Conditions: Hyperlipidemias
Keywords: hyperlipidemia heterozygous familial hypercholesterolemia atherosclerotic cardiovascular disease high cholesterol ASCVD HeFH LDL
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 382
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if Bempedoic Acid (BA) + Ezetimibe (EZE) in a fixed-dose combination (FDC) is effective and safe versus its individual components and placebo in patients with elevated LDL cholesterol treated with maximally tolerated statin therapy.

Detailed description:

Arms:
arm 1: Bempedoic acid (BA) + ezetimibe (EZE) fixed-dose combination (FDC) 180 mg/10 mg tablets taken orally once daily for 12 weeks arm 2: Bempedoic acid (BA) 180 mg tablets taken orally once daily for 12 weeks arm 3: Ezetimibe (EZE) 10 mg overencapsulated tablets taken orally once daily for 12 weeks arm 4: Placebos to match identical bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or identical bempedoic acid 180 mg tablet, or identical ezetimibe 10 mg capsule, taken orally, once daily for 12 weeks

Interventions: intervention 1: Bempedoic Acid + Ezetimibe Fixed-Dose Combination intervention 2: Bempedoic Acid intervention 3: Ezetimibe intervention 4: Placebos
Intervention descriptions: intervention 1: bempedoic acid + ezetimibe FDC 180 mg/10 mg tablet intervention 2: bempedoic acid 180 mg tablet intervention 3: ezetimibe 10 mg overencapsulated tablet intervention 4: placebo tablet or capsule to match bempedoic acid + ezetimibe fixed-dose combination (FDC) 180 mg/10 mg tablet, or bempedoic acid 180 mg tablet, or ezetimibe 10 mg capsule

Protocol document:
Prot_000.pdf: 
Confidential 
Page 1 of 116 
1.
TITLE PAGE
BEMPEDOIC ACID (ETC-1002) 
1002FDC-053 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF BEMPEDOIC ACID 
180 MG + EZETIMIBE 10 MG FIXED-DOSE COMBINATION 
COMPARED TO BEMPEDOIC ACID, EZETIMIBE, AND PLACEBO 
ALONE IN PATIENTS TREATED WITH MAXIMALLY TOLERATED 
STATIN THERAPY 
Study Phase: 
3 
IND Number: 
130707 
Indication: 
Treatment of hyperlipidemia 
Investigators: 
Approximately 125 sites located in North America  
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: 
03 August 2017 
Amendment 1: 
18 October 2017 
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. THE INFORMATION IN 
THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS REQUIRED BY FEDERAL OR STATE 
LAW OR REGULATIONS.  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: NCT03337308
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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2. 
SYNOPSIS 
Name of Sponsor: Esperion Therapeutics, Inc. 
Title of Study:  
A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of Bempedoic 
Acid 180 mg + Ezetimibe 10 mg Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and 
Placebo Alone in Patients Treated with Maximally Tolerated Statin Therapy  
Study Number:  1002FDC-053 
Phase of Development:  3 
Clinical Sites:  Approximately 125 sites located in North America 
Primary Objective: 
The co-primary objectives are to assess low-density lipoprotein cholesterol (LDL-C) lowering efficacy in 
patients receiving maximally tolerated statin therapy and treated for 12 weeks with bempedoic acid (BA) 
180 mg + ezetimibe (EZE) 10 mg fixed-dose combination (FDC) versus each of the following: 
• 
Placebo 
• 
BA 180 mg   
• 
EZE 10 mg 
Secondary Objectives: 
• 
To assess the efficacy of BA 180 mg + EZE 10 mg FDC versus placebo alone, BA alone, and 
EZE alone on high-sensitivity C-reactive protein (hs-CRP), high-density lipoprotein cholesterol 
(HDL-C), non-HDL-C, total cholesterol (TC), triglycerides (TG), and apolipoprotein B (apoB) 
after 12 weeks of treatment; 
• 
To characterize the safety and tolerability of BA 180 mg + EZE 10 mg FDC versus placebo 
alone, BA alone, and EZE alone through 12 weeks of treatment. 
Exploratory Objectives: 
• 
To assess the efficacy BA 180 mg + EZE 10 mg FDC versus placebo alone, BA alone, and EZE 
alone on percentage of patients attaining LDL-C <70 mg/dL after 12 weeks of treatment; 
• 
To characterize the plasma trough concentrations of BA and/or EZE when administered as BA 
180 mg + EZE 10 mg FDC, BA alone, and EZE alone. 
Study Design:  
This is a Phase 3, randomized, double-blind, parallel group, multicenter study of BA + EZE versus its 
individual components and placebo. Screening (S1) will occur within approximately 2 weeks prior to 
randomization.  Patients who are deemed not eligible for randomization at any point during screening will 
be notified by clinical site personnel regarding their eligibility status and considered screen failures.  
Approximately 350 eligible patients will be randomized 2:2:2:1 on Day 1/Week 0 (T1) to receive either 
BA 180 mg + EZE 10 mg FDC (N = 100), BA 180 mg (n = 100), EZE 10 mg (n = 100) or placebo 
(n = 50) for 12 weeks.  Randomized patients will return for clinic visits at Week 4 (T2), Week 8 (T3), and 
Week 12 (T4).  Patients who withdraw from investigational medicinal product (IMP) treatment will be 
asked to continue to be followed for safety and efficacy using the protocol-specified visit schedule and 
procedures. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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Eligible patients will have 1) documented atherosclerotic cardiovascular diseases (ASCVD), and/or 
2) heterozygous familial hypercholesterolemia (HeFH) and/or 3) multiple cardiovascular risk factors and 
will require additional LDL-C lowering therapy despite receiving maximally tolerated statin background 
therapy.  Maximally tolerated statin therapy may include statin regimens other than daily dosing or no 
statin at all (if not tolerated); please note that simvastatin ≥40 mg/day is prohibited.  A patient’s currently 
used and maximally tolerated statin therapy will be determined by the investigator based on their medical 
judgment and local standard of care.  Available sources, including the patient’s self-reported history of 
lipid-modifying therapy will also be considered.   
Patients will be stratified based on baseline/current statin intensity (high intensity statin versus other) and 
disease characteristics (ASCVD and/or HeFH versus multiple cardiovascular [CV] risk factors).  High 
intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day, all others will be 
categorized as ‘other’ for randomization and stratification purposes.  Definition of ASCVD and/or HeFH 
or multiple CV risk factors are provided in inclusion criteria.  Enrollment will be monitored and a cap 
may be placed, if necessary, to ensure appropriate distribution into either of the statin intensity categories. 
 
For details of study assessments, see the Appendix 1, Schedule of Events. 
Number of Patients (Planned):  Approximately 350 adult male and female patients. 
Duration of Study:  Total study duration will be approximately 14 weeks (2 weeks [up to 16 days] of 
screening and 12 weeks of treatment).  
Inclusion Criteria:  
1. Provision of written informed consent prior to any study-specific procedure; 
2. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at Week -2 
(Visit S1); 
3. Men and nonpregnant, nonlactating women.  
Women must be either:  
• 
Naturally postmenopausal reported by the patient and defined as: 
− 
≥55 years and ≥1 year without menses, or 
− 
<55 years and ≥1 year without menses with follicle-stimulating hormone (FSH) ≥40.0 IU/L); 
Study Visits 
Week: 
Visit Number: 
Screening 
12 Week Treatment 
↑ 
Wk 8 
T3 
↑ 
Wk 12 
T4 
↑ 
Wk 0 
TI 
↑ 
Wk -2 
S1 
↑ 
Wk 4 
T2 
EZE 10 mg (n=100) 
Placebo (n=50) 
BA 180 mg (n=100) 
BA 180 mg + EZE 10 mg FDC (n=100) 
Patients with 
↑LDL-C 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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• 
Surgically sterile including hysterectomy, bilateral oophorectomy, or tubal ligation or;  
• 
Women of childbearing potential willing to use at least 1 acceptable method of birth control.  The 
minimal requirement for adequate contraception should be functional on Day 1, continuing during 
the study period and for at least 30 days after the last dose of study drug.  Acceptable methods of 
birth control include: 
− 
oral, implantable, injectable or topical birth control medications; 
− 
placement of an intrauterine device with or without hormones; 
− 
barrier methods including condom or occlusive cap with spermicidal foam or spermicidal 
jelly; 
− 
vasectomized male partner who is the sole partner for this patient; 
− 
true abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception). 
Note:  There are no protocol-specific birth control requirements for men with partners who are able to 
become pregnant.  
4. Treated with maximally tolerated statin therapy at stable dose for at least 4 weeks prior to screening.  
Maximally tolerated statin therapy may include statin regimens other than daily dosing, such as no 
statin to very low doses. A patient’s maximally tolerated statin therapy will be determined by the 
investigator using their medical judgment and local standard of care. Available sources, including the 
patient’s self-reported history of lipid-modifying therapy will also be considered. 
5. Fasting LDL-C at Week -2 (Visit S1) while on maximally tolerated statin therapy:  
• 
ASCVD and or HeFH: ≥100 mg/dL (2.6 mmol/L); 
• 
Multiple cardiovascular risk factors: ≥130 mg/dL (3.4 mmol/L). 
Note: If a patient fails to meet LDL-C criterion, an optional single repeat visit/measurement can, at the 
discretion of the investigator, be completed up to a maximum of 10 days later. For those patients who 
have a repeat LDL-C measurement, the repeat value will be used to determine eligibility. 
6. Meeting the definition for at least 1 of the following 3 categories (ASCVD, HeFH, multiple 
cardiovascular risk factors): 
a. Documented ASCVD including 1 or more of the following:  
• 
Acute MI; 
• 
Silent MI; 
• 
Unstable angina; 
• 
Coronary revascularization procedure (e.g., percutaneous coronary intervention [PCI] or 
coronary artery bypass graft [CABG] surgery); 
• 
Clinically significant coronary heart disease (CHD) diagnosed by invasive or non-invasive 
testing (such as coronary angiography, stress test using treadmill, stress echocardiography, or 
nuclear imaging); 
• 
Symptomatic peripheral arterial disease (PAD) defined as: 
o peripheral vascular disease with symptoms of claudication or resting limb ischemia 
with either ankle brachial index <0.9, or 
o angiogram (including computed tomographic angiography [CTA]) showing ≥50% 
stenosis, or 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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o peripheral arterial revascularization (surgical or percutaneous) occurring greater than 
90 days prior to Visit S1, or 
o abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair 
occurring greater than 90 days prior to Visit S1, or 
o lower extremity amputation due to peripheral vascular disease occurring greater than 
90 days prior to Visit S1; 
• 
Cerebrovascular atherosclerotic disease defined by: 
o ischemic stroke occurring greater than 90 days prior to Visit S1, or 
o Carotid endarterectomy, carotid stenting, or more than 70% stenosis in a carotid 
artery determined by carotid ultrasound or angiogram occurring greater than 90 days 
prior to Visit S1. 
b. HeFH diagnosed by either genotyping or by clinical assessment using either the World Health 
Organization (WHO) criteria or the Dutch Lipid Clinical Network criteria with a score that is 
>8 points (see Appendix 4) or the Simon Broome Register Diagnostic criteria with an assessment 
of ‘Definite HeFH’ (see Appendix 5).  Patients with a diagnosis of HeFH may or may not also 
have ASCVD. 
 
OR 
 
c. Multiple cardiovascular risk factors defined as diabetes + 1 other risk factor or 3 risk factors that 
may include: 
a. Age (men ≥45 years; women ≥55 years) at Week -2 (Visit S1); 
b. Family history (coronary heart disease in a first degree relative, men <45 years; women 
<55 years); 
c. Smoking (current smoker); 
d. Hypertension (Systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg 
and/or on antihypertensive medications) at Week -2 (Visit S1); 
e. Low HDL-C (<40 mg/dL) at Week -2 (Visit S1); 
f. Coronary calcium score >95% for age/sex (see Appendix 6). 
Exclusion Criteria:  
1. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L) at Week -2 (Visit S1). 
Note:  If a patient fails to meet TG criterion, an optional single repeat visit/measurement can, at the 
discretion of the investigator, be completed up to a maximum of 10 days later.  For those patients who 
have a repeat TG measurement, the repeat value will be used to determine eligibility. 
2. Renal dysfunction or nephritic syndrome or a history of nephritis, including estimated glomerular 
filtration rate (eGFR) (using central laboratory determined Modification of Diet in Renal Disease 
[MDRD] formula) <30 mL/min/1.73 m2 at Week -2 (Visit S1) (Levey 2006).  
Note:  If a patient fails to meet eGRF criterion, an optional single repeat visit/measurement can, at the 
discretion of the investigator, be completed up to a maximum of 10 days later.  For those patients who 
have a repeat eGRF measurement, the repeat value will be used to determine eligibility. 
3. Body mass index (BMI) ≥40 kg/m2; 
4. Recent (within 3 months prior to the screening visit [Week -2 (Visit S1)] or between screening and 
randomization visits) myocardial infarction (MI), unstable angina leading to hospitalization, 
uncontrolled, symptomatic cardiac arrhythmia (or medication for an arrhythmia that was started or 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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dose changed within 3 months of screening), CABG, PCI, carotid surgery or stenting, cerebrovascular 
accident, transient ischemic attack (TIA), endovascular procedure or surgical intervention for 
peripheral vascular disease, or plans to undergo a major surgical or interventional procedure (e.g., 
PCI, CABG, carotid or peripheral revascularization).  Patients with implantable pacemakers or 
automatic implantable cardioverter defibrillators may be considered if deemed by the Investigator to 
be stable for the previous 3 months. 
5. Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) ≥160 mmHg and diastolic 
blood pressure (DBP) ≥100 mmHg after sitting quietly for 5 minutes.   
Note:  If a patient fails to meet SBP and/or DBP criteria, an optional single repeat visit/measurement 
can, at the discretion of the investigator, be completed up to a maximum of 10 days later.  For those 
patients who have a repeat blood pressure measurement, the repeat value will be used to determine 
eligibility.   
6. Uncontrolled diabetes including hemoglobin A1C (HbA1C) ≥10% at Week -2 (Visit S1); 
7. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper limit of 
normal (ULN) at Week -2 (Visit S1); 
8. Liver disease or dysfunction, including:  
• 
Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies 
(HCV-AB) at Week -2 (Visit S1), or 
• 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, and/or total 
bilirubin (TB) ≥2 × ULN at Week -2 (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:  If a patient fails to meet ALT and/or AST criteria, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a maximum of 
10 days later.  For those patients who have a repeat ALT and/or AST measurement, 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, patient can be enrolled. 
9. Gastrointestinal conditions or procedures (including weight loss surgery; e.g., Lap-Band® or gastric 
bypass) that may affect drug absorption; 
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL (100 g/L) at Week -2 
(Visit S1); 
11. 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; 
12. Unexplained creatine kinase (CK) >3 × ULN at screening up 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; 
13. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine abuse. 
Patients with amphetamine derivatives prescribed by and under the care of a health care practitioner 
can be enrolled after evaluation by the Investigator; 
14. Blood donation, blood transfusion, participation in a clinical study with multiple blood draws, major 
trauma, or surgery with or without blood loss within 30 days prior to randomization; 
15. Use of any experimental or investigational drugs within 30 days prior to screening; 
16. Previous enrollment in a BA clinical study; 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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17. Use of any of the following drugs within 5 weeks prior to screening (Visit S1) unless otherwise stated 
or a plan to use these drugs during the study is prohibited:  
• 
Systemic corticosteroids.  Topical and inhaled corticosteroids are allowed; 
• 
Simvastatin ≥40 mg/day; 
• 
Non-statin LDL-C-modifying therapies:   
− 
Fibrates  (including fenofibrate); 
− 
Niacin and derivatives; 
− 
Bile acid sequestants; 
− 
Ezetimibe; 
− 
Mipomersen or lomatipide (6 months prior to screening); 
− 
Apheresis; 
− 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (4 months prior to screening 
except PCSK9 small interfering RNA (siRNA), which are prohibited if used at any time in 
the past); 
− 
Cholesteryl ester transfer protein (CETP) inhibitors (12 months prior to screening); 
− 
Red yeast rice extract-containing products (2 weeks prior to screening); 
18. Starting or adjusting the dose of the following permitted drugs within 5 weeks prior to screening. 
These drugs are allowed as long as stable at least 5 weeks prior to screening (Visit S1) unless 
otherwise noted: 
• 
Hormone replacement; 
• 
Thyroid replacement; 
• 
Obesity medication (6 months prior to screening); 
• 
Omega 3 fatty acids; 
• 
Diabetes medications; 
19. Previous intolerance to ezetimibe; 
20. 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; 
21. An employee or contractor of the facility conducting the study, or a family member of the Principal 
Investigator, Co-Investigator, or Sponsor. 
Investigational Medicinal Product, Dosage and Mode of Administration:  
• 
BA 180 mg + EZE 10-mg FDC tablet and matching placebo tablet 
• 
BA 180-mg tablet and matching placebo tablet  
• 
EZE 10-mg capsule and matching placebo capsule 
All IMP will be ingested once daily at a similar time with or without food. 
Non-Investigational Medicinal Product  
All other background drugs including maximally tolerated statin therapy will be administered as 
prescribed by a physician. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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Criteria for evaluation: 
Lipid and Cardiometabolic Assessments: 
• 
Calculated LDL-C, HDL-C, non-HDL-C, TC, TG, and apoB  
− 
If TG exceeds 400 mg/dL (4.5 mmol/L) or LDL-C is <50 mg/dL (1.3 mmol/L), direct 
measure of LDL-C will be conducted and will be used in the analyses. 
• 
hs-CRP 
Safety Assessments: 
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of 
special interest (AESIs) will be reported by treatment group.  Other safety assessments will include 
clinical safety laboratories (including hematology, blood chemistry, HbA1C, and urinalysis), physical 
examination (PE) findings, vital signs, electrocardiogram (ECG) readings, and weight. 
Clinical Laboratory Assessments: 
• 
Hematology:  Hematocrit (Hct), Hgb, mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet count, red blood 
cell (RBC) count, white blood cell (WBC) count with differential (absolute values only). 
• 
Urinalysis (Dipstick):  Clarity, bilirubin, color, glucose, ketones, leukocyte esterase, nitrite, occult 
blood, pH, protein, specific gravity, urobilinogen. 
• 
Urinalysis (Microscopic):  Obtain centrally only if positive urine dipstick; bacteria, casts, crystals, 
epithelial cells, RBC, and WBC. 
• 
Serum Chemistry (fasting):  Albumin (ALB), alkaline phosphatase (ALK-P), ALT (or serum 
glutamic pyruvic transaminase [SGPT]), AST (or serum glutamic oxaloacetic transaminase 
[SGOT]), blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl), 
creatinine, CK, glucose, lactate dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), 
total and direct bilirubin, total protein, uric acid. 
• 
HbA1C. 
Other Screening Laboratories: 
HBsAg, HCV, serum (Visit S1), and urine (Visit T1) pregnancy test (only for females who are of 
childbearing potential), FSH (only for postmenopausal females <55 years), TSH. 
Plasma Trough IMP: 
Plasma trough concentrations of BA (ETC-1002 and its active metabolite ESP15228) and EZE 
(glucuronidated EZE and unconjugated EZE). 
Study Endpoints: 
The primary objectives of this study are demonstrated by three co-primary endpoints: 
• 
Percent change in LDL-C from baseline at Week 12 in BA 180 mg + EZE 10 mg FDC-treated arm 
compared to placebo arm; 
• 
Percent change in LDL-C from baseline at Week 12 in BA 180 mg + EZE 10 mg FDC arm 
compared to BA 180 mg arm; 
• 
Percent change in LDL-C from baseline at Week 12 in BA 180 mg + EZE 10 mg FDC-treated arm 
compared to EZE 10 mg arm. 
The study is considered to have successfully demonstrated its primary objective IF all 3 co-primary 
endpoints achieve statistical significance. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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Secondary endpoints: 
• 
Percent change from baseline at Week 12 in parameters below between the BA 180 mg + EZE 
10 mg FDC-treated arm and placebo arm, BA 180 mg-treated arm or EZE 10 mg arm: 
− 
hs-CRP; 
− 
Non-HDL-C; 
− 
TC; 
− 
ApoB; 
− 
TG; 
− 
HDL-C. 
Exploratory endpoints: 
• 
Proportion of patients attaining LDL <70 mg/dL at Week 12 in BA 180 mg + EZE 10 mg 
FDC-treated arm compared to BA 180 mg arm, EZE 10 mg arm and placebo arm; 
• 
Plasma trough concentrations at Weeks 4, 8, and 12 of BA (ETC-1002 and its active metabolite 
ESP15228) and EZE (glucuronidated EZE and unconjugated EZE) in BA 180 mg + EZE 10 mg 
FDC-treated arm, BA-treated arm, and/or EZE alone treated arm. 
Safety endpoints: 
• 
Patient incidence of TEAE; 
• 
Safety laboratory values, vital signs, PE findings, and ECGs. 
Statistical Methods: 
Sample Size 
The sample size of 100 patients per active treatment group and 50 placebo patients (2:2:2:1) in this study 
(350 patients total) is selected to provide adequate power for each of the co-primary endpoint as well as 
the co-primary endpoint family as a whole.  
Testing Procedures 
The co-primary endpoint family will be tested first, and each co-primary endpoint will be tested at alpha 
level of 0.05.  The testing will stop if any of the co-primary endpoints does not achieve statistical 
significance. The secondary endpoints will only be tested when ALL of the co-primary endpoints are 
significant.  A hierarchical testing procedure will be implemented within each comparison group on 
selected secondary endpoints.  
Each of the secondary endpoint within a comparison group will be tested only if previous endpoint is 
significant at the alpha level assigned for that comparison group, i.e., via a step-down procedure.  
A schematic representation for the statistical testing of the treatment comparisons and the co-primary and 
secondary efficacy endpoints is provided below. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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Analysis Populations 
The Full Analysis Set (FAS), used for all of the efficacy analyses, is defined as all randomized patients. 
The FAS is also known as the intention-to-treat (ITT) set of patients.  Patients in the FAS will be included 
in their randomized treatment group, regardless of their actual treatment.  
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized patients 
who received at least 1 dose of blinded study medication (IMP).  
The PK analysis set (PKS), used for all of the PK-related summaries, is defined as all patients in the SP 
who have at least 1 PK assessment unless major protocol deviations are identified to have affected the PK 
data or if key dosing or sampling information is missing.  
Disposition and Baseline Characteristics 
Disposition, including reason for withdrawal from the IMP and study, will be summarized by treatment 
group.  Demographic information and patient baseline characteristics including, but not limited to, 
gender, race, age, and baseline vital signs will also be summarized by treatment group. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the percent change from baseline to Week 12 in LDL-C.  Baseline is 
defined as the mean of the LDL-C values from Week -2 (Visit S1and predose Day 1/Week 0 (Visit T1).  
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with treatment 
group and randomization stratification as factors and baseline LDL-C as a covariate.   
Missing values for primary endpoint will be imputed using multiple imputation method, taking account 
for the adherence to the treatment.  For patients with missing data and no longer receiving treatment at 
Week 12, their LDL-C will be imputed as their baseline value, for those with missing data but still 
receiving treatment, their LDL-C value will be imputed using a regression model based imputation 
including treatment, stratification factor, baseline LDL-C as auxiliary variables.   


