Conditions: Hypercholesterolemia Atherosclerotic Cardiovascular Disease Statin Adverse Reaction
Keywords: hyperlipidemia cholesterol familial hypercholesterolemia atherosclerotic cardiovascular disease ASCVD HeFH LDL statin intolerance
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 345
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if bempedoic acid (ETC-1002) is effective and safe versus placebo in patients with elevated LDL cholesterol and who are statin-intolerant.

Detailed description:

Arms:
arm 1: bempedoic acid 180 mg tablet taken orally, daily. Patients remain on ongoing lipid-modifying therapy (not study provided) arm 2: Matching placebo tablet taken orally, daily. Patients remain on ongoing lipid-modifying therapy (not study provided)

Interventions: intervention 1: bempedoic acid intervention 2: placebo
Intervention descriptions: intervention 1: bempedoic acid 180 mg tablet intervention 2: Matching placebo tablet

Protocol document:
Prot_000.pdf: 
Confidential 
Page 1 of 153 
1.
TITLE PAGE
BEMPEDOIC ACID 
1002-046 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF BEMPEDOIC ACID (ETC-1002) 180 MG COMPARED TO PLACEBO 
ADDED TO BACKGROUND LIPID-MODIFYING THERAPY IN 
PATIENTS WITH ELEVATED LDL-C WHO ARE STATIN INTOLERANT 
Study Phase: 
3 
IND Number: 
106654 
EudraCT Number: 
NA 
Indication: 
Treatment of hyperlipidemia 
Investigators: 
Approximately 71 sites located in North America 
Sponsor: 
Esperion Therapeutics, Inc. 
3891 Ranchero Drive, Suite 150 
Ann Arbor, MI 48108 
Phone:  734-862-4840 
Fax:  734-582-9720 
Sponsor Contact: 
Medical Monitor: 
Version 
Date 
Original Protocol: 
Amendment 1: 
25 August 2016 
10 April 2017 
Confidentiality Statement 
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: NCT02988115
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 2 of 153 
2. 
SYNOPSIS 
Name of Sponsor:  Esperion Therapeutics, Inc.  
Name of Investigational Product:  Bempedoic acid (ETC-1002) film-coated tablets 
Name of Active Ingredient:  Bempedoic acid 
Title of Study:   
A Randomized, Double-Blind, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of 
Bempedoic Acid (ETC-1002) 180 mg Compared to Placebo Added to Background Lipid-Modifying 
Therapy in Patients with Elevated LDL-C Who are Statin Intolerant  
Study Number:  1002-046 
Phase of Development:  3 
Clinical Sites:  Approximately 71 sites located in North America  
Objectives:   
Primary:   
• 
To assess the 12-week efficacy of bempedoic acid 180 mg/day versus placebo in decreasing low-
density lipoprotein cholesterol (LDL-C) in statin intolerant patients with elevated LDL-C 
Secondary:   
• 
To evaluate the effect of 24-week treatment with bempedoic acid 180 mg/day versus placebo on 
LDL-C  
• 
To evaluate the effect of bempedoic acid 180 mg/day versus placebo on non-high-density 
lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), high-sensitivity C-reactive protein 
(hs-CRP), and apolipoprotein B (apoB) after 12 weeks of treatment  
• 
To evaluate the 24-week safety and tolerability of bempedoic acid 180 mg/day compared to 
placebo 
Tertiary: 


