Clinical trial NCT03051100
Conditions: Hypercholesterolemia
Keywords: hyperlididemia LDL cholesterol
Sponsor: Esperion Therapeutics, Inc.
Start date: 2017-01-19; Completion date: 2017-07-05
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if triplet therapy with bempedoic acid (ETC-1002) 180mg, ezetimibe 10mg, and atorvastatin 20mg is effective and safe versus placebo in patients with elevated LDL cholesterol.

Detailed description:

Arms: arm 1: Bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg taken orally, daily. arm 2: Matching placebos taken orally, daily.
Interventions: intervention 1: Bempedoic acid 180mg intervention 2: Ezetimibe 10mg intervention 3: Atorvastatin 20mg intervention 4: Placebo
Intervention descriptions: intervention 1: bempedoic acid 180 mg intervention 2: ezetimibe 10 mg intervention 3: atorvastatin 20 mg intervention 4: placebo

Protocol documents:
Prot_000.pdf: 
Confidential 
Page 1 of 71 
1.
TITLE PAGE
BEMPEDOIC ACID (ETC-1002) 
1002-038 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF TRIPLET THERAPY WITH BEMPEDOIC ACID (ETC-1002) 
180 MG, EZETIMIBE 10 MG, AND ATORVASTATIN 20 MG IN 
PATIENTS WITH ELEVATED LDL-C  
Study Phase: 
2 
IND Number: 
106,654 
EudraCT Number: 
N/A 
Indication: 
Treatment of hyperlipidemia 
Investigators: 
Approximately 20 sites located in US 
Sponsor: 
Esperion Therapeutics, Inc. 
3891 Ranchero Drive, Suite 150 
Ann Arbor, MI  48108 
Phone:  1-734-887-3903 
Fax:  1-734-913-5344 
Sponsor Contact: 
Medical Monitor: 
Version 
Date 
Original Protocol: 
11 November 2016 
Confidentiality Notice 
THIS CONFIDENTIAL INFORMATION IS ABOUT AN INVESTIGATIONAL DRUG PROVIDED FOR THE EXCLUSIVE 
USE OF INVESTIGATORS OF THIS DRUG AND IS SUBJECT TO RECALL AT ANY TIME. SUBJECT TO THE 
FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE STUDY 
WHO HAVE NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION. 
THESE RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL OR WRITTEN 
INFORMATION, SUPPLIED TO YOU BY ESPERION THERAPEUTICS, INC., WHICH IS DESIGNATED AS 
“PRIVILEGED” OR “CONFIDENTIAL.” 
NCT number: NCT03051100
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
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2.
SYNOPSIS
Name of Sponsor: Esperion Therapeutics, Inc. 
Name of Investigational Products:  
Bempedoic acid (ETC-1002) film-coated tablets 
Ezetimibe overencapsulated tablets 
Atorvastatin overencapsulated tablets 
Name of Active Ingredients: 
Bempedoic acid (ETC-1002) 
Ezetimibe  
Atorvastatin  
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and 
Safety of Triplet Therapy with Bempedoic Acid (ETC-1002) 180 mg, Ezetimibe 10 mg, and 
Atorvastatin 20 mg in Patients with Elevated LDL-C  
Study Number:  1002-038 
Phase of Development:  2 
Clinical Sites:  Approximately 20 sites located in United States (US) 
Primary Objective: 
•
To assess the low-density lipoprotein cholesterol (LDL-C) lowering effect of triplet therapy with
bempedoic acid (ETC-1002) 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg  versus placebo
administered daily for 6 weeks in patients with elevated LDL-C
Secondary Objectives: 
•
To assess the effect of triplet therapy versus placebo on non-high-density lipoprotein cholesterol
(non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), high-sensitivity C-reactive protein
(hs-CRP), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C)
•
To assess the effect of triplet therapy versus placebo on percent of patients achieving LDL-C level
<70 mg/dL
•
To assess the effect of triplet therapy versus placebo on percent of patients achieving LDL-C
reduction ≥50%
•
To assess the safety and tolerability of triplet therapy versus placebo
Study Hypothesis: 
The clinical hypothesis for this study is that triplet therapy with bempedoic acid 180 mg, ezetimibe 
10 mg, and atorvastatin 20 mg will significantly reduce LDL-C in patients treated daily for 6 weeks 
compared to placebo.  
Endpoints: 
The following endpoints will be used to evaluate the objectives of the study. 
Primary endpoint: 
•
Percent change from baseline to Week 6 in LDL-C


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
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Secondary endpoints: 
•
Percent change from baseline to Week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and HDL-C
•
Percent of patients with LDL-C <70 mg/dL at Week 6
•
Percent of patients with LDL-C reduction ≥50% from baseline to Week 6
Safety Endpoints:
•
Subject incidence of adverse events (AEs)
•
Clinical safety laboratory (including hematology, blood chemistry, and urinalysis) results
•
Vital signs and physical examination (PE) findings
Study Design: 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study.  
Patients will initially undergo screening at Week -6 (Visit S1).  Eligible patients will begin washout of 
all LDL-C lowering drugs and nutritional supplements at least 5 weeks prior to randomization.  Patients 
will return at Week -1 (Visit S2) for lipid and/or other assessments.  Patients who are deemed not 
eligible for randomization at any point during screening will be notified by clinical site personnel and 
considered screen failures.  At Week 0 (Visit T1), approximately 60 patients will be randomized in a 
ratio of 2:1 to receive either triplet therapy (bempedoic acid 180 mg + ezetimibe 10 mg + atorvastatin 
20 mg) or placebo once daily for 6 weeks.  Randomized patients will return for clinic visits at Week 3 
(Visit T2), and Week 6 (Visit T3). 
Number of Patients (Planned):  Approximately 60 adult male and female patients. 
Duration of Treatment:  Total treatment duration will be 12 weeks (6 weeks screening and 6 weeks 
treatment) with the option to extend screening by 1 additional week.  
Inclusion and Exclusion Criteria: 
Inclusion Criteria:  
1.
Provision of written informed consent prior to any study-specific procedure;
2.
Age ≥18 years or legal age of majority based on regional law, whichever is greater, at Week -6
(Visit S1);
3.
Fasting calculated LDL-C between 130-189 mg/dL at Week -1 (Visit S2) following washout of all
LDL-C-lowering drugs and nutritional supplements;
Note:  LDL-C may be repeated 1 time with the screening period extended up to 1 week.  For those
patients who have a repeat LDL-C, the mean of the first value and the repeat value will be used to
determine eligibility.
4.
Patient is sufficiently stable and suitable to undergo washout of all LDL-C-lowering drugs and
nutritional supplements for 12 weeks (with potential for 1 week extension) based on Investigator
assessment;
5.
Men and nonpregnant, nonlactating women.  Women must be one of the following:
a.
Naturally postmenopausal defined as ≥1 year without menses and:
i.
≥55 years, or
ii.
<55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L, or
b.
Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation, or
c.
Women of childbearing potential willing to use one acceptable method of birth control during
the study and for 30 days after the end of treatment including:
i.
birth control medications,


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Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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ii. placement of an intrauterine device with or without hormones, 
iii. barrier methods including condom or occlusive cap with spermicidal foam or spermicidal 
jelly, 
iv. vasectomized male partner who is the sole partner for this patient, 
v. true abstinence (not including periodic abstinence such as calendar, ovulation, 
symptothermal, postovulation methods, or withdrawal); 
There are no protocol-specific birth control requirements for men with partners who are able to become 
pregnant. 
 
Exclusion Criteria: 
1. Body mass index (BMI) >50 kg/m2; 
2. History of documented clinically significant cardiovascular disease including, but not limited to: 
a. Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary artery 
bypass graft, stroke, transient ischemic attack, cerebrovascular event, symptomatic carotid artery 
disease, or symptomatic peripheral arterial disease, 
b. Uncontrolled hypertension, defined as sitting mean systolic blood pressure (SBP) ≥160 mm Hg 
and/or diastolic blood pressure (DBP) ≥100 mm Hg after sitting quietly for 5 minutes.   
Note:  At the discretion of the investigator, a single repeat sitting mean SBP and DBP may be 
completed at a separate visit.  For those patients who have repeat sitting mean SBP and DBP 
assessment, the repeat values will be used to determine eligibility.   
c. An arrhythmia requiring medical intervention,   
d. Abdominal aortic aneurysm, 
e. New York Heart Association (NYHA) Class III and IV heart failure; 
3. Fasting TG >400 mg/dL at Week -1 (S2);  
Note:  TG may be repeated 1 time with the screening period extended up to 1 week.  For those 
patients who have a repeat TG, the repeat value will be used to determine eligibility.  
4. History of type 1 or type 2 diabetes or fasting glucose >125 mg/dL at Week -6 (Visit S1); 
5. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper limit 
of normal (ULN) at Week -6 (Visit S1); 
6. Liver disease or dysfunction, including:  
a. Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies 
(HCV-ABVivi) at Week -1 (Visit S2), or  
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, and/or total 
bilirubin (TB) ≥2 × ULN at Week -6 (Visit S1).  If TB ≥1.2 × ULN, a reflex indirect 
(unconjugated) bilirubin will be obtained and if consistent with Gilbert’s disease or if the patient 
has a history of Gilbert’s Disease, the patient may be enrolled in the study.  
Note:  At the discretion of the investigator, a single repeat of ALT, AST, and/or TB may be 
completed.  For those patients who have a repeat ALT, AST, and/or TB, the repeat value will be 
used to determine eligibility.  Also, if test for hepatitis C antibody is positive, but optional reflexive 
test for hepatitis C ribonucleic acid (RNA) is negative, the patient can be enrolled.  
7. Renal dysfunction or glomerulonephritis, including estimated glomerular filtration rate (eGFR; using 
central laboratory determined Modification of Diet in Renal Disease [MDRD] formula) <30 mL/min 
at Week -6 (Visit S1); 
Note:  At the discretion of the investigator, a single repeat of eGFR may be completed. For those 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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patients who have a repeat eGFR, the repeat value will be used to determine eligibility;  
8. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® or gastric 
bypass) that may affect drug absorption;  
9. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL at Week -6 
(Visit S1); 
10. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 
5 years.  Nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ 
are allowed;  
11. Unexplained creatine kinase (CK) >3 × ULN at any time prior to randomization (ie, not associated 
with recent trauma or physically strenuous activity).  Patients with an explained CK elevation must 
have single repeat CK ≤3 × ULN prior to randomization; 
12. History of drug or alcohol abuse within the last 2 years or reported current consumption of 
>14 alcoholic drinks/week, or any illicit drug use, history of amphetamine and derivatives abuse or 
cocaine abuse.  Subjects with amphetamine derivatives prescribed by and under the care of a health 
care practitioner can be enrolled after evaluation by the investigator;  
13. Blood donation, participation in a multiple blood draws, clinical study, major trauma, blood 
transfusion or surgery with or without blood loss within 30 days prior to randomization; 
14. Use of any experimental or investigational drugs within 30 days prior to screening; 
15. Previous enrollment in a bempedoic acid clinical study; 
16. Use of these prohibited drugs and/or nutritional supplements prior to randomization or planned use 
during the study:  
a. LDL-C lowering drugs and/or nutritional supplements (within 5 weeks prior to randomization), 
b. Probenecid or cyclosporine (within 2 weeks prior to randomization), 
c. Potent CYP3A4 inhibitors including amiodarone, azoles (fluconazole, itraconazole, 
ketoconazole, posaconazole, voriconazole), bosentan, clarithromycin, cobicistat, conivaptan, 
danazol, daptomycin, diltiazem, domperidone, erlotinib, erythromycin, fusidic acid, mibefradil, 
nefazodone, piperaquine, protease inhibitors (atazanavir, boceprevir, darunavir, delavirdine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tipranavir), 
quinupristin/dalfopristin, telithromycin, verapamil (within 2 weeks prior to randomization), 
d. Systemic corticosteroids (topical corticosteroids are allowed; within 5 weeks prior to 
randomization); 
17. Planned initiation or dosing changes of these allowed drugs prior to or during the study: 
a. Hormone replacement (within 5 weeks prior to randomization), 
b. Thyroid replacement (within 5 weeks prior to randomization), 
c. Obesity medication (within 3 months prior to randomization); 
18. A medical or situational (ie, geographical) finding that in the investigator’s opinion may 
compromise the patient’s safety or ability to complete the study; 
19. An employee or contractor of the facility conducting the study, or a family member of the principal 
investigator, co-investigator, or any Sponsor personnel. 
Investigational Medicinal Product, Dosage and Mode of Administration:  
• 
Bempedoic acid 180-mg tablets and matching placebo  
• 
Ezetimibe 10-mg overencapsulated tablets and similarly matching placebo capsules 
• 
Atorvastatin 20-mg overencapsulated tablets and similarly matching placebo capsules 
Investigational medicinal product (IMP) will be ingested once daily with or without food. 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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Non-Investigational Medicinal Product  
All other background drugs will be administered as prescribed by a physician 
Statistical Methods: 
Sample Size 
Analysis Populations 
The modified Intent-to-Treat (mITT) population, used for all of the efficacy analyses, is defined as all 
randomized patients who received at least 1 dose of study drug and have a baseline assessment and at 
least 1 postbaseline assessment, excluding any assessment taken more than 2 days after a dose of study 
drug.   
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized patients 
who received at least 1 dose of study medication.  Patients in the SP will be included in the treatment 
group that they actually received, regardless of their randomized treatment.  
Disposition and Baseline Characteristics 
Disposition, including reason for withdrawal from the IMP and study, will be summarized by treatment 
group.  Demographic information and patient characteristics including, but not limited to, gender, race, 
age, and baseline vital signs will also be summarized by treatment group. 
Primary and Secondary Efficacy Analysis 
The primary efficacy endpoint is the percent change from baseline to Week 6 in LDL-C.  Baseline is 
defined as the mean of the values from Week -1 (Visit S2) and predose Day 1/Week 0 (Visit T1).  An 
analysis of covariance (ANCOVA) with treatment group as factor and baseline LDL-C as covariate will 
be performed to compare triplet therapy versus placebo for the primary endpoint using the mITT 
population.  Missing values at Week 6 will be imputed using the last observation carried forward 
(LOCF) procedure (only post baseline values will be carried forward).  The least squares mean (LSM) 
and standard error (SE) will be provided for both treatment groups, along with the placebo-corrected 
LSM, its 95% confidence interval (CI), and associated p-value. 
Secondary efficacy endpoints, which include the percent change from baseline to Week 6 in additional 
lipid and cardiometabolic biomarkers, will be analyzed in a similar manner as the primary efficacy 
endpoint. Baseline for non-HDL-C, HDL-C, TC, and TG is defined as the mean of the values from 
Week -1 (Visit S2) and predose Day 1/Week 0 (Visit T1), while baseline for ApoB and hs-CRP is 
defined as the predose Day 1/Week 0 (Visit T1) value.   
Statistical testing of primary and secondary efficacy endpoints will be 2-sided and conducted at the 5% 
level of significance with no adjustment for multiple comparisons. 
Safety Analyses 
Descriptive summary will be provided for safety endpoints. 
The summarization of AEs will include only treatment-emergent AEs (TEAEs).  TEAEs and serious 
adverse events (SAEs) will be summarized by system organ class (SOC), severity, and relationship to 
IMP for each treatment group.  Deaths and withdrawal from the IMP or study due to AEs will each be 
summarized by treatment group. 
Clinical safety laboratories, including hematology, blood chemistry, glucose, and urinalysis; PE 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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findings; vital signs; and weight will be summarized by the value and by change from baseline in the 
value (where appropriate) at each post baseline time point. 
 