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Fixed-Dose Combination 
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Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
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Secondary Efficacy Analysis 
For the selected secondary endpoints (percent change from baseline to Week 12 in non-HDL-C, apoB, 
TC, and hsCRP), the data will be analyzed in the similar fashion as for the primary endpoints and then the 
step-down procedure as detailed above will be applied to the analysis results for each treatment 
comparison of interest (BA 180 mg + EZE 10 mg FDC versus placebo; BA 180 mg + EZE 10 mg FDC 
versus BA 180 mg; BA 180 mg + EZE 10 mg FDC versus EZE 10 mg). Other secondary endpoints based 
on HDL-C and TG will be analyzed separately outside of the step-down procedure.  For HDL-C, non-
HDL-C, TG, and TC, baseline is defined as the mean of the values from Week -2 (Visit S1) and predose 
Day 1/Week 0 (Visit T1), while baseline for apoB and hs-CRP is the predose Day 1/Week 0 value.  
Safety Analyses 
The summarization of AEs will include only TEAEs, any unfavorable and unintended sign, symptom, or 
disease occurred or worsened in severity since the first dose of the IMP until 30 days after study 
completion whether or not related to the product.  An SAE is defined as any untoward medical occurrence 
that occurs at any dose that results in death, is life-threatening, requires inpatient hospitalization, results in 
persistent or significant disability, or results in a congenital anomaly/birth defect.  TEAEs and SAEs will 
be summarized by system organ class (SOC), severity, and relationship to study drug for each treatment 
group.   
Clinical safety laboratories, including hematology, blood chemistry, HbA1C, glucose, and urinalysis; PE 
findings; vital signs; ECG readings; 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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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
4. 
INTRODUCTION ......................................................................................................22 
4.1. 
Cardiovascular Disease and LDL-C-Lowering Drugs ...............................................22 
4.2. 
Background on Bempedoic Acid ................................................................................24 
4.2.1. 
Mechanism of Action .................................................................................................24 
4.2.2. 
Nonclinical Experience ...............................................................................................24 
4.2.3. 
Previous Human Experience .......................................................................................25 
4.2.4. 
Dose Selection ............................................................................................................26 
4.3. 
Background on Ezetimibe ...........................................................................................26 
4.4. 
Risk Benefit Summary ................................................................................................26 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................27 
5.1. 
Objectives ...................................................................................................................27 
5.1.1. 
Primary Objectives .....................................................................................................27 
5.1.2. 
Secondary Objectives .................................................................................................27 
5.1.3. 
Exploratory Objective: ................................................................................................27 
5.2. 
Study Endpoints ..........................................................................................................27 
5.2.1. 
Primary Endpoint ........................................................................................................27 
5.2.2. 
Secondary Endpoints ..................................................................................................27 
5.2.3. 
Exploratory Endpoints ................................................................................................28 
5.2.4. 
Safety Endpoints .........................................................................................................28 
6. 
INVESTIGATIONAL PLAN .....................................................................................29 
6.1. 
Overall Study Design ..................................................................................................29 
6.2. 
Study Hypothesis ........................................................................................................29 
6.3. 
Estimated Study Duration ...........................................................................................29 


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6.4. 
Number of Clinical Sites ............................................................................................30 
6.5. 
Number of Patients .....................................................................................................30 
7. 
SELECTION OF PATIENTS.....................................................................................31 
7.1. 
Patient Inclusion Criteria ............................................................................................31 
7.2. 
Patient Exclusion Criteria ...........................................................................................33 
7.3. 
Patient Lifestyle and Dietary Guidelines ....................................................................36 
8. 
TREATMENT OF PATIENTS ..................................................................................37 
8.1. 
Administration of Investigational Medicinal Product ................................................37 
8.2. 
Prior and Concomitant Medications ...........................................................................37 
8.2.1. 
Required Medications .................................................................................................37 
8.2.2. 
Prohibited Medications and Dietary Supplement .......................................................38 
8.2.3. 
Permitted Medications ................................................................................................39 
8.3. 
Treatment Assignment, Randomization, and Blinding...............................................39 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................41 
9.1. 
Description of Investigational Medicinal Product ......................................................41 
9.2. 
Investigational Medicinal Product Supply and Control ..............................................41 
9.3. 
Packaging and Labeling ..............................................................................................42 
9.4. 
Investigational Medicinal Product Adherence ............................................................42 
9.5. 
Investigational Medicinal Product Accountability .....................................................42 
9.6. 
Investigational Medicinal Product Handling, Storage, and Disposal .........................43 
10. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS .........................44 
10.1. 
Informed Consent .......................................................................................................44 
10.2. 
Interactive Web Response System and eCRFs ...........................................................44 
10.3. 
Patient Identification Numbers ...................................................................................44 
10.4. 
Rescreening .................................................................................................................44 
10.5. 
Procedures and Schedule of Assessments ..................................................................44 
10.5.1. 
Screening Week -2 (Visit S1; Day -16 to Day -5) ......................................................44 


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10.5.2. 
Treatment Week 0 (Visit T1; Day 1) ..........................................................................45 
10.5.3. 
Treatment Week 4 (Visit T2; Day 29 ± 5 days) .........................................................46 
10.5.4. 
Treatment Week 8 (Visit T3; Day 57 ± 5 days) .........................................................47 
10.5.5. 
Treatment Week 12 (Visit T4; Day 85 ± 5 days)/End of Study or Early 
Termination .................................................................................................................47 
10.6. 
Discontinuations .........................................................................................................48 
10.6.1. 
Patients Inadvertently Enrolled ...................................................................................48 
10.6.2. 
Temporary Discontinuation of Investigational Medicinal Product ............................48 
10.6.3. 
Permanent Discontinuation of Investigational Medicinal Product .............................48 
10.6.4. 
Patient Discontinuation from the Study ......................................................................49 
10.6.5. 
Patients Lost to Follow-Up .........................................................................................49 
10.6.6. 
Discontinuation of Study Sites or the Study ...............................................................50 
11. 
ASSESSMENT OF EFFICACY ................................................................................51 
11.1. 
Assessments of Lipids and hs-CRP ............................................................................51 
12. 
ASSESSMENT OF SAFETY .....................................................................................52 
12.1. 
Safety Parameters .......................................................................................................52 
12.1.1. 
Demographic/Medical History ...................................................................................52 
12.1.2. 
Vital Signs ..................................................................................................................52 
12.1.3. 
Weight and Height ......................................................................................................52 
12.1.4. 
Physical Examination .................................................................................................52 
12.1.5. 
Electrocardiogram .......................................................................................................53 
12.1.5.1. 
Monitoring and Management of Abnormal Electrocardiograms ................................53 
12.1.6. 
Central Clinical Laboratory Tests ...............................................................................53 
12.1.6.1. 
Central Clinical Laboratory Parameters (Safety) .......................................................53 
12.1.6.2. 
Sample Collection, Storage, and Shipping .................................................................55 
12.1.6.3. 
Collection and Assessment of Plasma Trough IMP ...................................................55 
12.1.6.4. 
General Monitoring and Management of Abnormal Clinical Labs ............................55 


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12.1.6.5. 
Total Blood Volume of Central Clinical Laboratory Samples ...................................58 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................59 
13.1. 
Adverse Events ...........................................................................................................59 
13.1.1. 
Definition of Adverse Events .....................................................................................59 
13.1.2. 
Adverse Drug Reaction ...............................................................................................59 
13.1.3. 
Reporting for Adverse Events ....................................................................................59 
13.1.4. 
Severity .......................................................................................................................61 
13.1.5. 
Relationship ................................................................................................................61 
13.1.6. 
Monitoring and Follow-up of Adverse Events ...........................................................61 
13.1.7. 
Treatment-Emergent Adverse Events .........................................................................62 
13.2. 
Serious Adverse Events ..............................................................................................62 
13.2.1. 
Definition of Serious Adverse Event ..........................................................................62 
13.2.2. 
Events not Qualifying as Serious Adverse Events .....................................................62 
13.2.3. 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .........................................................................................................................63 
13.2.4. 
Reporting Serious Adverse Events .............................................................................63 
13.2.5. 
Reporting of Serious Adverse Events to Regulatory Authorities ...............................63 
13.2.6. 
Reporting of Patient Death .........................................................................................64 
13.2.7. 
Reports of Pregnancy ..................................................................................................64 
13.3. 
Adverse Events of Special Interest .............................................................................64 
13.4. 
Data Monitoring Committee .......................................................................................64 
13.5. 
Clinical Event Committee (CEC) ...............................................................................65 
14. 
STATISTICS ..............................................................................................................66 
14.1. 
General Considerations ...............................................................................................66 
14.2. 
Determination of Sample Size ....................................................................................66 
14.3. 
Analysis Populations ..................................................................................................66 
14.4. 
Disposition, Demographics, and Baseline Characteristics .........................................66 


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14.5. 
Co-Primary Endpoint Analysis ...................................................................................67 
14.6. 
Secondary Efficacy Endpoint Analyses ......................................................................67 
14.7. 
Exploratory Endpoints ................................................................................................68 
14.8. 
Safety Endpoints .........................................................................................................68 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................70 
15.1. 
Study Monitoring ........................................................................................................70 
15.2. 
Audits and Inspections ................................................................................................70 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................72 
17. 
ETHICS ......................................................................................................................73 
17.1. 
Institutional Review Board Approval .........................................................................73 
17.2. 
Ethical Conduct of the Study ......................................................................................73 
17.3. 
Written Informed Consent ..........................................................................................74 
17.4. 
Patient Confidentiality ................................................................................................74 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................75 
18.1. 
Inspection of Records .................................................................................................75 
18.2. 
Retention of Records ..................................................................................................75 
18.3. 
Case Report Forms and Study Records ......................................................................75 
19. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................77 
19.1. 
Investigators ................................................................................................................77 
19.2. 
Study Administrative Structure ..................................................................................78 
19.3. 
Amendments and Study Termination .........................................................................78 
19.4. 
Financial Disclosure ...................................................................................................79 
20. 
PUBLICATION AND DISCLOSURE POLICY .......................................................80 
21. 
LIST OF REFERENCES ............................................................................................81 
22. 
APPENDICES ............................................................................................................83 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................84 
APPENDIX 2. SPONSOR’S SIGNATURE ...............................................................................86 


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APPENDIX 3. INVESTIGATOR’S SIGNATURE....................................................................87 
APPENDIX 4. DUTCH LIPID CLINIC NETWORK CRITERIA FOR FAMILIAL 
HYPERCHOLESTEROLEMIA.................................................................................88 
APPENDIX 5. SIMON BROOME REGISTER DIAGNOSTIC CRITERIA FOR 
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA ...........................90 
APPENDIX 6. ESTIMATED PERCENTILES OF CAC BY AGE CATEGORY, 
GENDER, AND RACE/ETHNICITY .......................................................................92 
APPENDIX 7. SUMMARY OF CHANGES IN AMENDMENT 1 ..........................................94 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 2: 
Investigational Medicinal Products ............................................................................41 
Table 3: 
Central Clinical Laboratory Parameters (Lipids and hs-CRP) ...................................51 
Table 4: 
Central Clinical Laboratory Parameters (Safety) .......................................................54 
 
 


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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 
ASCVD 
Atherosclerotic cardiovascular diseases 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the curve during 24 hours 
BA 
Bempedoic acid 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CABG 
Coronary artery bypass graft 
CEC 
Clinical Event Committee 
CETP 
Cholesteryl ester transfer protein 
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 


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Abbreviation or Specialist Term 
Explanation 
CO2 
Carbon dioxide 
CRF 
Case report form 
CRO 
Contract research organization 
CTA 
Computed tomographic angiography 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
EZE 
Ezetimibe 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FDC 
Fixed-dose combination 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1C 
Hemoglobin A1C 
HBsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HCV-ABVivi 
Hepatitis C antibodies 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
Hgb 
Hemoglobin 
HMG-CoA 
3-hydroxy-3-methylglutaryl coenzyme A 
hs-CRP 
High-sensitivity C-reactive protein 


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Abbreviation or Specialist Term 
Explanation 
IB 
Investigator’s Brochure 
ICD 
Informed Consent Document 
ICH 
International Council for Harmonisation 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LFT 
Liver function test 
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 
MI 
Myocardial infarction 
Na 
Sodium 
NOAEL 
No-observed-adverse-effect level 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
PAD 
Peripheral arterial disease 
PCI 
Percutaneous coronary intervention 
PCSK9 
Proprotein convertase subtilisin kexin type 9 
PE 
Physical exam 
PK 
Pharmacokinetic(s) 
PKS 
Pharmacokinetic analysis set 
PT 
Prothrombin time 


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Abbreviation or Specialist Term 
Explanation 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SE 
Standard error 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
siRNA 
Small interfering ribonucleic acid 
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 
TIA 
Transient ischemic attack 
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 (BA) 180 mg + ezetimibe (EZE) 10-mg fixed-dose combination (FDC) is being 
developed to lower low-density lipoprotein cholesterol (LDL-C). 
Bempedoic acid (BA; ETC-1002) is an oral, first-in class, small molecule that is currently being 
investigated in Phase 3 clinical trials as a single agent in patients with primary hyperlipidemia 
who require additional LDL-C lowering.  Bempedoic acid 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 statins, up-regulates 
LDL-C receptors.  However, unlike statins, BA 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 BA.   
Ezetimibe (EZE; Zetia®) 10 mg was approved by the United States (US) Food and Drug 
Administration (FDA) for use to lower LDL-C, total cholesterol (TC), non-high-density 
lipoprotein-cholesterol (non-HDL-C), and apolipoprotein B (ApoB).  Ezetimibe was approved as 
monotherapy and in combination with statins in patients with primary hyperlipidemia, and in 
combination with fenofibrate in patients with mixed hyperlipidemia.  Ezetimibe has been 
approved as a FDC with more than 1 statin, and is currently marketed as an FDC of EZE and 
simvastatin (Vytorin®). 
It is recommended that patients at high risk for future CVD events receive maximally tolerated 
statin therapy (Stone 2013; Catapano 2016).  Despite receiving maximally tolerated statin 
therapy, many patients require additional therapy to further reduce LDL-C to an acceptable level.  
This Phase 3 study in patients treated with maximally tolerated statin background therapy is 
being conducted to characterize the magnitude of additional LDL-C lowering with an FDC of 
BA and EZE and to define the contribution to LDL-C lowering of each individual component. 
4.1. 
Cardiovascular Disease and LDL-C-Lowering Drugs   
Despite aggressive interventional and pharmacologic therapies, cardiovascular disease (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 US, based 
on 2011 death rate data, more than 2150 Americans die from CVD daily, an average of 1 death 
every 40 seconds (Mozaffarian 2015).  Of great concern, approximately 155,000 Americans 
dying from CVD are less than 65 years of age (Mozaffarian 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 


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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 EZE (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 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 EZE, 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 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 and EZE 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 on a 
background of maximally tolerated statin therapy is unknown.  


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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, BA 
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, BA is inactive in skeletal muscle.  This is consistent with the absence of ACSVL1 (the 
synthetase required to activate BA to ETC-1002-CoA and inhibit 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 BA 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 BA.  The long-term safety of BA and 
its metabolites regarding human skeletal muscle is not yet established.   
4.2.2. 
Nonclinical Experience 


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4.2.3. 
Previous Human Experience 


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4.2.4. 
Dose Selection 
4.3. 
Background on Ezetimibe 
Please see the EZE label. 
4.4. 
Risk Benefit Summary 
To date, the nonclinical and clinical data indicate that BA 180 mg has a favorable risk-benefit 
profile.  The ability of BA to achieve clinically meaningful LDL-C lowering while 
demonstrating a favorable tolerability profile in a variety of patient populations supports 
continued development of BA in Phase 3 studies.  
Several Phase 2 clinical studies have assessed the safety and efficacy of BA as add-on to statins 
or in combination with EZE.  These studies showed significant LDL-C lowering and a favorable 
safety profile.  
Please refer to the most recent IB for more detailed information regarding previous human 
experience. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Objectives 
5.1.1. 
Primary Objectives 
The co-primary objectives are to assess LDL-C lowering efficacy in patients receiving 
maximally tolerated statin therapy and treated for 12 weeks with BA 180 mg + EZE 10 mg FDC 
versus each of the following: 
• Placebo; 
• BA 180 mg; 
• EZE 10 mg. 
5.1.2. 
Secondary Objectives 
• To assess the efficacy of BA 180 mg + EZE 10 mg FDC versus placebo alone, BA 
alone, and EZE alone on high-sensitivity C-reactive protein (hs-CRP), non-HDL-C, 
TC, apoB, HDL-C, and TG after 12 weeks of treatment; 
• To characterize the safety and tolerability of BA 180 mg + EZE 10 mg FDC versus 
BA alone, EZE alone and placebo alone through 12 weeks of treatment. 
5.1.3. 
Exploratory Objective: 
• To assess the efficacy BA 180 mg + EZE 10 mg FDC versus placebo alone, BA 
alone, and EZE alone on percentage of patients attaining LDL-C <70 mg/dL after 
12 weeks of treatment; 
• To characterize the plasma trough concentrations of BA and/or EZE when 
administered as BA 180 mg + EZE 10 mg FDC, BA alone, and EZE alone. 
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 12 in LDL-C. 
5.2.2. 
Secondary Endpoints 
• Percent change from baseline to Week 12 in hsCRP, non-HDL-C, TC, ApoB, 
HDL-C, and TG. 


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5.2.3. 
Exploratory Endpoints 
• Percentage of patients attaining LDL-C <70 mg/dL at Week 12; 
• Plasma trough concentrations at Weeks 4, 8, and 12 of BA (ETC-1002 and its active 
metabolite ESP15228) and EZE (glucuronidated EZE and unconjugated EZE) in BA 
180 mg + EZE 10 mg FDC-treated arm, BA-treated arm, and/or EZE alone treated 
arm. 
5.2.4. 
Safety Endpoints 
• Patient incidence of AEs; 
• Clinical safety laboratory (including hematology, blood chemistry, and urinalysis) 
results; 
• Vital signs, electrocardiograms (ECGs) and physical examination (PE) findings. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a Phase 3, randomized, double-blind, parallel group, multicenter study of BA + EZE 
versus its individual components and placebo.  Screening (S1) will occur approximately within 
2 weeks prior to randomization.  Patients who are deemed not eligible for randomization at any 
point during screening will be notified by clinical site personnel regarding their eligibility status 
and considered screen failures.  Approximately 350 eligible patients will be randomized 2:2:2:1 
on Day 1/Week 0 (T1) to receive either BA 180 mg + EZE 10 mg FDC (N = 100), BA 180 mg 
(n = 100), EZE 10 mg (n = 100), or placebo (n = 50) for 12 weeks.  Randomized patients will 
return for clinic visits at Week 4 (T2), Week 8 (T3) and Week 12 (T4). Patients who withdraw 
from investigational medicinal product (IMP) treatment will be asked to continue to be followed 
for safety and efficacy using the protocol-specified visit schedule and procedures. 
Eligible patients will have documented atherosclerotic cardiovascular diseases (ASCVD), 
heterozygous familial hypercholesterolemia (HeFH), and/or multiple cardiovascular risk factors 
and require additional LDL-C-lowering therapy despite receiving maximally tolerated statin 
background therapy.  Maximally tolerated statin therapy may include statin regimens other than 
daily dosing or no statin at all (if not tolerated); however, doses of  simvastatin ≥40 mg/day are 
prohibited.  A patient’s currently used and maximally tolerated statin therapy will be determined 
by the investigator based on their medical judgment and local standard of care.  Available 
sources, including the patient’s self-reported history of lipid-modifying therapy will also be 
considered.   
Patients will be stratified based on baseline/current statin intensity (high intensity statin versus 
other) and disease characteristics (ASCVD and/or HeFH versus multiple CV risk factors).  High 
intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day, all others will 
be categorized as ‘other’ for randomization and stratification purposes.  Definition of ASCVD 
and/or HeFH or multiple CV risk factors are provided in inclusion criteria.  Enrollment will be 
monitored and a cap may be placed, if necessary, to ensure appropriate distribution into either of 
the statin intensity categories. 
6.2. 
Study Hypothesis 
The clinical hypothesis for this study is that BA 180 mg + EZE 10 mg FDC will significantly 
reduce LDL-C versus placebo, BA, and EZE in patients receiving maximum statin background 
therapy treated daily for 12 weeks.  Additionally, it is hypothesized that both BA and EZE 
significantly contribute to the LDL-C lowering efficacy of the FDC.  
6.3. 
Estimated Study Duration  
Total study duration will be approximately 14 weeks (2 weeks screening [up to 16 days] and 
12 weeks treatment). 