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Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 4 of 153 
Primary Endpoint 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in LDL-C 
Secondary Endpoints 
1. Percent change from baseline to Week 24 in LDL-C 
2. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP 
3. Absolute change from baseline to Weeks 12 and 24 in LDL-C 
Tertiary Endpoints 
Safety Endpoints 
1. Patient incidence of treatment-emergent adverse event (TEAE) 
2. Safety laboratory values and vital signs 
3. Cardiovascular event rates 
Number of patients (planned):  Approximately 300 adult male and female patients  
Diagnosis and Criteria for Inclusion: 
Key inclusion criteria 
1. Provision of written informed consent must be obtained prior to any study-specific procedure. 
2. Men and nonpregnant, nonlactating women.  Women must be either: 
• 
Naturally postmenopausal defined as ≥1 year without menses and:  
− 
≥55 years, or  
− 
<55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or 
• 
Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation; or 
• 
Women of childbearing potential must be willing to use 2 acceptable methods of birth control 
(unless they have agreed to follow the definition of true abstinence).  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: 
− 
oral, implanted, topical, or injectable 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 subject.  
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not acceptable 
methods of contraception).   
There are no protocol-specific birth control requirements for men with partners who are able to 
become pregnant. 
3. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at Week -5 
(Visit S1) 
4. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 5 of 153 
• 
Primary prevention ≥130 mg/dL (3.4 mmol/L)  
• 
Secondary prevention and/or heterozygous familial hypercholesterolemia (HeFH) ≥100 mg/dL 
(2.6 mmol/L) 
• 
All patients must have fasting LDL-C ≥70 mg/dL (1.8 mmol/L) at Week -1 (Visit S3) 
In the case of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use, the patient must 
have received 3 stable doses.  It is important that lipid values are measured at PCSK9i trough levels.  
Therefore, study visits should be scheduled in accordance with the patient’s PCSK9i injection 
regimen so that measurement of lipid values for all visits occurs before the PCSK9i injection but not 
greater than 48 hours before the next scheduled PCSK9i injection.  Patients who have discontinued 
investigational or commercial PCSK9 inhibitor must have had their last dose at least 4 months prior 
to Screening Visit S1. 
5. Requiring lipid-modifying therapy for the purpose of primary or secondary prevention of 
cardiovascular events. 
• 
Primary Prevention patients must as a minimum have a history of requiring lipid-modifying 
therapy based on local guidelines (for example, American College of Cardiology 
[ACC]/American Heart Association [AHA] guidelines, European Society of Cardiology 
[ESC]/European Atherosclerosis Society [EAS] guidelines, Canadian Cardiovascular Society 
guidelines). 
• 
Secondary prevention and/or HeFH patients must include those with a history of: 
− 
HeFH, defined by: 
− 
Genotyping or by clinical assessment using either the World Health Organization (WHO) 
criteria/Dutch Lipid Clinical Network Criteria with a score that is >8 points (see Appendix 5) 
or the Simon Broome Register Diagnostic Criteria with an assessment of ‘Definite HeFH’ 
(see Appendix 6).  
and/or 
− 
Coronary artery disease, defined by: 
○ MI (either ST-elevation MI or non-ST-elevation MI) occurring greater than 90 days prior 
to screening (Week -5 Visit S1), or 
○ Percutaneous coronary or surgical coronary revascularization, occurring greater than 
90 days prior to screening (Week -5 Visit S1), or 
○ Angiographic stenosis of >50% in a least 1 major coronary artery (native or graft vessel), 
as documented by selective coronary angiography or computed tomography angiography 
(CTA), or 
− 
Symptomatic peripheral arterial disease (PAD), defined by: 
○ Peripheral vascular disease with symptoms of claudication or resting limb ischemia with 
either ankle brachial index ≤0.9 performed by a vascular lab or angiogram (including 
CTA) showing ≥50% stenosis, or 
○ Peripheral arterial revascularization (surgical or percutaneous), occurring greater than 
90 days prior to screening (Week -5, Visit S1), or 
○ Abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair, occurring 
greater than 90 days prior to screening (Week -5, Visit S1), or 
○ Lower extremity amputation due to peripheral vascular disease, occurring greater than 
90 days prior to screening (Week -5, Visit S1), or 
− 
Cerebrovascular atherosclerotic disease defined by: 
○ Ischemic stroke occurring greater than 90 days prior to screening (Week -5 Visit S1), or 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 6 of 153 
○ 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 
screening (Week -5 Visit S1). 
6. Patient reported SI defined as an inability to tolerate 2 or more statins, one at a low dose, due to an 
adverse safety effect that started or increased during statin therapy and resolved or improved when 
statin therapy was discontinued.  
Low-dose statin therapy is defined as an average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, 
simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg.  
Please note that patients currently tolerating very-low-dose statin therapy (an average daily dose of 
rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg, pravastatin <40 mg, 
fluvastatin <40 mg, or pitavastatin <2 mg) are considered to be intolerant to that low-dose statin. 
Patients may continue taking very-low-dose statin therapy throughout the study provided that it is 
stable (used for at least 4 weeks prior to Screening Visit S1) and well tolerated.  
7. Written confirmation by both patient and principal investigator that the patient is statin intolerant as 
defined above and aware of the benefit of statin use to reduce the risk of MACE including 
cardiovascular death. 
Key exclusion criteria 
1. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L at Week -5 (Visit S1). 
Note:  A single repeat, fasting (minimum of 10 hours) of TG may be completed prior to initiation of 
the single-blind Run-in period.  For those patients who have a repeat TG, the repeat value will be 
used to determine eligibility. 
2. Renal dysfunction or a glomerulonephropathy, 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 -5 (Visit S1). 
Note: A single repeat of eGFR may be completed between Visits S1 and S2.  For those patients who 
have a repeat eGFR, the repeat value will be used to determine eligibility. 
3. Body mass index (BMI) ≥50 kg/m2 
4. Recent (within 3 months prior to the screening visit [Week -5 (Visit S1)] or between screening and 
randomization visits) 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), coronary artery bypass graft (CABG), percutaneous coronary intervention (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 (eg, 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/or 
diastolic blood pressure (DBP) ≥100 mmHg measured according to local standards. 
Note: At the discretion of the investigator, the time between Visits S1 and S2 can be extended by 
4 weeks for adjustments in blood pressure (BP) medications and/or additional assessment of BP, with 
the repeat assessment value used to determine eligibility.  Alternatively, patients can be rescreened if 
BP status has changed. 
6. Hemoglobin A1C (HbA1C) ≥10% at Week -5 (Visit S1). 
7. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper limit of 
normal (ULN) at Week -5 (Visit S1).  Patients stabilized on thyroid replacement therapy for at least 
6 weeks prior to randomization are allowed.  