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Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
4. 
INTRODUCTION ......................................................................................................16 
4.1. 
Cardiovascular Disease and LDL-C-Lowering Drugs ...............................................16 
4.2. 
Background on Bempedoic Acid ................................................................................17 
4.2.1. 
Mechanism of Action .................................................................................................17 
4.2.2. 
Nonclinical Experience ...............................................................................................18 
4.2.3. 
Previous Human Experience .......................................................................................18 
4.2.4. 
Dose Selection ............................................................................................................19 
4.3. 
Background on Ezetimibe ...........................................................................................20 
4.4. 
Background on Atorvastatin .......................................................................................20 
4.5. 
Risk Benefit Summary ................................................................................................20 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................21 
5.1. 
Objectives ...................................................................................................................21 
5.1.1. 
Primary Objective .......................................................................................................21 
5.1.2. 
Secondary Objectives .................................................................................................21 
5.2. 
Study Endpoints ..........................................................................................................21 
5.2.1. 
Primary Endpoint ........................................................................................................21 
5.2.2. 
Secondary Endpoints ..................................................................................................21 
5.2.3. 
Safety Endpoints .........................................................................................................21 
6. 
INVESTIGATIONAL PLAN .....................................................................................22 
6.1. 
Overall Study Design ..................................................................................................22 
6.2. 
Study Hypothesis ........................................................................................................22 
6.3. 
Estimated Study Duration and Period.........................................................................22 
6.4. 
Number of Centers ......................................................................................................22 


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6.5. 
Number of Patients .....................................................................................................22 
7. 
SELECTION OF PATIENTS.....................................................................................23 
7.1. 
Subject Inclusion Criteria ...........................................................................................23 
7.2. 
Subject Exclusion Criteria ..........................................................................................24 
7.3. 
Patient Lifestyle and Dietary Guidelines ....................................................................26 
8. 
TREATMENT OF PATIENTS ..................................................................................27 
8.1. 
Administration of Investigational Medicinal Product ................................................27 
8.2. 
Prior and Concomitant Medications ...........................................................................27 
8.2.1. 
Prohibited Medications and Dietary Supplement .......................................................27 
8.2.2. 
Permitted Medications ................................................................................................29 
8.3. 
Treatment Assignment, Randomization, and Blinding...............................................29 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................31 
9.1. 
Description of Investigational Medicinal Product ......................................................31 
9.2. 
Investigational Medicinal Product Supply and Control ..............................................32 
9.3. 
Packaging and Labeling ..............................................................................................32 
9.4. 
Investigational Medicinal Product Adherence ............................................................32 
9.5. 
Investigational Medicinal Product Accountability .....................................................32 
9.6. 
Investigational Medicinal Product Handling, Storage, and Disposal .........................33 
10. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS .........................34 
10.1. 
Informed Consent .......................................................................................................34 
10.2. 
Interactive Web Response System and eCRFs ...........................................................34 
10.3. 
Patient Identification Numbers ...................................................................................34 
10.4. 
Rescreening .................................................................................................................34 
10.5. 
Procedures and Schedule of Assessments ..................................................................34 
10.5.1. 
Screening Week -6 (Visit S1; Day -42 to Day -37) ....................................................34 
10.5.2. 
Screening Week -1 (Visit S2; Day -10 to -7) .............................................................35 
10.5.3. 
Treatment Week 0 (Visit T1; Day 1) ..........................................................................36 


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10.5.4. 
Treatment Week 3 (Visit T2; Day 22 ± 3 days) .........................................................37 
10.5.5. 
Treatment Week 6 (Visit T3; Day 43 ± 3 days)/End of Study or Early 
Termination .................................................................................................................37 
10.6. 
Patient Withdrawal From the Study ...........................................................................37 
11. 
ASSESSMENT OF EFFICACY ................................................................................39 
11.3 
Assessments of Lipids and hs-CRP ............................................................................39 
12. 
ASSESSMENT OF SAFETY .....................................................................................40 
12.1. 
Safety Parameters .......................................................................................................40 
12.1.1. 
Demographic/Medical History ...................................................................................40 
12.1.2. 
Vital Signs ..................................................................................................................40 
12.1.3. 
Weight and Height ......................................................................................................40 
12.1.4. 
Physical Examination .................................................................................................41 
12.1.5. 
Central Clinical Laboratory Tests ...............................................................................41 
12.1.5.1. 
Central Clinical Laboratory Parameters (Safety) .......................................................41 
12.1.5.2. 
Sample Collection, Storage, and Shipping .................................................................43 
12.1.5.3. 
General Monitoring and Management of Abnormal Clinical Labs ............................43 
12.1.5.4. 
Total Blood Volume of Central Clinical Laboratory Samples ...................................45 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................46 
13.1. 
Adverse Events ...........................................................................................................46 
13.1.1. 
Definition of Adverse Events .....................................................................................46 
13.1.2. 
Adverse Drug Reaction ...............................................................................................46 
13.1.3. 
Reporting for Adverse Events ....................................................................................46 
13.1.4. 
Severity .......................................................................................................................48 
13.1.5. 
Relationship ................................................................................................................48 
13.1.6. 
Monitoring and Follow-up of Adverse Events ...........................................................48 
13.1.7. 
Treatment-Emergent Adverse Events .........................................................................49 
13.2. 
Serious Adverse Events ..............................................................................................49 
13.2.1. 
Definition of Serious Adverse Event ..........................................................................49 


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13.2.2. 
Reporting Serious Adverse Events .............................................................................50 
13.2.3. 
Reporting of Patient Death .........................................................................................50 
13.2.4. 
Reports of Pregnancy and Lactation ...........................................................................50 
13.3. 
Adverse Events of Special Interest .............................................................................51 
14. 
STATISTICS ..............................................................................................................52 
14.1. 
General Considerations ...............................................................................................52 
14.2. 
Determination of Sample Size ....................................................................................52 
14.3. 
Analysis Populations ..................................................................................................52 
14.4. 
Disposition, Demographics, and Baseline Characteristics .........................................52 
14.5. 
Primary Endpoint Analysis .........................................................................................52 
14.6. 
Secondary Efficacy Endpoint Analyses ......................................................................53 
14.7. 
Safety Endpoints .........................................................................................................53 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................54 
15.1. 
Study Monitoring ........................................................................................................54 
15.2. 
Audits and Inspections ................................................................................................54 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
17. 
ETHICS ......................................................................................................................56 
17.1. 
Institutional Review Board Approval .........................................................................56 
17.2. 
Ethical Conduct of the Study ......................................................................................56 
17.3. 
Written Informed Consent ..........................................................................................57 
17.4. 
Patient Confidentiality ................................................................................................57 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
18.1. 
Inspection of Records .................................................................................................58 
18.2. 
Retention of Records ..................................................................................................58 
18.3. 
Case Report Forms and Study Records ......................................................................58 
19. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................60 
19.1. 
Investigators ................................................................................................................60 


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19.2. 
Study Administrative Structure ..................................................................................61 
19.3. 
Amendments and Study Termination .........................................................................61 
19.4. 
Financial Disclosure ...................................................................................................62 
20. 
PUBLICATION AND DISCLOSURE POLICY .......................................................63 
21. 
LIST OF REFERENCES ............................................................................................64 
22. 
APPENDICES ............................................................................................................66 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................67 
APPENDIX 2. SPONSOR’S SIGNATURES .............................................................................68 
APPENDIX 3. INVESTIGATOR’S SIGNATURE....................................................................71 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................13 
Table 2: 
Investigational Medicinal Products ............................................................................31 
Table 3: 
Central Clinical Laboratory Parameters (Lipids and hs-CRP) ...................................39 
Table 4: 
Central Clinical Laboratory Parameters (Safety) .......................................................42 
 
 


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Clinical Study Protocol 1002-038 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ACL 
Adenosine triphosphate-citrate lyase 
ACSVL1 
Very long-chain acyl-CoA synthetase 1 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse events of special interest 
Alb 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the curve during 24 hours 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CFR 
Code of Federal Regulations 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CK 
Creatine kinase 
Cl 
Chloride 
CNS 
Central nervous system 
CoA 
Acetyl-coenzyme A 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Contract research organization 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 


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Abbreviation or Specialist Term 
Explanation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
FDA 
US Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HCV-ABVivi 
Hepatitis C antibodies 
HDL-C 
High-density lipoprotein cholesterol 
Hgb 
Hemoglobin 
HMG-CoA 
3-hydroxy-3-methylglutaryl coenzyme A 
hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICD 
Informed Consent Document 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LFT 
Liver function test 
LOCF 
Last observation carried forward 
LSM 
Least squares mean 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDRD 
Modification of diet in renal disease 
MED ID 
Medication identification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MRI 
Magnetic resonance imaging 


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Abbreviation or Specialist Term 
Explanation 
Na 
Sodium 
NOAEL 
No-observed-adverse-effect level 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
NYHA 
New York Heart Association 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PE 
Physical exam 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SE 
Standard error 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SOP 
Standard operating procedures 
SP 
Safety population 
SUSAR 
Suspected and unexpected serious adverse reaction 
T2DM 
Type 2 diabetes mellitus 
TB 
Total bilirubin 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 


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4. 
INTRODUCTION 
Bempedoic acid (ETC-1002) is an oral, first-in class, small molecule designed to lower low-
density lipoprotein cholesterol (LDL-C).  It inhibits adenosine triphosphate-citrate lyase (ACL), 
an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the 
cholesterol biosynthesis pathway.  Bempedoic acid, like both statins and ezetimibe, up-regulates 
LDL-C receptors.  However, unlike statins, bempedoic acid does not inhibit cholesterol synthesis 
in muscle tissue, therefore it is anticipated that negative muscle-related adverse effects associated 
with statin use may be avoided by use of bempedoic acid.   
Hypercholesterolemic patients have several therapeutic options to lower LDL-C.  Statin and 
nonstatin therapies that lower LDL-C via upregulation of LDL receptors are associated with 
reduced cardiovascular disease (CVD) risk.  Bempedoic acid 180 mg, atorvastatin 20 mg, and 
ezetimibe 10 mg work by divergent mechanisms to lower LDL-C via up-regulation of LDL 
receptors.  This Phase 2 study in patients with elevated LDL-C is being conducted to characterize 
the magnitude of LDL-C lowering achievable with this oral triplet therapy.  
4.1. 
Cardiovascular Disease and LDL-C-Lowering Drugs   
Despite aggressive interventional and pharmacologic therapies, CVD is the number 1 cause of 
death globally (WHO 2015).  The Global Burden of Disease study estimated that 29.6% of all 
deaths worldwide (approximately 15.6 million deaths) were caused by CVD in 2010, more than 
all communicable, maternal, neonatal and nutritional disorders combined, and double the number 
of deaths caused by cancers (Nichols 2014).  In the United States (US), based on 2011 death rate 
data, more than 2150 Americans die from CVD daily, an average of 1 death every 40 seconds 
(Mozffarian 2015).  Of great concern, approximately 155,000 Americans dying from CVD are 
less than 65 years of age (Mozffarian 2015).  In Europe, CVD remains the most common cause 
of deaths, resulting in almost 2 times as many deaths as cancer (Townsend 2015). 
Elevated LDL-C is a major modifiable risk factor for the development of atherosclerosis and 
CVD (Sharrett 2001).  Evidence supporting LDL-C as a therapeutic target and surrogate for 
cardiovascular (CV) outcomes comes from interventional studies with LDL-C-lowering 
therapies, epidemiological studies, and genetic variants (both gain of function and loss of 
function).  Large randomized clinical studies aimed at lowering LDL-C show a consistent, 
log-linear relationship between LDL-C reduction and CV risk reduction, independent of the 
mechanism for LDL-C lowering (Kathiresan 2008; Baigent 2010; Robinson 2005; Stamler 1986, 
Silverman 2016).  A published patient-level meta-analysis including 26 statin trials and more 
than 160,000 participants, showed a consistent relationship between LDL-C reduction and CV 
outcomes (Baigent 2010).  This analysis showed that a 1 mmol/L (~39 mg/dL) reduction in 
LDL-C was associated with a 22% reduction in the 5-year incidence of major coronary events, 
revascularizations, and ischemic strokes.  More recently, a meta-analysis in 312,175 patients 
from 49 trials assessed the relationship between LDL-C reduction and CV outcomes when 
LDL-C reduction was due to statin therapy versus established nonstatin interventions that work 
primarily by upregulation of the LDL receptor such as diet, bile acid sequestrants, ileal bypass, 
and ezetimibe (Silverman 2016).  This meta-analysis reported that the relationship between 
LDL-C reduction and CV outcomes was similar regardless of whether LDL-C reduction was 


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derived from statin therapy or nonstatin interventions that upregulate the LDL receptor 
(Silverman 2016).  Thus, LDL-C lowering via upregulation the LDL receptor is largely accepted 
as a valid surrogate endpoint of CV risk reduction by clinicians and regulatory authorities 
(Stone 2013).  
Statins are central to the LDL-C-lowering strategy and are supported by a large body of data 
demonstrating robust effectiveness in lowering LDL-C and reducing the risk of CVD 
(Waters 2006, Grundy 2004).  However, there is increasing awareness of the limitations and 
risks of statin use.  Many individuals at risk for CVD fail to achieve LDL-C goals (Martin 
2013, Virani 2011).  In 2011, the Food and Drug Administration (FDA) mandated safety-
labeling changes limiting the use of high dose (80 mg) simvastatin due to safety concerns of 
muscle injury or myopathy (Egan 2011).  Although myopathy events are rare, a more widespread 
problem is various muscle side effects such as pain and weakness, particularly at high doses, 
leading to poor tolerability and lack of persistence on statin therapy (Cohen 2012).  
Other than statins, only a few drugs are approved to lower LDL-C.  Although LDL-C lowering is 
robust with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, use of these drugs 
is limited by mode of administration and other accessibility issues.  The oral drug ezetimibe, an 
intestinal cholesterol absorption inhibitor, lowers LDL-C by 18% in patients with primary 
hyperlipidemia (Knopp 2003).  Other oral LDL-C-lowering therapies include colesevelam, a bile 
acid sequestrant that lowers LDL-C by up to 18% but is limited by considerable gastrointestinal 
side effects (Insull 2001), while extended-release niacin in doses up to 2 g lowers LDL-C by up 
to 17% (Goldberg 1998).  Finally, fenofibrate, an activator of peroxisome proliferator-activated 
receptor alpha, lowers LDL-C by approximately 20% in patients with hypercholesterolemia 
(Knopp 1987), but may substantially increase LDL-C in patients with hypertriglyceridemia. 
An increasing body of evidence suggests that the absolute amount of LDL-C lowering is 
proportional to CVD risk reduction in statin and nonstatin therapies that lower LDL-C via 
upregulation of LDL receptors.  Bempedoic acid, atorvastatin, and ezetimibe are oral therapies 
that work by divergent mechanisms to lower LDL-C via up-regulation of LDL receptors.  The 
magnitude of LDL-C lowering that can be achieved by concurrent administration of these oral 
therapies is unknown.  
4.2. 
Background on Bempedoic Acid  
4.2.1. 
Mechanism of Action 
Bempedoic acid is a first-in-class small molecule that decreases cholesterol synthesis in the liver.  
Bempedoic acid is a prodrug that requires coenzyme A (CoA) activation by very long-chain 
acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA.  ETC-1002-CoA inhibits ACL, an enzyme 
upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway.  Like statins, 
bempedoic acid decreases liver cholesterol synthesis, which results in increased LDL receptor 
activity and LDL particle clearance from the blood.  
Both ETC-1002-CoA (via ACL inhibition) and statins (via HMG-CoA reductase inhibition) 
inhibit cholesterol synthesis in the liver, but an important differentiating feature is that unlike 
statins, bempedoic acid is inactive in skeletal muscle.  This is consistent with the absence of 
ACSVL1 (the synthetase required to activate bempedoic acid to ETC-1002-CoA and inhibit 


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ACL) expression in muscle tissue.  Evidence suggests that muscle-related adverse effects 
associated with statin use is a result of HMG-CoA reductase inhibition directly in skeletal muscle 
leading to a reduction of several downstream biological intermediates within the cholesterol 
synthesis pathway important for muscle cell function.  Since bempedoic acid is not activated to 
ETC-1002-CoA and does not inhibit cholesterol synthesis in muscle tissue, it is anticipated that 
negative muscle-related adverse effects associated with statin use may be avoided by use of 
bempedoic acid.  The long-term safety of bempedoic acid and its metabolites regarding human 
skeletal muscle is not yet established.   
4.2.2. 
Nonclinical Experience 
4.2.3. 
Previous Human Experience 


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4.2.4. 
Dose Selection 


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4.3. 
Background on Ezetimibe 
Please see the ezetimibe label. 
4.4. 
Background on Atorvastatin 
Please see the atorvastatin label. 
4.5. 
Risk Benefit Summary 
To date, the nonclinical and clinical data indicate that bempedoic acid 180 mg has a favorable 
risk-benefit profile.  The ability of bempedoic acid to achieve clinically meaningful LDL-C 
lowering while demonstrating a favorable tolerability profile in a variety of patient populations 
supports continued development of bempedoic acid in Phase 3 studies.  
Several Phase 2 clinical studies have assessed the safety and efficacy of bempedoic acid as add-
on to statins or in combination with ezetimibe.  These studies showed significant LDL-C 
lowering and a favorable safety profile.  The LDL-C lowering efficacy and safety of triplet 
therapy with bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg has not 
previously been assessed.  That is the purpose of this study.  
Please refer to the most recent IB for additional information regarding previous human 
experience. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
The primary objective is to assess the LDL-C lowering efficacy of triplet therapy with 
bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg versus placebo administered 
daily for 6 weeks in patients with elevated LDL-C. 
5.1.2. 
Secondary Objectives 
• To assess the effect of triplet therapy versus placebo on non-high-density lipoprotein 
cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), high-
sensitivity C-reactive protein (hs-CRP), TG, and HDL-C 
• To assess the effect of triplet therapy versus placebo on percent of patients achieving 
LDL-C level <70 mg/dL 
• To assess the effect of triplet therapy versus placebo on percent of patients achieving 
LDL-C reduction ≥50% 
• To assess the safety and tolerability of triplet therapy versus placebo  
5.2. 
Study Endpoints 
The following endpoints will be used to evaluate the objectives of the study. 
5.2.1. 
Primary Endpoint 
• Percent change from baseline to Week 6 in LDL-C 
5.2.2. 
Secondary Endpoints 
• Percent change from baseline to Week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and 
HDL-C 
• Percent of patients with LDL-C <70 mg/dL at Week 6 
• Percent of patients with LDL-C reduction ≥50% from baseline to Week 6 
5.2.3. 
Safety Endpoints 
• Subject incidence of adverse events 
• Clinical safety laboratory (including hematology, blood chemistry, and urinalysis) 
results 
• Vital signs and physical examination (PE) findings 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study.  Patients will initially undergo screening at Week -6 (Visit S1).  Eligible patients will 
begin washout of all LDL-C-lowering drugs and nutritional supplements at least 5 weeks prior to 
randomization.  Patients will return at Week -1 (S2) for lipid and/or other assessments.  Patients 
who are deemed not eligible for randomization at any point during screening will be notified by 
clinical site personnel and considered screen failures.  At Week 0 (Visit T1), approximately 
60 patients will be randomized in a ratio of 2:1 to receive either triplet therapy (bempedoic acid 
180 mg + ezetimibe 10 mg + atorvastatin 20 mg) or placebo once daily for 6 weeks.  
Randomized patients will return for clinic visits at Week 3 (Visit T2) and Week 6 (Visit T3).  
For details of study assessments, see the Schedule of Events in Appendix 1. 
6.2. 
Study Hypothesis 
The clinical hypothesis for this study is that triplet therapy with bempedoic acid 180 mg, 
ezetimibe 10 mg, and atorvastatin 20 mg will significantly reduce LDL-C in patients treated 
daily for 6 weeks versus placebo. 
6.3. 
Estimated Study Duration and Period 
Total treatment duration will be 12 weeks (6 weeks screening and 6 weeks treatment) with the 
option to extend screening by 1 additional week. 
6.4. 
Number of Centers 
Up to approximately 20 centers in the US will participate in this.  Additional sites may be invited 
to participate to ensure study timelines are met.  
6.5. 
Number of Patients 
The study will enroll approximately 60 adult male and female patients.  