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6.4. 
Number of Clinical Sites 
Approximately 125 sites in North America will participate in this study.  Additional sites may be 
invited to participate to ensure study timelines are met.  
6.5. 
Number of Patients 
The study will enroll approximately 350 adult male and female patients.  


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7. 
SELECTION OF PATIENTS 
Please note that eligible patients will have either documented ASCVD, HeFH, and/or multiple 
cardiovascular risk factors.   
7.1. 
Patient Inclusion Criteria 
1. Provision of written informed consent prior to any study-specific procedure; 
2. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at 
Week -2 (Visit S1); 
3. Men and nonpregnant, nonlactating women. 
Women must be either:  
• Naturally postmenopausal reported by the patient and defined as: 
− ≥55 years and ≥1 year without menses, or 
− <55 years and ≥1 year without menses with follicle-stimulating hormone (FSH) 
≥40.0 IU/L); 
• Surgically sterile including hysterectomy, bilateral oophorectomy, or tubal ligation 
or;  
• Women of childbearing potential willing to use at least 1 acceptable method of birth 
control.  The minimal requirement for adequate contraception should be functional on 
Day 1, continuing during the study period and for at least 30 days after the last dose 
of study drug.  Acceptable methods of birth control include: 
− oral, implantable, injectable or topical birth control medications; 
− placement of an intrauterine device with or without hormones; 
− barrier methods including condom or occlusive cap with spermicidal foam or 
spermicidal jelly; 
− vasectomized male partner who is the sole partner for this patient; 
− true abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods], declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception). 
Note:  There are no protocol-specific birth control requirements for men with partners 
who are able to become pregnant.  
4. Treated with maximally tolerated statin therapy at stable dose for at least 4 weeks prior to 
screening.  Maximally tolerated statin therapy may include statin regimens other than 
daily dosing, such as no statin to very low doses. A patient’s maximally tolerated statin 
therapy will be determined by the investigator using their medical judgment and local 


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standard of care. Available sources, including the patient’s self-reported history of lipid-
modifying therapy will also be considered. 
5. Fasting LDL-C at Week -2 (Visit S1) while on maximally tolerated statin therapy:  
• ASCVD and or HeFH: ≥100 mg/dL (2.6 mmol/L); 
• Multiple cardiovascular risk factors: ≥130 mg/dL (3.4 mmol/L). 
Note: If a patient fails to meet LDL-C criterion, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later. For those patients who have a repeat LDL-C measurement, 
the repeat value will be used to determine eligibility. 
6. Meeting the definition for at least 1 of the following 3 categories (ASCVD, HeFH, 
multiple cardiovascular risk factors): 
a. Documented ASCVD including 1 or more of the following:  
− Acute MI; 
− Silent MI; 
− Unstable angina; 
− Coronary revascularization procedure (e.g., percutaneous coronary intervention 
[PCI] or coronary artery bypass graft [CABG] surgery); 
− Clinically significant CHD diagnosed by invasive or non-invasive testing (such as 
coronary angiography, stress test using treadmill, stress echocardiography, or 
nuclear imaging); 
− Symptomatic peripheral arterial disease (PAD) defined as: 
○ peripheral vascular disease with symptoms of claudication or resting limb 
ischemia with either ankle brachial index <0.9, or 
○ angiogram (including computed tomographic angiography [CTA]) showing 
≥50% stenosis, or 
○ peripheral arterial revascularization (surgical or percutaneous) occurring 
greater than 90 days prior to Visit S1, or 
○ abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair 
occurring greater than 90 days prior to Visit S1, or 
○ lower extremity amputation due to peripheral vascular disease occurring 
greater than 90 days prior to Visit S1; 


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− Cerebrovascular atherosclerotic disease defined by: 
○ ischemic stroke occurring greater than 90 days prior to Visit S1, or 
○ Carotid endarterectomy, carotid stenting, or more than 70% stenosis in a 
carotid artery determined by carotid ultrasound or angiogram occurring 
greater than 90 days prior to Visit S1. 
b. HeFH diagnosed by either genotyping or by clinical assessment using either the 
World Health Organization (WHO) criteria or the Dutch Lipid Clinical Network 
criteria with a score that is >8 points (see Appendix 4) or the Simon Broome Register 
Diagnostic criteria with an assessment of ‘Definite HeFH’ (see Appendix 5).  Patients 
with a diagnosis of HeFH may or may not also have ASCVD. 
OR 
c. Multiple cardiovascular risk factors defined as diabetes + 1 other risk factor or 3 risk 
factors that may include: 
a. Age (men ≥45 years; women ≥55 years) at Week -2 (Visit S1); 
b. Family history (coronary heart disease in a first degree relative, men <45 years; 
women <55 years); 
c. Smoking (current smoker); 
d. Hypertension (Systolic blood pressure ≥140 mmHg, diastolic blood pressure 
≥90 mmHg and/or on antihypertensive medications) at Week -2 (Visit S1); 
e. Low HDL-C (<40 mg/dL) at Week -2 (Visit S1); 
f. Coronary calcium score >95% for age/sex (see Appendix 6). 
7.2. 
Patient Exclusion Criteria 
1. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L) at Week -2 
(Visit S1). 
Note:  If a patient fails to meet TG criterion, an optional single repeat visit/measurement 
can, at the discretion of the investigator, be completed up to a maximum of 10 days later.  
For those patients who have a repeat TG measurement, the repeat value will be used to 
determine eligibility. 
2. Renal dysfunction or nephritic syndrome or a history of nephritis, including estimated 
glomerular filtration rate (eGFR) (using central laboratory determined Modification of 
Diet in Renal Disease [MDRD] formula) <30 mL/min/1.73 m2 at Week -2 (Visit S1) 
(Levey 2006).  
Note:  If a patient fails to meet eGRF criterion, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later.  For those patients who have a repeat eGRF measurement, the 
repeat value will be used to determine eligibility. 


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3. Body mass index (BMI) ≥40 kg/m2; 
4. Recent (within 3 months prior to the screening visit [Week -2 (Visit S1)] or between 
screening and randomization visits) myocardial infarction (MI), unstable angina leading 
to hospitalization, uncontrolled, symptomatic cardiac arrhythmia (or medication for an 
arrhythmia that was started or dose changed within 3 months of screening), CABG, PCI, 
carotid surgery or stenting, cerebrovascular accident, transient ischemic attack (TIA), 
endovascular procedure or surgical intervention for peripheral vascular disease, or plans 
to undergo a major surgical or interventional procedure (e.g., PCI, CABG, carotid or 
peripheral revascularization).  Patients with implantable pacemakers or automatic 
implantable cardioverter defibrillators may be considered if deemed by the Investigator to 
be stable for the previous 3 months. 
5. Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) ≥160 mmHg 
and diastolic blood pressure (DBP) ≥100 mmHg after sitting quietly for 5 minutes.   
Note:  If a patient fails to meet SBP and/or DBP criteria, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later.  For those patients who have a repeat blood pressure 
measurement, the repeat value will be used to determine eligibility.   
6. Uncontrolled diabetes including hemoglobin A1C (HbA1C) ≥10% at Week -2 (Visit S1); 
7. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the 
upper limit of normal (ULN) at Week -2 (Visit S1); 
8. Liver disease or dysfunction, including:  
• Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C 
antibodies (HCV-AB) at Week -2 (Visit S1), or 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, 
and/or total bilirubin (TB) ≥2 × ULN at Week -2 (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:  If a patient fails to meet ALT and/or AST criteria, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later.  For those patients who have a repeat ALT and/or AST 
measurement, 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, patient can be enrolled. 
9. Gastrointestinal conditions or procedures (including weight loss surgery; e.g., Lap-Band® 
or gastric bypass) that may affect drug absorption; 
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL (100 g/L) 
at Week -2 (Visit S1); 


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11. 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 
12. Unexplained creatine kinase (CK) >3 × ULN at screening up to randomization (i.e., 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; 
13. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine 
abuse. Patients with amphetamine derivatives prescribed by and under the care of a health 
care practitioner can be enrolled after evaluation by the Investigator; 
14. Blood donation, blood transfusion, participation in a clinical study with multiple blood 
draws, major trauma, or surgery with or without blood loss within 30 days prior to 
randomization; 
15. Use of any experimental or investigational drugs within 30 days prior to screening.; 
16. Previous enrollment in a BA clinical study; 
17. Use of any of the following drugs within 5 weeks prior to screening (Visit S1) unless 
otherwise stated or a plan to use these drugs during the study is prohibited:  
• Systemic corticosteroids.  Topical and inhaled corticosteroids are allowed. 
• Simvastatin ≥40 mg/day; 
• Non-statin LDL-C-modifying therapies:   
− Fibrates  (including fenofibrate); 
− Niacin and derivatives; 
− Bile acid sequestants; 
− Ezetimibe; 
− Mipomersen or lomatipide (6 months prior to screening); 
− Apheresis; 
− PCSK9 inhibitors (4 months prior to screening except PCSK9 small interfering 
RNA (siRNA), which are prohibited if used at any time in the past); 
− Cholesteryl ester transfer protein (CETP) inhibitors (12 months prior to 
screening); 
− Red yeast rice extract-containing products (2 weeks prior to screening); 
18. Starting or adjusting the dose of the following permitted drugs within 5 weeks prior to 
screening. These drugs are allowed as long as stable at least 5 weeks prior to screening 
(Visit S1) unless otherwise noted: 
• Hormone replacement; 
• Thyroid replacement; 


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• Obesity medication (6 months prior to screening); 
• Omega 3 fatty acids; 
• Diabetes medications; 
19. Previous intolerance to ezetimibe; 
20. 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; 
21. An employee or contractor of the facility conducting the study, or a family member of the 
Principal Investigator, Co-Investigator, or Sponsor. 
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 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 BA 180 mg + 
EZE 10 mg FDC, BA 180 mg, EZE 10 mg, or placebo once daily.  Each daily allotment of IMP 
is comprised of 2 tablets and 1 capsule provided in a blister package.  Patients will be instructed 
to ingest IMP orally once daily with or without food at a similar time every day.  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 day.  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, with the exception of statins (particularly those 
that were not tolerated due to an adverse effect), which will be recorded if taken at any point in 
the past. 
8.2.1. 
Required Medications 
Patients will be required to be on maximally tolerated statin therapy with dose stable for at least 
4 weeks prior to screening (Visit S1). Maximally tolerated statin includes statin regimens other 
than daily dosing, including no to very low doses.  A patient’s currently used and maximally 
tolerated statin therapy will be determined by the investigator based on their medical judgment 
and local standard of care.  Available sources, including the patient’s self-reported history of 
lipid-modifying therapy will also be considered.  Statins may include: 
• Atorvastatin (Lipitor®) (other than sponsor provided) 
• Fluvastatin (Lescol®) 
• Lovastatin (Mevacor®, Altoprev™)  
• Pravastatin (Pravachol®)  


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• Rosuvastatin Calcium (Crestor®)  
• Simvastatin (Zocor®); please note that doses ≥40 mg/day are prohibited 
• Pitavastatin (Livalo®) 
8.2.2. 
Prohibited Medications and Dietary Supplement 
Use of any of the following drugs either in mono or combination therapy within 5 weeks prior to 
Visit S1 (unless otherwise stated) or a plan to use these drugs during the study is prohibited:  
• Systemic corticosteroids.  Topical and inhaled corticosteroids are allowed; 
• Simvastatin ≥40 mg/day; 
• Select non-statin LDL-C-modifying therapies:   
− Fibrates including gemfibrozil (Lopid®), fenofibrate (Antara®, Lofibra®, Tricor®, 
and Triglide™, Lipantil®, Supralip®), clofibrate (Atromid-S), ciprofibrate 
(Modalim®), bezafibrate (Bezalip®); 
− Niacin and derivatives including Niaspan® Rx and over-the-counter niacin 
(crystalline >500 mg/day or slow release or timed release at any dose); 
− Bile acid sequestants including Cholestyramine (Questran®, Questran® Light, 
Prevalite®, Locholest®, Locholest® Light); colestipol (Colestid®); colesevelam 
HCl (WelChol®, Cholestagel®); 
− Ezetimibe (Zetia®, Ezetrol®) other than that which is study-supplied; 
− Mipomersen or lomatipide (6 months prior to screening); 
− Apheresis; 
− PCSK9 inhibitors (4 months prior to screening except PCSK9 siRNA, which are 
prohibited if used at any time in the past); 
− CETP inhibitors (12 months prior to screening); 
− Red yeast rice extract-containing products (2 weeks prior to screening). 
Other Drugs: 
• Probenecid or cyclosporine; 
• 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. 


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8.2.3. 
Permitted Medications 
Patients in this study may be using a wide range of concomitant medications, according to local 
standard of care for their medical conditions.  Permitted medications must be stable for at least 
2 weeks prior to Visit S1 (Week -2) with the exception of the medications described below. 
The following permitted medications that may impact plasma lipid levels are allowed provided 
that they are stable at least 5 weeks prior to screening (Visit S1) unless otherwise noted: 
• Hormone replacement; 
• Thyroid replacement; 
• Obesity medication (6 months prior to screening); 
• Omega 3 fatty acids; 
• Diabetes medications.  
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 BA 180 mg + EZE 10 mg FDC, BA 180 mg, EZE 
10 mg or placebo.  The randomization will be stratified by baseline statin intensity (high 
intensity vs. other) and disease characteristics (ASCVD and/or HeFH vs. multiple CV risk 
factors).  Only atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day are considered high 
intensity statin and all others will be considered as ‘other’ for randomization purpose.  The 
criteria for determining these 2 stratification factors are further detailed in Section 7.1).  The 
investigator or designee will utilize Interactive Web Response System (IWRS) during the visit to 
randomize the patient and obtain the appropriate IMP container via medication identification 
numbers (MED ID).  A patient is considered to be randomized when the corresponding 
randomization box is checked within the eCRF. 
Randomization 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; an independent bio-analytical lab will be aware of treatment 
assignment only to support PK sample analysis.   
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 
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 


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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, 
ApoB, hs-CRP, 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: 
Product Name: 
Investigational Medicinal Product 
Ezetimibe 
Placebo to Match Ezetimibe 
Dosage Form: 
Over-encapsulated 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: 
Product Name: 
Investigational Medicinal Product 
Bempedoic acid + ezetimibe FDC 
Placebo to Match Bempedoic acid + 
ezetimibe FDC 
Dosage Form: 
Tablets 
Tablets 
Unit Dose: 
180 mg/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: 
Please see Pharmacy Manual for detailed storage requirements and instructions and additional 
information. 
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. 


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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 packs.  Each blister pack will contain a 9-day 
supply and 4 blister packs will be provided in the 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 tablets 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); 
• 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; 


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• Nonstudy disposition (e.g., 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, and IWRS is contacted via eCRFs.  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 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 two 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 -2 (Visit S1; Day -16 to Day -5) 
The screening period will begin with a screening visit that will occur within approximately 
2 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: 
• Assess AEs and serious adverse events (SAEs) (starting from signing the informed 
consent document); 
• Demographics; 
• Clinically relevant medical history; 


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• 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:  
− TSH; 
− Hematology, blood chemistry, and urinalysis; 
− Serology (including HBsAg, hepatitis C virus [HCV] antibody); 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG); 
− Serum pregnancy test (in female patients of childbearing potential) or FSH (only 
in postmenopausal women <55 years of age); 
− HbA1C; 
• 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 
return for Visit T1 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). 
Note:  An unscheduled visit may be completed no more than 10 days after the screening visit 
if patient fails to meet entry criteria for LDL-C, TG, DBP, SBP, eGFR, ALT, AST, serology 
and/or CK entry criterion at the discretion of the investigator if warranted.  For those patients 
who have a repeat measurement, the repeat value will be used to determine eligibility. 
10.5.2. 
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, ECG 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.  
At randomization, patients will be stratified based on baseline/current statin intensity (High vs. 
Other) and disease characteristics (ASCVD and/or HeFH vs. multiple CV risk factors).  High 
intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day, all others will 
be categorized as ‘other’ for randomization and stratification purposes.  Definition of ASCVD 
and/or HeFH or multiple CV risk factors are provided in inclusion criteria.  


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The patient will undergo the following assessments and procedures: 
• Concomitant medication review (ongoing); 
• Assess AEs and SAEs; 
• PE; 
• ECG; 
• Urine pregnancy test (in female patients of childbearing potential); 
• Review inclusion/exclusion criteria to establish patient eligibility; 
• Randomize the patient and obtain MED ID number for double-blind IMP; 
• 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; 
• Dispense double-blind IMP and provide dosing and storage instructions. 
10.5.3. 
Treatment Week 4 (Visit T2; Day 29 ± 5 days) 
Patients will undergo the following assessments and procedures: 
• 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); 
• Trough PK sample; 
• 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. 


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10.5.4. 
Treatment Week 8 (Visit T3; Day 57 ± 5 days) 
Patients will undergo the following assessments and procedures: 
• 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); 
• Trough PK sample; 
• 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. 
10.5.5. 
Treatment Week 12 (Visit T4; Day 85 ± 5 days)/End of Study or Early 
Termination 
Patients will undergo the following assessments and procedures: 
• 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; 
• Trough PK sample; 
• ECG; 
• Return of IMP; assessment and recording of IMP adherence. 


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10.6. 
Discontinuations 
10.6.1. 
Patients Inadvertently Enrolled  
The inclusion and exclusion criteria for enrollment must be followed exactly and completely.  If 
a patient who does not meet enrollment criteria is inadvertently enrolled, the Medical Monitor 
should be contacted within 24 hours of identification.  If it is determined after discussion with 
the Medical Monitor that, in considering patient safety, it is appropriate to continue IMP 
(documentation of this is necessary), the patient will continue on IMP and be monitored for all 
visits and testing (including laboratory measures) for the duration of the study.  If after 
discussion with the Medical Monitor it is determined that the patient should not continue IMP, 
IMP will be discontinued, but the patient will remain in the study to be evaluated for 
concomitant medications, and efficacy and safety endpoints until the end of the study visit. 
Patients inadvertently enrolled under the following criteria should be discontinued from IMP (but 
remain in the study): 
• Female patients who are pregnant or are breastfeeding or who do not agree to use at 
least 1 reliable methods of birth control during the study (unless they have agreed to 
follow the definition of true abstinence); 
• Any clinically significant medical condition that according to the investigator could 
interfere with participation in the study; 
• Unable or unwilling to comply with protocol requirements, or deemed by the 
investigator to be unfit for the study; 
• Have a history of drug, alcohol, or substance abuse within the past 6 months, as 
assessed by the investigator. 
If a patient stops IMP for any of the above exclusion criteria following discussion with the 
Medical Monitor, then investigators should notify the Sponsor (or designee).  The reason for the 
patient’s inadvertent enrollment should be documented in the patient’s record. 
10.6.2. 
Temporary Discontinuation of Investigational Medicinal Product 
There may be situations in which IMP is temporarily discontinued at the discretion of the 
investigator.  IMP should be restarted as soon as possible based on investigator judgment.  The 
number of days the IMP was not taken, and the reason for temporary discontinuation, should be 
documented in the patient’s medical record.  There is no limit to the amount of time patient can 
be off IMP prior to restarting. 
Investigators should contact the Medical Monitor if IMP is temporarily discontinued and this 
should occur prior to IMP discontinuation if possible. 
10.6.3. 
Permanent Discontinuation of Investigational Medicinal Product 
There may be situations where it may be necessary for a patient to permanently discontinue IMP. 
Investigators should contact the Medical Monitor prior to permanent IMP discontinuation to 
discuss the situation.  If IMP is permanently discontinued, the patient will remain in the 


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study to be evaluated for concomitant medications, efficacy and safety endpoints until the 
final study visit.  If the patient is unwilling or unable to return for follow-up visits in person, 
alternatives such as telephone contact visits per the Schedule of Events, or telephone follow up at 
the end of the study should be used to collect as much data as possible.  The follow-up frequency 
will be documented in the eCRF. 
The reason for permanent discontinuation of IMP should be documented in the eCRF.  If the 
discontinuation of IMP is due to an AE, the event should be documented in the eCRF.  Some 
possible reasons that may lead to permanent early IMP discontinuation include: 
• In the opinion of the investigator, any AE or a significant change in a laboratory value 
that warrants permanent discontinuation of IMP therapy.  Investigators are advised to 
call the Medical Monitor prior to making such a decision; 
• Illness, condition, or procedural complication (including AEs) affecting the patient’s 
ability to participate or requiring prohibited medication.  Investigators are advised to 
call the Medical Monitor prior to making such a decision; 
• Female patients who become pregnant or are breastfeeding or who do not agree to use 
at least 1 reliable methods of birth control during the study (unless they have agreed 
to follow the definition of true abstinence) will be permanently discontinued from 
IMP; 
• The patient requests to stop IMP permanently; 
• The patient study blind is broken; 
• Enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.  If after discussion with the study Medical 
Monitor it is determined that the patient should not continue IMP, IMP will be 
discontinued; 
• Patient moves away and it is impossible to come to this or any other trial site for 
visits as required by protocol. 
10.6.4. 
Patient Discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be 
uncommon, occurring only if the patient explicitly withdraws consent. At the time of 
discontinuing from the study, the Medical Monitor should be contacted, and, if possible, an early 
discontinuation visit should be conducted, per the Study Schedule. The patient will be 
permanently discontinued both from the IMP and from the study at that time. During the study 
closeout period, survival (vital) status will be collected within legal and ethical boundaries for all 
patients randomized who withdrew their participation from the study. 
10.6.5. 
Patients Lost to Follow-Up 
A patient would be considered potentially lost to follow-up if he or she repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.  Site personnel are expected 


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to make diligent attempts to contact patients who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.  Investigators are advised to call the Medical 
Monitor prior to concluding patient is lost to follow-up.  Vital status will be collected within 
legal and ethical boundaries during the study closeout period.  If vital status is determined, the 
patient will not be considered lost to follow-up. 
10.6.6. 
Discontinuation of Study Sites or the Study 
The Sponsor may suspend enrollment or discontinue a site at any time. A written statement will 
be provided to the investigator, the IRB or IEC, and regulatory authorities, if required.  
Possible reasons for site discontinuation include, but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality; 
• Inaccurate or incomplete data collection on a chronic basis; 
• Falsification of records; 
• Failure to adhere to the protocol; 
• Lack of study oversight by the Principal Investigator and/or designee. 
If any serious or nonserious AEs have occurred at such a clinical site, all documentation relating 
to the event(s) must be obtained. 
The Sponsor will retain responsibility for discontinuation of the study. The study will be 
discontinued if necessary for medical, safety, regulatory or other reasons consistent with 
applicable laws, regulations, and Good Clinical Practice (GCP). 