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 7 of 153 
8. Liver disease or dysfunction, including: 
• 
Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies 
(HCV-ABVivi) at Week -5 (Visit S1). 
• 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, and/or total 
bilirubin (TB) ≥1.2 × ULN at Week -5 (Visit S1).  If TB ≥1.2 × ULN, a reflex indirect 
(unconjugated) bilirubin will be obtained and if consistent with Gilbert’s disease or if the patient 
has a history of Gilbert’s Disease, the patient may be enrolled in the study.  
Note:  At the discretion of the investigator, a single repeat of ALT, AST, and/or TB may be 
completed prior to randomization.  For those patients who have a repeat ALT and/or AST, 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; eg, Lap-Band® or gastric 
bypass) that may affect drug absorption. 
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10 g/dL at Week -5 (Visit S1).   
11. Persistent poor compliance or lack of tolerance with single-blind, placebo study drug (ie, ingesting 
<80% average of planned doses) assessed at the T1 visit prior to randomization. 
12. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 
5 years.  Non-metastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ 
are allowed. 
13. 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.   
14. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine abuse.  
Patients taking amphetamine derivatives for medical reasons such as attention deficit disorder or 
taking prescription opioids or other meds for chronic pain that have been stable, without evidence of 
abuse, and prescribed by and under the care of a health care practitioner can be enrolled after 
evaluation by the Investigator. 
15. Blood donation, participation in a clinical study with multiple blood draws, major trauma, blood 
transfusion, or major surgery with or without blood loss within 30 days prior to randomization. 
16. Use of any experimental or investigational drugs within 30 days.   
17. Previous enrollment in an Esperion bempedoic acid clinical study. 
18. Use of, or a plan to initiate, these prohibited therapies/supplements during the study: 
• 
Mipomersen (must be stopped at least 6 months prior to Week -5 [Visit S1]), 
• 
Lomitapide or apheresis therapy (must be stopped at least 3 months prior to Week -5 [Visit S1]),  
• 
Red yeast rice extract and berberine-containing products must be stopped at least 2 weeks prior to 
Week -5 [Visit S1]),  
• 
Use of an investigational cholesterol ester transfer protein (CETP-I) within the last 2 years 
(except evacetrapib within the last 3 months).   
• 
Statins are prohibited at average daily doses of rosuvastatin ≥5 mg, atorvastatin ≥10 mg, 
simvastatin ≥10 mg, lovastatin ≥20 mg, pravastatin ≥40 mg, fluvastatin ≥40 mg, or pitavastatin 
≥2 mg. 
Note:  Patients can be on any available lipid-modifying therapy with the exception of the 
exclusions listed above as long as they have been stable on oral medications for 4 weeks prior to 
Screening Visit S1 and are taken at a consistent time each day.   
19. Planned initiation or changes to the following drugs:   


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 8 of 153 
• 
Hormone replacement (6 weeks prior to randomization) 
• 
Thyroid replacement (6 weeks prior to randomization) 
• 
Diabetes medications (4 weeks prior to randomization) 
• 
Obesity medication (4 weeks prior to randomization) 
• 
PCSK9 inhibitors:  Patients who are currently on a stable, commercially available PCSK9 
inhibitor (alirocumab or evolocumab) must have had at least 3 doses prior to Visit S1.  Patients 
who were previously (either investigational or commercial) on a PCSK9 inhibitor, must wait at 
least 4 months after last dose prior to screening (Week -5, Visit S1). 
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. 
22. Pregnant, breastfeeding, or intending to become pregnant within 30 days after last dose of study drug. 
23. Patients who have enrolled in a study of an experimental small interfering RNA (siRNA) inhibitor of 
PCSK9. 
24. In patients taking very low dose statins, gemfibrozil is excluded per the co-administration prescribing 
instructions.   
Test product, dose, and mode of administration:   
• 
Bempedoic acid 180-mg tablets 
• 
Matching placebo tablets 
All study drug (bempedoic acid or placebo) will be ingested once daily with or without food 
Duration of treatment: 
The duration of treatment will be a 5-week screening period followed by a 24-week treatment period. 
Criteria for evaluation: 
Efficacy: 
Lipid and Cardiometabolic Assessments: 
• 
Calculated LDL-C, HDL-C, non-HDL-C, TC, TG, apoB, and hs-CRP 
− 
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. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 9 of 153 
Safety: 
Safety Assessments: 
Adverse events and SAEs will be collected and reported.  Clinical endpoints will be collected and 
adjudicated by an independent CEC.  Other safety assessments will include clinical safety laboratories 
(including hematology, blood chemistry, coagulation, HbA1C, fasting glucose, 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 
• 
Coagulation:  Prothrombin time (PT) and International Normalized Ratio (INR) 
In patients receiving anticoagulant therapy PT/INR must be evaluated at Visit T1 and 3 to 5 days 
post Visit T1 using local or central lab  
• 
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: 
• 
Serum pregnancy test (only for females who are of childbearing potential) with urine pregnancy 
test at T1, FSH (naturally postmenopausal females <55 years of age at screening and >1 year 
without menses) 
• 
HBsAg, hepatitis C virus (HCV) 
• 
TSH 
Other Assessments: 
• 
Trough plasma concentrations of bempedoic acid and its metabolite ESP15228 will be collected 
before dose at Weeks 4, 12, and 24 
Safety and Monitoring: 
Monitoring and Management Plans for Triglyceride Elevations: 
Elevated Triglycerides: 
Patients may continue to use stable doses of TG-lowering medications during the study.  An adjunctive 
therapy plan is in place for those patients whose TG values meet the protocol-defined threshold criteria.  
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.  Beginning at Week 4 (Visit T2), 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.  The investigator will initiate the following 
plan: 
• 
Any patient with TG >1000 mg/dL (11.3 mmol/L) will be reminded to fast for at least 10 hours 
and will return to clinic within 1 week for a repeat, fasting TG sample to confirm the TG value 