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7. 
SELECTION OF PATIENTS 
7.1. 
Subject Inclusion Criteria 
Each patient must meet the following criteria to be eligible for this study. 
1. Provision of written informed consent prior to any study-specific procedure; 
2. Age ≥18 years or legal age of majority based on regional law, whichever is greater, at 
Week -6 (Visit S1); 
3. Fasting calculated LDL-C between 130-189 mg/dL at Week -1 (Visit S2) following 
washout of all LDL-C-lowering drugs and nutritional supplements; 
Note:  LDL-C may be repeated 1 time with the screening period extended up to 1 week.  
For those patients who have a repeat LDL-C, the mean of the first value and the repeat 
value will be used to determine eligibility.  
4. Patient is sufficiently stable and suitable to undergo washout of all LDL-C-lowering 
drugs and nutritional supplements for 12 weeks (with potential for 1 week extension) 
based on Investigator assessment; 
5. Men and nonpregnant, nonlactating women.  Women must be one of the following: 
a. Naturally postmenopausal defined as ≥1 year without menses and: 
i. ≥55 years, or 
ii. <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L, or 
b. Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal 
ligation, or 
c. Women of childbearing potential willing to use one acceptable method of birth 
control during the study and for 30 days after the end of treatment including: 
i. birth control medications, 
ii. placement of an intrauterine device with or without hormones, 
iii. barrier methods including condom or occlusive cap with spermicidal foam or 
spermicidal jelly, 
iv. vasectomized male partner who is the sole partner for this patient, 
v. true abstinence (not including periodic abstinence such as calendar, ovulation, 
symptothermal, postovulation methods, or withdrawal); 
There are no protocol-specific birth control requirements for men with partners who are able to 
become pregnant. 


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7.2. 
Subject Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate: 
1. Body mass index (BMI) >50 kg/m2; 
2. History of documented clinically significant cardiovascular disease including, but not 
limited to: 
a. Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, cerebrovascular event, 
symptomatic carotid artery disease, or symptomatic peripheral arterial disease, 
b. Uncontrolled hypertension, defined as sitting mean systolic blood pressure (SBP) 
≥160 mm Hg and/or diastolic blood pressure (DBP) ≥100 mm Hg after sitting quietly 
for 5 minutes.   
Note:  At the discretion of the investigator, a single repeat sitting mean SBP and DBP 
may be completed at a separate visit.  For those patients who have repeat sitting mean 
SBP and DBP assessment, the repeat values will be used to determine eligibility.   
c. An arrhythmia requiring medical intervention,   
d. Abdominal aortic aneurysm, 
e. New York Heart Association (NYHA) Class III and IV heart failure; 
3. Fasting TG >400 mg/dL at Week -1 (S2);  
Note:  TG may be repeated 1 time with the screening period extended up to 1 week.  For 
those patients who have a repeat TG, the repeat value will be used to determine 
eligibility.  
4. History of type 1 or type 2 diabetes or fasting glucose >125 mg/dL at Week -6 (Visit S1); 
5. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the 
upper limit of normal (ULN) at Week -6 (Visit S1); 
6. Liver disease or dysfunction, including:  
a. Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C 
antibodies (HCV-ABVivi) at Week -1 (Visit S2), or  
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, 
and/or total bilirubin (TB) ≥2 × ULN at Week -6 (Visit S1).  If TB ≥1.2 × ULN, a 
reflex indirect (unconjugated) bilirubin will be obtained and if consistent with 
Gilbert’s disease or if the patient has a history of Gilbert’s Disease, the patient may be 
enrolled in the study.  
Note:  At the discretion of the investigator, a single repeat of ALT, AST, and/or TB may 
be completed.  For those patients who have a repeat ALT, AST, and/or TB, the repeat 
value will be used to determine eligibility.  Also, if test for hepatitis C antibody is 
positive, but optional reflexive test for hepatitis C ribonucleic acid (RNA) is negative, the 
patient can be enrolled.  


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7. Renal dysfunction or glomerulonephritis, including estimated glomerular filtration rate 
(eGFR; using central laboratory determined Modification of Diet in Renal Disease 
[MDRD] formula) <30 mL/min at Week -6 (Visit S1); 
Note:  At the discretion of the investigator, a single repeat of eGFR may be completed. 
For those patients who have a repeat eGFR, the repeat value will be used to determine 
eligibility;  
8. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® 
or gastric bypass) that may affect drug absorption;  
9. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL at 
Week -6 (Visit S1); 
10. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in 
the past 5 years.  Nonmetastatic basal or squamous cell carcinoma of the skin and 
cervical carcinoma in situ are allowed;  
11. Unexplained creatine kinase (CK) >3 × ULN at any time prior to randomization (ie, not 
associated with recent trauma or physically strenuous activity).  Patients with an 
explained CK elevation must have single repeat CK ≤3 × ULN prior to randomization; 
12. History of drug or alcohol abuse within the last 2 years or reported current consumption 
of >14 alcoholic drinks/week, or any illicit drug use, history of amphetamine and 
derivatives abuse or cocaine abuse.  Subjects with amphetamine derivatives prescribed by 
and under the care of a health care practitioner can be enrolled after evaluation by the 
investigator;  
13. Blood donation, participation in a multiple blood draws, clinical study, major trauma, 
blood transfusion or surgery with or without blood loss within 30 days prior to 
randomization; 
14. Use of any experimental or investigational drugs within 30 days prior to screening; 
15. Previous enrollment in a bempedoic acid clinical study; 
16. Use of these prohibited drugs and/or nutritional supplements prior to randomization or 
planned use during the study:  
a. LDL-C lowering drugs and/or nutritional supplements (within 5 weeks prior to 
randomization), 
b. Probenecid or cyclosporine (within 2 weeks prior to randomization), 
c. Potent CYP3A4 inhibitors including amiodarone, azoles (fluconazole, itraconazole, 
ketoconazole, posaconazole, voriconazole), bosentan, clarithromycin, cobicistat, 
conivaptan, danazol, daptomycin, diltiazem, domperidone, erlotinib, erythromycin, 
fusidic acid, mibefradil, nefazodone, piperaquine, protease inhibitors (atazanavir, 
boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, lopinavir, nelfinavir, 
ritonavir, saquinavir, telaprevir, tipranavir), quinupristin/dalfopristin, telithromycin, 
verapamil (within 2 weeks prior to randomization), 


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d. Systemic corticosteroids (topical corticosteroids are allowed; within 5 weeks prior to 
randomization); 
17. Planned initiation or dosing changes of these allowed drugs prior to or during the study: 
a. Hormone replacement (within 5 weeks prior to randomization), 
b. Thyroid replacement (within 5 weeks prior to randomization), 
c. Obesity medication (within 3 months prior to randomization); 
18. A medical or situational (ie, geographical) finding that in the investigator’s opinion may 
compromise the patient’s safety or ability to complete the study; 
19. An employee or contractor of the facility conducting the study, or a family member of the 
principal investigator, co-investigator, or any Sponsor personnel. 
7.3. 
Patient Lifestyle and Dietary Guidelines 
Patients will fast for a minimum of 10 hours prior to collection of all laboratory samples (water 
and concomitant medications, but not IMP are permitted).  
Beginning at screening, patients will be counseled to follow a heart healthy diet as per local or 
regional guidelines and should be encouraged (as able) to participate in a stable, regular exercise 
program throughout the study.  


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8. 
TREATMENT OF PATIENTS 
8.1. 
Administration of Investigational Medicinal Product 
During the Treatment Period, patients will be randomized to receive IMP of either bempedoic 
acid 180 mg + ezetimibe 10 mg + atorvastatin 20 mg or placebo once daily.  Each daily 
allotment of IMP is comprised of one bempedoic acid tablet, one overencapsulated ezetimibe 
tablet and one overencapsulated atorvastatin tablet provided in a blister package.  The placebo 
blister pack will contain the corresponding matching placebo of the three drugs.  Patients will be 
instructed to ingest IMP orally once daily with or without food.  On clinic visit days, patients 
will be instructed to delay ingestion of IMP until all study procedures have been completed.  
If the patient forgets to take IMP on nonclinic visit days, it may be taken up to 12 hours later the 
same day.  After that time, the patient should not take IMP that day and should resume ingestion 
of IMP the following morning.  Details describing the reasons for missed doses should be 
documented in the patient’s medical records and electronic case report form (eCRF).  Extra IMP 
is provided and can be used, if needed, prior to the next visit or to replace an allotment of IMP 
that cannot be used because it is lost or damaged. 
Other details regarding IMP, including description, supply and control, accountability, handling, 
and disposal are provided in Section 9.  
8.2. 
Prior and Concomitant Medications 
Patients will be questioned about their concomitant medication use at each clinic visit.  All 
concomitant medication taken chronically or intermittently during the study must be recorded 
with indication, total daily dose, and start and stop dates of administration. 
The Prior/Concomitant case report form (CRF) will be used to record medications, herbal 
remedies, vitamins, other nutritional supplements, and over-the-counter medications taken within 
6 weeks prior to screening and during the study. 
8.2.1. 
Prohibited Medications and Dietary Supplement 
Patients will be required to stop taking all prescription or nonprescription drugs or nutritional 
supplements taken for the purpose of lipid regulation at least 5 weeks prior to randomization 
(approximately Study Day -35).  Use of any drug(s) listed below either in mono or combination 
therapy are prohibited during the study: 
Statins (within 5 weeks prior to randomization): 
• Atorvastatin (Lipitor®) (other than sponsor provided) 
• Fluvastatin (Lescol®) 
• Lovastatin (Mevacor®, Altoprev™)  
• Pravastatin (Pravachol®)  
• Rosuvastatin Calcium (Crestor®)  


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• Simvastatin (Zocor®)  
• Pitavastatin (Livalo®) 
Selective cholesterol and/or bile acid absorption inhibitors (within 5 weeks prior to 
randomization): 
• Ezetimibe (Zetia®, Ezetrol®)  
• Cholestyramine (Questran®, Questran® Light, Prevalite®, Locholest®, Locholest® 
Light) 
• Colestipol (Colestid®) 
• Colesevelam HCl (WelChol®, Cholestagel®) 
Fibrates (within 5 weeks prior to randomization): 
• Gemfibrozil (Lopid®) 
• Fenofibrate (Antara®, Lofibra®, Tricor®, and Triglide™, Lipantil®, Supralip®) 
• Clofibrate (Atromid-S) 
• Ciprofibrate (Modalim®) 
• Bezafibrate (Bezalip®) 
PCSK9 inhibitors (within 5 weeks prior to randomization): 
• Evolocumab (Repatha®) 
• Alirocumab (Praluent®) 
Other Lipid Regulating Drugs (within 5 weeks prior to randomization): 
• Niacin (Niaspan® Rx and OTC) 
• Omega-3-acid Ethyl Esters (Lovaza® and OTC fish oil) 
• Statin fixed dose combinations (eg, Atozet®, Vytorin®, Inegy®) 
Lipid Altering Nutritional Supplements (within 5 weeks prior to randomization):  
• Berberine 
• Psyllium (Metamucil®) 
• Green tea extract 
• Niacin (crystalline >500 mg/day or slow release or timed release at any dose) 
• Sitostanol (found in oral nutritional supplements and some margarines, such as 
Benecol) 
• Beta-sitosterol (found in oral nutritional supplements and some margarines, such as 
Promise Activ) 
• Cholestin (red yeast rice, also known as monascus purpureus extract) 


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• Pantothine  
• Policosanol 
Other Drugs: 
• Probenecid or cyclosporine (within 2 weeks prior to randomization) 
• Potent CYP3A4 inhibitors including amiodarone, azoles (fluconazole, itraconazole, 
ketoconazole, posaconazole, voriconazole), bosentan, clarithromycin, cobicistat, 
conivaptan, danazol, daptomycin, diltiazem, domperidone, erlotinib, erythromycin, 
fusidic acid, mibefradil, nefazodone, piperaquine, protease inhibitors (atazanavir, 
boceprevir, darunavir, delavirdine, fosamprenavir, indinavir, lopinavir, nelfinavir, 
ritonavir, saquinavir, telaprevir, tipranavir), quinupristin/dalfopristin, telithromycin, 
verapamil (within 2 weeks prior to randomization) 
• Systemic corticosteroids (topical corticosteroids are allowed (within 5 weeks prior to 
randomization) 
8.2.2. 
Permitted Medications 
Permitted medications must be stable for at least 2 weeks prior to Visit S1 (Week -6) with the 
exception of the following: 
• Hormone replacement (within 5 weeks prior to randomization) 
• Thyroid replacement (within 5 weeks prior to randomization) 
• Obesity medication (within 3 months prior to randomization) 
8.3. 
Treatment Assignment, Randomization, and Blinding 
During the Treatment Period, patients will receive double-blind IMP.  At Day 1 (Visit T1), 
patients will be randomized to receive either bempedoic acid 180 mg/day + ezetimibe 10 mg + 
atorvastatin 20 mg or placebo.  The investigator or designee will utilize Interactive web response 
system (IWRS) during the visit to obtain a randomization number and the appropriate IMP 
container via medication identification numbers (MED ID).  A patient is considered to be 
randomized when they have been assigned a randomization number by IWRS. 
The randomization number will be determined by a computer-generated random code and will 
correspond to a treatment group according to patient’s sequential entrance into the study. The 
randomization schedule for blinding of treatment assignment will be generated by the contract 
research organization (CRO), provided to IWRS, and released only after the study is complete 
and the database is locked.  
During the Treatment Period, Sponsor, site personnel, CRO, and patient will all be unaware of 
patient’s treatment assignment. 
Blinding of treatment must be maintained for all patients unless, in the opinion of the 
investigator, the safety of the patient may be at risk.  Only under the rarest of circumstances 
should the investigator consider breaking the blind and only when medical/supportive care 
cannot be provided without determining if the patient is receiving active drug treatment.  In the 


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event that the blind needs to be broken prior to completion of the study, the investigator should 
contact the appropriate Medical Monitor by telephone.  If the blind must be broken prior to 
consultation with the Medical Monitor, contact must be made within 24 hours of breaking the 
blind.  
At the initiation of the study, the clinical site will be instructed on procedures for breaking the 
blind via the IWRS.  In all cases of breaking the blind, the investigator must document in the 
patient’s medical record the date, time, and reason for breaking the blind, and the names of 
personnel involved. 
Post-randomization values for individual laboratory measures for LDL-C, non-HDL-C, TC, TG 
and HDL-C that may inadvertently suggest treatment assignment will not be available to 
personnel from the clinical site, the patient, the Sponsor, or the CRO.  While knowledge of these 
values does not truly ‘unblind,’ the collection of these lab assessments by the investigator, all 
collaborating physicians, or the patients locally (outside the study visits) is strongly discouraged. 
Investigators should not perform testing of these analytes at the local lab during the conduct of 
the study. 


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9. 
INVESTIGATIONAL MEDICINAL PRODUCT  
9.1. 
Description of Investigational Medicinal Product 
Table 2: 
Investigational Medicinal Products 
Product Name: 
Investigational Medicinal Product 
Bempedoic acid 
Placebo to Match Bempedoic Acid 
Dosage Form: 
Film-coated tablets 
Film-coated tablets 
Unit Dose: 
180 mg 
Not applicable 
Container/Closure: 
9 count blister card with child resistant 
closures 
9 count blister card with child resistant 
closures  
Route of Administration: 
Oral, daily at approximately the same 
time, with or without food 
Oral, daily at approximately the same 
time, with or without food 
Physical Description: 
Manufacturer 
(Fill/Finish): 
Product Name: 
Investigational Medicinal Product 
Ezetimibe 
Placebo to Match Ezetimibe 
Dosage Form: 
Overencapsulated tablets 
Capsules 
Unit Dose: 
10 mg 
Not applicable 
Container/Closure: 
9-count blister card with child-resistant 
closures 
9-count blister card with child-resistant 
closures 
Route of Administration: 
Oral, daily at approximately the same 
time, with or without food 
Oral, daily at approximately the same 
time, with or without food 
Physical Description: 
TBD 
TBD 
Manufacturer 
(Fill/Finish): 
TBD 
Product Name: 
Investigational Medicinal Product 
Atorvastatin 
Placebo to Match Atorvastatin 
Dosage Form: 
Overencapsulated  tablets 
Capsules 
Unit Dose: 
20 mg 
Not applicable 
Container/Closure: 
9-count blister card with child-resistant 
closures 
9-count blister card with child-resistant 
closures 
Route of Administration: 
Oral, daily at approximately the same 
time, with or without food 
Oral, daily at approximately the same 
time, with or without food 
Physical Description: 
TBD 
TBD 
Manufacturer 
(Fill/Finish): 
TBD 


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Please see Pharmacy Manual for detailed storage requirements and instructions. 
9.2. 
Investigational Medicinal Product Supply and Control 
The Sponsor will supply the IMP for this study as described above.  IMP will be distributed and 
released in accordance with regional and local requirements during the conduct of the study. 
The MED ID number (an identifier on the IMP packaging) will be obtained via IWRS and used 
to select double-blind IMP from available clinical supplies at the clinical site.  
IMP will be dispensed by the investigator or other qualified site personnel only to appropriate 
patients who have provided written informed consent. 
9.3. 
Packaging and Labeling 
Double-blind IMP will be packaged in blister pack.  Each blister pack will contain a 9-day 
supply and 3 blister packs will be provided in drug kit.  
The IMP labels will include protocol number, MED ID number, patient identification number, 
lot number, site number and investigator name in addition to standard language regarding 
warnings and regulations, administration and storage of the product.  
9.4. 
Investigational Medicinal Product Adherence 
At each clinic visit during the Treatment Period, designated clinical site staff will assess patient 
IMP intake adherence by counting the number of doses that are returned as unused and by 
querying the patient with regards to daily intake.  If the patient has not taken multiple doses as 
instructed, the patient will be queried for a reason, findings will be documented, and the patient 
will be counseled on the importance of carefully following all dosing instructions.  Factors 
contributing to poor adherence will be determined and, if possible, remedied.  Patients 
demonstrating poor adherence during the Treatment Period will continue to be counseled on the 
importance of carefully following all dosing instructions, but will not be removed from the study. 
9.5. 
Investigational Medicinal Product Accountability 
Patients will be instructed to return all packaging and unused IMP at every visit for assessment 
of adherence and drug accountability.  
Accurate records of the receipt of all IMP shipped by the Sponsor (or designee) and the 
disposition of that IMP must be maintained.  
IMP records or logs must comply with applicable regulations, local law, and guidelines, and 
should include: 
• Amount received/placed in storage area 
• Amount currently in storage area 
• MED ID number for all IMP 
• Dates and initials of person(s) responsible for IMP inventory (including 
entry/movement/disposition) 


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• Date and amount of IMP dispensed to each patient, including unique patient 
identifiers 
• Date that IMP was returned by patient, assessment of adherence, and relevant 
documentation of discrepancies 
• Nonstudy disposition (eg, lost, broken, wasted) 
• Amount returned to Sponsor (or designee)/destroyed or amount destroyed per local 
standard operating procedure (SOP) following accountability by site monitor. 
9.6. 
Investigational Medicinal Product Handling, Storage, and Disposal 
The Principal Investigator will ensure that all IMP is stored in a secured area, under 
recommended storage conditions
 
in accordance with applicable 
regulatory requirements for investigational drugs.  Access to IMP will be limited to those clinical 
site personnel authorized by the investigator.  Upon completion or termination of the study, all 
IMP and used and unused IMP packaging must be returned to the Sponsor (or designee) for 
eventual destruction unless otherwise authorized by the Sponsor.  All IMP returns must be 
accompanied by the appropriate documentation. 