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11. 
ASSESSMENT OF EFFICACY  
11.1. 
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 criterion below.  If this criterion has not been 
met, these blood samples will NOT be collected.  If this criterion 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 are allowed)  
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 12.1.6. 
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.  
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.   
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 
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; 


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• 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. 
Electrocardiogram 
ECG collection will be preceded by a 10-minute rest time during which the patient will remain in 
the supine position. At each time point, ECGs will be collected prior to blood collection. ECGs 
will be assessed using machine readings and physician review. 
12.1.5.1. Monitoring and Management of Abnormal Electrocardiograms 
If a clinically significant ECG abnormality not present at baseline (screening) is determined by 
the Investigator to be related to study drug, the abnormality will be discussed with the Sponsor 
personnel or the authorized Medical Monitor, and followed and evaluated with additional tests (if 
necessary) until the underlying cause is determined or the event is brought to an acceptable 
resolution. Additional clinical and laboratory information will be collected and carefully 
documented in order to better characterize the ECG abnormality and rule out alternative causes.  
ECG findings determined to be a clinically significant change from baseline should be reported 
as an AE regardless of causality. 
Unscheduled ECG assessments will be completed at the discretion of the Investigator. 
12.1.6. 
Central Clinical Laboratory Tests 
12.1.6.1. 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 
• 
Nitrite 
• 
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 that in the investigator’s 
judgment requires monitoring, 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 
Other Sample Collection 
• 
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 >1 year 
without menses) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Plasma trough investigational medicinal product 
(IMP) 
12.1.6.2. 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.  
12.1.6.3. Collection and Assessment of Plasma Trough IMP 
Plasma trough IMP will be measured at Weeks 4, 8, and 12.  A single 6-mL whole blood sample 
will be collected and processed by the site according to instructions provided in the manual 
provided by the Central Laboratory.  At the time of sample collection, the date and time of blood 
draw and the last 2 doses of study medication will also be collected.  Samples will be shipped to 
the central clinical laboratory and subsequently forwarded to a bio-analytical lab for 
measurement and analysis.   
Plasma trough IMP concentrations will be measured and analyzed using validated methods and 
will include BA (ETC-1002 and its active metabolite ESP15228) and EZE (glucuronidated EZE 
and unconjugated EZE). 
12.1.6.4. 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 report to document their 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 study drug.  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 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. 


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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. 
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. 
12.1.6.4.1. 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.  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. 


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12.1.6.4.2. 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 patient should receive further assessment and investigation into the cause, assess 
whether there is renal injury and measure CK approximately weekly or more 
frequently if clinically indicated until resolution.  If CK levels continue to rise; IMP 
should be discontinued.   
• If the repeat CK assessment confirms an unexplained (i.e., 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.  
12.1.6.4.3. Monitoring and Management of Elevated TG 
Patients may continue to use stable doses of TG-lowering medications (except fibrates) during 
the study.  Post-randomization, TG results will be masked to investigators in order to maintain 
the blind; however, a threshold has been set to notify investigators and provide an opportunity to 
adjust the patient’s standard of care regimen. If the TG level exceeds 1000 mg/dL (11.3 mmol/L) 
while on treatment, the investigator will receive notification from the central laboratory that the 
patient has met or exceeded the protocol defined threshold criteria for TG.  
• Any patient with initial report of TG >1000 mg/dL (11.3 mmol/L), will be counseled 
on healthy dietary guidelines, and reminded to take IMP and other background 
medications as directed and fast for at least 10 hours prior to repeat TG assessment. 
• Patient will return to clinic within 1 week for a repeat, fasting TG assessment to 
confirm the TG value meets the threshold criteria.  


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• Any patient with a confirmed TG >1000 mg/dL (11.3 mmol/L) will have TG 
lowering medications (except fibrates) adjusted or added if possible to lower TG.  
Changes in medications will be documented on the case report form.  These 
medications will not be provided by the sponsor.  
12.1.6.4.4. Monitoring and Management of Potential Hypoglycemia and Metabolic Acidosis 
Patients will be educated by the Investigator or designee 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 by the Investigator or designee 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.  
12.1.6.5. 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 PK 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 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. 
An AE can be:  
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, 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; 
• Any deterioration in nonprotocol-required measurements of laboratory value or other 
clinical test (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug; 
• TEAEs are defined as AEs that begin or worsen after the first dose of study drug; 
• Adverse drug reaction (ADR; see Section 13.1.2). 
13.1.2. 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an ADR. “Responses” to a medicinal product means that a causal relationship 
between a medicinal product and an AE is at least a reasonable possibility (i.e., 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 (e.g., 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 to 
study completion or discontinuation) will be collected on the AE eCRF.  Patients should be 
instructed to report any AE that they experience to the Investigator through 30 days following 
study completion or discontinuation.  Beginning with Visit S1 (Week -2), Investigators should 
make an assessment for AEs at each visit and record the event on the appropriate AE eCRF.  
Any SAE that occurs from the time of signing informed consent through 30 days following study 
completion should be reported to the Sponsor per Section 13.2.4. 
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, 


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the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, transfusion) 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 changes in severity or seriousness at any time 
during the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at baseline and significantly worsen during the study 
should be reported as AEs.  The Investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is 
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 
investigational drug. For each AE, the following information will be recorded: 
• Description of the event (e.g., 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 study drug. 
A cluster of signs and symptoms that results from a single cause should be reported as a single 
AE (e.g., fever, elevated 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 
the relationship of AEs to study drug administration should be determined by the Investigator or 
study physician after thorough consideration of all facts that are available. 
Additional information will be collected regarding muscle-related AEs that may include, but may 
not necessarily be limited to, a muscle-related questionnaire, with questions regarding type of 
muscle-related symptoms, location of the muscle-related AE, and potential cause of the muscle-
related AE. 


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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 study drug and the 
AE. The degree of “relatedness” of the AE to the study drug 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 for regulatory reporting purposes.  
• Possible:  Temporal association, but other etiologies are likely the cause.  However, 
involvement of the study drug cannot be excluded.  
• Probable:  Temporal association, other etiologies are possible but unlikely.  The event 
may respond if the study drug is discontinued.  
• Definite:  Established temporal association with administration of the study drug with 
no other more probable cause.  Typically, the event should resolve when the study 
drug 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. 
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, 
stabilization of the event(s), or until the patient is lost to follow-up or dies. 


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Patients with AEs that are ongoing at study completion or study withdrawal must be followed 
until resolution or for 30 days after the last study visit, whichever comes first. 
13.1.7. 
Treatment-Emergent Adverse Events 
TEAE are defined as AEs that begin or worsen after the first dose of study drug until 30 days 
after study completion or as defined in the study-specific statistical analysis plan.  
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:  Hospitalization is defined as a formal inpatient admission. This will not include 
admissions under “23-hour Observational Status”, an Emergency Room visit without hospital 
admission or an Urgent Care visit and therefore, such events will not be recorded as an SAE 
under this criterion. Admission to the hospital for social or situational reasons (e.g., 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. 
13.2.2. 
Events not Qualifying as Serious Adverse Events 
The following is not considered an SAE and therefore does not need to be reported as such:  
• Overdose of either Esperion study drug or concomitant medication unless the event 
meets SAE criteria (e.g., hospitalization).  However, the event should still be captured 
as a nonserious AE on the appropriate eCRF page 


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13.2.3. 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events 
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 central (or local where appropriate) laboratory.  
In some cases, significant changes in lab values within the normal range will require similar 
judgment. For criteria of reporting abnormal lab values as AE, see Section 12.1.6.4. 
13.2.4. 
Reporting Serious Adverse Events 
All SAEs, regardless of relationship to study drug, occurring from the time of informed consent 
until 30 days following study completion, must be reported by the Principal Investigator or 
designee to the authorized Medical and Safety Services within 24 hours of the Principal 
Investigator or the clinical site becoming aware of the occurrence.  For most patients this will be 
30 days following their Week 12 (Visit T4) visit.  All SAEs that the Investigator considers 
related to study drug that occur after the 30-day follow-up of the study period must be reported 
to the Sponsor. 
To report the SAE, complete the SAE information in the clinical electronic data capture (EDC) 
database within 24 hours of becoming aware of the occurrence.  Additional information, such as 
diagnostic test results or hospital discharge summary can be sent via email 
(drugsafety@esperion.com) or via fax (+1-734-887-3988). 
The Investigator is required to submit SAE reports to the IRB/IEC 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 study drug 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 (e.g., patient discharge summary or autopsy reports) to 
the safety contact information provided on the SAE report form. 
13.2.5. 
Reporting of Serious Adverse Events to Regulatory Authorities 
The Sponsor (and/or designee) is responsible for submitting expedited reports of suspected and 
unexpected serious adverse reactions (SUSARS) to the appropriate regulatory authorities. All 
Investigators participating in ongoing clinical studies with the study drug will be notified by the 
Sponsor (or designee) of SUSARs. SUSARS must be communicated as soon as possible to the 
appropriate IRB/IEC by the investigator, as applicable and/or reported in accordance with local 
laws and regulations. Investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor. 
SAEs that are anticipated to occur in this patient population will be collected and reported by the 
Investigator as described in Section 13.2.4.  However, these events will not be submitted to the 


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regulatory authorities as expedited reports unless they meet SUSAR criteria.  These events that 
are considered to be exempt from expedited reporting include the following clinical endpoints:  
• CV death; 
• Nonfatal MI; 
• Nonfatal stroke; 
• Unstable angina requiring hospitalization; 
• Coronary revascularization; 
• Heart failure requiring hospitalization; 
• Noncoronary arterial revascularization. 
13.2.6. 
Reporting of Patient Death 
The death of any patient during the study, or within the 30-day follow-up period after they have 
completed the study (regardless of the cause), must be reported as detailed in Section 13.2.4.   
13.2.7. 
Reports of Pregnancy  
If a female patient becomes pregnant during the study or within 30 days after the last dose of 
study drug, the investigator is to stop dosing with study drug(s) immediately.  A pregnancy is not 
considered to be an AE or an SAE; however, it must be reported to the Sponsor / SAE designee 
using the paper Pregnancy Report Form within the same timelines as an SAE.  A pregnancy 
should be followed through to outcome, whenever possible.  Once the outcome of the pregnancy 
is known, the paper Pregnancy Outcome Report Form should be completed and reported to the 
Sponsor.  Adverse events or SAEs that occur during pregnancy will be assessed and processed 
according to the AE or SAE processes using the appropriate AE CRF.  Patients who become 
pregnant will discontinue IMP immediately and complete the End of Study evaluations.  
13.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) include metabolic acidosis (clinical laboratories), 
hepatic, muscular (AE and CK evaluation), new onset diabetes/hyperglycemia, renal, 
cardiovascular, and neurocognitive/neurologic events.  Specific monitoring guidelines are 
provided in the case of AEs uncovered through laboratory evaluations.   
13.4. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) responsible for monitoring Phase 3 BA 
studies will be informed of this study and available for ad hoc review of specific data if needed.  
However, due to the study’s relatively short enrollment period and treatment duration, the DMC 
will not review data from this study on an ongoing basis.  


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13.5. 
Clinical Event Committee (CEC) 
A blinded independent expert Clinical Event Committee (CEC) responsible for adjudicating 
clinical endpoints including all major cardiovascular events from Phase 3 BA studies will be 
informed of this study and available for ad hoc review of specific data if needed.  However, due 
to the study’s relatively short enrollment period and treatment duration, the CEC will not 
routinely adjudicate clinical endpoints from this study.  


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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 
statistical analysis plan (SAP).  The SAP will supersede the protocol if there are any differences 
between the 2 documents in the plans or descriptions 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 patients, mean, 
median, standard deviation (SD) or standard error (SE), first and third quartiles, minimum, and 
maximum.  For categorical variables, the frequency and percentage will be given.  
14.2. 
Determination of Sample Size 
The sample size of 100 patients per active treatment group and 50 patients in the placebo arm 
(2:2:2:1) of this study (350 patients total) was selected to provide adequate power for each of the 
co-primary endpoint as well as the co-primary endpoint family as a whole.  
14.3. 
Analysis Populations  
The full analysis set (FAS), used for all of the efficacy analyses, is defined as all randomized 
patients.  Patients in FAS will be analyzed in the treatment group they are randomized to 
regardless of the treatment received. 
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of blinded IMP.  Patients in the SP will be included in the 
treatment group that they actually received, regardless of their randomized treatment.  
The PK analysis set (PKS), used for all of the PK-related summaries, is defined as all patients in 
the SP who have at least 1 PK assessment unless major protocol deviations are identified to have 
affected the PK data or if key dosing or sampling information is missing. 
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 baseline characteristics including, but 
not limited to, gender, race, age, and baseline vital signs will also be summarized by treatment 
group. 


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14.5. 
Co-Primary Endpoint Analysis 
The co-primary efficacy endpoints consist of three comparisons of the percent change from 
baseline to Week 12 in LDL-C: FDC vs. placebo, FDC vs. EZE; and FDC vs. BA. 
Each of the comparisons will be carried out using an analysis of covariance (ANCOVA) model 
including treatment group and stratification factors as factors and baseline LDL-C as covariate. 
Baseline LDL-C is defined as the mean of the values from Week -2 (Visit S1) and pre-dose 
Day 1/Week 0 (Visit T1).   
Missing values for primary endpoint will be imputed using multiple imputation (MI) method 
(MI), taking account for the adherence to the treatment.  For patients with missing data and no 
longer receive treatment at Week 12, their LDL-C will be imputed as their baseline value; for 
those with missing data but still receiving treatment, their LDL-C value will be imputed using a 
regression based model including treatment, stratification factors, baseline LDL-C as auxiliary 
variables.  Approximately 200 datasets will be imputed.  The imputed datasets will be analyzed 
using the ANCOVA model described above and the results from the analysis of each imputed 
dataset will be combined using Rubin’s method.  The final results will include the least squares 
mean (LSM), SE, 95% confidence interval (CI) and associated p-values for each treatment 
group, as well as for each treatment group comparison of interests.   
The details of the ANCOVA model and multiple imputations will be further described in the 
SAP. 
Each of the comparisons within the co-primary endpoint family will be conducted at a 
significance level of 0.05. If and only if all three testing achieve statistical significance, the study 
is claimed to meet its primary objective and the hypothesis testing will continue to secondary 
endpoints, otherwise all statistical comparisons for secondary endpoints are considered 
descriptive only. 
14.6. 
Secondary Efficacy Endpoint Analyses 
Secondary efficacy endpoints, which include the percent change from baseline to Week 12 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 -2 (Visit S1) 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.   
As described in Section 14.5, if co-primary endpoint family achieves statistical significance, a 
list of selected secondary endpoints will be tested in sequential order within each comparison 
group. The alpha allocation among the three comparison groups is: alpha = 0.02 for FDC vs. 
EZE or FDC vs. BA; alpha = 0.01 for FDC vs. Pbo 


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All other secondary endpoints not included in the step-down procedure will be tested at 
significant level of 0.05 without multiplicity adjustment. 
14.7. 
Exploratory Endpoints 
The proportion of patients achieving an LDL-C <70 mg/dL after 12-week treatment will be 
summarized for each treatment group and the comparison between FDC vs. EZE; FDC vs. BA, 
and FDC vs. placebo will be based on Chi-sq test or Fisher’s exact test.  No missing data 
imputation will be applied to this analysis.  
Descriptive summary for plasma trough concentrations of BA and/or EZE will be provided at 
Weeks 4, 8, and 12 by treatment group.  
Further details will be provided in the SAP. 
14.8. 
Safety Endpoints 
Descriptive statistics will be provided for summary of TEAEs and other safety assessments. 
TEAEs, SAEs, related AEs, and AESIs will be summarized by system organ class (SOC), 
severity, and relationship to study drug for each treatment group.  Fatal AE, AEs leading to 
discontinuation of IMP or study, will each be summarized by treatment group.  
Clinical safety laboratories, including hematology, blood chemistry, coagulation, HbA1C, 
glucose, and urinalysis; PE findings; vital signs; ECG readings; and weight will be summarized 
by the value and by change/percent change from baseline (where appropriate) at each protocol 
scheduled time point. 


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Hepatic Safety 
Liver-associated enzymes and TB will be summarized by the value and change from baseline in 
the value, by treatment group and visit. In addition, the number and percent of patients with 
abnormal values for ALT, AST, and TB will be summarized. These summaries of patients with 
abnormal values will be performed overall; by normal baseline; and by abnormal baseline for 
each of ALT, AST and TB. Hy’s law criteria (≥3 × ULN for either ALT or AST, with 
accompanying TB >2 × ULN) will also be applied to the data; any potential Hy’s law cases will 
be listed separately.  Note: In the case of patients with Gilbert’s disease, TB will be fractionated 
and the determination of 2 × ULN will be based upon direct (conjugated) bilirubin. 
Musculoskeletal Safety 
AESIs of muscle related symptoms will be summarized by treatment group.  CK levels will be 
summarized by the value and change from baseline in the value, by treatment group and visit.  In 
addition, the number and percent of patients with abnormal CK values will be summarized.  
These summaries of patients with abnormal CK will be performed overall; by normal baseline 
CK; and by abnormal baseline CK.  
Diabetes and Hyperglycemia 
Cases of new onset of diabetes will be recorded as AEs and will be summarized using the 
appropriate SOC.  These events will be summarized by severity, and relationship to study drug 
for each treatment group.  Glucose and HbA1C will be summarized at scheduled time point. 
Renal Safety 
Baseline eGFR will be summarized by treatment group for actual value and for baseline eGFR 
categories.  Shift tables of eGFR category from baseline over the study, will be provided by 
treatment group.  Shift tables of urine protein (negative/positive) from baseline over the study, 
will be provided by treatment group.  Values of CK over the study will be summarized by 
treatment group and by baseline eGFR category.   
Neurocognitive Events 
Neurocognitive events will be evaluated by routine safety monitoring of PE findings and AEs.  
Neurocognitive events will be identified using prespecified Medical Dictionary for Regulatory 
Activities (MedDRA) terms and will be summarized by SOC, severity, and relationship to IMP 
for each treatment group. 


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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 Council for 
Harmonisation (ICH) and GCP guidelines, national and international 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 (e.g., 
laboratory reports, clinic notes, study drug dispensing log, pharmacy records, patient sign-in 
sheets, patient-completed questionnaires, telephone logs, ECGs) required to confirm information 
contained in the eCRFs. 
The monitoring strategy for the study foresees a risk-based monitoring approach, in line with the 
relevant FDA and European Medicines Agency (EMA) recommendations, and will be described 
in detail by the study-specific risk-based-monitoring plan. 
A monitoring visit should include a review of the essential clinical study documents (regulatory 
documents, case report forms, 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. 
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 to be 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 or EMA (or other regulatory authority) to 
verify that the study was conducted in accordance with protocol requirements, as well as the 
applicable regulations and guidelines. 


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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 / 
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 or IEC.  For 
locations participating within the US, the IRB must comply with the provisions specified in 
21 Code of Federal Regulations (CFR) Part 56, ICH and GCP guidelines, and applicable 
pertinent state and federal requirements.  For locations participating outside of the US, the IRB 
or IEC must comply with the applicable requirements of each participating location, including 
ICH and GCP guidelines, except where a waiver is applicable. 
IRBs and IECs 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 or IEC 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 or IECs 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 or IEC 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 or IEC.  This 
includes notification to the IRB or IEC 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 or IEC, and submission 
of final study reports and summaries to the IRB or IEC. 
It is the responsibility of each clinical site to submit information to the appropriate IRB or EC for 
annual review and annual re-approval. 
The Investigator must promptly inform their IRB or IEC 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 ICH/GCP, applicable regulatory requirements, and policies and procedures as 
outlined by the ethical requirements for IRB or IEC 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, EMA, or 
other appropriate regulatory authorities. Monitoring and auditing visits by the Sponsor or 


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authorized designee will be scheduled with the appropriate staff at mutually agreeable times 
periodically throughout the study. 
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 Investigational New Drug (IND) 
application, the Investigator must sign and return a completed Form FDA 1572 “Statement of 
Investigator” to the Sponsor (or designee). For European Union (EU) investigators, equivalent 
information contained within the FDA 1572 form may be requested unless a waiver has been 
requested and received by the Sponsor from the FDA. 
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 be notified 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. 
17.4. 
Patient Confidentiality 
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 the Sponsor’s 
authorized representative).  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 
Sponsor’s authorized representative.  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 IEC, or national 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 the Sponsor’s authorized representative) 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 or IEC 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, study drug 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 (e.g., IRB or IEC correspondence, clinical study materials and supplies shipment 


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manifests, 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 handwritten or computer-generated document that 
contains medical information or test results that have been collected for or in support of the 
protocol specifications (e.g., laboratory reports, clinic notes, study drug disposition log, 
pharmacy records, patient sign-in sheets, patient completed questionnaires, telephone logs, 
X-rays, and ECGs).  All draft, preliminary, and pre/final iterations of a final report are also 
considered to be source documents (e.g., 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 study drug 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 study drug, 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 for each patient 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 a timely manner according to the CRF completion guidelines. 