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meets the threshold criteria  
• 
Any patient with a confirmed TG >1000 mg/dL (11.3 mmol/L) may initiate standard-of-care 
therapy (however, gemfibrozil may not be added) to lower TG using a patient-specific 
prescription.  The initiation of this medication will be documented on the case report form as a 
concomitant medication with the associated start date.  These medications will not be provided by 
the sponsor. 
• 
Patients continuing to exceed the TG threshold after maximizing the standard-of-care triglyceride-
lowering therapy will be discontinued from investigational medicinal product (IMP) treatment 
and will be asked to continue to be followed for safety using the protocol-specified visit schedule. 
Monitoring and Management of Potential AEs and Adverse Events of Special Interest (AESI) 
Potential AEs: 
Based on findings in nonclinical models, potential AEs include reversible hypoglycemia and 
metabolic acidosis.  Potential cases of reversible hypoglycemia and metabolic acidosis will be 
identified by routine safety monitoring of AEs and clinical safety laboratories. 
Musculoskeletal Safety: 
Patients with CK abnormalities will also be reviewed for any other lab changes, such as creatinine, 
and any reported AEs or SAEs.  Musculoskeletal events will be identified and evaluated by routine 
safety monitoring of PE findings and AEs.  
Hepatic:  
Hepatic function will be monitored throughout with the clinical safety labs.  More detailed 
investigation will occur per the instructions in the protocol body if the safety clinical laboratory 
results are 3 times or more than the ULN.  
Renal:   
Renal function will be monitored throughout with clinical safety labs.  More detailed instructions are 
in the protocol body. 
Diabetes and Hyperglycemia: 
Cases of new onset of diabetes will be recorded as AEs.  Clinical laboratories, including HbA1C and 
glucose, will also be evaluated across treatment groups during this study and all ongoing studies to 
identify potential cases of new onset of diabetes. 
Neurocognitive Events: 
Neurocognitive events will be identified and evaluated by routine safety monitoring of PE findings 
and AEs.  
Clinical Endpoints: 
Clinical endpoints will be monitored and adjudicated by an independent expert CEC for this study 
and other ongoing studies in the bempedoic acid program. 
Routine cardiovascular monitoring will include review of cardiovascular AEs, SAEs, standard vital 
signs, and ECGs. 
Further details on occurrence and monitoring are available in the Investigator’s Brochure (IB). 
Statistical methods: 
Sample Size 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in LDL-C.   


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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 the treatment they actually 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 study medication.  Patients in the SP will be included in the treatment 
group that they actually received, regardless of their randomized treatment.   
Primary Endpoint  
The primary efficacy endpoint is the percent change from baseline to Week 12 in LDL-C.  The primary 
efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with treatment group and 
patient type (primary prevention; secondary prevention) as factors and baseline LDL-C as a covariate.  
Baseline LDL-C is defined as the mean of the LDL-C values from Week -1 (Visit S3) and predose 
Day 1/Week 0 (Visit T1).  The ANCOVA will be performed using the FAS, with patients included in 
their randomized treatment group regardless of the treatment they actually received.  Two methods for 
data handling will be used:  the first is observed case data only, while the second will involve 
specification of the missing data mechanism using a pattern mixture model (PMM).  The primary analysis 
will be that from the PMM, while the observed case analysis will be used as confirmatory.  The PMM 
will be used to specify different imputation strategies depending on whether the patient is still on study 
treatment.  Imputed datasets will be analyzed using ANCOVA with the treatment and patient type 
(primary prevention; secondary prevention) as factors and baseline LDL-C as a covariate.  Approximately 
200 imputed datasets will be created, with results from the analysis of each imputed dataset combined 
using Rubin’s method.  For each type of ANCOVA (observed case; imputation via PMM), the least 
squares mean (LSM) and standard error (SE) will be provided for both treatment groups, along with the 
placebo-corrected LSM, its 95% confidence interval (CI) and associated p-value. 
Secondary and Tertiary Efficacy Endpoints 
Secondary efficacy endpoints are also of interest for this study, in terms of controlling the overall Type I 
error rate, a gatekeeping or stepdown approach will be used to test the primary efficacy endpoint and then 
specific secondary efficacy endpoints sequentially in order to preserve the study-wise Type I error rate. 
The sequence for the stepdown procedure in this study is as follows: 
1. Test the primary efficacy endpoint: percent change from baseline to Week 12 in LDL-C  
2. Test the percent change from baseline to Week 24 in LDL-C 
3. Test the percent change from baseline to Week 12 in non-HDL-C 
4. Test the percent change from baseline to Week 12 in TC 
5. Test the percent change from baseline to Week 12 in apoB 
6. Test the percent change from baseline to Week 12 in hs-CRP   
In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, two-sided. 
Statistical significance at each step is required in order to test the next hypothesis.  If the primary endpoint 
meets the criteria for statistical significance, then the percent change from baseline to Week 24 in LDL-C 
will be tested; and so forth. 
For the remaining secondary efficacy endpoints and the tertiary efficacy endpoints, a significance level of 
0.05 will be used; given the large number of remaining endpoints, the p-values for those endpoints will be 
considered descriptive. 
Percent change from baseline to Week 24 in LDL-C; change from baseline to Weeks 12 and 24 in 
LDL-C; percent change from baseline to Weeks 12
in
 non-HDL-C,
TC, apoB, and 