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10. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
10.1. 
Informed Consent 
The patient must be adequately informed of the nature and risks of the study and understand the 
Informed Consent Document (ICD).  It is the investigator’s responsibility that no study-related 
procedure will be performed until the patient has been completely informed of the study, has 
freely consented to take part in the study, and has signed and dated an ICD approved by the 
Sponsor (or designee) and the Institutional Review Board (IRB).  The written ICD should be 
prepared in the local language(s) of the potential patient population.  
10.2. 
Interactive Web Response System and eCRFs 
Data will be captured on eCRFs. Randomization, IMP (re)ordering, IMP distribution, and patient 
status tracking will occur via IWRS.  Instructions for these systems and additional contact time 
points for IWRS will be provided separately. 
10.3. 
Patient Identification Numbers 
A unique patient identification number will be assigned to each patient to identify each patient 
throughout the study.  Patient identification numbers will be assigned sequentially by IWRS at 
the time of informed consent during the screening module transaction and is comprised of 
protocol, site, and patient-specific numbers. 
10.4. 
Rescreening 
Patients who are screening failures due to stability requirements for a condition or concurrent 
medication or other reason may be considered for rescreening after consultation with the Sponsor 
(or designee).  If rescreened, these patients must also be re-consented and screening procedures 
must be repeated.  If a patient is a screen failure, or if a patient discontinues from the study, their 
patient ID number will not be assigned to another patient.  
10.5. 
Procedures and Schedule of Assessments 
The study is comprised of 2 distinct periods: screening and double-blind treatment.  
The schedule of study events is provided in Appendix 1.  However, a patient can be seen at any 
time for reasons of safety.  
10.5.1. 
Screening Week -6 (Visit S1; Day -42 to Day -37) 
The screening period will begin with a screening visit that will occur 6 weeks prior to 
randomization.  Visit S1 will allow the investigator to assess the patient’s preliminary eligibility. 
After the patient provides written informed consent (see Section 10.1), the patient will undergo 
the following assessments and procedures at Visit S1: 
• Assess AEs and serious adverse events (SAEs) (starting from signing the informed 
consent document) 


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• Demographics 
• Clinically relevant medical history  
• Prior and concomitant medication review 
• Review of all inclusion/exclusion criteria that can be assessed at this time 
• Height (cm), and weight (kg) 
• Vital signs  
• Central clinical laboratory evaluations:  
− Thyroid-stimulating hormone (TSH)  
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
− Serum pregnancy test (in female patients of childbearing potential) or follicle-
stimulating hormone (FSH) (on postmenopausal women <55 years of age) 
• Dietary and lifestyle counselling 
• Contact IWRS to register the patient  
Patients who meet all enrollment criteria that can be assessed following review of the Visit S1 
central clinical laboratory results (available several days after Visit S1) will be instructed to 
washout of all lipid-regulating drugs and nutritional supplements and to maintain consistent diet 
and exercise patterns throughout the study.  Patients who fail to meet any entry criterion that can 
be assessed at Visit S1 are considered to be screen failures and are not required to return for 
additional visits (although a patient can be seen at any time for safety reasons). 
10.5.2. 
Screening Week -1 (Visit S2; Day -10 to -7) 
The patient will undergo the following assessments and procedures at Visit S2: 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs  
• Central clinical laboratory evaluations:  
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
− Serology (including hepatitis B surface antigen [HBsAg], hepatitis C virus [HCV] 
antibody) 
• Dietary and lifestyle counselling  
Note: 
• The screening period can be extended by an additional week and an additional visit 
may be completed prior to Visit T1 if patient fails to meet LDL-C and/or TG entry 
criterion.  If this optional visit is completed, the mean of values from Visit S2 and the 
additional visit will be used to determine eligibility. 


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• An additional visit and/or assessment between Visit S1 and Visit T1 MAY be 
completed if the patient fails to meet diastolic blood pressure (DBP), systolic blood 
pressure (SBP), TSH, estimated glomerular filtration rate (eGFR), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), serology and/or creatine 
kinase (CK) entry criteria.  Patients may qualify for randomization after any 
associated medications have been adjusted and stabilized and the repeat assessment 
meets entry criteria. 
10.5.3. 
Treatment Week 0 (Visit T1; Day 1) 
Prior to scheduling Visit T1, screening results will be reviewed to determine whether the patient 
continues to meet eligibility criteria.  At Visit T1, a physical exam and urine pregnancy test will 
also be completed prior to randomization.  Patients not meeting all entry criteria at any point 
prior to randomization will be screen failures. 
If the patient has met all inclusion criteria and none of the exclusion criteria, the patient may be 
randomized into the double-blind Treatment Period.  
Patients are considered randomized once all eligibility criteria are confirmed and a 
randomization number is obtained by the IWRS on the day of first dose.  
The patient will undergo the following assessments and procedures at Day 1 (Visit T1): 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs  
• PE 
• Review inclusion/exclusion criteria to establish patient eligibility 
• Weight 
• Vital signs 
• Central clinical laboratory evaluations:  
- Hematology, blood chemistry, and urinalysis 
- Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
- ApoB and hs-CRP 
• Urine pregnancy test (in female patients of childbearing potential) 
• IWRS contact to obtain the patient randomization number and MED ID number for 
double-blind IMP 
• Dispense double-blind IMP and provide dosing and storage instructions 
• Dietary and lifestyle counselling 


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10.5.4. 
Treatment Week 3 (Visit T2; Day 22 ± 3 days) 
Patients will undergo the following assessments and procedures at Week 3 (Visit T2): 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs 
• Weight 
• Vital signs 
• Central clinical laboratory evaluations:  
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL C, HDL C, non-HDL C, and TG)  
• Return of IMP; assessment and recording of IMP dosing adherence 
• IWRS contact to obtain new MED ID number for double-blind IMP  
• Dispense double-blind IMP and provide dosing and storage instruction 
• Dietary and lifestyle counselling 
10.5.5. 
Treatment Week 6 (Visit T3; Day 43 ± 3 days)/End of Study or Early 
Termination 
Patients will undergo the following assessments and procedures at Week 6 and/or End of 
Study/Early Termination: 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs 
• PE 
• Weight 
• Vital signs 
• Central clinical laboratory evaluations: 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
− ApoB and hs-CRP 
• Return of IMP; assessment and recording of IMP adherence 
10.6. 
Patient Withdrawal From the Study 
Patients must remain in the study until the last scheduled visit at Study Day 43 (Visit T3) to be 
considered as having completed participation in the study. 
The patient’s decision to participate in the clinical study is voluntary.  Patients may refuse to 
continue in the study and/or withdraw from participation in this study at any time, for any reason, 


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specified or unspecified, and without penalty or loss of benefits to which the patient is otherwise 
entitled. 
It is the right and duty of the Investigator to interrupt the treatment of any patient whose health or 
well-being may be threatened by continuation in this study.  Such patients should be withdrawn 
from the study and should not be continued under a modified regimen. 
Patients who are withdrawn from the study may not re-enter.  The reasons for withdrawal from 
this study may include: 
• AE 
• Patient’s withdrawal of consent 
• Failure to comply with the protocol 
• Lost to follow-up 
• Illness, condition, or procedural complication affecting the patient’s ability to 
participate or requiring prohibited medication 
• The Sponsor or Investigator terminates the study 
• In the Investigator’s judgment, it is deemed in the best interest of the patient to 
discontinue his/her participation in the study 
• Any other reason 
If a patient is lost to follow-up, every reasonable effort must be made by the clinical site 
personnel to contact the patient and determine the reason for discontinuation/withdrawal.  The 
measures taken to follow-up must be documented. 


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11. 
ASSESSMENT OF EFFICACY  
11.3 Assessments of Lipids and hs-CRP 
Central clinical laboratory samples will be collected and analyzed for the parameters detailed 
in Table 3.  LDL-C will be calculated or measured directly if TG are >400 mg/dL or LDL-C is 
<50 mg/dL.  
Blood draws for lipids (not safety) must meet the criteria below.  If these criteria have not been 
met, these blood samples will NOT be collected.  If these criteria can be met by rescheduling 
clinic visit to occur within 3 days, these blood samples will be collected at the rescheduled 
clinic visit only.  
• Blood samples will be drawn after a minimum 10-hour fast (water and concomitant 
medications [but not IMP] is allowed)  
• Blood samples will be drawn only if patient ingested IMP the previous day 
Patients are to be in a seated position during the blood collection. Collection schedule and 
instructions are provided in the Central Clinical Laboratory Manual.  A description of the sample 
collection, storage, and shipping as well as monitoring and management of abnormal laboratories 
are described in Section 12.1.5. 
When vital signs and laboratory samples are to be collected at the same time point, vital sign 
measurements will precede laboratory sample collection.  
Table 3: 
Central Clinical Laboratory Parameters (Lipids and hs-CRP) 
Clinical Laboratory Test  
Clinical Laboratory Test 
Basic Lipid Parameters 
Other Parameters 
• 
Total cholesterol (TC) 
• 
Calculated low-density lipoprotein cholesterol 
(LDL-C) and non-HDL-C 
• 
High-density lipoprotein cholesterol (HDL-C) 
• 
Triglycerides (TG) 
• 
High-sensitivity C-reactive protein (hs-CRP) 
• 
Apolipoprotein B (ApoB) 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
At all clinic visits, investigators will review all safety information including vital signs, AEs, 
SAEs, and concomitant medications and will ensure that the collected data are recorded into the 
appropriate eCRF.  Additionally, central clinical laboratory samples will be collected and sent 
for analysis and the investigator will review the results to ensure continued patient safety while 
participating in the study.  
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee if appropriate. 
The investigator is responsible for the appropriate medical care of patients during the study. 
The investigator is responsible for following AEs that are serious or that caused the patient to 
discontinue before completing the study until the event is resolved or stable.  Frequency of 
follow-up evaluation is left to the discretion of the investigator. 
12.1.1. 
Demographic/Medical History 
Demographic data and a complete medical history will be obtained from the patient.  For medical 
history, conditions that are relevant and/or clinically significant should be captured with at least a 
start date (month and year) and whether the condition is ongoing or resolved.  All surgeries 
regardless of date should be reported.  
12.1.2. 
Vital Signs 
Vital signs will include DBP and SBP as well as heart rate. 
Vitals will be collected prior to blood collection.  Blood pressure (BP) and heart rate will be 
measured using a calibrated, fully automated machine with a cuff that is appropriate to the size 
of the upper arm.  If a fully automated machine is not available, BP may be measured manually.  
The same method (either automated or manual) and the same arm (right or left) must be used 
throughout the study.  The patient should be in a seated position with feet touching the floor.  
Patients should be seated quietly for at least 5 minutes in a chair with their backs supported, their 
feet flat on the ground, and their arms bared and supported at heart level.  At each clinic visit, 
2 BP measurements will be collected at 1- to 2-minute intervals.   
12.1.3. 
Weight and Height  
Body weight will be measured on a calibrated scale in the morning while fasted and after 
voiding.  
Height will be measured using standard clinic procedures.  
Body mass index (BMI) will be calculated systematically using the formula:  
BMI (kg/m2) = weight in kg/(height in meters)2 


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12.1.4. 
Physical Examination 
Physical examinations will include an assessment of the following: 
• General appearance 
• Skin 
• Eyes, ears, nose, and throat 
• Head and neck 
• Extremities 
• Musculoskeletal examination 
• Respiratory examination 
• Cardiovascular assessment, including rhythm and presence of cardiac abnormalities 
• Abdominal examination 
• Neurologic examination including documentation of the presence of abnormalities in 
mental status and motor and sensory function 
• Any additional assessments necessary to establish baseline status or evaluate 
symptoms or adverse experiences 
Documentation of the PE findings will be included in the source documentation at the clinical 
site.  Significant findings prior to the start of IMP will be recorded on the Medical 
History/Current Medical Conditions page of the eCRF.  Only changes from baseline physical 
examination findings that meet the definition of an AE will be recorded on the AE page of the 
eCRF. 
12.1.5. 
Central Clinical Laboratory Tests 
12.1.5.1. Central Clinical Laboratory Parameters (Safety) 
Patients will be in a seated position during the blood collection.  Clinical laboratory parameters 
and tests will include those listed in Table 4.  Collection schedule, schedule of laboratory 
parameters by visit, and instructions are in the Clinical Laboratory Manual provided by Central 
Laboratory. 


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Table 4: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
• 
Hematology 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin concentration 
(MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood (RBC) cell count 
• 
White blood (WBC) cell count with differential 
(absolute values only) 
Blood Chemistry (serum, fasting) 
• 
Albumin (Alb) 
• 
Alkaline phosphatase (Alk-P) 
• 
Alanine aminotransferase (ALT; SGPT) 
• 
Aspartate aminotransferase (AST; SGOT) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine kinase (CK) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total and direct bilirubin (TB) 
• 
Total protein 
• 
Uric acid 
Urinalysis (Dipstick) 
• 
Clarity 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Urinalysis (Microscopic) – only if urine dipstick 
abnormal 
• 
Bacteria 
• 
Casts 
• 
Crystals 
• 
Epithelial cells 
• 
Red blood cells (RBC) 
• 
White blood cells (WBC) 
Coagulation – ONLY in patients receiving 
anticoagulant therapy measured only at Visit T1 and 
3 to 5 days post Visit T1 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 


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Table 4: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Other Screening Labs 
 
• 
Hepatitis B surface antigen (HBsAg), hepatitis C 
virus (HCV), optional reflexive Hepatitis C 
RNA only if HCV is positive 
• 
Serum and urine pregnancy test (only for 
females of childbearing potential) 
• 
Follicle-stimulating hormone (FSH; only for 
postmenopausal females <55 years old) 
• 
Thyroid-stimulating hormone (TSH) 
 
12.1.5.2. Sample Collection, Storage, and Shipping 
Central clinical laboratory samples will be collected by appropriate clinical site personnel and 
then shipped according to a separate laboratory manual provided by the Central Laboratory. 
Samples will be processed by the Central Laboratory.  
12.1.5.3. General Monitoring and Management of Abnormal Clinical Labs 
It is the investigator’s responsibility to review the results of all laboratory tests as they become 
available and to sign and date the review.  For each laboratory test outside of the laboratory 
normal range, the investigator needs to ascertain if this is a clinically significant change from 
baseline for the individual patient, with baseline defined as the last value or observation before 
the first dose of double-blind IMP.  The investigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory test. 
If a laboratory value is determined to be an abnormal and a clinically significant change from 
baseline for the patient, the investigator should determine if it qualifies as an AE, and if yes, an 
appropriate eCRF will be completed.  All clinically significant laboratory abnormalities 
occurring during the study that were not present at baseline should be followed and evaluated 
with additional tests if necessary, until diagnosis of the underlying cause or resolution.  Specific 
monitoring and management guidelines for laboratories of special interest are outlined in the 
sections below. 
12.1.5.3.1. Monitoring and Management of Elevated Liver Function Tests 
If at any time after randomization a patient experiences a new ALT and/or AST >3 × ULN, the 
patient will undergo repeat confirmatory liver function test (LFT) assessment as soon as is 
reasonably possible, preferably within 3 to 7 days of the laboratory result becoming available.  
Repeat LFT assessment will include: 1) measurement of ALT, AST, alkaline phosphatase, total 
and direct bilirubin, prothrombin time (PT)/international normalized ratio (INR), eosinophil 
count, CK; 2) history of concomitant medication use; 3) history of exposure to environmental 
chemical agents, including ethanol; and 4) query for related symptoms.  Additionally, further 
testing such as antihepatitis A virus (total), HBsAg (confirmation of screening measurement), 


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HCV (confirmation of screening measurement), and anti-cytomegalovirus/immunoglobulin M.  
Epstein-Barr, liver ultrasound or magnetic resonance imaging (MRI) scanning may be warranted 
to rule out additional pathology depending on clinical presentation and should be discussed with 
the Sponsor personnel or the authorized Medical Monitor.  Although samples will be collected, 
some repeat LFT parameters may not be measured until elevation is confirmed.  
• If repeat LFT assessment confirms ALT and/or AST >3 × ULN but ≤5 × ULN, 
consideration should be given to administering no further doses of IMP.  At the 
investigator’s discretion, IMP may be interrupted and the patient rechallenged with 
IMP after LFTs have returned to baseline levels.  
• If repeat LFT assessment confirms ALT and/or AST >5 × ULN and no alternative 
reason for elevation is identified, patient should discontinue IMP.  At the 
investigator’s discretion, IMP may be interrupted and the patient rechallenged with 
IMP after LFTs have returned to baseline levels.  
• If repeat LFT assessment confirms ALT and/or AST >3 × ULN in addition to any of 
the following and no alternative reason for elevation is identified, patient should 
discontinued IMP and be given no further IMP treatment: 
− TB >2 × ULN 
− INR >1.5 × ULN (unless the patient is on stable dose of anticoagulation 
medication) 
− Appearance or worsening of right upper abdominal discomfort, anorexia, fatigue, 
nausea, vomiting, fever, rash, or eosinophilia 
12.1.5.3.2. Monitoring and Management of Elevated Creatine Kinase 
If at any time after randomization a patient experiences a marked CK elevation >5 × ULN, the 
patient will undergo repeat confirmatory assessment as soon as is reasonably possible, preferably 
within 3 to 7 days of the laboratory result becoming available.  If initial CK elevation is >10 × 
ULN, patients will be instructed to discontinue IMP immediately (instead of continuing IMP 
until repeat lab value is assessed).  It is very important that repeat confirmatory assessment occur 
as soon as possible (within a day of stopping IMP).  
Repeat CK assessment will include query for the nature, duration and intensity of any muscle 
symptoms; review possible predisposing factors, such as unaccustomed exercise, heavy alcohol 
intake, viral illness (consider performing serology), concomitant medications, and/or other 
conditions which can cause myopathy; physical examination for muscle tenderness, weakness, 
and rash; measure serum creatinine, dipstick urinalysis ± microscopy if indicated; and basic 
metabolic panel.  
• If the repeat CK assessment confirms an unexplained (ie, not associated with recent 
trauma or physically strenuous activity) CK abnormality >5 × ULN, if asymptomatic 
the investigator with input from the Sponsor may consider continuing IMP with 
continued CK assessments every 1-2 weeks.  