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19. 
ADMINISTRATIVE CONSIDERATIONS 
19.1. 
Investigators 
The Investigator must agree to the responsibilities and obligations listed below, as specified by 
the appropriate FDA/EMA 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 study drugs are 
being used for investigational purposes and ensure that the requirements relating to 
obtaining informed consent and IRB/IEC 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 study drug; 
• 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/IEC will be responsible for the initial and continuing 
review and approval of the clinical investigation; 
• Agree to promptly report to the IRB/IEC 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/IEC 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  
• DIRECTIVE 2001/20/EC:   
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf  


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• Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance: 
http://www.fda.gov/cder/guidance/959fnl.pdf 
19.2. 
Study Administrative Structure 
Investigational medicinal product (IMP) supply chain details can be found in the pharmacy 
manual. 
Central Laboratory: 
TBD 
Bio-analytic Laboratory: 
Randomization, IWRS, Medical Writing: 
TBD 
Statistical Analysis, Study Management and Monitoring, Data Management, Programming: 
TBD 
Medical and Safety Services including Medical Monitoring: 
Cell phone #: 
Email:
TBD – Corresponding CRO Medical and Safety Monitoring 
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 or 
IEC approval. Documentation of amendment approval by the Investigator and IRB or IEC 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 or IEC 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 


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any departure from the protocol and the source documents will describe the departure and the 
circumstances requiring it. 
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 study drug such that his or her research might be biased by such 
incentive. 


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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, EMA, 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 
Investigator. 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.  


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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. 
Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 
2016 ESC/EAS Guidelines for the Management of Dyslipidemias: The Task Force for the 
Management of Dyslipidemias of the European Society of Cardiology (ESC) and European 
Atherosclerosis Society (EAS) Developed with the special contribution of the European 
Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 
2016;253:281-344. 
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. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54. 


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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. 
Mozaffarian 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. 
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. 
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. 
 


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22. 
APPENDICES 
Appendix 1. 
Schedule of Events  
Appendix 2.  Sponsor’s Signature 
Appendix 3.  Investigator’s Signature 
Appendix 4.  Dutch Lipid Clinic Network Criteria for Familial Hypercholesterolemia  
Appendix 5.  Simon Broome Register Diagnostic Criteria for Heterozygous Familial 
Hypercholesterolemia 
Appendix 6.  Estimated Percentiles of CAC by Age Category, Gender, and Race/Ethnicity 
Appendix 7.  Summary of Changes in Amendment 1 
 


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APPENDIX 1. SCHEDULE OF EVENTS  
Visit 
S11 
T1 
T2 
T3 
T42 
Week 
-2 
0 
4 
8 
12/EOS 
Procedure 
Day -16 to -5 
Day 1 
Day 29 ± 5 
Day 57 ± 5 
Day 85 ± 5 
Informed Consent 
X 
 
 
 
 
Enrollment Criteria 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant\Prohibited Medications 
X 
X 
X 
X 
X 
Adverse Event Recording 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
X 
Weight3 
X 
X3 
X 
X 
X 
Height/BMI 
X 
 
 
 
 
12-Lead ECG4 
 
X 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
Serology6 
X 
 
 
 
 
Serum Pregnancy/FSH 7 
X 
 
 
 
 
Urine Pregnancy  
 
X 
 
 
 
TSH 
X 
 
 
 
 
Clinical Safety Labs8 
X 
X 
X 
X 
X 
Basic Fasting Lipids9 
X 
X 
X 
X 
X 
Special Fasting Lipids and Other 
Biomarkers10 
 
X 
 
 
X 
HbA1C 
X 
 
 
 
 
Plasma Trough Study Drug 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
Double Blind Drug Dispensing 
 
X 
X 
X 
 
Drug Return 
 
 
X 
X 
X 
BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone, HbA1C = hemoglobin A1C; 
TSH = thyroid-stimulating hormone. 
NOTE: For patients who withdraw from IMP treatment, they will continue to have visits according to the protocol 
schedule. Safety assessments should include clinical safety and basic lipid laboratories (except for apoB and 
hs-CRP), adverse events, PE, vital signs, and ECGs. For patients who withdraw from IMP treatment, but refuse to 
come to the clinic for assessments, assessments will take place by phone. The telephone contacts will occur 
according the protocol schedule with information regarding current health status and to collect information on AEs 
(e.g., recent procedures, hospitalizations, and if the patient has died, the cause of death). 


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1 An optional visit approximately 10 days later MAY be completed if patient fails to meet specified entry criteria.  If 
this optional visit is completed, the repeat value 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 (e.g., coats). 
4 Single 12-lead ECG will be collected prior to any blood sample collection. 
5 Vital signs will include SBP, DBP, and HR, and will be collected prior to any blood sample collection.  Patient 
will rest for 5 minutes prior to assessments. 
6 Serology for Hep B antigen, Hep C antibody. 
7 FSH completed in appropriate postmenopausal women only; pregnancy test completed in non-postmenopausal 
women only. 
8 Clinical safety labs include hematology, blood chemistry, and urinalysis.  Coagulation panel only if receiving 
anticoagulants that in the investigator’s judgement requires monitoring (then test at T1 and repeat 3-5 days after 
starting IMP). 
9 Basic fasting lipids include total cholesterol, calculated LDL-C, HDL-C, non-HDL-C, and triglycerides. 
10 Includes apoB and hs-CRP. 


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APPENDIX 2. SPONSOR’S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the 
Efficacy and Safety of Bempedoic Acid 180 mg + Ezetimibe 10 mg 
Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and 
Placebo Alone in Patients Treated with Maximally Tolerated Statin 
Therapy 
Study Number: 
1002FDC-053 
Final Date: 
18 October 2017 
 
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:  
 
 
 
 
 


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APPENDIX 3. INVESTIGATOR’S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the 
Efficacy and Safety of Bempedoic Acid 180 mg + Ezetimibe 10 mg 
Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and 
Placebo Alone in Patients Treated with Maximally Tolerated Statin 
Therapy 
Study Number: 
1002FDC-053 
Final Date: 
18 October 2017 
 
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:  
 
 
 


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APPENDIX 4. DUTCH LIPID CLINIC NETWORK CRITERIA FOR 
FAMILIAL HYPERCHOLESTEROLEMIA 
Dutch Lipid Clinic Network Diagnostic Criteria for Familial Hypercholesterolemia1,2,3 
Diagnostic Scoring for Familial Hypercholesterolemia 
 
CRITERIA 
POINTS 
POSSIBLE 
Family History 
First-degree relative with known prematurea coronary and vascular disease, OR 
First-degree relative with known LDL-C above the 95th percentile 
1 
First-degree relative with tendinous xanthomata and/or arcus cornealis, OR 
Children aged less than 18 years with LDL-C level above the 95th percentile 
2 
Clinical History 
Patient with prematurea coronary artery disease 
2 
Patient with prematurea cerebral or peripheral artery disease 
1 
Physical Examination 
Tendinous xanthomata 
6 
Arcus cornealis prior to age 45 years 
4 
Cholesterol Levels mg/dL (mmol/L) 
LDL-C ≥330 mg/dL (≥8.5 mmol/L) 
8 
LDL-C 250-329 mg/dL (6.5-8.4 mmol/L) 
5 
LDL-C 190-249 mg/dL (5.0-6.4 mmol/L) 
3 
LDL-C 155-189 mg/dL (4.0-4.9 mmol/L) 
1 
DNA Analysis 
Functional mutation in the LDLR, apoB, or PCSK9 gene 
8 
apoB = apolipoprotein B; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein 
receptor; FH = familial hypercholesterolemia; PCSK9 = Proprotein convertase subtilisin/kexin type 9. 
a Premature ≤55 years in men; ≤60 years in women 
Scoring: 
Diagnosis (Diagnosis Based Upon Total Score Obtained) 
Definite Familial Hypercholesterolemia 
>8 
Probable Familial Hypercholesterolemia 
6-8 
Possible Familial Hypercholesterolemia 
3-5 
Unlikely Familial Hypercholesterolemia 
<3 


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References: 
1. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic 
heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J 
Epidemiol. 2004;160:407-20. 
2. Haase A, Goldberg AC. Identification of people with heterozygous familial 
hypercholesterolemia. Curr Opin Lipidol. 2012;23:282-9. 
3. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is 
underdiagnosed and undertreated in the general population: guidance for clinicians to 
prevent coronary heart disease: consensus statement of the European Atherosclerosis 
Society. Eur Heart J. 2013;34:2478-3490a. 
 


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APPENDIX 5. SIMON BROOME REGISTER DIAGNOSTIC CRITERIA 
FOR HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA 
Simon Broome Diagnostic Criteria for Familial Hypercholesterolemia1  
Definite Familial Hypercholesterolemia: 
• Required laboratory = high cholesterol levels: 
− Adult = Total cholesterol levels >290 mg/dL (7.5 mmol/L) or LDL-C 
>190 mg/dL (4.9 mmol/L) 
− Child less than 16 years of age = Total cholesterol levels >260 mg/dL 
(6.7 mmol/L) or LDL-C >155 mg/dL (4.0 mmol/L) 
• Plus at least one of the two: 
− Plus physical finding = tend xanthomas, or tendon xanthomas in first or second 
degree relative 
OR 
− DNA-based evidence of an LDL-receptor mutation, familial defective apoB-100, 
or PCSK9 mutation 
Possible Familial Hypercholesterolemia: 
• Required laboratory = high cholesterol levels: 
− Adult = Total cholesterol levels >290 mg/dL (7.5 mmol/L) or LDL-C 
>190 mg/dL (4.9 mmol/L) 
− Child less than 16 years of age = Total cholesterol levels >260 mg/dL 
(6.7 mmol/L) or LDL-C >155 mg/dL (4.0 mmol/L) 
• Plus at least one of the two: 
− Family history of myocardial infarction at: 
▪ 
Age 60 years or younger in first degree relative 
▪ 
Age 50 years or younger in second degree relative 
OR 
− Family history of elevated total cholesterol 
▪ 
Greater than 290 mg/dL (7.5 mmol/L) in adult first or second degree relative 
▪ 
Greater than 260 mg/dL (6.7 mmol/L) in child, brother or sister aged younger 
than 16 years 


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References: 
1. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic 
heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J 
Epidemiol. 2004;160:407-20. 
 


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APPENDIX 6. ESTIMATED PERCENTILES OF CAC BY AGE 
CATEGORY, GENDER, AND RACE/ETHNICITY 
Percentiles by Race 
Women, n 
Men, n 
Age, y 
Age, y 
45–54 
55–64 
65–74 
75–84 
45–54 
55–64 
65–74 
75–84 
White, n 
379 
356 
379 
194 
321 
325 
375 
174 
25th 
0 
0 
0 
20 
0 
0 
21 
103 
50th 
0 
0 
13 
106 
0 
28 
145 
385 
75th 
0 
16 
119 
370 
22 
155 
540 
1200 
90th 
8 
102 
391 
921 
110 
452 
1345 
2933 
95th 
31 
209 
674 
1535 
207 
743 
2271 
4619 
Chinese, n 
109 
107 
103 
52 
102 
94 
102 
50 
25th 
0 
0 
0 
0 
0 
0 
0 
11 
50th 
0 
0 
5 
32 
0 
5 
34 
81 
75th 
0 
18 
70 
146 
14 
67 
174 
305 
90th 
12 
105 
246 
398 
89 
242 
487 
769 
95th 
44 
213 
436 
656 
184 
429 
803 
1299 
Black, n 
274 
241 
278 
110 
214 
192 
206 
98 
25th 
0 
0 
0 
0 
0 
0 
0 
23 
50th 
0 
0 
0 
47 
0 
0 
32 
141 
75th 
0 
5 
77 
214 
2 
40 
191 
516 
90th 
9 
74 
310 
582 
45 
173 
575 
1281 
95th 
38 
173 
561 
953 
105 
318 
945 
2176 
Hispanic, n 
218 
196 
169 
86 
205 
177 
149 
75 
25th 
0 
0 
0 
0 
0 
0 
1 
36 
50th 
0 
0 
1 
45 
0 
3 
56 
153 
75th 
0 
2 
51 
205 
9 
75 
247 
494 
90th 
2 
50 
203 
557 
88 
291 
666 
1221 
95th 
18 
118 
361 
917 
195 
512 
1091 
1943 


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Reference: 
McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery 
calcium by race, gender, and age results from the Multi-Ethnic Study of Atherosclerosis 
(MESA). Circulation. 2006;113:30-7. 


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APPENDIX 7. SUMMARY OF CHANGES IN AMENDMENT 1 
 
SUMMARY OF CHANGES 
CLINICAL STUDY PROTOCOL 
 
Study Number: 
1002FDC-053 
Study Title: 
A Randomized, Double-Blind, Parallel Group Study to 
Evaluate the Efficacy and Safety of Bempedoic Acid 
180 mg + Ezetimibe 10 mg Fixed-Dose Combination 
Compared to Bempedoic Acid, Ezetimibe, and Placebo 
Alone in Patients Treated with Maximally Tolerated 
Statin Therapy 
Protocol Version Incorporating 
Current Summary of Changes: 
Amendment 1:  18 October 2017 
Preceding Protocol Version: 
Original Protocol:  03 August 2017 
Investigational Product Name: 
ETC-1002 
Conventions used in this Summary of Changes Document 
1. The text immediately preceding and following a change to the protocol is included for 
each change in order to provide the reviewer with a reference point to identify the change 
in the protocol. 
2. All locations (ie, section numbers and/or header text) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
3. The original text is from the preceding protocol version. 
4. In the “New Text”, all substantive text added to the protocol is italicized. 
5. In the “New Text”, text deleted from the protocol is indicated in strikethrough font. 
Summary and Justification of Changes 
The protocol was amended for the following: 
• Made administrative changes throughout protocol where required to correct 
inconsistencies, add clarification, or correct errors. 
• Added instructions for collection, processing, and analysis of plasma trough 
bempedoic acid and ezetimibe concentrations.  This new assessment was added to 
generate additional data describing these plasma trough IMP concentrations in a large 
clinical study.   


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• Added instruction to delay ingestion of IMP on clinic visit days until all study 
procedures have been completed.  This instruction was added to enable accurate 
analysis of plasma trough IMP concentrations.  
• Modified description of drug kit to indicate that 4, not 3, blister packs would be 
provided in each kit.  Four blister packs are needed to supply sufficient drug for 
4-week intervals between treatment visits. 
• Modified instruction for acceptable contraception to functional, not started, on Day 1 
to ensure adequate coverage while IMP is being administered. 
• Added instruction to record prior use of statin at any point in the past, not just within 
6 weeks prior to screening.  Extended statin history will provide additional details 
regarding statins that may have been stopped in the past due to intolerable adverse 
effects.   
• Added comment to exclusion criterion that if test for hepatitis C antibody is positive, 
but optional reflexive test for hepatitis C RNA is negative, patient can be enrolled. 
• Removed erroneous statements that DMC and CEC would review data from this 
study on an ongoing basis. 
• Added instruction to inclusion criteria that multiple risk factors of blood pressure, age 
and HDL-C should be assessed at Week -2 (Visit S1). 
• Added clarification that ezetimibe is prohibited unless it is study supplied.  
• Removed reference to randomization number since no specific number is generated. 
• Added a definition for the PK analysis population. 
• Added detail that an independent bio-analytical lab will be aware of treatment 
assignment during the treatment period only to support pharmacokinetic sample 
analysis. 
 


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CHANGE 1 
REVISION OF TITLE PAGE VERSION INFORMATION 
Location: 
Title Page  
Original Text: 
 
Version 
Date 
 
 
Original Protocol: 
03 August 2017 
 
New Text: 
 
Version 
Date 
 
 
Original Protocol: 
03 August 2017 
 
 
Amendment 1: 
18 October 2017 
 
 
CHANGE 2 
REVISION TO EXPLORATORY OBJECTIVES 
Location:   
Section 2, Synopsis; Section 5.1.3, Exploratory Objective 
Original Text: 
• To assess the efficacy BA 180 mg + EZE 10 mg FDC versus placebo alone, BA 
alone, and EZE alone on percentage of patients attaining LDL-C <70 mg/dL after 
12 weeks of treatment 
New Text: 
• To assess the efficacy BA 180 mg + EZE 10 mg FDC versus placebo alone, BA 
alone, and EZE alone on percentage of patients attaining LDL-C <70 mg/dL after 
12 weeks of treatment; 
• To characterize the plasma trough concentrations of BA and/or EZE when 
administered as BA 180 mg + EZE 10 mg FDC, BA alone, and EZE alone. 
 
CHANGE 3 
ADDITION OF CRITERIA FOR EVALUATION 
Location:   
Section 2, Synopsis 
New Text: 
Plasma Trough IMP 
Plasma trough concentrations of BA (ETC-1002 and its active metabolite ESP15228) and 
EZE (glucuronidated EZE and unconjugated EZE) 
 


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CHANGE 4 
REVISION TO STUDY ENDPOINTS 
Location:   
Section 2, Synopsis; Section 5.2.3, Exploratory Endpoints 
Original Text: 
Exploratory endpoints: 
• Proportion of patients attaining LDL <70 mg/dL at Week 12 in BA 180 mg + EZE 
10 mg FDC-treated arm compared to BA 180 mg arm, EZE 10 mg arm and placebo 
arm 
New Text: 
Exploratory endpoints: 
• Proportion of patients attaining LDL <70 mg/dL at Week 12 in BA 180 mg + EZE 
10 mg FDC-treated arm compared to BA 180 mg arm, EZE 10 mg arm and placebo 
arm; 
• Plasma trough concentrations at Weeks 4, 8, and 12 of BA (ETC-1002 and its 
active metabolite ESP15228) and EZE (glucuronidated EZE and unconjugated 
EZE) in BA 180 mg + EZE 10 mg FDC-treated arm, BA-treated arm, and/or EZE 
alone treated arm. 
 
CHANGE 5 
REVISION TO INCLUSION CRITERIA 
Location:   
Section 2, Synopsis; Section 7.1, Patient Inclusion Criteria 
Original Text: 
3. Men and nonpregnant, nonlactating women,  
Women must be either:  
• Naturally postmenopausal reported by the patient and defined as: 
− ≥55 years and ≥1 year without menses, or 
− <55 years and ≥1 year without menses with follicle-stimulating hormone (FSH) 
≥40.0 IU/L),  
• Surgically sterile including hysterectomy, bilateral oophorectomy, or tubal ligation 
or;  
• Women of childbearing potential willing to use at least 1 acceptable method of birth 
control.  The minimal requirement for adequate contraception should be started on 
Day 1, continuing during the study period and for at least 30 days after the last dose 
of study drug.  Acceptable methods of birth control include: 


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6. Meeting the definition for at least 1 of the following 3 categories (ASCVD, HeFH, multiple 
cardiovascular risk factors): 
c. Multiple cardiovascular risk factors defined as diabetes + 1 other risk factor or 3 risk 
factors that may include: 
a. Age (men ≥45 years; women ≥55 years)   
b. Family history (coronary heart disease in a first degree relative, men <45 years; 
women <55 years)   
c. Smoking (current smoker) 
d. Hypertension (Systolic blood pressure ≥140 mmHg, diastolic blood pressure 
≥90 mmHg and/or on antihypertensive medications) 
e. Low HDL-C (<40 mg/dL) 
f. Coronary calcium score >95% for age/sex (see Appendix 6) 
New Text: 
3. Men and nonpregnant, nonlactating women,  
Women must be either:  
• Naturally postmenopausal reported by the patient and defined as: 
− ≥55 years and ≥1 year without menses, or 
− <55 years and ≥1 year without menses with follicle-stimulating hormone (FSH) 
≥40.0 IU/L),  
• Surgically sterile including hysterectomy, bilateral oophorectomy, or tubal ligation 
or;  
• Women of childbearing potential willing to use at least 1 acceptable method of birth 
control.  The minimal requirement for adequate contraception should be 
startedfunctional on Day 1, continuing during the study period and for at least 
30 days after the last dose of study drug.  Acceptable methods of birth control 
include: 
6. Meeting the definition for at least 1 of the following 3 categories (ASCVD, HeFH, multiple 
cardiovascular risk factors): 
c. Multiple cardiovascular risk factors defined as diabetes + 1 other risk factor or 3 risk 
factors that may include: 
a. Age (men ≥45 years; women ≥55 years) at Week -2 (Visit S1); 
b. Family history (coronary heart disease in a first degree relative, men <45 years; 
women <55 years); 
c. Smoking (current smoker); 


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d. Hypertension (Systolic blood pressure ≥140 mmHg, diastolic blood pressure 
≥90 mmHg and/or on antihypertensive medications) at Week -2 (Visit S1); 
e. Low HDL-C (<40 mg/dL) at Week -2 (Visit S1); 
f. Coronary calcium score >95% for age/sex (see Appendix 6) 
 
CHANGE 6 
REVISION TO EXCLUSION CRITERIA 
Location:   
Section 2, Synopsis; Section 7.2, Patient Exclusion Criteria 
Original Text: 
8. Liver disease or dysfunction, including: 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, 
and/or total bilirubin (TB) ≥2 × ULN at Week -2 (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:  If a patient fails to meet ALT and/or AST criteria, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later.  For those patients who have a repeat ALT and/or AST 
measurement, the repeat value will be used to determine eligibility.   
New Text: 
8. Liver disease or dysfunction, including: 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, 
and/or total bilirubin (TB) ≥2 × ULN at Week -2 (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:  If a patient fails to meet ALT and/or AST criteria, an optional single repeat 
visit/measurement can, at the discretion of the investigator, be completed up to a 
maximum of 10 days later.  For those patients who have a repeat ALT and/or AST 
measurement, 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, patient can be enrolled. 
 