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hs-CRP will each be analyzed using ANCOVA with treatment group and patient type (primary 
prevention; secondary prevention) as factors and the relevant baseline as a covariate.  Baseline for 
non-HDL-C,
 and TC will be defined as the mean of the lipid values from Week -1 (Visit S3) 
and predose Day 1/Week 0 (Visit T1).  Baseline for apoB and hs-CRP will be defined as the predose 
Day 1/Week 0 (Visit T1) value.  Each ANCOVA will be performed using the FAS, with patients included 
in their randomized treatment group regardless of the treatment they actually received.  Only observed 
case data will be included in each analysis (no imputation will be performed for missing data).  For each 
lipid parameter and analysis time point, the LSM and SE will be provided for both treatment groups, 
along with the placebo-corrected LSM, its 95% CI and associated p-value. 
For all continuous efficacy endpoints (percent change from baseline in LDL-C,
 non-HDL-C, TC, 
 apoB, and hs-CRP; change from baseline in LDL-C; to Weeks 12 and 24, as appropriate), the 
ANCOVA assumption of normality will be assessed.  If non-normality of the data is found at any time 
point for any parameter, either the data will be transformed so that it is normally distributed or a 
nonparametric test will be used instead of the planned ANCOVA. 
Additional Post-randomization Adjunctive Triglyceride-lowering Therapy: 
The number and percent of patients in each treatment group requiring additional (post-randomization) 
TG-lowering therapy will be summarized.  The medications will be summarized by treatment group. 
Safety Analyses 
The summarization of AEs will include TEAEs.  TEAEs and SAEs will be summarized by system organ 
class (SOC), severity, and relationship to study drug for each treatment group.  These AE summaries will 
include cumulative incidence (percent of patients experiencing the AE) and patient-year adjusted 
incidence rates.  If appropriate, absolute and relative risk differences will be calculated using both 
cumulative incidence and incidence rates.  Deaths, withdrawal from study treatment due to AEs, and 
withdrawal from the study due to AEs 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 from baseline in the value (where appropriate) at each post baseline time point. 
Hepatic Safety 
For liver-associated enzymes and TB, the number and percent of patients with abnormal values for ALT, 
AST, and TB will be summarized.  Hy’s law criteria (≥3 × ULN for either ALT or AST, with 
accompanying TB >2 × ULN in the absence of other known causes) will also be applied to the data; any 
potential Hy’s law cases will be listed separately.  For patients with Gilbert’s disease, conjugated (direct 
bilirubin) will be used for the evaluation.   
Musculoskeletal Safety 
AEs of muscle-related symptoms will be summarized by treatment group.  In addition, the number and 
percent of patients with abnormal CK values will be summarized.   
Diabetes/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. 


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Renal Safety 
Baseline eGFR and values of CK will be summarized by treatment group and by baseline eGFR 
categories.  Shift tables of eGFR category from baseline over the study, will be provided by treatment 
group.  Finally, muscle-related AEs will be summarized by treatment group and by baseline eGFR 
category. 
Neurocognitive Events 
Neurocognitive events will be identified and evaluated by routine safety monitoring of PE findings and 
AEs.  Summarization of neurocognitive events will occur using prespecified Medical Dictionary for 
Regulatory Activities (MedDRA) terms and will be performed by treatment group. 
Clinical endpoints 
Clinical endpoints using standardized definitions will be adjudicated by an independent blinded expert 
CEC for all ongoing Phase 3 studies in the bempedoic acid program.  Investigator-reported clinical 
endpoints and adjudicated clinical endpoints will be summarized by event type and treatment group.  
Additional details regarding the clinical endpoints and their definitions will be included in CEC Charter.   
Pharmacokinetics 
Three pharmacokinetic (PK) samples will be collected.  Plasma concentrations of bempedoic acid and its 
metabolite ESP15228 will be determined in patients who are receiving bempedoic acid, who have 
compliance ≥80%, and who have taken a dose of bempedoic acid within 2 days of the sample collection.  
All patients, site personnel, and study personnel will remain blinded to treatment assignment throughout 
the duration of the study.  Personnel performing the bioanalytical analysis of bempedoic acid 
concentrations will be unblinded in order to assay the appropriate samples during the study.  Plasma 
concentrations of bempedoic acid and ESP15228 will be summarized using descriptive statistics by time 
point. 
 


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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
ABBREVIATIONS AND DEFINITIONS .................................................................20 
4. 
INTRODUCTION ......................................................................................................25 
4.1. 
Overview of the Disease Under Study ........................................................................25 
4.2. 
Overview of Bempedoic Acid ....................................................................................26 
4.2.1. 
Mechanism of Action .................................................................................................26 
4.2.2. 
Pharmacokinetics and Pharmacology .........................................................................26 
4.2.3. 
Dose Selection ............................................................................................................27 
4.3. 
Nonclinical Experience ...............................................................................................27 
4.4. 
Clinical Experience .....................................................................................................27 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
5.1. 
Study Objectives .........................................................................................................29 
5.1.1. 
Primary Objective .......................................................................................................29 
5.1.2. 
Secondary Objectives .................................................................................................29 
5.1.3. 
Tertiary Objective .......................................................................................................29 
5.2. 
Study Endpoints ..........................................................................................................29 
5.2.1. 
Primary Endpoint ........................................................................................................29 
5.2.2. 
Secondary Endpoints ..................................................................................................29 
5.2.3. 
Tertiary Endpoints ......................................................................................................29 
5.2.4. 
Safety Endpoints .........................................................................................................30 
6. 
INVESTIGATIONAL PLAN .....................................................................................30 
6.1. 
Overall Study Design ..................................................................................................30 
6.2. 
Study Population and Selection ..................................................................................30 
6.2.1. 
Inclusion Criteria ........................................................................................................31 
6.2.2. 
Exclusion Criteria .......................................................................................................33 
6.3. 
Patient Identification, Randomization, and Blinding .................................................36 