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• If the repeat CK assessment confirms an unexplained (ie, not associated with recent 
trauma or physically strenuous activity) CK abnormality as listed below, the patient 
should discontinue IMP:  
− >5 × ULN that is associated with symptoms of muscle pain, muscle weakness, or 
dark urine; or  
− >10 × ULN, even in the absence of symptoms.  
• At the investigator’s discretion, IMP may be interrupted and the patient rechallenged 
with IMP after CK has returned to the baseline level.  
12.1.5.3.3. Monitoring and Management of Elevated LDL-C  
Post-randomization, LDL-C results will be masked to investigators in order to maintain the 
blind. The central laboratory will notify the investigator if the patient’s LDL-C level is 
≥220 mg/dL.  The patient will return to the clinic for a repeat fasting blood lipid sample to 
confirm that the LDL-C value meets the threshold criteria.  The patients will be counseled on 
healthy dietary guidelines and reminded to take IMP.  If confirmed, the patient will discontinue 
IMP.  
12.1.5.3.4. Monitoring and Management of Elevated TG 
Post-randomization, TG results will be masked to investigators in order to maintain the blind.  
The central laboratory will notify the investigator if patient’s TG level is >1000 mg/dL.  The 
patients will be counseled on healthy dietary guidelines and reminded to take IMP.  The patient 
will return to the clinic for a repeat fasting blood lipid sample to confirm that the TG value meets 
the threshold criteria. If confirmed, the patient will discontinue IMP.  
12.1.5.3.5. Monitoring and Management of Potential Hypoglycemia and Metabolic Acidosis 
Patients will be educated on the signs and symptoms of hypoglycemia.  If such signs and 
symptoms are experienced, patients will be advised to report them to the study site 
(see Section 13.3 for additional details).  
Clinical laboratories will be assessed to determine any signs of anion gap metabolic acidosis.  If 
laboratories are consistent with metabolic acidosis, immediate follow up with the patient for 
further medical evaluation of the acidosis will occur (see Section 13.3 for additional details).  
This event should be captured as an AE.  
12.1.5.4. Total Blood Volume of Central Clinical Laboratory Samples 
The total number of venipunctures and total volume of whole blood collected during the study 
will be limited to that needed for safety, efficacy, and biomarker assessment.  Total whole blood 
volume collected over the study duration is not to exceed approximately 250 mL for each patient. 


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13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1. 
Adverse Events 
13.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, including control, and which does not necessarily have a 
causal relationship with treatment.  The investigator is responsible for ensuring that any AEs 
observed by the investigator or reported by the patient are recorded in the patient’s medical 
record.  
An AE can be: 
• Any unfavorable and unintended sign/symptom including an abnormal laboratory 
finding or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease 
• Laboratory abnormality or diagnostic test abnormalities (eg, electrocardiogram 
[ECG] or X-ray) should be reported as an AE if one of the following occurs: 
− Treatment required due to the abnormality 
− Discontinuation of IMP 
− Per Investigator judgement 
• TEAEs are defined as AEs that begin or worsen after the first dose of IMP 
administration as defined in the statistical analysis plan (SAP) 
13.1.2. 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction (ADR).  “Responses” to a medicinal product means that a 
causal relationship between the medicinal product and an AE is at least a reasonable possibility 
(ie, the relationship cannot be ruled out). 
An unexpected ADR is defined as an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, IB for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). 
13.1.3. 
Reporting for Adverse Events 
All AEs occurring during the course of the study (starting from signing informed consent 
through 30 days after study completion/discontinuation) will be collected on the AE eCRF.  
Patients should be instructed to report any AE that they experience to the investigator.  
Investigators should make an assessment for AEs at each visit and record the event on the 
appropriate AE eCRF.  


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Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the eCRF.  However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the eCRF.  Additionally, 
the condition that led to a medical or surgical procedure should be recorded as an AE, not the 
procedure.  
Any medical condition already present at screening or baseline should not be reported as an AE 
unless the medical condition or signs or symptoms present at baseline worsens in severity or 
seriousness at any time during the study.  In this case, it should be reported as an AE. 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory.  In some cases, significant 
changes in lab values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically 
significant 
Significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant.  Any abnormal test 
that is determined to be an error does not require reporting as an AE. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the IMP.  
For each AE, the following information will be recorded: 
• Description of the event (eg, headache) 
• Date of onset 
• Date of resolution (or that the event is continuing) 
• Action taken as a result of the event 
• Seriousness of the event 
• Severity of the event 
• Outcome of the event 
• Investigator’s assessment of relationship to IMP. 
A cluster of signs and symptoms that results from a single cause should be reported as a single 
AE (eg, fever, elevated white blood cells [WBC], cough, abnormal chest X-ray, etc, can all be 
reported as “pneumonia”). 
The investigator will carefully evaluate the comments of the patient and the response to 
treatment in order that he/she may judge the true nature and severity of the AE.  The question of 


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the relationship of AEs to IMP administration should be determined by the investigator or study 
physician after thorough consideration of all facts that are available. 
13.1.4. 
Severity 
It is the investigator’s responsibility to assess the intensity (severity) of an AE.  
The severity of the AE will be characterized as mild, moderate, or severe according to the 
following definitions: 
• Mild: Events are usually transient and do not interfere with the patient’s daily 
activities 
• Moderate: Events introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities  
• Severe: Events interrupt the patient’s usual daily activity, are incapacitating with 
inability to do usual activities, or significantly affect clinical status and warrant 
intervention and/or close follow-up  
Note: A severe AE need not be serious and an SAE need not, by definition, be severe. 
13.1.5. 
Relationship 
It is the investigator’s responsibility to assess the relationship between the IMP and the AE.  The 
degree of “relatedness” of the AE to the IMP may be described using the following scale: 
• Not Related:  No temporal association and other etiologies are likely the cause  
• Unlikely:  While cannot be definitively ruled as not related to IMP, a causal 
association is remote, and other etiologies are more likely to be the cause.  For 
reporting and summarization, events assessed as Unlikely to be related to IMP will be 
considered as Not Related to IMP. 
• Possible:  Temporal association, but other etiologies are likely the cause.  However, 
involvement of the IMP cannot be excluded. 
• Probable:  Temporal association, other etiologies are possible but unlikely.  The event 
may respond if the IMP is discontinued. 
• Definite:  Established temporal association with administration of the IMP with no 
other more probable cause.  Typically, the event should resolve when the IMP is 
discontinued and recur on re-challenge. 
13.1.6. 
Monitoring and Follow-up of Adverse Events 
Patients having AEs will be monitored with relevant clinical assessments and laboratory tests, as 
determined by the investigator.  All follow-up results are to be reported to the Sponsor personnel 
or the authorized Medical Monitor.  Any actions taken and follow up results must be recorded 
either on the appropriate page of the eCRF or in appropriate follow-up written correspondence, 
as well as in the patient’s source documentation.  Follow-up laboratory results should be filed 
with the patient’s source documentation. 


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For all AEs that require the patient to be discontinued from the study, relevant clinical 
assessments and laboratory tests must be repeated at appropriate intervals until final resolution or 
stabilization of the event(s). 
Patients with AEs related to IMP that are ongoing at study discontinuation or completion must be 
followed until resolution or for 30 days after study completion, whichever comes first, with the 
exception of patients reporting SAEs (see Section 13.2.2). 
13.1.7. 
Treatment-Emergent Adverse Events 
TEAE are defined as AEs that begin or worsen after the first dose of IMP administration as 
defined in the SAP. 
13.2. 
Serious Adverse Events 
13.2.1. 
Definition of Serious Adverse Event  
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:  
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or substantial disruption of 
the ability to conduct normal life functions 
• Is a congenital anomaly/birth defect 
• An important medical event 
NOTE: An emergency room visit without hospital admission does not meet inpatient 
hospitalization criterion, nor does hospitalization for an elective or outpatient procedure 
scheduled or planned before signing of informed consent.  However, unexpected complications 
and/or prolongation of hospitalization that occur during elective or outpatient surgery should be 
recorded as AEs and assessed for seriousness.  Admission to the hospital for social or situational 
reasons (eg, no place to stay, live too far away to come for hospital visits) will not be considered 
inpatient hospitalizations.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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13.2.2. 
Reporting Serious Adverse Events 
All SAEs occurring from the time of informed consent until 30 days following study 
completion/discontinuation must be reported by the Principal Investigator or designee to the 
designated Safety contact within 24 hours knowledge of the event.  All SAEs that the 
investigator considers related to IMP that occur after the 30-day follow-up period of the study 
period must be reported to the Sponsor.  
To report the SAE, the SAE form in electronic data capture (EDC) should be completed within 
24 hours of becoming aware of the event.  If you have questions, please call the designated 
Safety contact for assistance.   
Detailed instructions and contact information for the Safety designee will be provided in the SAE 
Completion Guidelines.  
The investigator is required to submit SAE reports to their IRB in accordance with local 
requirements.  All investigators involved in studies using the same investigational product will 
receive any safety alert notifications for onward submission to their local IRB as required.  All 
reports sent to investigators will be blinded. 
All SAEs should be recorded on the eCRF and source documents.  Criteria for documenting the 
relationship to IMP and severity will be the same as those previously described. 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
and submit any supporting documentation (eg, patient discharge summary or autopsy reports) to 
designated Safety contact.  
The Sponsor (and/or legally transferred designee) will report SAEs and suspected and 
unexpected serious adverse reactions (SUSARs) as required by global regulatory authorities, 
IRBs, and/or investigators/institutions in compliance with all reporting requirements according to 
local regulations, laws, and Good Clinical Practices (GCPs).  The investigator should notify their 
IRB of SAEs occurring at their site and other SAE reports received from the Sponsor, in 
accordance with local procedures and statutes.  
13.2.3. 
Reporting of Patient Death 
The death of any patient during the study or within 30 days after study discontinuation or 
completion must be reported as an SAE. 
13.2.4. 
Reports of Pregnancy and Lactation 
Although not considered an SAE (unless an event occurs with a serious outcome), pregnancy 
will be collected by the designated Safety contact.  If a female patient should become pregnant 
during the course of the study, the Principal Investigator or designee must contact the designated 
Safety contact within 24 hours of knowledge of the pregnancy.  In addition, a Pregnancy report 
form must be completed and submitted to the Safety contact. 


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Patients who become pregnant must discontinue study medication immediately and will continue 
to be followed until the pregnancy is completed.  Once the outcome of the pregnancy is known, 
the Pregnancy Outcome report form must be completed and submitted to the Safety contact.  
Patients who lactate during the study may be required to discontinue study medication. 
13.3. 
Adverse Events of Special Interest 
Muscle:  Muscle events have been associated with statins (Thompson 2003) and other lipid-
lowering therapies and are mentioned in the product information for these therapies. Muscle 
symptoms through AE review, CK elevations, and symptoms of potential myopathy will be 
closely monitored.  
Hepatic:  Hepatic function will be monitored throughout with the clinical safety labs. More 
detailed investigation will occur if the safety clinical laboratory results are >3 × ULN. 
Neurocognitive events:  Theoretically, it is possible that lipid-lowering agents that disrupt 
cholesterol homeostasis in the brain could impact neurological function, and there have been 
reports of cognitive impairment (eg, memory loss) associated with the use of statin drugs 
(FDA 2012). Summarization of events will occur using prespecified Medical Dictionary for 
Regulatory Activities (MedDRA) terms outlined in the SAP. 


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14. 
STATISTICS 
14.1. 
General Considerations 
The statistical analyses described in this section will be performed as further outlined in the SAP, 
which will be finalized prior to the end of the study.  The SAP will supersede the protocol if 
there are any differences between the 2 documents in the plans for data analysis.  The SAP will 
be included as an appendix in the clinical study report for this protocol. 
In general, summary statistics for continuous variables will include the number of subjects, 
mean, median, standard deviation or standard error, first and third quartiles, minimum, and 
maximum.  For categorical variables, the frequency and percentage will be given.  
14.2. 
Determination of Sample Size 
14.3. 
Analysis Populations  
The modified Intent-to-Treat (mITT) population, used for all of the efficacy analyses, is defined 
as all randomized patients who received at least 1 dose of IMP and have a baseline assessment 
and at least 1 postbaseline assessment, excluding any assessment taken more than 2 days after a 
dose of IMP.   
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of study medication.  Patients in the SP will be included in 
the treatment group that they actually received, regardless of their randomized treatment.  
14.4. 
Disposition, Demographics, and Baseline Characteristics 
Disposition, including reason for withdrawal from the IMP and study, will be summarized by 
treatment group.  Demographic information and patient characteristics including, but not limited 
to, gender, race, age, and baseline vital signs will also be summarized by treatment group. 
14.5. 
Primary Endpoint Analysis 
The primary efficacy endpoint is the percent change from baseline to Week 6 in LDL-C.  
Baseline is defined as the mean of the values from Week -1 (Visit S2) and predose 
Day 1/Week 0 (Visit T1).  An analysis of covariance (ANCOVA) with treatment group as factor 
and baseline LDL-C as covariate will be performed to compare triplet therapy versus placebo for 
the primary endpoint using the mITT population (Section 14.3).  Missing values at Week 6 will 
be imputed using the last observation carried forward (LOCF) procedure (only postbaseline 


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values will be carried forward).  The least squares mean (LSM) and standard error (SE) will be 
provided for both treatment groups, along with the placebo-corrected LSM, its 95% confidence 
interval (CI), and associated p-value. 
14.6. 
Secondary Efficacy Endpoint Analyses 
Secondary efficacy endpoints, which include the percent change from baseline to Week 6 in 
additional lipid and cardiometabolic biomarkers, will be analyzed in a similar manner as the 
primary efficacy endpoint.  Baseline for non-HDL C, HDL-C, TC, and TG is defined as the 
mean of the values from Week -1 (Visit S2) and predose Day 1/Week 0 (Visit T1), while 
baseline for ApoB and hs-CRP is defined as the predose Day 1/Week 0 (Visit T1) value.   
Statistical testing of primary and secondary efficacy endpoints will be 2-sided and conducted at 
the 5% level of significance with no adjustment for multiple comparisons. 
14.7. 
Safety Endpoints 
Descriptive summary will be provided for safety endpoints.  
The MedDRA will be used to code all AE to a system organ class (SOC) and a preferred term.   
The summarization of AEs will include only TEAEs defined as AEs that begin or worsen after 
first dose of IMP administration as defined in the SAP.  All TEAEs, SAEs, AEs leading to 
withdrawal of IMP, fatal AEs and AEs of special interest will be summarized by SOC and 
preferred term in descending order of frequency by treatment group.  
Clinical safety laboratories, including hematology, blood chemistry, glucose, and urinalysis; PE 
findings; vital signs; and weight will be summarized by the value and by change or percent 
change from baseline in the value (where appropriate) at each postbaseline time point.  


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
The Sponsor (or its authorized representative) has the obligation to follow this study closely to 
ensure that the study is conducted in accordance with the protocol, International Conference on 
Harmonisation (ICH) and GCP guidelines, national regulatory requirements, and the current 
Declaration of Helsinki throughout its duration by means of personal visits to the investigator’s 
facilities and other communications.  
These visits will be conducted to evaluate the progress of the study, verify the rights and 
well-being of the patients are protected, and verify the reported clinical study data are accurate, 
complete, and verifiable from source documents.  This includes review of ICDs, results of tests 
performed as a requirement for participation in this study, and any other medical records 
(eg, laboratory reports, clinic notes, IMP dispensing log, pharmacy records, patient sign-in 
sheets, patient-completed questionnaires, and telephone logs) required to confirm information 
contained in the eCRFs. 
A monitoring visit should include a review of the essential clinical study documents (regulatory 
documents, CRFs, medical records and source documents, drug disposition records, patient 
informed consent forms, etc) as well as discussion on the conduct of the study with the 
investigator and staff.  These documents should be redacted by the site in accordance with local 
law. 
The monitor should conduct these visits as frequently as appropriate for the clinical study.  The 
investigator and staff should be available during these visits for discussion of the conduct of the 
study as well as to facilitate the review of the clinical study records and resolve/document any 
discrepancies found during the visit.  
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the clinical site by signature and date on the study-specific monitoring log. 
15.2. 
Audits and Inspections 
Representatives of the Sponsor or its authorized clinical quality assurance group may visit a 
clinical site at any time during the study to conduct an audit of the study in compliance with 
regulatory guidelines and company policy.  These audits will require access to all study records, 
including source documents, for inspection and comparison with the eCRFs.  Patient privacy 
must be respected.  The investigator and clinical site personnel are responsible for being present 
and available for consultation during routinely scheduled site audit visits conducted by the 
Sponsor or its authorized representative.  
The clinical study may also be inspected by the FDA to verify that the study was conducted in 
accordance with protocol requirements, as well as the applicable regulations and guidelines. 
In the event the investigator is contacted by regulatory authorities who wish to conduct an 
inspection of the clinical site, the investigator will promptly notify the Sponsor of all such 
requests and will promptly forward a copy of all such inspection reports. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor (or 
designee) may conduct a quality assurance audit.  Please see Section 15.2 for more details 
regarding the audit process. 