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CHANGE 7 
REMOVAL OF CEC AND DMC REVIEW STATEMENTS 
Location:   
Section 2, Synopsis, Criteria for Evaluation; Section 13.2.1, Definition of Serious Adverse Event 
Original Text: 
Lipid and Cardiometabolic Assessments: 
• Calculated LDL-C, HDL-C, non-HDL-C, TC, TG, and apoB  
− If TG exceeds 400 mg/dL (4.5 mmol/L) or LDL-C is ≤50 mg/dL (1.3 mmol/L), 
direct measure of LDL-C will be conducted and will be used in the analyses 
• hs-CRP 
Safety Assessments: 
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events 
of special interest (AESIs) will be reported by treatment group.  Clinical endpoints will be 
collected and adjudicated by an independent Clinical Event Committee (CEC).  Other safety 
assessments will include clinical safety laboratories (including hematology, blood chemistry, 
HbA1C, and urinalysis), physical examination (PE) findings, vital signs, electrocardiogram 
(ECG) readings, and weight. 
New Text: 
Lipid and Cardiometabolic Assessments: 
• Calculated LDL-C, HDL-C, non-HDL-C, TC, TG, and apoB  
− If TG exceeds 400 mg/dL (4.5 mmol/L) or LDL-C is ≤<50 mg/dL (1.3 mmol/L), 
direct measure of LDL-C will be conducted and will be used in the analyses 
• hs-CRP 
Safety Assessments: 
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events 
of special interest (AESIs) will be reported by treatment group.  Clinical endpoints will be 
collected and adjudicated by an independent Clinical Event Committee (CEC).  Other safety 
assessments will include clinical safety laboratories (including hematology, blood chemistry, 
HbA1C, and urinalysis), physical examination (PE) findings, vital signs, electrocardiogram 
(ECG) readings, and weight. 
 
Original Text: 
13.2.1 
Definitions of Serious Adverse Event 
Any clinical endpoints that meet SAE criteria will be reported as SAEs.  The Clinical Event 
Committee (CEC) will adjudicate clinical endpoints in a blinded fashion, but the Data 
Monitoring Committee (DMC) will review clinical endpoints and SAEs in an unblinded fashion. 


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New Text: 
13.2.1 
Definitions of Serious Adverse Event 
Any clinical endpoints that meet SAE criteria will be reported as SAEs.  The Clinical Event 
Committee (CEC) will adjudicate clinical endpoints in a blinded fashion, but the Data 
Monitoring Committee (DMC) will review clinical endpoints and SAEs in an unblinded fashion. 
 
CHANGE 8 REVISIONS TO ANALYSIS POPULATIONS 
Location:   
Section 2, Synopsis, Analysis Population; Section 14.3, Analysis Populations 
Original Text: 
Analysis Populations 
The Full Analysis Set (FAS), used for all of the efficacy analyses, is defined as all randomized 
patients. The FAS is also known as the intention-to-treat (ITT) set of patients.  Patients in the 
FAS will be included in their randomized treatment group, regardless of their actual treatment.  
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of blinded study medication (IMP).  
New Text: 
Analysis Populations 
The Full Analysis Set (FAS), used for all of the efficacy analyses, is defined as all randomized 
patients. The FAS is also known as the intention-to-treat (ITT) set of patients.  Patients in the 
FAS will be included in their randomized treatment group, regardless of their actual treatment.  
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of blinded study medication (IMP).  
The PK analysis set (PKS), used for all of the PK-related summaries, is defined as all patients 
in the SP who have at least 1 PK assessment unless major protocol deviations are identified to 
have affected the PK data or if key dosing or sampling information is missing. 
Original Text: 
14.3 
Analysis Population 
The full analysis set (FAS), used for all of the efficacy analyses, is defined as all randomized 
patients.  Patients in FAS will be analyzed in the treatment group they are randomized to 
regardless of the treatment received. 
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of blinded IMP.  Patients in the SP will be included in the 
treatment group that they actually received, regardless of their randomized treatment. 


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New Text: 
14.3 
Analysis Population 
The full analysis set (FAS), used for all of the efficacy analyses, is defined as all randomized 
patients.  Patients in FAS will be analyzed in the treatment group they are randomized to 
regardless of the treatment received. 
The Safety Population (SP), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of blinded IMP.  Patients in the SP will be included in the 
treatment group that they actually received, regardless of their randomized treatment. 
The PK analysis set (PKS), used for all of the PK-related summaries, is defined as all patients 
in the SP who have at least 1 PK assessment unless major protocol deviations are identified to 
have affected the PK data or if key dosing or sampling information is missing. 
 
CHANGE 9 
REVISION TO ADMINISTRATION OF IMP 
Location:   
Section 8.1, Administration of Investigational Medicinal Product 
Original Text: 
During the Treatment Period, patients will be randomized to receive IMP of either BA 180 mg + 
EZE 10 mg FDC, BA 180 mg, EZE 10 mg, or placebo once daily.  Each daily allotment of IMP 
is comprised of 2 tablets and 1 capsule provided in a blister package.  Patients will be instructed 
to ingest IMP orally once daily with or without food at a similar time every day.  
New Text: 
During the Treatment Period, patients will be randomized to receive IMP of either BA 180 mg + 
EZE 10 mg FDC, BA 180 mg, EZE 10 mg, or placebo once daily.  Each daily allotment of IMP 
is comprised of 2 tablets and 1 capsule provided in a blister package.  Patients will be instructed 
to ingest IMP orally once daily with or without food at a similar time every day.  On clinic visit 
days, patients will be instructed to delay ingestion of IMP until all study procedures have been 
completed. 
 
CHANGE 10 
REVISION TO PRIOR AND CONCOMITANT MEDICATIONS 
Location: 
Section 8.2, Concomitant Medications 
Original Text: 
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. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 103 of 116 
New Text: 
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, with the exception of statins (particularly those 
that were not tolerated due to an adverse effect), which will be recorded if taken at any point in 
the past. 
 
CHANGE 11 
REVISION TO PROHIBITED MEDICATIONS AND DIETARY 
SUPPLEMENT 
Location: 
Section 8.2.2, Prohibited Medications and Dietary Supplement 
Original Text: 
− Ezetimibe (Zetia®, Ezetrol®) 
New Text: 
− Ezetimibe (Zetia®, Ezetrol®) other than that which is study supplied; 
 
CHANGE 12 
REVISION TO TREATMENT ASSIGNMENT, RANDOMIZATION, 
AND BLINDING 
Location: 
Section 8.3, Treatment Assignment, Randomization, and Blinding 
Original Text: 
During the Treatment Period, patients will receive double-blind IMP.  At Day 1 (Visit T1), 
patients will be randomized to receive either BA 180 mg + EZE 10 mg FDC, BA 180 mg, EZE 
10 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. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 104 of 116 
New Text 
During the Treatment Period, patients will receive double-blind IMP.  At Day 1 (Visit T1), 
patients will be randomized to receive either BA 180 mg + EZE 10 mg FDC, BA 180 mg, EZE 
10 mg or placebo.  The randomization will be stratified by baseline statin intensity (high 
intensity vs. other) and disease characteristics (ASCVD and/or HeFH vs. multiple CV risk 
factors).  Only atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day are considered high 
intensity statin and all others will be considered as ‘other’ for randomization purpose.  The 
criteria for determining these 2 stratification factors are further detailed in Section 7.1).  The 
investigator or designee will utilize Interactive Web Response System (IWRS) during the visit to 
obtain a randomization numberrandomize the patient and obtain 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 IWRSthe corresponding 
randomization box is checked within the eCRF. 
The rRandomization 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; an independent bio-analytical lab will be aware of treatment 
assignment only to support PK sample analysis. 
 
CHANGE 13 
REVISION TO PACKAGING AND LABELING 
Location: 
Section 9.3, Packaging and Labeling 
Original Text: 
Double-blind IMP will be packaged in blister packs.  Each blister pack will contain a 9-day 
supply and 3 blister packs will be provided in the drug kit.  
New Text: 
Double-blind IMP will be packaged in blister packs.  Each blister pack will contain a 9-day 
supply and 34 blister packs will be provided in the drug kit. 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 105 of 116 
CHANGE 14 
REVISION TO IWRS AND ECRFS 
Location:   
Section 10.2, Interactive Web Response System and eCRFs 
Original Text: 
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. 
New Text: 
Data will be captured on eCRFs, and IWRS is contacted via 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. 
 
CHANGE 15 
REVISION TO STUDY PROCEDURES 
Location:   
Section 10.5.2, Treatment Week 0 (Visit T1; Day 1) 
Original Text: 
At randomization, patients will be stratified based on baseline/current statin intensity (High vs. 
Other) and disease characteristics (ASCVD and/or HeFH vs. multiple cardiovascular [CV] risk 
factors).  High intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 
20-40 mg/day, all others will be categorized as ‘other’ for randomization and stratification 
purposes.  Definition of ASCVD and/or HeFH or multiple CV risk factors are provided in 
inclusion criteria.  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: 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs  
• PE 
• ECG 
• Urine pregnancy test (in female patients of childbearing potential) 
• Review inclusion/exclusion criteria to establish patient eligibility 
• IWRS contact to obtain the patient randomization number and MED ID number for 
double-blind IMP 
• Weight 
• Vital signs 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 106 of 116 
• 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 
• Dispense double-blind IMP and provide dosing and storage instructions 
New Text: 
At randomization, patients will be stratified based on baseline/current statin intensity (High vs. 
Other) and disease characteristics (ASCVD and/or HeFH vs. multiple cardiovascular [CV] risk 
factors).  High intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 
20-40 mg/day, all others will be categorized as ‘other’ for randomization and stratification 
purposes.  Definition of ASCVD and/or HeFH or multiple CV risk factors are provided in 
inclusion criteria.  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: 
• Concomitant medication review (ongoing) 
• Assess AEs and SAEs  
• PE 
• ECG 
• Urine pregnancy test (in female patients of childbearing potential) 
• Review inclusion/exclusion criteria to establish patient eligibility 
• IWRS contact to obtain the Randomize the patient randomization number and obtain 
MED ID number for double-blind IMP 
• 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 
• Dispense double-blind IMP and provide dosing and storage instructions 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 107 of 116 
CHANGE 16 
REVISION TO STUDY PROCEDURES 
Location:   
Section 10.5.3, Treatment Week 4 (Visit T2; Day 29 ± 5 days) 
Original Text: 
Patients will undergo the following assessments and procedures: 
• 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 
New Text: 
Patients will undergo the following assessments and procedures: 
• 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) ; 
• Trough PK sample; 
• 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. 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 108 of 116 
Location: 
Section 10.5.4, Treatment Week 8 (Visit T3; Day 57 ± 5 days) 
Original Text: 
Patients will undergo the following assessments and procedures: 
• 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 
New Text: 
Patients will undergo the following assessments and procedures: 
• 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); 
• Trough PK sample; 
• 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. 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 109 of 116 
Location: 
Section 10.5.5, Treatment Week 12 (Visit T4; Day 85 ± 5 days)/End of Study or Early 
Termination 
Original Text: 
Patients will undergo the following assessments and procedures: 
• 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 
• ECG 
• Return of IMP; assessment and recording of IMP adherence 
New Text: 
Patients will undergo the following assessments and procedures: 
• 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; 
• Trough PK sample; 
• ECG; 
• Return of IMP; assessment and recording of IMP adherence. 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 110 of 116 
CHANGE 17 
REVISION TO CENTRAL CLINICAL LABORATORY 
PARAMETERS (SAFETY) 
Location:   
Section 12.1.6.1, Table 4, Central Clinical Laboratory Parameters (Safety) 
Original Text: 
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 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 111 of 116 
Table 4: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
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 that in the investigator’s 
judgment requires monitoring, measured only at 
Visit T1 and 3 to 5 days post Visit T1 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
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 >1 year 
without menses) 
• 
Thyroid-stimulating hormone (TSH) 
 
 
New Text: 
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 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 112 of 116 
Table 4: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Urinalysis (Dipstick) 
• 
Creatine kinase (CK) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total and direct bilirubin (TB) 
• 
Total protein 
• 
Uric acid 
• 
Clarity 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrite 
• 
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 that in the investigator’s 
judgment requires monitoring, measured only at 
Visit T1 and 3 to 5 days post Visit T1 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
Other Screening Labs 
Other Sample Collection 
• 
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 >1 year 
without menses) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Plasma trough investigational medicinal 
product (IMP) 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 113 of 116 
CHANGE 18 
ADDITION OF CENTRAL CLINICAL LABORATORY PARAMETER 
Location:   
Section 12.1.6.3, Collection and Assessment of Plasma Trough IMP 
New Text: 
12.1.6.3. Collection and Assessment of Plasma Trough IMP 
Plasma trough IMP will be measured at Weeks 4, 8, and 12.  A single 6-mL whole blood 
sample will be collected and processed by the site according to instructions provided in the 
manual provided by the Central Laboratory.  At the time of sample collection, the date and 
time of blood draw and the last 2 doses of study medication will also be collected.  Samples will 
be shipped to the central clinical laboratory and subsequently forwarded to a bio-analytical lab 
for measurement and analysis.   
Plasma trough IMP concentrations will be measured and analyzed using validated methods 
and will include BA (ETC-1002 and its active metabolite ESP15228) and EZE 
(glucuronidated EZE and unconjugated EZE). 
 
CHANGE 19 REVISIONS TO TOTAL BLOOD VOLUME SAMPLES 
Location:   
Section 12.1.6.5, Total Blood Volume of Central Clinical Laboratory Sample 
Original Text: 
12.1.6.4 
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 and efficacy assessment.  Total whole blood volume 
collected over the study duration is not to exceed approximately 250 mL for each patient. 
New Text: 
12.1.6.45 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, and efficacy, and PK assessment.  Total whole blood 
volume collected over the study duration is not to exceed approximately 250 mL for each patient. 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 114 of 116 
CHANGE 20 REVISIONS TO EXPLORATORY ENDPOINTS 
Location:   
Section 14.7, Exploratory Endpoints 
Original Text: 
The proportion of patients achieving an LDL-C <70 mg/dL will be summarized for each 
treatment group and the comparison between FDC vs. EZE; FDC vs. BA, and FDC vs. placebo 
will be based on Chi-Sq test or Fisher’s exact test.  No multiplicity adjustment will be performed. 
Further details will be provided in the SAP. 
New Text: 
The proportion of patients achieving an LDL-C <70 mg/dL after 12-week treatment will be 
summarized for each treatment group and the comparison between FDC vs. EZE; FDC vs. BA, 
and FDC vs. placebo will be based on Chi-Ssq test or Fisher’s exact test.  No missing data 
imputation will be applied to this analysismultiplicity adjustment will be performed. 
Descriptive summary for plasma trough concentrations of BA and/or EZE will be provided at 
Weeks 4, 8, and 12 by treatment group. 
Further details will be provided in the SAP. 
 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 115 of 116 
CHANGE 21 REVISIONS TO SCHEDULE OF EVENTS 
Location:   
Appendix 1, Schedule of Events table 
Original Text: 
Visit 
S11 
T1 
T2 
T3 
T42 
Week 
-2 
0 
4 
8 
12/EOS 
Procedure 
Day -16 to -5 
Day 1 
Day 29 ± 5 
Day 57 ± 5 
Day 85 ± 5 
Informed Consent 
X 
 
 
 
 
Enrollment Criteria 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant\Prohibited Medications 
X 
X 
X 
X 
X 
Adverse Event Recording 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
X 
Weight3 
X 
X3 
X 
X 
X 
Height/BMI 
X 
 
 
 
 
12-Lead ECG4 
 
X 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
Serology6 
X 
 
 
 
 
Serum Pregnancy/FSH 7 
X 
 
 
 
 
Urine Pregnancy  
 
X 
 
 
 
TSH 
X 
 
 
 
 
Clinical Safety Labs8 
X 
X 
X 
X 
X 
Basic Fasting Lipids9 
X 
X 
X 
X 
X 
Special Fasting Lipids and Other 
Biomarkers10 
 
X 
 
 
X 
HbA1C 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Double Blind Drug Dispensing 
 
X 
X 
X 
 
Drug Return 
 
 
X 
X 
X 


Bempedoic Acid 180 mg + Ezetimibe 10 mg  
Fixed-Dose Combination 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002FDC-053 
Amendment 1, 18 October 2017 
 
Confidential 
Page 116 of 116 
New Text: 
Visit 
S11 
T1 
T2 
T3 
T42 
Week 
-2 
0 
4 
8 
12/EOS 
Procedure 
Day -16 to -5 
Day 1 
Day 29 ± 5 
Day 57 ± 5 
Day 85 ± 5 
Informed Consent 
X 
 
 
 
 
Enrollment Criteria 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant\Prohibited Medications 
X 
X 
X 
X 
X 
Adverse Event Recording 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
X 
Weight3 
X 
X3 
X 
X 
X 
Height/BMI 
X 
 
 
 
 
12-Lead ECG4 
 
X 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
Serology6 
X 
 
 
 
 
Serum Pregnancy/FSH 7 
X 
 
 
 
 
Urine Pregnancy  
 
X 
 
 
 
TSH 
X 
 
 
 
 
Clinical Safety Labs8 
X 
X 
X 
X 
X 
Basic Fasting Lipids9 
X 
X 
X 
X 
X 
Special Fasting Lipids and Other 
Biomarkers10 
 
X 
 
 
X 
HbA1C 
X 
 
 
 
 
Plasma Trough Study Drug 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
Double Blind Drug Dispensing 
 
X 
X 
X 
 
Drug Return 
 
 
X 
X 
X 
 


Signature Page for VV-CLIN-000153 v1.0
Signature Page for VV-CLIN-000153 v1.0
Approval
18-Oct-2017 20:21:52 GMT+0000
Approval
19-Oct-2017 14:14:50 GMT+0000
Approval
19-Oct-2017 14:47:43 GMT+0000
Approval
23-Oct-2017 05:56:10 GMT+0000
Approval
23-Oct-2017 13:34:31 GMT+0000
Approval
25-Oct-2017 01:03:03 GMT+0000
Approval
25-Oct-2017 16:17:25 GMT+0000