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7. 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................38 
7.1. 
Investigational Medicinal Product Supply and Control ..............................................38 
7.2. 
Administration of Investigational Medicinal Product ................................................38 
7.3. 
Concomitant Medications ...........................................................................................39 
7.3.1. 
Lipid-Regulating Medications and Supplements........................................................39 
7.3.2. 
Prohibited Medications ...............................................................................................40 
7.3.3. 
Allowable Medications ...............................................................................................41 
7.4. 
Patient Lifestyle and Dietary Guidelines ....................................................................41 
7.5. 
Treatment Compliance ................................................................................................41 
8. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS .........................43 
8.1. 
Informed Consent .......................................................................................................43 
8.2. 
Confirmation of Statin Intolerance (SI) ......................................................................43 
8.3. 
Procedures and Schedule of Assessments ..................................................................43 
8.3.1. 
Screening Week -5 (Visit S1; Day -35 ± 7 days) .......................................................47 
8.3.2. 
Screening Week -4 (Visit S2; Day -28 ±3) .................................................................48 
8.3.3. 
Screening Week -1 (Visit S3; Day -7 ±3) ...................................................................48 
8.3.4. 
Week 0 (Visit T1; Day 1) ...........................................................................................48 
8.3.5. 
Treatment Week 4 (Visit T2; Day 29 ±3 days) ..........................................................49 
8.3.6. 
Treatment Week 8 Phone Call (Visit T3; Day 57 ±3 days) ........................................50 
8.3.7. 
Treatment Week 12 (Visit T4; Day 85 ±3 days) ........................................................50 
8.3.8. 
Treatment Week 24/EOS (Visit T5; Day 169 ±7 days) ..............................................51 
8.4. 
Early Withdrawal from Study or Treatment ...............................................................51 
8.4.1. 
Procedures for Early Withdrawal ...............................................................................52 
8.4.2. 
Patients Lost to Follow-Up .........................................................................................53 
8.4.3. 
Discontinuation of Study Sites or the Study ...............................................................53 
8.5. 
Overdose .....................................................................................................................53 
9. 
ASSESSMENT OF EFFICACY ................................................................................54 
9.1. 
Efficacy Parameters ....................................................................................................54 


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9.2. 
Clinical Efficacy Laboratory Tests .............................................................................54 
10. 
ASSESSMENT OF SAFETY .....................................................................................55 
10.1. 
Safety Parameters .......................................................................................................55 
10.1.1. 
Demographic/Medical History ...................................................................................55 
10.1.2. 
Vital Signs ..................................................................................................................55 
10.1.3. 
Weight, Height, and Body Mass Index .......................................................................55 
10.1.4. 
Physical Examination .................................................................................................56 
10.1.5. 
Electrocardiogram .......................................................................................................56 
10.1.5.1. 
Monitoring and Management of Abnormal Electrocardiograms ................................56 
10.1.6. 
Clinical Laboratory Tests ...........................................................................................57 
10.1.6.1. 
Laboratory Parameters (Safety) ..................................................................................57 
10.1.6.2. 
Clinical Laboratory Tests (PK) ...................................................................................58 
10.1.6.3. 
Sample Collection, Storage, and Shipping .................................................................58 
10.1.6.4. 
General Monitoring and Management of Abnormal Clinical Labs ............................58 
10.1.6.5. 
Total Blood Volume of Clinical Laboratory Samples ................................................59 
10.2. 
Adverse and Serious Adverse Events .........................................................................59 
10.2.1. 
Definition of Adverse Event .......................................................................................59 
10.2.2. 
Adverse Drug Reaction ...............................................................................................59 
10.2.3. 
Reporting ....................................................................................................................60 
10.2.4. 
Severity of Adverse Events ........................................................................................61 
10.2.5. 
Relationship ................................................................................................................61 
10.2.6. 
Monitoring and Follow-up of Adverse Events ...........................................................62 
10.2.7. 
Treatment-Emergent Adverse Event ..........................................................................62 
10.2.7.1. 
Definition of Serious Adverse Event ..........................................................................62 
10.2.7.2. 
Definition of Serious Adverse Event Events or Outcomes not Qualifying as 
Serious Adverse Events ..............................................................................................63 
10.2.7.3. 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .........................................................................................................................63 