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17. 
ETHICS 
17.1. 
Institutional Review Board Approval 
Before initiation of the study, the investigator must obtain approval or favorable opinion of the 
research protocol, ICD, and any material related to patient recruitment from an IRB.  For 
locations participating within the US, the IRB must comply with the provisions specified in 
21 Code of Federal Regulations (CFR) Part 56 and GCP guidelines, and applicable pertinent 
state and federal requirements.  
IRBs must be constituted according to the applicable laws.  It is the responsibility of each 
clinical site to submit the protocol, IB, patient informed consent, patient recruitment materials (if 
applicable), and other documentation as required by the IRB for review and approval.  A copy of 
the written approval must be provided to the Sponsor.  
The documentation should clearly mention the approval/favorable opinion of the protocol, the 
patient informed consent form, and patient recruitment materials (if applicable), including 
respective version dates.  The written approval and a list of the voting members, their titles or 
occupations, and their institutional affiliations must be obtained from the IRBs and provided to 
the Sponsor prior to the release of clinical study supplies to the clinical site and commencement 
of the study.  If any member of the IRB has direct participation in this study, written notification 
regarding his or her abstinence from voting must also be obtained. 
Clinical sites must adhere to all requirements stipulated by their respective IRB.  This includes 
notification to the IRB regarding: protocol amendments, updates to the ICD, recruitment 
materials intended for viewing by patients, aggregate safety reports required by regulatory 
competent authorities, serious and unexpected AEs, reports and updates regarding the ongoing 
review of the study at intervals specified by the respective IRB, and submission of final study 
reports and summaries to the IRB. 
It is the responsibility of each clinical site to submit information to the appropriate IRB for 
annual review and annual re-approval. 
The investigator must promptly inform their IRB of all SAEs or other safety information 
reported from the patient or the Sponsor. 
17.2. 
Ethical Conduct of the Study 
The investigator agrees, when signing the protocol, to conduct the study in accordance with 
ethical principles that have their origin in the current revision of the Declaration of Helsinki and 
are consistent with GCP, applicable regulatory requirements, and policies and procedures as 
outlined by the ethical requirements for IRB review and ICDs. 
The investigator agrees to allow monitoring and auditing of all essential clinical study documents 
by the Sponsor or its authorized representatives and inspection by the FDA.  Monitoring and 
auditing visits by the Sponsor or authorized designee will be scheduled with the appropriate staff 
at mutually agreeable times periodically throughout the study. 


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The investigator will assure proper implementation and conduct of the study, including those 
study-related duties delegated to other appropriately qualified individuals.  The investigator will 
assure that study staff cooperates with monitoring and audits, and will demonstrate due diligence 
in recruiting and screening study patients.  The investigator must sign and return to the Sponsor 
the “Investigator’s Signature” page (see Appendix 3) and provide a copy of current curriculum 
vitae.  For this study and all studies conducted under an IND, the investigator must sign and 
return a completed Form FDA 1572 “Statement of Investigator” to the Sponsor (or designee). 
17.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Patients must also clearly understand that they are free to discontinue from the study at any time.  
The patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures on the Sponsor agreed ICD.  Updates to the ICD during the conduct of the study will 
be communicated by written letter from the Sponsor to the investigator.  The ICD should be 
provided in the appropriate language of the patient population.  
The Principal Investigator(s) must maintain the original, signed ICD.  A copy of the signed ICD 
must be given to the patient. 
17.4. 
Patient Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained.  
The names and identities of all research patients will be kept in strict confidence and will not 
appear on eCRFs or other records provided to or retained by the Sponsor (or designee).  If a 
patient’s name appears on any document, it must be redacted and replaced with the patient 
identifier before a copy of the document is supplied to the Sponsor (or designee).  The ICD must 
include appropriate statements explaining that patient data will be confidential and what actions 
will be taken to ensure patient confidentiality. 
Any other confidentiality requirements specified by the site, IRB, or local regulations will be 
adhered to and detailed appropriately in the ICD. 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Inspection of Records 
Applicable regulations require the Sponsor (or designee) to inspect all documents and records to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) for the patients in this study.  These regulations also allow the Sponsor’s records to be 
inspected by authorized representatives of the regulatory agencies.  The investigator will permit 
study-related monitoring, audits, IRB review, and regulatory inspections by providing direct 
access to source data/documents.  Direct access includes permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of a clinical study. 
18.2. 
Retention of Records 
In compliance with the ICH/GCP guidelines, the investigator/Institution agrees to retain and 
maintain all study records that support the data collected from each patient, as well as all study 
documents as specified in ICH/GCP, Section 8 Essential Documents for the Conduct of a 
Clinical Trial.  The investigator agrees to contact the Sponsor before destroying or relocating any 
study documentation and is expected to take measures to prevent accidental or premature 
destruction of these documents.  
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept responsibility.  
The Sponsor must be contacted in writing regarding the name and address of the new person 
responsible as well as the disposition of document storage.  Under no circumstances shall the 
investigator relocate or dispose of any study documents before having obtained written approval 
from the Sponsor. 
Essential records (including eCRFs, source documents, IMP disposition records, signed patient 
ICDs, AE reports, and other regulatory documents) as required by the applicable regulations, 
must be maintained for 2 years after a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after formal discontinuation of 
clinical development of the investigational product. 
It is the responsibility of the Sponsor to inform the investigator/Institution as to when these 
documents no longer need to be retained. 
18.3. 
Case Report Forms and Study Records 
Access to eCRFs will be provided to the clinical site.  As part of the responsibilities assumed by 
participating in the study, the investigator agrees to maintain adequate case histories for the 
patients treated as part of the research under this protocol.  The investigator agrees to maintain 
accurate source documentation and eCRFs as part of the case histories.  
Study records are comprised of source documents, eCRFs, and all other administrative 
documents (eg, IRB correspondence, clinical study materials and supplies shipment manifests, 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 59 of 71 
monitoring logs, and correspondence).  A study-specific binder will be provided with 
instructions for the maintenance of study records. 
Source documentation is defined as any hand-written or computer-generated document that 
contains medical information or test results that have been collected for or in support of the 
protocol specifications (eg, laboratory reports, clinic notes, IMP disposition log, pharmacy 
records, patient sign-in sheets, telephone logs, X-rays, and ECGs).  All draft, preliminary, and 
pre/final iterations of a final report are also considered to be source documents (eg, faxed and 
hard copy of laboratory reports, faxed and hard copy of initial results, and final report).  
The investigator agrees to allow direct access to all essential clinical study documents for the 
purpose of monitoring and/or auditing by the Sponsor or its authorized representatives and 
inspection by the appropriate regulatory authorities. 
Data reflecting the patient’s participation with the IMP under investigation are to be reported to 
the Sponsor.  The data are to be recorded on the eCRFs and/or other media provided or approved 
by the Sponsor.  
A completed eCRF must be submitted for each patient who receives IMP, regardless of duration.  
All supportive documentation submitted with the eCRF, such as laboratory or hospital records, 
should be clearly identified with the study and patient number.  Any personal information, 
including patient name, should be removed or rendered illegible to preserve individual 
confidentiality.  The eCRF should not be used as a source document unless otherwise specified 
by the Sponsor.  
Neither the Sponsor nor a service provider contracted to analyze data and complete the study 
report is permitted to interpret a blank answer; therefore, all fields should be completed.  All 
requested information must be entered on the eCRFs.  If an item is not available or is not 
applicable, this fact should be indicated as not available (N/A) or not done (N/D); do not leave a 
field blank.  
Each set of completed eCRFs must be signed and dated by the investigator acknowledging 
review and that the data are accurate and complete.  The completed database is to be returned to 
the Sponsor as soon as practical after completion by the mechanism prescribed for the protocol. 
It is essential that all dates appearing on the Sponsor’s patient data collection forms for 
laboratory tests, cultures, etc, be the dates on which the specimens were obtained or the 
procedures performed.  The eCRFs will be electronically signed by the investigator and dated as 
verification of the accuracy of the recorded data.  All data collection forms should be completed 
within 48 hours following the evaluation. 


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Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 60 of 71 
19. 
ADMINISTRATIVE CONSIDERATIONS 
19.1. 
Investigators 
The investigator must agree to the responsibilities and obligations listed below, as specified by 
the appropriate FDA regulatory requirements or ICH/GCP guidelines: 
• Agree to conduct the study in accordance with the relevant current protocol 
• Agree to personally conduct or supervise the described investigation(s) 
• Agree to inform any patients, or persons used as controls, that the IMP are being used 
for investigational purposes and ensure that the requirements relating to obtaining 
informed consent and IRB review and approval are met  
• Agree to report adverse experiences that occur during the course of the 
investigation(s)  
• Read and understand the information in the IB, including the potential risks and side 
effects of the IMP 
• Ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments 
• Maintain adequate and accurate records and make those records available for 
inspection  
• Ensure that an appropriate IRB will be responsible for the initial and continuing 
review and approval of the clinical investigation 
• Agree to promptly report to the IRB all changes in the research activity and all 
unanticipated problems involving risks to patients or others 
• Agree to not make changes in the research without IRB approval, except where 
necessary to eliminate apparent hazards to patients 
• Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements. 
• Refer also to: 
− FDA Regulations Related to GCP and Clinical Trials: 
http://www.fda.gov/oc/gcp/regulations.html 
− Guidance and Information Sheets on GCP in FDA-Regulated Clinical Trials: 
http://www.fda.gov/oc/gcp/guidance.html 
− Guidance for IRBs and Clinical Investigators: 
http://www.fda.gov/oc/ohrt/irbs/default.htm 
− Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance: 
http://www.fda.gov/cder/guidance/959fnl.pdf 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 61 of 71 
19.2. 
Study Administrative Structure 
Central Laboratory: 
Randomization, IWRS, Medical Writing: 
TBD 
Statistical Analysis, Study Management and Monitoring, Data Management, Programming: 
Medical and Safety Services including Medical Monitoring: 
Cell phone #: 
 
Email:
Office phone #: 
Cell phone #:  
Email:
19.3. 
Amendments and Study Termination 
Changes to the research covered by this protocol must be implemented by formal protocol 
amendment.  All amendments to the protocol must be initiated by the Sponsor and signed and 
dated by the investigator.  Protocol amendments must not be implemented without prior IRB 
approval.  Documentation of amendment approval by the investigator and IRB must be provided 
to the Sponsor or its authorized representative.  When the change(s) involve only logistic or 
administrative aspects of the study, the IRB only needs to be notified.  
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator will contact the Medical Monitor. Except in emergency situations, this contact 
should be made before implementing any departure from the protocol.  In all cases, contact with 
the Medical Monitor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action.  The data recorded on the eCRF and source documents will reflect 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 62 of 71 
any departure from the protocol and the source documents will describe the departure and the 
circumstances requiring it. 
The Sponsor reserves the right to terminate this study at any time.  
19.4. 
Financial Disclosure 
Prior to the start of the study, investigators will release sufficient and accurate financial 
information that permits the Sponsor to demonstrate that an investigator and all study relevant 
assigned personnel have no personal or professional financial incentive regarding the future 
approval or disapproval of the IMP such that his or her research might be biased by such 
incentive. 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 63 of 71 
20. 
PUBLICATION AND DISCLOSURE POLICY 
It is understood by the investigator that the information and data included in this protocol may be 
disclosed to and used by the investigator’s staff and associates as may be necessary to conduct 
this clinical study. 
All information derived from this clinical study will be used by the Sponsor (or designee) and 
therefore, may be disclosed by the Sponsor (or designee) as required to other clinical 
investigators, to the FDA, European Medicines Agency, and to other government agencies, or in 
connection with intellectual property filings or publications.  In order to allow for the use of the 
information derived from this clinical study, it is understood by the investigator that there is an 
obligation to provide the Sponsor with complete test results and all data from this clinical study.  
The investigator agrees to maintain this information in confidence, to use the information only to 
conduct the study, and to use the information for no other purpose without the Sponsor’s prior 
written consent (or as otherwise may be permitted pursuant to a written agreement with the 
Sponsor or its designee). 
The results of the study will be reported in a clinical study report prepared by the Sponsor (or 
designee), which will contain eCRF data from all clinical sites that conducted the study. 
The Sponsor shall have the right to publish data from the study without approval from the 
individual investigators.  Manuscript(s) and abstract(s) may only be prepared through 
cooperation between the Sponsor (or designee) and the study investigator(s).  If an investigator 
wishes to publish information from the study, a copy of the manuscript must be provided to the 
Sponsor for review in accordance with the provisions of such investigator’s written agreement 
with the Sponsor (or designee) before submission for publication or presentation.  If requested by 
the Sponsor in writing, the investigator will withhold such publication in accordance with the 
provisions of such agreement. 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 64 of 71 
21. 
LIST OF REFERENCES 
Baigent C, Blackwell L, Emberson J, et al. Cholesterol Treatment Trialists’ (CTT) Collaboration. 
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 
170 000 participants in 26 randomised trials. Lancet. 2010;376:1670-81. 
Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in America and gaps in 
patient education (USAGE): an internet-based survey of 10,138 current and former statin users. 
Clinical Lipidol. 2012;6:208-15. 
Egan A and Colman E. Weighing the benefits of high-dose simvastatin against the risk of 
myopathy. N Engl J Med. 2011;365:285-7. 
Food and Drug Administration (2012). FDA announces safety changes in labeling for some 
cholesterol-lowering drugs [Press release]. Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm293623.htm  
Goldberg AC. Clinical trial experience with extended-release niacin (Niaspan): dose-escalation 
study. Am J Cardiol. 1998;82:35U–8U. 
Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, et al. Implications 
of recent clinical trials for the National Cholesterol Education Program Adult Treatment 
Panel III Guidelines. Circulation. 2004;110:227-39. 
Insull W, Toth P, Mullican W, Hunninghake D, Burke S, Donovan J, et al. Effectiveness of 
colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary 
hypercholesterolemia: a 24-week randomized controlled trial. Mayo Clin Proc. 2001;76:971–82. 
Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, et al. Polymorphisms 
associated with cholesterol and risk of cardiovascular events. New Engl J Med. 
2008:358;12:1240-9. 
Knopp RH, Brown WV, Dujovne CA, Farquhar JW, Feldman EB, Goldberg AC, et al. Effects of 
fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am 
J Med 1987;83:50–9. 
Knopp RH, Dujovne CA, LeBeaut A, Lipka LJ, Suresh R, Veltri EP, et al. Evaluation of the 
efficacy, safety and tolerability of ezetimibe in primary hypercholesterolemia: a pooled analysis 
from two controlled phase III clinical studies. Int J Clin Pract 2003;57:363–8. 
Martin SS, Gosch K, Kulkarni KR, Spertus JA, Mathews R, Ho PM, et al. Modifiable factors 
associated with failure to attain low-density lipoprotein cholesterol goal at 6 months after acute 
myocardial infarction. Am Heart J. 2013;165:26-33.e3. 
Mozffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al, for the writing 
group Members. Heart Disease and Stroke Statistics—2015 Update. A Report from the 
American Heart Association. Circ. 2015;131:e29-322. 
Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: 
epidemiological update. Eur Heart J. 2014; 35:2950-9. 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
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Page 65 of 71 
Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond 
cholesterol reduction: A meta-regression analysis. J Am Coll Cardiol. 2005 Nov 
15;46(10):1855-62. Epub 2005 Oct 24. 
Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, et al. Atherosclerosis 
Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein 
cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density 
subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 
2001;104:1108-13. 
Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association 
between lowering LDL-C and cardiovascular risk reduction among different therapeutic 
interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289-97. 
Stamler J, Wentworth D, Neaton J. Is relationship between serum cholesterol and risk for 
premature death from coronary heart disease continuous and graded? JAMA. 
1986;256(20):823-8. 
Stone NJ, Robinson J, Lichtenstein AH, et al. for the Heart Association Task Force on Practice 
Guidelines Cardiovascular Risk in Adults. 2013 ACC/AHA Guideline on the Treatment of Blood 
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circ, DOI: 
10.1161/01.cir.0000437738.63853.7a 
Townsend N, Nichols M, Scarborough P, Rayner M. Cardiovascular disease in Europe – 
epidemiological update 2015. Eur Heart J. 2015;36(40):2696-705. 
Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003:289:1681-90. 
Virani SS, Woodard LD, Chitwood SS, Landrum CR, Urech TH, Wang D, et al. Frequency and 
correlates of treatment intensification for elevated cholesterol levels in patients with 
cardiovascular disease. Am Heart J. 2011;162:725-732.e1. 
Waters DD. What the statin trials have taught us. Am J Cardiol. 2006;98:129-34. 
World Health Organization (WHO) Fact Sheet No 317 Updated January 2015. 
 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 66 of 71 
22. 
APPENDICES 
Appendix 1. 
Schedule of Events  
Appendix 2.  Sponsor’s Signatures 
Appendix 3.  Investigator’s Signature 
 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 67 of 71 
APPENDIX 1. SCHEDULE OF EVENTS  
Schedule of Events  
Visit 
S1 
S21 
T1 
T2 
T4 
Week 
-6 
-1 
0 
3 
6/EOS/ET2 
Procedure 
Day 
-42 to -37 
Day 
-10 to -7 
Day 1 
Day 
22 ± 3 
Day 
43 ± 3 
Informed Consent 
X 
 
 
 
 
Enrollment Criteria 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant\Prohibited Medications 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
Physical Exam 
 
 
X 
 
X 
Weight3 
X 
 
X 
 
X 
Height/BMI 
X 
 
 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
Serology5 
 
X 
 
 
 
Serum Pregnancy/FSH 6 
X 
 
 
 
 
Urine Pregnancy6  
 
 
X 
 
 
TSH 
X 
 
 
 
 
Clinical Safety Labs7 
X 
 
X 
X 
X 
Basic Fasting Lipids8 
X 
X 
X 
X 
X 
Special Fasting Lipids and Other 
Biomarkers9 
 
