 simvastatin/atorvastatin PK blood sample collection will follow the same schedule as Day –7 (predose [0], 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours 
postdose). 
x Subjects will be discharged on Day 30 following Hour 48 procedures. 
 


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Appendix 3. 
Clinical Laboratory Tests 
Laboratory Tests 
Hematologya 
Clinical Chemistrya 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration  
Phosphorus 
Leukocytes (WBC) 
Magnesium 
Cell Morphology 
Glucose (fasting) 
Absolute/relative/% counts of: 
Blood urea nitrogen (BUN) 
Neutrophils 
Total cholesterol 
Lymphocytes 
Total protein 
Monocytes 
Albumin 
Eosinophils 
Total bilirubin 
Basophils 
Alkaline phosphatase (ALP) 
Platelets 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysisa 
Creatinine 
Specific gravity 
Gamma-glutamyl transferase (GGT) 
pH 
 
Protein 
Additional tests (lipid panel, biomarker analyses) 
Glucose 
Apoliproprotein B100 
Ketones 
Apoliproprotein C3 
Bilirubin 
β hydroxybutyrate, 
Urobilinogen 
Free fatty acids (FFA) 
Blood 
Low-density lipoprotein cholesterol (LDL-c) 
Nitrite 
Creatinine 
Lipoprotein (a) 
 
High-density lipoprotein cholesterol (HDL-c) 
Ethanol testingbc 
Insulin 
Urine drug screenbc 
Triglycerides (TG) 
Hepatitis B surface antigenb 
 
Hepatitis C antibodyb 
 
HIVc 
 
Pregnancy test (urine, in females only) 
 
Serum FSH (in postmenopausal females only) 
 
Thyroid stimulating hormone (optional) 
 
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells. 
a Results will be reported and/or validated by the Central Laboratory at the time of initial testing. 
b Performed at screening only 
c Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit. 
 


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Appendix 4. 
Study Governance, Regulatory and Ethical 
Considerations 
Informed Consent 
The investigator is responsible for: 
• ensuring that the subject understands the potential risks and benefits of participating in 
the study. 
• 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 trial. 
Ethical Review 
The investigator must provide assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to Chorus before 
the study may begin at the investigative site(s).  Chorus or its representatives must approve the 
ICF before it is used at the investigative site(s).  All informed consent forms 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 
• informed consent forms 
• relevant curricula vitae 
Regulatory Considerations 
This study will be conducted in accordance with: 
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines  
2) applicable ICH GCP Guidelines  
3) applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party organization. 


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Protocol Signatures 
The sponsor’s responsible medical officer, (
 Chief Medical officer, 
Chorus) will approve the protocol, confirming that, to the best of his or her knowledge, the 
protocol accurately describes the planned design and conduct of the study.  
After reading the protocol, the investigator will sign the protocol signature page and send a copy 
of the signed page to a Chorus representative. 
Final Report Signature 
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, Chorus or its representatives will do the 
following: 
• provide instructional material to the study sites, as appropriate. 
• provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures. 
• make periodic visits to the study site. 
• be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
• review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection. 
• conduct a quality review of the database. 
In addition, Chorus 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, Chorus, 
and/or regulatory agencies at any time.  Investigators will be given notice before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents. 
Data Collection Tools/Source Data 
PPD
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. 


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Study and Site Closure 
Discontinuation of Study Site 
Study site participation may be discontinued if Chorus, 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 Chorus judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 


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Appendix 5. 
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Chorus or its designee CRP. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologyab 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Conjugated bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibodya 
AST 
 
GGT 
CPK  
Anti-smooth muscle antibody (or anti-actin 
antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by Chorus-designated local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability 
 


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Appendix 6. 
Blood Sampling Summary 
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, clinical laboratories, and bioanalytical assays) during the study.  
Fewer venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment. 
Protocol I8Q-MC-GSEA Sampling Summary  
Part A 
Purpose 
Maximum Blood 
Volume per Sample 
(mL) 
Maximum Number of Blood 
Samples 
Maximum Total 
Volume (mL) 
Per Period 
Study Duration 
Screening testsab 
10 
4 
9 
90 
Clinical laboratory testsa 
15 
4 
15 
225 
Serum creatinine 
4 
1 
4 
16 
Pharmacokinetics 
4 
12 
36 
144 
Pharmacodynamics 
Serum triglycerides & non-HDLc 
4 
9 
27 
108 
Biomarker analysis 
4 
2 
6 
24 
Pharmacogenomics 
10 
1 
3 
30 
Total 
51 
34 
102 
637 
Total for clinical purposes (rounded up to nearest 10 mL) 
640 
Part B 
Purpose 
Maximum Blood 
Volume per Sample 
(mL) 
Maximum Number of Blood 
Samples 
Maximum Total 
Volume (mL) 
Screening testsab 
10 
4 
40 
Clinical laboratory testsa 
15 
12 
180 
Pharmacokinetics  
LY3202328 and 
Simvastatin/atorvastatin 
4 
34 
136 
Pharmacodynamics 
 
 
 
Serum triglycerides & HDL-c 
(for non-HDLc calculations) 
4 
23 
92 
Fasting lipid panels (LDL-c, 
FFA, β-hydroxybutyrate, 
ApoB100) 
4 
7 
28 
ApoC3, Lp(a), PCSK9 
4 
5 
20 
Biomarker plasma and serum 
4 
3 
12 
Pharmacogenomics 
10 
1 
10 
Total 
55 
86 
518 
Total for clinical purposes (rounded up to nearest 10 mL) 
520 
a Additional samples may be drawn if needed for safety purposes. 
b Hematology and blood chemistry (see inclusion criteria [5] through [7]).