SAP_001.pdf: 
Esperion Therapeutics, Inc.
Version 1.1, June 08, 2018
Protocol: ETC-1002FDC-053
Statistical Analysis Plan
Confidential
Page 1 of 26
Statistical Analysis Plan
Title:
A Randomized, Double-Blind, Parallel Group Study to Evaluate the 
Efficacy and Safety of Bempedoic Acid 180 mg + Ezetimibe 10 mg Fixed 
Dose Combination Compared to Bempedoic Acid, Ezetimibe, and Placebo 
Alone in Patients Treated with Maximally Tolerated Statin Therapy.
Protocol:
ETC-1002FDC-053
Clinical Phase:
3
Product:
ETC-1002FDC
Version (Date):
Statistical Analysis Plan – Final Version 1.1 (June 08, 2018)
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 : cdb918fc-b465-4b44-8ee5-5b3a77d6034f
NCT number: NCT03337308
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Esperion Therapeutics, Inc.
Version 1.1, June 08, 2018
Protocol: ETC-1002FDC-053
Statistical Analysis Plan
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Table of Contents
1
List of Abbreviations .................................................................................................. 4
2
Introduction................................................................................................................. 6
3
Study Objectives and Endpoints................................................................................. 6
3.1
Objectives............................................................................................................. 6
3.2
Endpoints.............................................................................................................. 6
Primary Endpoint.......................................................................................... 7
3.2.1
Secondary Endpoint...................................................................................... 7
3.2.2
Exploratory Endpoints .................................................................................. 7
3.2.3
Safety Endpoints........................................................................................... 7
3.2.4
4
Study Design............................................................................................................... 7
4.1
Study Design ........................................................................................................ 7
4.2
Randomization ..................................................................................................... 8
4.3
Sample Size Justification ..................................................................................... 9
5
Statistical and Analytical Plans................................................................................... 9
5.1
General Statistical Considerations ....................................................................... 9
5.2
Statistical Analysis Plans ................................................................................... 10
Analysis Population .................................................................................... 10
5.2.1
Baseline Definition ..................................................................................... 10
5.2.2
Protocol Violations and Deviations ............................................................ 11
5.2.3
Patient Disposition...................................................................................... 11
5.2.4
Demographic and Baseline Characteristics ................................................ 11
5.2.5
Medical History .......................................................................................... 12
5.2.6
Prior Medications and Concomitant Medications/Procedures.................... 12
5.2.7
Study Drug Exposure and Compliance....................................................... 12
5.2.8
5.3
Efficacy Endpoints and Analyses....................................................................... 13
Co-Primary Endpoint Analysis................................................................... 13
5.3.1
Secondary and Exploratory Efficacy Endpoint Analyses........................... 14
5.3.2
Sensitivity Analyses for Efficacy Endpoints .............................................. 15
5.3.3
Exploratory Endpoints ................................................................................ 16
5.3.4
5.4
Safety Endpoints and Analyses.......................................................................... 17
Adverse Events (AEs)................................................................................. 17
5.4.1
Adverse Events of Special Interest (AESIs)............................................... 18
5.4.2
Laboratory Evaluations............................................................................... 19
5.4.3
Physical Examinations (PEs)...................................................................... 21
5.4.4
Vital Signs................................................................................................... 22
5.4.5
Electrocardiogram (ECG)........................................................................... 22
5.4.6
6
Reference .................................................................................................................. 22
7
Appendices................................................................................................................ 23
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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
ASCVD
Atherosclerotic cardiovascular diseases
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic classification
BA
Bempedoic acid
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
Ca
Calcium
CI
Confidence interval
CK
Creatine kinase
CO2
Carbon dioxide
CRF
Case Report Form
CRO
Contract research organization
CV
Cardiovascular
DBP
Diastolic blood pressure
eCRF
Electronic case report form
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
EOS
End of Study
EZE
Ezetimibe
FAS
Full analysis set
FDA
Food and drug administration
FDC
Fixed-dose combination
FSH
Follicle-stimulating hormone
Hct
Hematocrit
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
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
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Abbreviation or Specialist Term
Explanation
LDL-C
Low-density lipoprotein cholesterol
LSM
Least square mean
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
non-HDL-C
Non-high-density lipoprotein cholesterol
PE
Physical examination
PK
Pharmacokinetic(s) 
PMM
Pattern mixture model
PT
Preferred term
RBC
Red blood cell
SAS
Statistical analysis system
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SD
Standard Deviation
SE
Standard error
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System organ class 
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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2
Introduction
The purpose of this document is to describe the statistical methods, data derivations and 
data summaries to be employed in ETC-1002FDC-053. 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-1002FDC-053 (Protocol 
Amendment 1, October 18, 2017).
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 co-primary objectives are to assess LDL-C lowering efficacy in patients receiving 
maximally tolerated statin therapy and treated for 12 weeks with BA 180 mg + EZE 10 
mg FDC versus each of the following: 
• Placebo 
• BA 180 mg 
• EZE 10 mg 
The secondary objectives are:
• To assess the efficacy of BA 180 mg + EZE 10 mg FDC versus placebo alone, BA 
alone, and EZE alone on high-sensitivity C-reactive protein (hs-CRP), non-HDL-C, TC,  
ApoB, HDL-C, and TG after 12 weeks of treatment
• To characterize the safety and tolerability of BA 180 mg + EZE 10 mg FDC versus BA 
alone, EZE alone and placebo alone through 12 weeks of treatment
The exploratory objectives are:
• To assess the efficacy BA 180 mg + EZE 10 mg FDC versus placebo alone, BA alone, 
and EZE alone on percentage of patients attaining LDL-C <70 mg/dL after 12 weeks of 
treatment
• To characterize the plasma trough concentrations of BA and/or EZE when administered 
as BA 180 mg + EZE 10 mg FDC, BA alone, and EZE alone
3.2
Endpoints
The following endpoints will be used to evaluate the objectives of the study.
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Primary Endpoint
3.2.1
• Percent change from baseline to Week 12 in LDL-C
Secondary Endpoint
3.2.2
• Percent change from baseline to Week 12 in hs-CRP, non-HDLC, TC, ApoB, HDL-C, 
and TG.
Exploratory Endpoints
3.2.3
• Percentage of patients attaining LDL-C <70 mg/dL after 12 weeks of treatment.
• Plasma trough concentrations at Weeks 4, 8, and 12 of BA (ETC 1002 and its active 
metabolite ESP15228) and EZE (glucuronidated EZE and unconjugated EZE) in BA 180 
mg + EZE 10 mg FDC-treated arm, BA-treated arm, and/or EZE alone treated arm.
Safety Endpoints
3.2.4
• Patient incidence of adverse events (AEs)
• Clinical safety laboratory (including hematology, blood chemistry, and urinalysis) 
results
• Vital signs, electrocardiograms (ECGs) and physical examination (PE) findings
4
Study Design
4.1
Study Design
This is a Phase 3, randomized, double-blind, parallel group, multicenter study of BA + 
EZE versus its individual components and placebo. Screening (S1) will occur 
approximately within 2 weeks prior to randomization. Patients who are deemed not 
eligible for randomization at any point during screening will be notified by clinical site 
personnel regarding their eligibility status and considered screen failures. Approximately 
350 eligible patients will be randomized 2:2:2:1 on Day 1/Week 0 (T1) to receive either 
BA 180 mg + EZE 10 mg FDC (N = 100), BA 180 mg (n = 100), EZE 10 mg (n = 100), 
or placebo (n = 50) for 12 weeks. Randomized patients will return for clinic visits at 
Week 4 (T2), Week 8 (T3) and Week 12 (T4). Patients who withdraw from 
investigational medicinal product (IMP) treatment will be asked to continue to be 
followed for safety and efficacy using the protocol-specified visit schedule and 
procedures. 
Eligible patients will have documented atherosclerotic cardiovascular diseases (ASCVD), 
heterozygous familial hypercholesterolemia (HeFH), and/or multiple cardiovascular risk 
factors and require additional LDL-C-lowering therapy despite receiving maximally 
tolerated statin background therapy. Maximally tolerated statin therapy may include 
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statin regimens other than daily dosing or no statin at all (if not tolerated); however, doses 
of simvastatin ≥40 mg/day are prohibited. A patient’s currently used and maximally 
tolerated statin therapy will be determined by the investigator based on their medical 
judgment and local standard of care. Available sources, including the patient’s self-
reported history of lipid-modifying therapy will also be considered.
Patients will be stratified based on baseline/current statin intensity (high intensity statin 
versus other) and disease characteristics (ASCVD and/or HeFH versus multiple CV risk 
factors). High intensity statin includes atorvastatin 40-80 mg/day and rosuvastatin 20-40 
mg/day, all others will be categorized as ‘other’ for randomization and stratification 
purposes. Definition of ASCVD and/or HeFH or multiple CV risk factors are provided in 
inclusion criteria. Enrollment will be monitored and a cap may be placed, if necessary, to 
ensure appropriate distribution into either of the statin intensity categories.
The Study Flow Chart is presented in Figure 1.
Figure 1: Study Flow Chart
For details of study assessments, see the Schedule of Events in Appendix 1.
4.2
Randomization 
During the Treatment Period, patients will receive double-blind IMP.  At Day 1
(Visit T1), patients will be randomized to receive either BA 180 mg + EZE 10 mg FDC, 
BA 180 mg, EZE 10 mg or placebo with 2:2:2:1 ratio.
The randomization will be stratified by baseline statin intensity (high intensity vs. other) 
and disease characteristics (ASCVD and/or HeFH vs. multiple CV risk factors).  Only 
atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day are considered high intensity 
statin and all others will be considered as ‘other’ for randomization purpose.
Study Visits
Week:
Visit Number:
Screening
12 Week Treatment
ј
Wk 8
T3
ј
Wk 12
T4
ј
Wk 0
TI
ј
Wk -2
S1
ј
Wk 4
T2
EZE 10 mg (n=100)
Placebo (n=50)
BA 180 mg (n=100)
BA 180 mg + EZE 10 mg FDC (n=100)
Patients with 
јLDL-C
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The criteria for determining these 2 stratification factors are further detailed in criteria 
for selection of patients in protocol.  The investigator or designee will utilize IWRS 
during the visit to randomize the patient and obtain the appropriate IMP container via 
medication identification numbers.  A patient is considered to be randomized when the 
corresponding randomization box is checked within the eCRF.
4.3
Sample Size Justification
The sample size of 100 patients per active treatment group and 50 patients in the placebo 
arm (2:2:2:1) of this study (350 patients total) was selected to provide adequate power for 
each of the co-primary endpoint as well as the co-primary endpoint family as a whole. 
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, SD or standard error (SE), 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, 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. 
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5.2
Statistical Analysis Plans
Analysis Population
5.2.1
5.2.1.1
Full Analysis Set (FAS)
The full analysis set (FAS), used for all of the efficacy analyses, is defined as all 
randomized patients. Patients in FAS will be analyzed in the treatment group they are 
randomized to regardless of the treatment received.
5.2.1.2
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 blinded IMP. Patients in the SP will 
be included in the treatment group that they actually received, regardless of their 
randomized treatment.
5.2.1.3
Treatment Completer Analysis Set 
Treatment completer analysis set a subset of full analysis set and will include subjects 
who complete 12-week treatment as indicated on the end of treatment CRF and have non-
missing LDL-C value at Week 12.
5.2.1.4
PK Analysis Set (PKS)
The PK analysis set (PKS), used for all of the PK-related summaries, is defined as all 
patients in the SP who have at least 1 PK assessment unless major protocol deviations are 
identified to have affected the PK data or if key dosing or sampling information is
missing. All PK samples with data available will be included in the summary unless the 
sample time is outside of 18 to 30 hours window since last dose of study drug or dosing 
and/or sampling time are missing.
PK result listing will list all results regardless of 
sampling window.
Baseline Definition
5.2.2
Baseline LDL-C is defined as the mean of the values from Week -2 (Visit S1) and pre-
dose Day 1/Week 0 (Visit T1) (i.e., the last two non-missing values on or prior to Day 
1). If only one value is available then that single value will be used as baseline.
Baseline for non-HDL-C, HDL-C, TC, and TG is defined as the mean of the values 
Visit
S1
T1 
T2 
T3 
T4
Slotted Study Week
-2
0
4
8
12/EOS 
Target Study Day
Day -13
Day 1
Day 29
Day 57
Day 85
Analysis Visit 
Windows
[-∞, -1]
[1]
[2,34]
[35, 62]
[63, +∞]
Protocol defined 
visit window
Day -16 to -5
Day 1 
Day 29 ± 5 
Day 57 ± 5 
Day 85 ± 5 
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from Week -2 (Visit S1) and pre-dose Day 1/Week 0 (Visit T1) (i.e., the last two non-
missing values on or prior to Day 1). If only one value is available then that single 
value will be used as baseline.
Baseline for ApoB and hs-CRP is defined as the pre-dose Day 1/Week 0 (Visit T1) 
value (i.e. the last non-missing value on or prior to Day 1). If this is not available, then 
the last non-missing value prior to the first dose of double-blind study medication 
(including unscheduled assessments) will be used as baseline.
Baseline of other laboratory parameters, vital signs and physical examination is defined 
as the last non-missing value prior to the first dose of study drug.
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 source data 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, and all protocol deviations will be listed.
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 patient baseline characteristics including, but not limited 
to, gender, race, age, and baseline vital signs will 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 FAS population: age (years), age 
will be summarized as a continues variable and by age group (18-40, 41-64, 65-74, and 
>=75), gender, race, ethnicity, height (cm), weight (kg), body mass index (BMI) (kg/m2),
BMI group (<25, 25-<30, >=30 kg/m2), eGFR, systolic and diastolic blood pressure 
(mmHg), heart rate, history of diabetics and hypertension, background statin therapy, 
disease characteristics, tobacco history, alcohol history, 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.
Subgroups Variables
5.2.6
1) Gender (male vs. female)
2) Age (< 65 yrs. vs. ≥65 yrs.)
3) Baseline CVD risk category (ASCVD and/or HeFH vs. multiple CV risk factors)
4) Baseline statin intensity (high intensity vs. other)
5) Race (white vs. other)
6) Baseline LDL category (< 130 mg/dL vs. ≥130 - <160 mg/dL vs. ≥160 mg/dL)
(efficacy only)
7) History of diabetes (yes vs. no)
8) Body Mass Index (BMI) (< 25, 25 - < 30, ≥ 30 kg/m2)
In case the number of patients within a subgroup is too small for a meaningful analysis,
the analyses may not be performed or the subgroup levels may be combined.
Medical History 
5.2.7
General medical history will be summarized by treatment group by system organ class 
(SOC) and preferred term (PT) using Medical Dictionary for Regulatory Activities 
(MedDRA), as well as overall, for safety population and presented in a by-patient 
listing.  Where appropriate, terms will be coded using the latest version of MedDRA.    
Prior Medications and Concomitant Medications/Procedures
5.2.8
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
5.2.9
The length of exposure to study drug (FDC, BA, EZE 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.  Length of exposure will be summarized by treatment group using descriptive 
statistics for the safety population. 
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The overall compliance to study drug calculated based on tablet count will be 
summarized by treatment group using summary statistics. The number and percentage 
of patients who were compliant with taking study drug will be summarized by 
treatment group for the safety population for the following categories <80%; >= 80%. 
Overall compliance will be calculated as: 100* (Total Dispensed Tablets - Total 
Returned Tablets) / Treatment Duration in day. Overall compliance during the study 
will be calculated by using study drug dispensation data.
The study drug administration and compliance data, including reasons for poor 
compliance, will be listed for each patient.
5.3
Efficacy Endpoints and Analyses 
All the efficacy endpoints and analyses will be done by using FAS (Full analysis set), and 
Treatment Completer Analysis Set.
Co-Primary Endpoint Analysis
5.3.1
The co-primary efficacy endpoints consist of three comparisons of the percent change 
from baseline to Week 12 in LDL-C: FDC vs. placebo, FDC vs. EZE; and FDC vs. BA.
In cases where triglycerides (TG) is >400 mg/dL or LDL-C is ≤50 mg/dL, a measured 
LDL (LDL-M) will be used instead of LDL-C for the analysis of that time point.  If both 
values are available, the LDL-M will be used.
An ANCOVA with treatment group and randomization stratification as factors and 
baseline LDL-C as a covariate will be performed to compare treatment groups (LDL-C: 
FDC vs. placebo, FDC vs. EZE; and FDC vs. BA) for the primary endpoint using the 
FAS. In case of number of subjects within a stratum is too small for a meaningful 
analysis, the strata may be combined to obtain larger cell size. The least squares mean 
(LSM) and SE, 95% confidence interval (CI) and associated p-values for each treatment 
groups, as well as for each treatment group comparison of interests. To account for 
possibility of unequal variances between the groups, the ANCOVA model will be 
implemented within mixed model framework where <repeated/group=> option will be
used to allow separate estimation of residual variances for different groups.
Each of the comparisons within the co-primary endpoint family will be conducted at a 
significance level of 0.05. If and only if all three testing achieve statistical significance, 
the study is claimed to meet its primary objective and the hypothesis testing will continue 
to secondary endpoints, otherwise all statistical comparisons for secondary endpoints are 
considered descriptive only.
An example Statistical Analysis System (SAS) code for ANCOVA analysis is shown as 
below:
PROC MIXED DATA=adxx ;
class armcd stratum;
model pchg = blres armcd stratum / solution ddfm=kenwardroger;
repeated/ group=armcd;
lsmeans armcd / diff;
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Missing values for primary endpoint will be imputed using multiple imputation method, 
taking account for the adherence to the treatment. For patients with missing data and no 
longer receiving treatment at Week 12 (defined as lab date is > 7 days post last dose of 
IMP), their LDL-C will be imputed as their baseline value, for those with missing data 
but still receiving treatment, their LDL-C value will be imputed using a regression model 
based imputation model including treatment, stratification factor, baseline LDL-C as 
auxiliary variables. The imputation will be performed for 200 times and imputed datasets 
will be analyzed using an ANCOVA model with treatment, stratification as factors and 
baseline LDL-C as a covariate. Approximately 200 imputed datasets will be created;
results from the analysis of each imputed dataset will be combined using Rubin’s method. 
The final combined least squares mean (LSM) and standard error (SE) will be provided 
for both treatment groups, along with the LSM for each treatment comparison, its 95% 
confidence interval (CI) and associated p-value.  More details will be provided in the 
programming specifications.
Secondary and Exploratory Efficacy Endpoint Analyses
5.3.2
Key secondary efficacy endpoints, which include the percent change from baseline to 
Week 12 in LDL-C, non-HDL-C, TC, and apoB, will be analyzed in a similar manner as 
the primary efficacy endpoint.  
For hsCRP, a non-parametric (Wilcoxon rank-sum test) analysis with Hodges-Lehmann 
estimates and confidence interval will be performed because based on historical 
knowledge, publication precedence (Brendan etc., 2006) and recent data available, 
hsCRP is known to be skewed by extreme values and have non-normal distribution. 
HDL and TGs will be summarized using descriptive statistics for the observed value 
and the change/percent change from baseline at each protocol scheduled visits.
If co-primary endpoint family achieves statistical significance, a list of selected 
secondary endpoints will be tested in sequential order within each comparison group. The 
alpha allocation among the three comparison groups is: alpha = 0.01 for FDC vs. Placebo
alpha = 0.02 for FDC vs. EZE; alpha = 0.02 for FDC vs. BA.
Missing values for these secondary endpoints will be imputed using multiple imputations 
method as described for primary endpoint. All other secondary endpoints not included in 
the step-down procedure (Figure 2) will be tested at significant level of 0.05 without 
multiplicity adjustment. Only observed data will be used for these analysis.
Other secondary endpoints of HDL-C and TGs will be summarized using descriptive 
statistics at week 12.
By-visit summary for all efficacy endpoints (LDL-C, non-HDL-C, TC, ApoB, hsCRP, 
HDL-C and TGs) using FAS and treatment completer set will be provided for both 
conventional and standard units.
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Sensitivity Analyses for Efficacy Endpoints
5.3.3
Sensitivity analyses will be performed for the co-primary endpoints and key secondary 
endpoints using:
x
Treatment completer analysis set using FAS with no imputation for missing data
x
Observed data from the FAS with no imputation for missing data
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Figure 2: The statistical testing of the treatment comparisons
Subgroup Analysis for Co-primary Endpoints
5.3.4
The co-primary endpoints for LDL-C will be analyzed within subgroups described in 
section 5.2.6. The treatment and subgroup interaction will be examined by including
treatment, subgroup, baseline and treatment by subgroup interaction term in the 
ANCOVA model for the overall population first. No imputation will be performed on
missing data for subgroup analyses. In case the number of subjects within a 
subgroup/treatment is too small for a meaningful analysis or small cell size is causing
convergence issue, the analyses may not be performed or the subgroup levels may be 
combined.
A forest plot of treatment effect for each of the LDL-C endpoint comparison within each 
subgroup will be provided.
Exploratory Endpoints
5.3.5
Percent of patients with LDL-C <70 mg/dL after Week 12 will be summarized by 
treatment group. Comparisons between treatment groups (FDC vs. EZE, FDC vs. BA, 
and FDC vs. placebo) on the proportion of patients achieving an LDL-C <70 mg/dL after 
12 week treatment will be performed using Fisher’s exact test or Pearson’s chi-square test
on observed data, i.e. the denominator will be number of patients who have LDL-C value 
at week 12.
Descriptive summary for plasma trough concentrations of BA and/or EZE will be 
provided at Weeks 4, 8, and 12 by treatment group.
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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 
worsened on or after the date of first dose of double-blind IMP until 30 days after last 
dose of IMP). All TEAEs, SAEs, related AEs, Adverse events of special interest (AESIs) 
will be summarized by MedDRA SOC, severity and relationship to study drug for each 
treatment group. Fatal AE, AEs leading to discontinuation of IMP or study, will each be 
summarized by treatment group.
Clinical safety laboratories, including hematology, blood chemistry, coagulation (for 
subjects taking anti-coagulation medication only), glucose (by history of diabetics), and 
urinalysis; PE findings; vital signs; ECG readings; and weight will be summarized by the 
value and by change/percent change from baseline (where appropriate) at each protocol 
scheduled time point.
Adverse Events (AEs)
5.4.1
AEs will be coded using the latest version of MedDRA 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).
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 ‘Possibly’, ‘Probably’, ‘Definitely’ or if 
relationship to study drug is missing.
Overviews of TEAEs will include total number of TEAEs and patient incidence of 
TEAE, TE SAE, related TEAE, related TE SAE, AESI, TEAE leading to withdrew of 
IMP, Fatal TEAE. Individual TEAE summary will be presented by treatment group 
containing the following counts and percentages for:
x
patients with TEAEs by SOC and PT
x
patients with TEAEs by descending order of frequency of PT
x
patients with treatment-related TEAEs by SOC and PT
x
patients with treatment-related TEAEs by PT
x
patients with TE SAEs by SOC and PT
x
patients with TE SAEs by PT
x
patients with treatment-related TE SAEs by SOC and PT
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x
withdrawal from study drug due to TEAEs by SOC and PT
x
Fatal TEAEs by SOC and PT
x
Patients with at least one AESI by AESI category and SOC and PT
x
Patients with serious AESI by AESI category and SOC and PT