 
X 
 
X 
Dietary and Lifestyle Counselling 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
Double Blind IMP Dispensing 
 
 
X 
X 
 
IMP Return 
 
 
 
X 
X 
BMI = body mass index; FSH = follicle-stimulating hormone, TSH = thyroid-stimulating hormone, EOS = End of 
Study, ET = Early Termination. 
1 An optional visit approximately 1 week later MAY be completed if patient fails to meet a lipid entry criterion.  If this 
optional visit is completed, the mean of the LDL-C values, or TG values, will be used to determine eligibility.  
2 All procedures will be completed at end of study or early termination. 
3 Body weight will be measured in the morning while fasting, using consistent scales, after voiding, and without shoes 
and outerwear (eg, coats).  
4 Vital signs will include SBP, DBP, and heart rate, and will be collected prior to any blood sample collection.  Patient 
will rest for 5 minutes prior to assessments. 
5 Serology for Hep B antigen, Hep C antibody. 
6 FSH completed in appropriate postmenopausal women only; pregnancy test completed in non-postmenopausal women 
only. 
7 Clinical safety labs include hematology, blood chemistry, and urinalysis.  Coagulation panel ONLY in patients 
receiving anticoagulants measured only at T1 and repeat 3-5 days after starting IMP. 
8 Basic fasting lipids include total cholesterol, calculated LDL-C, HDL-C, non-HDL-C, and triglycerides. 
9 Includes ApoB and hs-CRP 
 


Bempedoic Acid (ETC-1002) 
Clinical Study Protocol I 002-038 
Esperion Therapeutics, Jnc. 
Final, 11 November 2016 
APPENDIX 2. SPONSOR'S SIGNATURES 
Study Title: 
Study Number: 
Final Date: 
A Randomized, Double-Blind, Placebo-Controlled, Par~Jlel Group Study 
to Evaluate the Efficacy and Safety of Triplet Therapy with Bernpedoie 
Acid (ETC-I 002) 180 mg, Ezetimibe I 0 rug, aod Atorva!;tHtin 20 mg in 
Patients with Elevated LDL-C 
1002-038 
1l November2016 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The following personnel contributed to writing and/or approving this protocol: 
Signed. 
Date: \5 No" '20\b 
Confidential 
Page 68 of71 


Bempedoic Acid (ETC-1002) 
Clillical Study Protocol 1002-038 
Bsperion Thempeulics, Inc. 
Fin.ii, 11November2016 
StodyTIUt: 
Sntd)' Numbtr: 
Flo1I Datt: 
A Randomized. Double-Blind. Pl11cebo-Contr01led. Parallel Group Study 
to Evaluate the Efficacy and Safety of Triplet Therapy with Bempedoic 
Acid (ETC-1002) 180 UllL Ezetiruibe 10 mg. and Atorvai.tatin 20 mg in 
Patients with Elevnted LDL-C 
1002-038 
LI ~ove01ber 2016 
·nm cllnJcal study protocol was subject to crilicnl review and bas beeu approved by Ille Sponsor. 
The followiug pcrsoMel contributed to wri1u1s audlor approving this protocol: 
Date: 
11/14/2016 
--------
Coofidcutinl 
Page69 of71 


Bempedoic Acid (ETC-I 002) 
Clinical Study Protocol I 002-038 
Esperion Therapeutics, Inc. 
Final, l 1 November 2016 
Study Title: 
Study Number: 
FinaJ Date: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study 
to Evaluate the Efficacy and Safety of Triplet Therapy with Bempedoic 
Acid (ETC-1002) 180 mg, Ezetimibe 10 mg, and Atorvastatin 20 mg in 
Patients with Elevated LDL-C 
1002-038 
11 November 2016 
This clinical study protocol was subject to critical review and has been approved by the Sponsor. 
The following personnel contributed to writing and/or approving this protocol: 
Development 
Signed: 
Date: 
11/15/2016 
Confidential 
Page 70 of71 


Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-038 
Final, 11 November 2016 
 
Confidential 
Page 71 of 71 
APPENDIX 3. INVESTIGATOR’S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study 
to Evaluate the Efficacy and Safety of Triplet Therapy with Bempedoic 
Acid (ETC-1002) 180 mg, Ezetimibe 10 mg, and Atorvastatin 20 mg in 
Patients with Elevated LDL-C 
Study Number: 
1002-038 
Final Date: 
11 November 2016 
 
I have read the protocol described above.  I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol.  
 
 
Signed:  
Date:  
 
Name and Credentials:  
Title:  
Affiliation:  
Address:  
Phone Number:  
 
 
 

SAP_001.pdf: 
Esperion Therapeutics, Inc. 
Version 2.0, July 03, 2017
Protocol: ETC-1002-038 
Statistical Analysis Plan
Confidential 
Page 1 of 18
Statistical Analysis Plan 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy and Safety of Triplet Therapy with Bempedoic Acid 
(ETC-1002) 180 mg, Ezetimibe 10 mg, and Atorvastatin 20 mg in Patients 
with Elevated LDL-C  
Protocol: 
ETC-1002-038 
Clinical Phase: 
2 
Product: 
ETC-1002 
Version (Date): 
Statistical Analysis Plan – Version 2.0 (July 03, 2017) 
Status: 
Final 
Prepared by: 
 
On behalf of: 
Esperion Therapeutics 
Confidentiality statement: 

The information provided in this document is strictly confidential.

The recipients of the SAP must not disclose the confidential information contained within this
document or any related information to other persons without the permission of the sponsor.

In addition, the recipients of the SAP must keep this confidential document in a controlled
environment which prevents unauthorized access to the document.
DocUUID : 4d830059-a909-45a6-95d8-f7f0eaccd93f
NCT number: NCT03051100
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Esperion Therapeutics, Inc. 
Version 2.0, July 03, 2017
Protocol: ETC-1002-038 
Statistical Analysis Plan
Confidential 
Page 2 of 18
Prepared at 
 by: 
Reviewed at 
 by: 
 
Date 
Approved at 
 by: 
 
Date 
 
Date 
(
 signs this document instead of 
 
since
is OOO.) 
 
Date 
DocUUID : 4d830059-a909-45a6-95d8-f7f0eaccd93f
e320d079-81e7-4489-a492-2479a385701a
05 Jul 2017 06:17:044+0000
I approve this document.
5e9eb6ba-ac95-46d1-aa92-422b0263855d
05 Jul 2017 06:19:038+0000
I approve this document.
46ae2ef9-034f-40e5-9bb5-774b9b7a9b25
05 Jul 2017 13:41:010+0000
I approve this document.
46ae2ef9-034f-40e5-9bb5-774b9b7a9b25
05 Jul 2017 13:41:010+0000
I approve this document.


Esperion Therapeutics, Inc. 
Version 2.0, July 03, 2017
Protocol: ETC-1002-038 
Statistical Analysis Plan
Confidential 
Page 3 of 18
Revision History 
Ite
m 
No. 
Version 
Affecte
d 
Description of change 
1 
1.0 
Section 5.1 General Statistical Considerations: Changed Analysis visit 
window. 
From 
To 
2 
1.0 
Section 5.2.6 Medical History: Removed mITT population set. 
3 
1.0 
Section 5.3.1 & 5.3.2: Updated for non-parametric analysis. 
DocUUID : 4d830059-a909-45a6-95d8-f7f0eaccd93f


Esperion Therapeutics, Inc. 
Version 2.0, July 03, 2017
Protocol: ETC-1002-038 
Statistical Analysis Plan
Confidential 
Page 4 of 18
Table of Contents 
1 
List of Abbreviations .................................................................................................. 5 
2 
Introduction ................................................................................................................. 7 
3 
Study Objectives and Endpoints ................................................................................. 7 
3.1 
Objectives ............................................................................................................. 7 
3.2 
Primary Endpoints ................................................................................................ 7 
 
Primary Endpoint .......................................................................................... 7 
3.2.1
 
Secondary Endpoints .................................................................................... 7 
3.2.2
 
Safety Endpoints ........................................................................................... 8 
3.2.3
4 
Study Design ............................................................................................................... 8 
4.1 
Study Design ........................................................................................................ 8 
4.2 
Randomization ..................................................................................................... 8 
4.3 
Sample Size Justification ..................................................................................... 8 
5 
Statistical and Analytical Plans ................................................................................... 9 
5.1 
General Statistical Considerations ....................................................................... 9 
5.2 
Statistical Analysis Plans ..................................................................................... 9 
 
Analysis Sets ................................................................................................. 9 
5.2.1
 
Baseline Definition ..................................................................................... 10 
5.2.2
 
Protocol Violations and Deviations ............................................................ 10 
5.2.3
 
Patient Disposition ...................................................................................... 10 
5.2.4
 
Demographic and Baseline Characteristics ................................................ 10 
5.2.5
 
Medical History .......................................................................................... 11 
5.2.6
 
Prior Medications and Concomitant Medications/Procedures .................... 11 
5.2.7
 
Study Drug Exposure and Compliance ....................................................... 11 
5.2.8
5.3 
Efficacy Endpoints and Analyses ....................................................................... 12 
 
Primary Endpoint Analysis ......................................................................... 12 
5.3.1
 
Secondary Efficacy Endpoint Analyses ...................................................... 12 
5.3.2
5.4 
Safety Endpoints and Analyses .......................................................................... 13 
 
Adverse Events (AEs) ................................................................................. 13 
5.4.1
 
Adverse Events of Special Interest ............................................................. 14 
5.4.2
 
Laboratory Evaluations ............................................................................... 15 
5.4.3
 
Physical Examinations (PEs) ...................................................................... 17 
5.4.4
 
Vital Signs ................................................................................................... 17 
5.4.5
6 
Reference .................................................................................................................. 17 
7 
Appendices ................................................................................................................ 18 
DocUUID : 4d830059-a909-45a6-95d8-f7f0eaccd93f


Esperion Therapeutics, Inc. 
Version 2.0, July 03, 2017
Protocol: ETC-1002-038 
Statistical Analysis Plan
Confidential 
Page 5 of 18
1 List of Abbreviations  
Abbreviation or Specialist Term 
Explanation 
AE
Adverse event
AESI 
Adverse events of special interest 
ALB
Albumin
ALK-P
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA 
Analysis of covariance 
ApoB
Apolipoprotein B
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
Ca
Calcium
CI
Confidence interval
CK
Creatine kinase
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRF 
Case Report Form 
DBP 
Diastolic blood pressure 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
FSH
Follicle-stimulating hormone
HBsAg 
Hepatitis B surface antigen 
Hct
Hematocrit
HCV
Hepatitis C virus
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
hs-CRP
High-sensitivity C-reactive protein 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
mITT
Modified Intention-to-treat
IWRS 
Interactive web response system 
LDH
Lactate dehydrogenase
LOCF 
Last observation carried forward 
LSM
Least square mean
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
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Abbreviation or Specialist Term 
Explanation 
non-HDL-C
Non-high-density lipoprotein cholesterol 
PE
Physical exam
PK 
Pharmacokinetic(s)  
PMM 
Pattern mixture model 
PT
Prothrombin time
MedDRA PT 
MedDRA Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SE
Standard error
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SOP 
Standard operating procedures 
SP
Safety population
TB
Total bilirubin
TC
Total cholesterol
TEAE 
Treatment-emergent adverse event 
TG
Triglycerides
TSH
Thyroid-stimulating hormone
ULN 
Upper limit of normal  
WBC 
White blood cell 
WHO 
World Health Organization 
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Statistical Analysis Plan
 
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2 Introduction 
The purpose of this document is to describe the statistical methods, data derivations and 
data summaries to be employed in ETC-1002-038. The preparation of this statistical 
analysis plan (SAP) has been based on International Conference on Harmonisation (ICH) 
E3 and E9 Guidelines and in reference to Protocol ETC-1002-038 (Protocol Final, 
November 11, 2016).  
The SAP will supersede the protocol in the event of any differences between the two 
documents in the plans for data analysis, and the protocol will be amended if appropriate. 
The SAP will be included as an appendix in the clinical study report for this protocol. 
3 Study Objectives and Endpoints 
3.1 Objectives 
The primary objective for this study is to assess the LDL-C lowering efficacy of triplet 
therapy with bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg versus 
placebo administered daily for 6 weeks in patients with elevated LDL-C. 
The secondary objectives are: 
• To assess the effect of triplet therapy versus placebo on non-high-density lipoprotein 
cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), high-
sensitivity C-reactive protein (hs-CRP), TG, and HDL-C 
• To assess the effect of triplet therapy versus placebo on percent of patients achieving 
LDL-C level <70 mg/dL 
• To assess the effect of triplet therapy versus placebo on percent of patients achieving 
LDL-C reduction ≥50% 
• To assess the safety and tolerability of triplet therapy versus placebo 
3.2 Primary Endpoints 
The following endpoints will be used to evaluate the objectives of the study. 
 Primary Endpoint 
3.2.1
• Percent change from baseline to Week 6 in LDL-C 
 Secondary Endpoints 
3.2.2
• Percent change from baseline to Week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and 
HDL-C 
• Percent of patients with LDL-C <70 mg/dL at Week 6 
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• Percent of patients with LDL-C reduction ≥50% from baseline to Week 6 
 Safety Endpoints 
3.2.3
• Patient incidence of adverse events 
• Clinical safety laboratory (including hematology, blood chemistry, and urinalysis) 
results 
• Vital signs and physical examination (PE) findings 
4 Study Design 
4.1 Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study. Patients will initially undergo screening at Week -6 (Visit S1). Eligible 
patients will begin washout of all LDL-C-lowering drugs and nutritional supplements at 
least 5 weeks prior to randomization. Patients will return at Week -1 (S2) for lipid and/or 
other assessments. Patients who are deemed not eligible for randomization at any point 
during screening will be notified by clinical site personnel and considered screen failures. 
At Week 0 (Visit T1), approximately 60 patients will be randomized in a ratio of 2:1 to 
receive either triplet therapy (bempedoic acid 180 mg + ezetimibe 10 mg + atorvastatin 
20 mg) or placebo once daily for 6 weeks. Randomized patients will return for clinic 
visits at Week 3 (Visit T2) and Week 6 (Visit T3). Total treatment duration will be 12 
weeks (6 weeks screening and 6 weeks treatment) with the option to extend screening by 
1 additional week. Up to approximately 20 centers in the US will participate in this. 
Additional sites may be invited to participate to ensure study timelines are met. 
For details of study assessments, see the Schedule of Events in Appendix 1. 
4.2 Randomization  
The randomization number will be determined by a computer-generated random code and 
will correspond to a treatment group according to patient’s sequential entrance into the 
study. The randomization schedule for blinding of treatment assignment will be generated 
by the contract research organization (CRO), provided to IWRS, and released only after 
the study is complete and the database is locked. A patient is considered to be 
randomized when they have been assigned a randomization number by IWRS. 
4.3 Sample Size Justification 
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5 Statistical and Analytical Plans 
5.1 General Statistical Considerations 
In general, summary statistics for continuous variables will include the number of 
patients, mean, median, standard deviation or standard error, first and third quartiles, 
minimum, and maximum. Minimum and maximum will be presented same number of 
decimal places as reported/collected, one additional decimal place for mean and median, 
and two additional decimal places for SD. 
For categorical variables, the frequency and percentage will be given. Percentage will be 
presented with one decimal place. All categories will be presented (even if no patients are 
counted in the category). Counts of zero in any category will be presented without 
percentage.  
Data will be presented on listings in order of patient/patient, assessment date and 
assessment (in order collected on CRF, unless specified otherwise). Dates will be 
presented in format DDMMMYYYY. 
The visit schedules and window are shown below.  
5.2 Statistical Analysis Plans 
 Analysis Sets 
5.2.1
5.2.1.1 Safety Population (SP) 
The Safety Population (SP), used for all of the safety summaries, is defined as all 
randomized patients who received at least 1 dose of study medication. Patients in the SP 
will be included in the treatment group that they actually received, regardless of their 
randomized treatment. 
5.2.1.2 Modified Intent-to-Treat Population (mITT)  
The modified Intent-to-Treat (mITT) population, used for all of the efficacy analyses, is 
defined as all randomized patients who received at least 1 dose of Investigational 
medicinal product (IMP) and have a baseline assessment and at least 1 post-baseline 
assessment, excluding any assessment taken more than 2 days after a dose of IMP. 
Visit 
S1 
S2 
T1 
T2 
T3, EOS 
Slotted Study Week 
-6 
-1 
0 
3 
6 
Target Study Day 
-42 
-7 
1 
22 
43 
Analysis Visit 
Windows 
[-∞,-37] 
[-36,-1] 
[1] 
[2,28] 
[29,+∞] 
Protocol defined 
visit window 
-42 to -37 
-10 to -7 
1 
22±3 
43±3 
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Patients in the mITT will be included in their randomized treatment group, regardless of 
their actually received treatment. 
 Baseline Definition 
5.2.2
Baseline for LDL-C, non-HDL-C, HDL-C, TC, and TG is defined as the mean of the 
values from Week -1 (Visit S2) and predose Day 1/Week 0 (Visit T1), while baseline for 
ApoB and hs-CRP is defined as the predose Day 1/Week 0 (Visit T1) value. If only one 
value is available either at Week -1 or Week 0, then that value will be used as baseline. 
Baseline of other laboratory evaluations and vital signs is defined as the last value prior 
to the first dose of study medication, except baseline of blood pressure is defined as mean 
of 2 measures at same visit. 
 Protocol Violations and Deviations 
5.2.3
A full list of protocol violations and deviations will be compiled and reviewed by the 
clinical team to identify major versus minor violations/deviations before final database 
lock. For violations at study entry, patients will be assessed against the inclusion and 
exclusion criteria of the protocol. For on-study deviations, compliance with the protocol 
will be examined using blinded review of the database with regard to prohibited 
therapies, and timing and availability of planned assessments. The determination of major 
versus minor protocol deviations will be conducted prior to the database lock. Any 
protocol deviation related to inclusion/exclusion criteria will be summarized in table as 
well as listing. Any major on-study protocol deviation will also be summarized by 
treatment group. 
 Patient Disposition  
5.2.4
Disposition, including reason for withdrawal from IMP and the study, will be 
summarized by treatment group. In addition, the number of patients who withdraw from 
the study and withdraw from study drug will be summarized by discontinuation reason. 
 