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10.2.7.4. 
Reporting of Serious Adverse Events .........................................................................63 
10.2.7.5. 
Reporting of Serious Adverse Events to Regulatory Authorities ...............................64 
10.2.7.6. 
Reports of Pregnancy ..................................................................................................64 
10.2.8. 
Reporting of Patient Death .........................................................................................65 
10.2.9. 
Recording of Adverse Events and Serious Adverse Events .......................................65 
10.2.10. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................65 
10.2.11. 
Adverse Events of Special Interest (AESI) ................................................................65 
10.2.11.1. Potential Adverse Events Based on Findings in Bempedoic Acid Clinical 
Studies.........................................................................................................................66 
10.2.11.2. Potential Adverse Events Based on Findings in Nonclinical Models ........................67 
10.2.11.3. Adverse Events Associated with Other Lipid-Lowering Therapies ...........................67 
10.2.12. 
Monitoring and Management of Elevated Triglycerides ............................................71 
10.3. 
Data Monitoring Committee (DMC) ..........................................................................71 
10.4. 
Clinical Event Committee (CEC) ...............................................................................71 
11. 
STATISTICS ..............................................................................................................73 
11.1. 
General Considerations ...............................................................................................73 
11.2. 
Sample Size ................................................................................................................73 
11.3. 
Analysis Populations ..................................................................................................73 
11.4. 
Disposition, Demographics and Baseline Characteristics ..........................................73 
11.5. 
Primary Endpoint Analysis .........................................................................................73 
11.6. 
Secondary and Tertiary Endpoint Analysis ................................................................74 
11.7. 
Safety Analysis ...........................................................................................................75 
11.8. 
Pharmacokinetics ........................................................................................................76 
11.9. 
Interim Analysis and Data Monitoring Committee ....................................................76 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................77 
12.1. 
Study Monitoring ........................................................................................................77 
12.2. 
Audits and Inspections ................................................................................................77 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 


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14. 
ETHICS ......................................................................................................................80 
14.1. 
Institutional Review Board/Independent Ethics Committee Approval ......................80 
14.2. 
Ethical Conduct of the Study ......................................................................................80 
14.3. 
Written Informed Consent ..........................................................................................81 
14.4. 
Patient Confidentiality ................................................................................................81 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................82 
15.1. 
Inspection of Records .................................................................................................82 
15.2. 
Retention of Records ..................................................................................................82 
15.3. 
Case Report Forms and Study Records ......................................................................82 
16. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................84 
16.1. 
Investigators ................................................................................................................84 
16.2. 
Study Administrative Structure ..................................................................................85 
16.3. 
Amendments ...............................................................................................................85 
16.4. 
Financial Disclosure ...................................................................................................85 
17. 
PUBLICATION AND DISCLOSURE POLICY .......................................................86 
18. 
REFERENCES ...........................................................................................................87 
19. 
APPENDICES ............................................................................................................89 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................90 
APPENDIX 2. SPONSOR’S SIGNATURE ...............................................................................92 
APPENDIX 3. INVESTIGATOR’S SIGNATURE....................................................................96 
APPENDIX 4. STATIN INTOLERANCE CONFIRMATION FORM .....................................97 
APPENDIX 5. DUTCH LIPID CLINIC NETWORK CRITERIA FOR FAMILIAL 
HYPERCHOLESTEROLEMIA.................................................................................98 
APPENDIX 6. SIMON BROOM REGISTER DIAGNOSTIC CRITERIA FOR 
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA .........................100 
APPENDIX 7. SUMMARY OF CHANGES AMENDMENT 1 .............................................102 
 


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LIST OF TABLES 
Table 1: 
Investigational Product ...............................................................................................39 
Table 2: 
Schedule of Events (Subject Visit Schedule) .............................................................44 
Table 3: 
Clinical Efficacy Laboratory Tests .............................................................................54 
Table 4: 
Clinical Laboratory Parameters (Safety) ....................................................................57 
 
LIST OF FIGURES 
Figure 1: 
1002-046 Study Design ..............................................................................................30 
 


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3. 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation  
Definition 
ACC 
American College of Cardiology 
ACL 
Adenosine triphosphate-citrate lyase 
ACS 
Acyl-CoA synthetase 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AHA 
American Heart Association 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
apoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC0-24 
Area under the curve during 24 hours 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CABG 
Coronary artery bypass graft 
CEC 
Clinical Events Committee 
CETP 
Cholesterol ester transfer protein 
CFR 
Code of Federal Regulations 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CK 
Creatine kinase 
Cl 
Chloride 
Cmax 
Time to peak maximum concentration 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 


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Abbreviation  
Definition 
CoA 
Acetyl-coenzyme A 
CO2 
Carbon dioxide 
CRO 
Contract research organization 
CTA 
Computed tomography angiography 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
EAS 
European Atherosclerosis Society 
EC 
Executive committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ESC 
European Society of Cardiology 
ETC-1002 
Bempedoic acid 
EU 
European Union 
FAS 
Full analysis set 
FDA 
US Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HbA1C 
Glycosylated hemoglobin, Type 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 


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Abbreviation  
Definition 
hr 
Hour 
HR 
Heart rate 
hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICD 
Informed Consent Document 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IWRS 
Interactive web response system 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LFT 
Liver function test 
LS 
Least squares 
LSM 
Least squares mean 
MACE 
Major adverse cardiovascular event 
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 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NA 
Not applicable 
NLA 
National Lipid Association 


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Abbreviation  
Definition 
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) 
PMM 
Pattern mixture model 
PT 
Prothrombin time 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SE 
Standard error 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SI 
Statin intolerant 
siRNA 
small interfering ribonucleic acid 
SOC 
System organ class 
SP 
Safety population 
SUSAR 
Suspected and unexpected serious adverse reaction 
t½  
Terminal elimination half-life 
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 
TQT 
Thorough QT/QTc 
ULN 
Upper limit of normal 