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 AESI, SAEs, AEs resulting in withdrawal of study drug, and 
AEs with a fatal outcome for safety population.
Adverse Events of Special Interest (AESIs)
5.4.2
AESIs
include hepatic
disorders (including increase from baseline
in hepatic 
aminotransferases), musculoskeletal events (AE and CK evaluation), new onset 
diabetes/hyperglycemia, renal events, metabolic acidosis and/or hypoglycemia, and 
neurocognitive/neurologic events. The list of AESI terms is pre-defined by the Esperion 
and is included in Appendix 2.
x
AESIs of muscle related symptoms will be summarized by treatment group. CK 
levels will be summarized by the value and change from baseline in the value, by 
treatment group and visit. In addition, the number and percent of patients with 
abnormal CK (> 5 × ULN, > 10 × ULN) values will be summarized. These 
summaries of patients with abnormal CK will be performed overall; by normal 
baseline CK; and by abnormal baseline CK.
x
Cases of new onset of diabetes will be recorded as AEs and will be summarized 
using the appropriate SOC. These events will be summarized by severity, and 
relationship to study drug for each treatment group. Fasting glucose will be 
summarized at scheduled time point by history of diabetics.
x
Neurocognitive events will be evaluated by routine safety monitoring of PE 
findings and AEs. Neurocognitive events will be identified using pre-specified 
MedDRA terms and will be summarized by SOC, severity, and relationship to 
IMP for each treatment group
AESI will be presented in a listing and summarized by AESI category, SOC, PT and 
treatment group. 
Subgroup Analysis for Adverse Events
5.4.3
The TEAE, related TEAE, TE SAE, and AESI summaries by SOC and PT will be 
provided for relevant subgroups described in 5.2.6 with the exception of baseline LDL 
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category. 
Laboratory Evaluations
5.4.4
Continuous laboratory parameters (serum chemistry, hematology, coagulation for those 
who received anti-coagulation therapy patients), urinalysis, urinalysis [microscopic]) 
listed in Table 4; and fasting glucose will be summarized using descriptive statistics for 
the observed value and the change/percent change from baseline at each protocol 
scheduled visits by history of diabetics. Missing values for any of the laboratory
evaluations will not be imputed; that is, only observed case data will be used. Categorical 
urinalysis data will be provided in the listing.
As part of the AESI evaluation, below safety lab abnormality will be summarized by 
treatment group. All post-baseline lab values are being considered. Further details are 
provided in Section 5.4.4.1 through 5.4.4.4.
• ALT or AST (> 3x ULN and >5xULN)
• TB (> 2x ULN)
• Potential Hy’s Law case: (ALT and/or AST > 3xULN with concurrent TB > 2xULN)
• CK (> 5x ULN) and (>10x ULN)
• Fasting Glucose (mg/dL) (≤50, and ≥126) by history of diabetics
• Creatinine (change from baseline for >1 mg/dL)
• eGFR (< 15 mL/min/1.73m2, 15 –< 30 mL/min/1.73m2)
• Hgb (g/dL) (decrease from baseline for ≥2 g/dL)
• Hgb (<8 g/dL)
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Table 4:
Clinical Laboratory Parameters (Safety)
Hematology
Blood Chemistry (serum, fasting)
x
Hematocrit (Hct)
x
Hemoglobin (Hgb)
x
Mean corpuscular hemoglobin 
(MCH)
x
Mean corpuscular hemoglobin 
concentration (MCHC)
x
Mean corpuscular volume (MCV)
x
Platelet count
x
Red blood (RBC) cell count
x
White blood (WBC) cell count with 
differential (absolute values only)
Urinalysis (Dipstick)
x
Clarity
x
Bilirubin
x
Color
x
Glucose
x
Ketones
x
Leukocyte esterase
x
Nitrate
x
Occult blood
x
pH
x
Protein
x
Specific gravity
x
Urobilinogen
Urinalysis (Microscopic)-only if urine 
dipstick abnormal
x
Bacteria
x
Casts
x
Crystals
x
Epithelial cells
x
Red blood cell (RBC)
x
WBC
x
Albumin (ALlb)
x
Alkaline phosphatase (AlLk-P)
x
Alanine aminotransferase 
(ALT; SGPT)
x
Aspartate aminotransferase 
(AST; SGOT)
x
Blood urea nitrogen (BUN)
x
Calcium (Ca)
x
Carbon dioxide (CO2)
x
Chloride (Cl)
x
Creatinine
x
Creatine kinase (CK)
x
Glucose
x
Lactate dehydrogenase (LDH)
x
Phosphorus
x
Potassium (K)
x
Sodium (Na)
x
Total and direct bilirubin (TB)
x
Total protein
x
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)
x
Prothrombin time 
x
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 by
treatment groups. 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 
hyperglycemia, and renal safety.
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5.4.4.1
Hepatic Safety
Liver-associated enzymes and TB will be summarized by the value and change from 
baseline in the value, by treatment group and visit. In addition, the number and percent of 
patients with abnormal values for ALT (> 3 × ULN, > 5 × ULN), AST (> 3 × ULN, > 5 × 
ULN, and TB (> 2×ULN)” will be summarized. These summaries of patients with 
abnormal values will be performed overall safety population; by normal baseline; and by 
abnormal baseline for each of ALT, AST and TB. Hy’s law criteria (>3 × ULN for either 
ALT or AST, with accompanying TB >2 × ULN) will also be applied to the data; any 
potential Hy’s law cases will be listed separately. Note: In the case of patients with 
Gilbert’s disease, TB will be fractionated and the determination of 2 × ULN will be based 
upon direct (conjugated) bilirubin.
5.4.4.2
Musculoskeletal Safety
CK levels will be summarized by the value and change from baseline in the value, by 
treatment group and visit as well as baseline eGFR category. In addition, the number and 
percent of patients with abnormal CK values (>5 x ULN, > 10 x ULN) will be 
summarized for overall safety population. These summaries of patients with abnormal 
CK will be performed overall, normal baseline CK, and abnormal baseline CK. 
5.4.4.3
Diabetes and Glycemia
For fasting serum glucose, a shift table from baseline with the number and percent of 
patients will be categorized as below:
Fasting glucose: >= 126 mg/dL; 100-125 mg/dL, and < 100 mg/dL. These tables will be 
summarized by history of Diabetes.
Descriptive summary for fasting serum glucose will be provided by history of diabetics
and treatment group at each scheduled visit.
5.4.4.4
Renal Safety
Baseline eGFR will be summarized by treatment group for actual value and for baseline 
eGFR categories. Shift tables of eGFR category from baseline over the study, will be 
provided by treatment group. Shift tables of urine protein (negative/positive) from 
baseline over the study, will be provided by treatment group. Values of CK over the 
study will be summarized by treatment group and by baseline eGFR category.  
Physical Examinations (PEs)
5.4.5
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.
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Vital Signs
5.4.6
Actual values and changes from baseline in vital signs (SBP, DBP, heart rate, weight)
will be summarized using descriptive statistics by treatment group and post-baseline time 
point on the observed values.
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.
Electrocardiogram (ECG)
5.4.7
Shift tables for ECG data from baseline to end-of-study will be provided by treatment 
group. The data will be categorized as ‘Normal’; ‘Abnormal, not clinically significant’; 
and ‘Abnormal, clinically significant.’ Baseline is defined as the last value prior to the 
first dose of study medication. Listings of ECG data will include only those records 
where the baseline ECG was either ‘Normal’ or ‘Abnormal, not clinically significant’, 
but the end-of-study ECG was marked as ‘Abnormal, clinically significant’.
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. ICH Topic E3: Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95- adopted December 1995).
6. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 –
adopted March 1998).
7. Brendan M.Everett, Tobias Kurth, Julie E.Buring, Paul M.Ridker. “The Relative 
Strength of C-Reactive Protein and Lipid Levels as Determinants of Ischemic 
Stroke Compared With Coronary Heart Disease in Women.” Journal of the 
American College of Cardiology (2006), Volume 48, Issue 11, Pages 2235-2242.
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7
Appendices
Appendix 1: Schedule of Events (Patient Visit Schedule)
Visit
S11
T1
T2
T3
T42
Week
-2
0
4
8
12/EOS
Procedure
Day -16 to -5
Day 1
Day 29 ± 5
Day 57 ± 5
Day 85 ± 5
Informed Consent
X
Enrollment Criteria
X
X
Demographics
X
Medical History
X
Concomitant\Prohibited Medications
X
X
X
X
X
Adverse Event Recording
X
X
X
X
X
Physical Exam
X
X
Weight3
X
X3
X
X
X
Height/BMI
X
12-Lead ECG4
X
X
Vital Signs5
X
X
X
X
X
Serology6
X
Serum Pregnancy/FSH 7
X
Urine Pregnancy 
X
TSH
X
Clinical Safety Labs8
X
X
X
X
X
Basic Fasting Lipids9
X
X
X
X
X
Special Fasting Lipids and Other 
Biomarkers10
X
X
HbA1C
X
Plasma Trough Study Drug
X
X
X
Randomization
X
Double Blind Drug Dispensing
X
X
X
Drug Return
X
X
X
1 An optional visit approximately 10 days later MAY be completed if patient fails to meet specified entry 
criteria.  If this optional visit is completed, the repeat value 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 (e.g., coats).
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4 Single 12-lead ECG will be collected prior to any blood sample collection.
5 Vital signs will include SBP, DBP, and HR, and will be collected prior to any blood sample collection.  
Patient will rest for 5 minutes prior to assessments.
6 Serology for Hep B antigen, Hep C antibody.
7 FSH completed in appropriate postmenopausal women only; pregnancy test completed in non-
postmenopausal women only.
8 Clinical safety labs include hematology, blood chemistry, and urinalysis.  Coagulation panel only if 
receiving anticoagulants that in the investigator’s judgement requires monitoring (then test at T1 and 
repeat 3-5 days after starting IMP).
9 Basic fasting lipids include total cholesterol, calculated LDL-C, HDL-C, non-HDL-C, and triglycerides.
10Includes apoB and hs-CRP.
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Appendix 2: AESI (Adverse Event of Special Interest)
AESI Category
Associated MedDRA Preferred Terms
Creatine kinase elevations
Blood creatine phosphokinase abnormal
Creatine kinase elevations
Blood creatine phosphokinase increased
Creatine kinase elevations
Blood creatine phosphokinase MM abnormal
Creatine kinase elevations
Blood creatine phosphokinase MM increased
New onset or worsening diabetes mellitus
Blood glucose abnormal
New onset or worsening diabetes mellitus
Blood glucose increased
New onset or worsening diabetes mellitus
Diabetes mellitus
New onset or worsening diabetes mellitus
Diabetes mellitus inadequate control
New onset or worsening diabetes mellitus
Diabetic ketoacidosis
New onset or worsening diabetes mellitus
Glucose tolerance impaired
New onset or worsening diabetes mellitus
Glucose urine present
New onset or worsening diabetes mellitus
Glycosuria
New onset or worsening diabetes mellitus
Glycosylated haemoglobin increased
New onset or worsening diabetes mellitus
Hyperglycaemia
New onset or worsening diabetes mellitus
Impaired fasting glucose
New onset or worsening diabetes mellitus
Ketoacidosis
New onset or worsening diabetes mellitus
Ketosuria
New onset or worsening diabetes mellitus
Ketosis
New onset or worsening diabetes mellitus
Type 2 diabetes mellitus
New onset or worsening diabetes mellitus
Urine ketone body present
Hepatic enzyme elevations
Alanine aminotransferase abnormal
Hepatic enzyme elevations
Alanine aminotransferase increased
Hepatic enzyme elevations
Aspartate aminotransferase abnormal
Hepatic enzyme elevations
Aspartate aminotransferase increased
Hepatic enzyme elevations
Blood bilirubin abnormal
Hepatic enzyme elevations
Blood bilirubin increased
Hepatic enzyme elevations
Hepatic enzyme abnormal
Hepatic enzyme elevations
Hepatic enzyme increased
Hepatic enzyme elevations
Hypertransaminaseaemia
Hepatic enzyme elevations
Liver function test abnormal
Hepatic enzyme elevations
Liver function test increased
Hepatic enzyme elevations
Transaminases abnormal
Hepatic enzyme elevations
Transaminases increased
Hypoglycemia
Blood glucose abnormal
Hypoglycemia
Blood glucose decreased
Hypoglycemia
Hypoglycaemia
Hypoglycemia
Hypoglycaemic coma
Hypoglycemia
Hypoglycaemic encephalopathy
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AESI Category
Associated MedDRA Preferred Terms
Hypoglycemia
Hypoglycaemic seizure
Hypoglycemia
Shock hypoglycaemic 
Metabolic acidosis
Metabolic acidosis
Muscular disorders
Muscular weakness
Muscular disorders
Muscle necrosis
Muscular disorders
Muscle spasms
Muscular disorders
Myalgia
Muscular disorders
Myoglobin blood increased
Muscular disorders
Myoglobin blood present
Muscular disorders
Myoglobin urine present
Muscular disorders
Myoglobinaemia
Muscular disorders
Myoglininuria
Muscular disorders
Myopathy
Muscular disorders
Myopathy toxic
Muscular disorders
Necrotizing myositis
Muscular disorders
Pain in extremity
Muscular disorders
Rhabdomyolysis
Neurocognitive disorder
Amnesia
Neurocognitive disorder
Cognitive disorder
Neurocognitive disorder
Confusional state
Neurocognitive disorder
Disorientation
Neurocognitive disorder
Memory impairment
Neurocognitive disorder
Mental status changes
Renal disorders
Acute kidney injury
Renal disorders
Acute prerenal failure
Renal disorders
Blood creatinine abnormal
Renal disorders
Blood creatinine increased
Renal disorders
Blood urea abnormal
Renal disorders
Blood urea increased
Renal disorders
Blood urea nitrogen/Creatinine ratio increased
Renal disorders
Creatinine renal clearance abnormal
Renal disorders
Creatinine renal clearance decreased
Renal disorders
Glomerular filtration rate abnormal
Renal disorders
Glomerular filtration rate decreased
Renal disorders
Oliguria
Renal disorders
Prerenal  failure
Renal disorders
Renal failure
Renal disorders
Renal function test abnormal
Renal disorders
Renal impairment
Gout
Gout
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Esperion Therapeutics, Inc. 
Dec 24, 2018 
Protocol: ETC-1002FDC-053 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 1 of 5 
 
 
Addendum to Statistical Analysis Plan 
Title: 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the 
Efficacy and Safety of Bempedoic Acid 180 mg + Ezetimibe 10 mg 
Fixed Dose Combination Compared to Bempedoic Acid, Ezetimibe, 
and Placebo Alone in Patients Treated with Maximally Tolerated 
Statin Therapy. 
Protocol: 
ETC-1002FDC-053 
Clinical Phase: 
3 
Product: 
ETC-1002FDC 
Date: 
Dec 24, 2018  
 
 
 


 
Esperion Therapeutics, Inc. 
Dec 24, 2018 
Protocol: ETC-1002FDC-053 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 2 of 5 
 
Addendum to the Statistical Analysis Plan for Study 1002FDC-053 
An Ad-hoc Sensitivity Analysis 
 
Esperion completed the planned analysis as described in Study 1002FDC-053 SAP for all 
data collected in the study.  During an in-depth review of the data, after unblinding, a data 
issue was identified that involved three sites.  A formal investigation to assess the root 
cause of the data issue was launched.  After review of the investigative results, the 
conclusion led us to question the data collected at three sites 
 
  
 
 
  
To answer the question and ensure the integrity of the data and related analysis and quality, 
we propose to conduct sensitivity analysis. The focus of the sensitivity analysis is to 
examine if the data issue impacts the efficacy and safety results of the trial.  We will repeat 
selected key analyses after excluding all 81 patients from these 3 sites, 
and 
  
After excluding patients from these 3 sites 
, we will provide tables 
for disposition and demographics. We will repeat the statistical analyses for: 
1. The co-primary efficacy endpoints, which consist of three comparisons of the percent 
change from baseline to Week 12 in LDL-C: bempedoic acid-ezetimibe fixed dose 
combination (FDC) vs. placebo, FDC vs. ezetimibe, and FDC vs. bempedoic acid;  
2. Key secondary efficacy endpoints which include the percent change from baseline to 
Week 12 in non-HDL-C, TC, apoB, and hsCRP; 
3. Overview of treatment emergent adverse events; and  
4. Laboratory parameter of interested including ALT and AST abnormalities. The clinical 
relevance and statistical significance for the results will be re-evaluated for the primary 
and key secondary endpoints.  
The safety profile will also be reviewed during the sensitivity analysis. The list of tables 
for 
sensitivity 
analysis 
is 
provided 
in 


 
Esperion Therapeutics, Inc. 
Dec 24, 2018 
Protocol: ETC-1002FDC-053 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 3 of 5 
 
Table 1. 


 
Esperion Therapeutics, Inc. 
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Protocol: ETC-1002FDC-053 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 4 of 5 
 
Table 1. 
List of Tables for Study 1002FDC-053 Sensitivity Analysis.  
T14.1.1.1 
Patient Disposition 
T14.1.2.1 
Demographic and Baseline Characteristics - Safety Population   
T14.1.2.2 
Demographic and Baseline Characteristics - Full Analysis Set 
T14.2.1.1.1 
Primary Analysis: Percent Change from Baseline in Low-density 
Lipoprotein Cholesterol (LDL-C) at Week 12 (Multiple Imputation (MI)) 
Full Analysis Set 
T14.2.1.1.3 
Sensitivity Analysis: Percent Change from Baseline in Low-density 
Lipoprotein Cholesterol (LDL-C) at Week 12 (Observed Data) Treatment 
Completer Analysis Set 
T14.2.1.2.1 
Statistical Analysis of Percent Change from Baseline in High-sensitivity 
C-reactive Protein (hsCRP) at Week 12  via Non-parametric Approach 
(Observed Data) Full Analysis Set 
T14.2.1.3.1 
Statistical Analysis of Percent Change from Baseline in Non-High-density 
Lipoprotein Cholesterol (Non-HDL-C) at Week 12 (Multiple Imputation 
(MI)) Full Analysis Set 
T14.2.1.4.1 
Statistical Analysis of Percent Change from Baseline in Apolipoprotein B 
(apo-B) at Week 12 (Multiple Imputation (MI)) Full Analysis Set 
T14.2.1.5.1 
Statistical Analysis of Percent Change from Baseline in Total Cholesterol 
at Week 12 (Multiple Imputation (MI) Full Analysis Set 
T14.2.2.1 
Low-density Lipoprotein Cholesterol (LDL-C) Values and Changes and 
Percent Changes from Baseline (Conventional Unit) - Full Analysis Set 
T14.2.7.1 
Summary for Bempedoic Acid Plasma Concentrations by Visit - PK 
Analysis Set 
T14.2.7.2 
Summary for Ezetimibe Plasma Concentrations by Visit - PK Analysis 
Set 
T14.3.1.1.1 
Overview of Treatment-emergent Adverse Events - Safety Population 


 
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Protocol: ETC-1002FDC-053 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 5 of 5 
 
T14.3.1.2.1 
Treatment-emergent Adverse Events (TEAEs) by System Organ Class 
and Preferred Term - Safety Population 
T14.3.1.2.2 
Treatment-emergent Serious Adverse Events (TE SAEs) by System Organ 
Class and Preferred Term - Safety Population 
T14.3.1.2.3 
Treatment-emergent Adverse Events (TEAEs) Resulting in Withdrawal of 
IMP by System Organ Class and Preferred Term - Safety Population 
T14.3.1.2.5 
Treatment-emergent Adverse Events of Special Interest (AESIs) by 
System Organ Class and Preferred Term - Safety Population 
T14.3.1.4.1 
Study-Drug Related Treatment-emergent Adverse Events (TEAEs) by 
System Organ Class and Preferred Term - Safety Population 
T14.3.5.1a 
Laboratory Parameters of Interest: Laboratory Abnormalities - Safety 
Population 
Subset of 
T14.3.4.1.1 
Values, Change from Baseline and Percent Change from Baseline in 
Serum Chemistry Lab Values for uric acid, hemoglobin and creatinine – 
Safety Population 
 
  


 
Esperion Therapeutics, Inc. 
Dec 17, 2018 
Protocol: ETC-1002FDC-053 
Addendum II to Statistical Analysis Plan 
 
Confidential 
Page 1 of 2 
 
 
Addendum II to Statistical Analysis Plan 
Title: 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the 
Efficacy and Safety of Bempedoic Acid 180 mg + Ezetimibe 10 mg 
Fixed Dose Combination Compared to Bempedoic Acid, Ezetimibe, 
and Placebo Alone in Patients Treated with Maximally Tolerated 
Statin Therapy. 
Protocol: 
ETC-1002FDC-053 
Clinical Phase: 
3 
Product: 
ETC-1002FDC 
Date: 
Dec 17, 2018  
 
 
 


 
Esperion Therapeutics, Inc. 
Dec 17, 2018 
Protocol: ETC-1002FDC-053 
Addendum II to Statistical Analysis Plan 
 
Confidential 
Page 2 of 2 
 
Addendum II to the Statistical Analysis Plan for Study 1002FDC-053 
Post-hoc Analysis 
Esperion completed the planned analyses as described in Study 1002FDC-053 SAP for all 
data collected in the study.  After unblinding, some issues of clinical interest were 
identified.  The following is the listing of the tables to address these issues.  
Listing of Tables:  
Table 17.2.1.1 
 
Statin at Baseline by Anatomic Therapeutic Chemical Class and Preferred 
Term 
Full Analysis Set 
Table 17.3.1.1  
 
Post-Randomization Abnormal Liver Function Summary 
Safety Population 
Table 17.4.1.1.1 Laboratory Parameters of Interest: Laboratory Abnormalities 
Subjects on High Intensity Statin at Baseline 
Safety Population 
Table 17.4.1.1.2 Laboratory Parameters of Interest: Laboratory Abnormalities 
Subjects on Other Intensity Statin at Baseline 
Safety Population 
Table 17.4.1.1.3
 
 
 
Laboratory Parameters of Interest: Laboratory Abnormalities 
Subjects on No Statin at Baseline 
Safety Population 
Table 17.5.1.1.1
 
 
 
Percent Change from Baseline in Low-density Lipoprotein Cholesterol 
(LDL-C) at Week 12 by Calculated Baseline Statin Intensity (Observed Data) 
Full Analysis Set 
Table 17.5.1.1.2 Percent Change from Baseline in Low-density Lipoprotein Cholesterol 
(LDL-C) at Week 12 by Calculated Baseline Statin Intensity (Observed Data) 
Treatment Completer Analysis Set