 Demographic and Baseline Characteristics 
5.2.5
Demographic information and important patient baseline characteristics including, but 
not limited to, gender, race, age, and baseline lipid parameter values will also be 
summarized by treatment group. 
 
The following demographic and baseline characteristics will be summarized by treatment 
group, as well as overall, for safety population and for mITT population: age (years), 
gender, race, ethnicity, height (cm), weight (kg), body mass index (kg/m2), systolic and 
diastolic blood pressure (mmHg), fasting lipid parameters (TC [mg/dL], calculated LDL-
C [mg/dL], HDL-C [mg/dL], non-HDL-C [mg/dL] and TG [mg/dL]), apoB (mg/dL), and 
hs-CRP (mg/dL).  
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Data will be summarized using descriptive statistics for continuous variables and using 
counts and percentages for categorical variables by treatment group and overall. Age will 
be summarized as a continuous variable and by age group (18-40, 41-64, 65-74, and 
>=75). 
 Medical History  
5.2.6
General medical history will be summarized by treatment group, as well as overall, for 
safety population and presented in a by-patient listing.  Where appropriate, terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.1 or 
later.     
 Prior Medications and Concomitant Medications/Procedures 
5.2.7
Prior medications are defined as medications that ended prior to the initiation of double-
blind study drug. Concomitant medications are defined as medications that were ongoing 
at the time of double-blind study drug initiation or new medications that started post 
double-blind study drug initiation and within 30 days following the date of the last dose 
of study drug. 
 
Medications, including prior statin medications, will be coded using WHO Drug (Sept 
2016, or later). The frequency of use of prior medications and use of concomitant 
medications will be summarized by treatment group, as well as overall, for the safety 
population according to Anatomical Therapeutic Chemical (ATC) class and preferred 
term. Prior medications, concomitant medications, and concomitant procedures will be 
listed for each patient.  
 Study Drug Exposure and Compliance 
5.2.8
The length of exposure to study drug (triplet therapy or placebo) will be calculated as the 
number of days from the first dose of double-blind study drug to the last dose of double-
blind study drug, regardless if the patient missed one or more doses of study drug.  If last 
dose of study treatment is missing, then the last IMP return date will be used for 
imputation of end of treatment date. Length of exposure will be summarized by treatment 
group using descriptive statistics for the safety population.  
The number and percentage of patients who were compliant with taking study drug will 
be summarized by treatment group and post-baseline time point for the safety population 
for the following categories 0 - <50%; >=50 - <80%; >= 80%. Compliance at each Visit 
(x) will be assessed by counting the number of tablets that are returned as unused study 
drug and querying the patient regarding daily intake and calculated using the formula: 
100* (Number Dispensed at Visit x-1 – Number Returned at Visit x) / (Duration in days 
between Visit x and Visit x-1).  Compliance at each visit and overall compliance during 
the study will be calculated by programmer.  
The study drug administration and compliance data, including reasons for poor 
compliance, will be listed for each patient. 
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5.3 Efficacy Endpoints and Analyses  
For all efficacy endpoints and analyses, the modified Intent-to-Treat (mITT) population 
will be used.  
 Primary Endpoint Analysis 
5.3.1
The primary efficacy endpoint is the percent change from baseline to Week 6 in LDL-C.  
LDL-C value will be measured directly if TG are >400 mg/dL or LDL-C is <50 mg/dL. 
Baseline is defined as the mean of the values from Week -1 (Visit S2) and predose Day 
1/Week 0 (Visit T1). Percent change from baseline is defined as (observed value-
baseline)/baseline*100. 
An analysis of covariance (ANCOVA) with treatment group as factor and baseline LDL-
C as a covariate will be performed to compare triplet therapy versus placebo for the 
primary endpoint using the mITT population. The least squares mean (LSM) and 
standard error (SE) will be provided for both treatment groups, along with the placebo-
corrected LSM, its 95% confidence interval (CI), and associated p-value.  Statistical 
testing of primary efficacy endpoint will be 2-sided and conducted at the 5% level of 
significance. To account for potential unequal variance between the treatment groups, the 
ANCOVA model will be implemented within mixed model framework and the 
repeated/group= option will be used to allow estimating the residual variances separately 
between the groups. Q-Q plot will be performed to assess normality of data by treatment. 
If the assumptions were severely violated, non-parametric rank based approach will be 
considered. 
An example sas code for ANCOVA analysis is shown as below: 
PROC MIXED DATA=adxx; 
           class usubjid armcd ; 
           model chg = blres armcd  / solution ddfm=kenwardroger; 
repeated/ group=armcd; 
           lsmeans armcd / diff=control (‘0’) cl; 
Missing data for the primary endpoint will be imputed using the last post-baseline 
observation carried forward (LOCF) procedure (only post-baseline values will be carried 
forward).  
A Secondary analysis for the primary endpoint will be conducted use observed data only.  
 Secondary Efficacy Endpoint Analyses 
5.3.2
Secondary endpoints based on percent change from baseline to Week 6 in additional lipid 
and cardiometabolic biomarkers, will be analyzed in a similar manner as the primary 
efficacy endpoint. Baseline for non-HDL-C, HDL-C, TC, and TG is defined as the mean 
of the values from Week -1 (Visit S2) and predose Day 1/Week 0 (Visit T1), while 
baseline for ApoB and hs-CRP is defined as the predose Day 1/Week 0 (Visit T1) value. 
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An analysis of covariance (ANCOVA) with treatment group as factor and baseline as a 
covariate will be performed to compare triplet therapy versus placebo for the secondary 
endpoints using the mITT population. Missing values at Week 6 will be imputed using 
the last observation carried forward (LOCF) procedure (only post-baseline values will be 
carried forward). The least squares mean (LSM) and standard error (SE) will be provided 
for both treatment groups, along with the placebo-corrected LSM, its 95% confidence 
interval (CI), and associated p-value. Q-Q plot will be performed to assess normality of 
data by treatment. If the assumptions were severely violated, non-parametric rank based 
approach will be considered.  
Statistical testing of secondary efficacy endpoints will be 2-sided and conducted at the 
5% level of significance with no adjustment for multiple comparisons, and all p-values 
will be considered descriptive only.  
Analyses using observed data only for the secondary efficacy endpoints will also be 
performed.  
Percent of patients with LDL-C <70 mg/dL at Week 6 and LDL-C reduction ≥50% from 
baseline at Week 6 will be summarized by treatment group. Comparisons between 
treatment groups will be performed using Fisher’s exact test or Pearson’s chi-square test 
on observed data and LOCF data. 
Lipid and cardiometabolic data from all visits will be listed. 
5.4 Safety Endpoints and Analyses 
For all safety endpoints, the safety population (SP) will be used. Descriptive summary 
will be provided for safety endpoints. 
The summarization of AEs will include only TEAEs (defined as AEs that begin or 
worsen after the first dose of double-blind IMP until 30 days after last dose of IMP). All 
TEAEs, SAEs, AEs leading to withdrawal of IMP, fatal AEs and AEs of special interest 
will be summarized by MedDRA SOC and preferred term in descending order of 
frequency by treatment group. 
Clinical safety laboratories, including hematology, blood chemistry, glucose, and 
urinalysis; PE findings; vital signs; and weight will be summarized by the value and by 
change or percent change from baseline in the value (where appropriate) at each 
postbaseline time point. 
 Adverse Events (AEs) 
5.4.1
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.1 or later and will be categorized by system organ class (SOC) and preferred 
term (PT). Patients with AEs that are ongoing at study completion or study withdrawal 
must be followed until resolution, until determined to be stable/chronic, or for 30 days 
after the last study visit, whichever comes first. Summary tables will focus on TEAEs; 
however, listings will include all AEs (with non-TEAEs flagged). 
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In summary tables, TEAEs will be counted as “Not Related” if relationship to study drug 
was recorded as ‘Not Related’ or “Unlikely”. Events will be counted as “Related” if 
relationship to study drug was recorded as ‘Possible’, ‘Probable’, ‘Definite’ or if 
relationship to study drug is missing. 
The severity of the AE will be characterized as mild, moderate, or severe, to the 
following definitions: 
• 
Mild: Events are usually transient and do not interfere with the patient’s daily 
activities 
• 
Moderate: Events introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities  
• 
Severe: Events interrupt the patient’s usual daily activity, are incapacitating with 
inability to do usual activities, or significantly affect clinical status and warrant 
intervention and/or close follow-up  
 
Overviews of TEAEs will be presented by treatment group containing the following 
counts and percentages for: 
 patients with TEAEs 
 patients with TEAEs by SOC and PT 
 patients with TEAEs by maximum severity 
 patients with treatment-related TEAEs 
 patients with treatment-emergent serious adverse events (TE SAEs)  
 patients with TE SAEs by SOC and PT 
 patients with TE SAEs by maximum severity 
 patients with treatment-related TE SAEs  
 withdrawal from study drug due to TEAEs 
 
AE summaries will include cumulative incidence (percent of patients experiencing the 
AE). If appropriate, absolute and relative risk differences will be calculated using both 
cumulative incidence and incidence rates.  
 
The AE overview summaries will count a patient at most once in each AE category (at 
the “highest/most extreme” designation of each category regardless of preferred term) 
and percentages will be based on the total number of patients in the safety population. 
In addition to a comprehensive listing of all AEs (with non-TEAEs flagged), separate 
listings will be generated for SAEs, AEs resulting in withdrawal of study drug, and AEs 
with a fatal outcome. 
 Adverse Events of Special Interest 
5.4.2
Adverse events of special interest (AESI) include hepatic disorders (including changes in 
hepatic aminotransferases), musculoskeletal events (AE and CK evaluation), new onset 
diabetes/hyperglycemia, renal events, metabolic acidosis and/or hypoglycemia, and 
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neurocognitive/neurologic events. These events will be pulled out of the AE databases by 
SOC and PT, and will be identified as safety monitoring endpoints. 
 Hepatic safety will be assessed via liver-associated enzymes (eg, ALT, AST) and 
total bilirubin. 
 Musculoskeletal safety will be assessed via AEs involving muscle related 
symptoms.  Changes in creatine kinase (CK) values will also be summarized.   
 New onset diabetes/hyperglycemia will be assessed via AEs and monitoring of 
glucose.   
 Renal safety will be assessed via eGFR measurements, changes in serum 
creatinine and blood urea nitrogen values, as well as CK values. 
 Neurocognitive events will be assessed by routine monitoring of PE findings and 
AEs.   
 Hypoglycemia will be assessed by routine clinical laboratories and AEs and  
summarized based on AE evaluations 
 Metabolic acidosis occurrences will be monitored by routine laboratories and 
summarized based on AE evaluations. 
AESI will be presented in a listing and summarized by SOC, PT and treatment group. 
Muscle-related TEAEs will be summarized by SOC, PT, and baseline eGFR category. 
 Laboratory Evaluations 
5.4.3
Continuous laboratory parameters (serum chemistry, hematology), urinalysis, urinalysis 
[microscopic]) listed in Table 4; and glucose will be summarized using descriptive 
statistics for the observed value and the change from baseline for all post-baseline study 
visits. Missing values for any of the laboratory evaluations will not be imputed; that is, 
only observed case data will be used. Baseline is defined as the last value prior to the first 
dose of study medication. Categorical urinalysis data will be provided in the listing. 
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Table 4: 
Clinical Laboratory Parameters (Safety) 
Hematology 
Blood Chemistry (serum, fasting) 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Mean corpuscular hemoglobin 
(MCH) 
 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
Mean corpuscular volume (MCV) 
 
Platelet count 
 
Red blood (RBC) cell count 
 
White blood (WBC) cell count with 
differential (absolute and %) 
Urinalysis (Dipstick) 
 
Clarity 
 
Bilirubin 
 
Color 
 
Glucose 
 
Ketones 
 
Leukocyte esterase 
 
Nitrate 
 
Occult blood 
 
pH 
 
Protein 
 
Specific gravity 
 
Urobilinogen  
 
Urinalysis (Microscopic)-only if urine 
dipstick abnormal 
 Bacteria 
 Casts 
 Crystals 
 Epithelial cells 
 Red blood cell (RBC) 
 WBC 
 Albumin (Alb) 
 Alkaline phosphatase (Alk-P) 
 Alanine aminotransferase 
(ALT; SGPT) 
 Aspartate aminotransferase 
(AST; SGOT) 
 Blood urea nitrogen (BUN) 
 Calcium (Ca) 
 Carbon dioxide (CO2) 
 Chloride (Cl) 
 Creatinine 
 Creatine kinase (CK) 
 Glucose 
 Lactate dehydrogenase (LDH) 
 Phosphorus 
 Potassium (K) 
 Sodium (Na) 
 Total and direct bilirubin (TB) 
 Total protein 
 Uric acid 
 
Coagulation (In all patients at screening, 
then only in patients receiving 
anticoagulant therapy that in the 
investigator’s judgment require 
monitoring at Visit T1 and 3 to 5 days 
post Visit T1 ) 
 Prothrombin time (PT) 
 International normalized ration 
(INR) 
 
 
The number and percentage of patients with laboratory abnormalities (i.e., laboratory 
values outside the stated laboratory normal range) will be summarized at each time point 
(i.e., including baseline and post-baseline time points) for each laboratory parameter. The 
determination of laboratory abnormalities will take into account any unscheduled 
laboratory assessments.  Additional lab-related summaries will be provided as follows for 
hepatic safety, musculoskeletal safety, diabetes and glycemia, and renal safety. 
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 Physical Examinations (PEs) 
5.4.4
Listings of PE data will include only those records where the body system at the baseline 
PE was normal, but the body system at a post-baseline PE was marked as ‘Change from 
previous exam, clinically significant.’  Only changes from baseline physical examination 
findings that meet the definition of an AE will be recorded on the AE page of the eCRF 
and will be summarized with other AEs. 
 Vital Signs 
5.4.5
Actual values and changes from baseline in vital signs (heart rate, systolic blood pressure, 
diastolic blood pressure, weight, height [baseline only], and BMI) will be summarized 
using descriptive statistics by treatment group and post-baseline time point on the 
observed values. Baseline is defined as the last value prior to the first dose of study 
medication, except baseline of blood pressure is defined as mean of 2 measures at same 
visit. 
Vital signs data will be listed for each patient, with increases from baseline of >15 mmHg 
in systolic or diastolic blood pressure flagged. 
For vital signs, observed values and changes from baseline will be summarized for all 
post-baseline study visits. 
6 Reference 
1. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, et 
al. Atherosclerosis Risk in Communities Study Group. Coronary Heart 
Disease Prediction from Lipoprotein Cholesterol Levels, Triglycerides, 
Lipoprotein(A), Apolipoproteins A-I and B, and HDL Density Subfractions. 
The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 
2001;104:1108-13. 
2. World Health Organization (WHO) Fact Sheet No 317 Updated January 2015. 
3. Robinson JG. Management of Familial Hypercholesterolemia: A Review of 
the recommendations from the National Lipid Association Expert Panel on 
Familial Hypercholesterolemia. J Managed Care Pharm. 2013;19(2):139-49. 
4. Haase A, Goldberg AC. Identification of people with heterozygous familial 
hypercholesterolemia. Curr Opin Lipidol. 2012;23:282-9. 
5. Glynn RJ, Laird NM, and Rubin DB. (1986). Selection modelling versus 
mixture modelling with nonignorable nonresponse. In H. Wainer (ed.), 
Drawing Inferences from Self-Selected Samples, pp. 115–142. New York: 
Springer. 
 
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7 Appendices 
Appendix 1: Schedule of Events (Patient Visit Schedule) 
 
Screen 
Treatment 
Visit 
S1 
S2
1
 
T1 
T2 
T3 
Week  
-6 
-1 
0 
3 
6/EOS/ET
2
 
Procedure  
Day -42 to -37 
Day -10 to -7
Day 1
Day 22 ± 3 
Day 43 ± 3
Informed Consent 
X 
 
 
 
 
Enrollment Criteria 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant\Prohibite
d Medications 
X 
X 
X 
X 
X 
Adverse Event 
Recording 
 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
X 
Weight3 
X 
 
X 
 
X 
Height/BMI 
X 
 
 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
Serology5 
 
X 
 
 
 
Serum Pregnancy 
and/or FSH6 
X 
 
 
 
 
Urine Pregnancy6 
 
 
X 
 
 
TSH 
X 
 
 
 
 
Clinical Safety Labs7 
X 
 
X 
X 
X 
Basic Fasting Lipid8 
X 
X 
X 
X 
X 
Special Fasting Lipids 
and Other Biomarkers9 
 
 
X 
 
X 
Dietary and Lifestyle 
Counselling 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
Double-blind IMP 
Dispensing 
 
 
X 
X 
 
IMP Drug Return 
 
 
 
X 
X 
 
BMI = body mass index; FSH = follicle-stimulating hormone, TSH = thyroid-stimulating hormone, EOS = End of Study, ET = 
Early Termination. 
1 An optional visit approximately 1 week later MAY be completed if patient fails to meet a lipid entry criterion. If this optional 
visit is completed, the mean of the LDL-C values, or TG values, will be used to determine eligibility. 
2 All procedures will be completed at end of study or early termination. 
3 Body weight will be measured in the morning while fasting, using consistent scales, after voiding, and without shoes and 
outerwear (eg, coats). 
4 Vital signs will include SBP, DBP, and heart rate, and will be collected prior to any blood sample collection. Patient will rest 
for 5 minutes prior to assessments. 
5 Serology for Hep B antigen, Hep C antibody. 
6 FSH completed in appropriate postmenopausal women only; pregnancy test completed in non-postmenopausal women only. 
7 Clinical safety labs include hematology, blood chemistry, and urinalysis. Coagulation panel ONLY in patients receiving 
anticoagulants measured only at T1 and repeat 3-5 days after starting IMP. 
8 Basic fasting lipids include total cholesterol, calculated LDL-C, HDL-C, non-HDL-C, and triglycerides. 
9 Includes ApoB and hs-CRP 
 
 
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