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Abbreviation  
Definition 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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4. 
INTRODUCTION 
4.1. 
Overview of the Disease Under Study 
Bempedoic acid (ETC-1002) is an inhibitor of adenosine triphosphate-citrate lyase (ACL) 
(adenosine triphosphate [ATP] citrate lyase), an enzyme upstream of 3-hydroxy-3-methylglutaryl 
coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway.  It is an oral first-
in-class small molecule designed to lower low-density lipoprotein cholesterol (LDL-C) levels in 
patients with high cardiovascular risk unable to meet their treatment goals with currently 
available lipid-lowering therapies. 
More people die annually from cardiovascular disease (CVD) than from any other disease.  CVD 
remains the leading cause of death among Europeans, Americans, and other populations around 
the world (WHO 2015).  In the United States (US), based on 2011 data, more than 
2,150 Americans die from CVD per day, an average of 1 death every 40 seconds (Mozffarian 
2015).  The relationship between CVD and elevations in LDL-C is undisputed.  Many clinical 
studies have demonstrated that lowering elevated levels of LDL-C reduces the risk of heart 
attacks, stroke, and death (Baigent 2010).  More than half of the adult population has high 
cholesterol; therefore, lowering elevated LDL-C is a very important step in the battle against 
heart disease.  It is also known that elevation of high-sensitivity C-reactive protein (hs-CRP; a 
measure of systemic inflammation) has been associated with increased cardiovascular (CV) risk 
(Bikdeli 2011; Vidula 2008), and lowering hs-CRP with statin therapy—independent of the level 
of LDL-C achieved with the statin treatment—significantly reduces recurrent coronary events 
(Ridker 2005).  Given the evidence, hs-CRP is included as a risk indicator in the Reynolds Risk 
algorithm (Ridker 2007) and in clinical practice guidelines for the management of dyslipidemia 
(Jacobson 2014; Stone 2013).  The Reynolds Risk score, which includes hs-CRP, has proved to 
be an excellent CV risk assessment tool (DeFilippis 2011). 
The use of HMG-CoA reductase inhibitors, or statins, is one of the most important advances in 
the management of CVD, decreasing CV morbidity and mortality by approximately 25% in 
eligible patients (Joy 2009).  However, tolerability is an important barrier to statin adherence.  
Muscle complaints, which encompass a range of conditions from myalgia to rare but life-
threatening rhabdomyolysis, represent a major cause of statin discontinuation in clinical practice 
(Joy 2009).  In addition, a range of other signs and symptoms may lead to discontinuation, 
including elevated liver enzymes, gastric upset, diarrhea, constipation, rash, headache, dizziness, 
mental confusion, forgetfulness, and erectile dysfunction (Eckel 2010).  The statin intolerant (SI) 
patient population constitutes a major public health concern.  
Guidelines now recommend very aggressive lowering of LDL-C in high-risk individuals to 
levels below 100 mg/dL and often under 70 mg/dL (Jacobson 2014) or reduction of ≥50% 
(Stone 2013).  Worldwide, statins are used by tens of millions in order to achieve these 
aggressive lipid goals.  Recent guidelines for the treatment of hypercholesterolemia are likely to 
further increase the number of patients taking statins, possibly to as many as 1 in 3 American 
adults.  Consequently, as the number of statin-treated patients grows, the problem of statin 
intolerance will increase in importance as a public health concern.  Current guidelines recognize 
that some patients develop intolerable side effects with statins.  These guidelines recommend 


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patients be treated with the maximum-appropriate intensity of a statin that does not cause adverse 
effects (Stone 2013).  
4.2. 
Overview of Bempedoic Acid 
4.2.1. 
Mechanism of Action 
Bempedoic acid is a first-in-class small molecule inhibitor of ACL, an enzyme upstream of 
HMG-CoA in the cholesterol biosynthesis pathway.  Bempedoic acid is a prodrug that requires 
activation in liver to ETC-1002-coenzyme A (ETC-1002-CoA), which mediates competitive 
inhibition of ACL.  Inhibition of ACL by ETC-1002-CoA decreases cholesterol synthesis in liver 
leading to increased LDL receptor (LDLR) expression and LDL particle clearance from the 
blood.  Therefore, inhibition of ACL by ETC-1002-CoA reduces LDL-C via the same pathway 
as HMG-CoA reductase inhibition by statins. 
An important differentiating feature of bempedoic acid is that, unlike statins, it does not inhibit 
cholesterol synthesis in skeletal muscle.  The enzyme required to convert bempedoic acid to 
ETC-1002-CoA is not present in skeletal muscle.  Therefore, bempedoic acid is not anticipated 
to mediate the adverse effects associated with inhibition of biological intermediates within the 
cholesterol biosynthesis pathway in skeletal muscle; however, the safety of bempedoic acid and 
its metabolites regarding human skeletal muscle is not yet established. 
4.2.2. 
Pharmacokinetics and Pharmacology 
In both single- and multiple-dose studies, bempedoic acid is well absorbed (with a time to peak 
maximum concentration [Cmax] of approximately <4 hours).  The Cmax of bempedoic acid and 
ESP15228 increased in proportion to increasing dose.  The terminal elimination half-life (t½) 
ranged from 15 to 27 hours for bempedoic acid and 20 to 33 hours for ESP15228. 
In clinical drug-drug interaction studies, bempedoic acid 240 mg showed less than a 2-fold 
increase in the exposure of atorvastatin 10 mg, simvastatin 20 mg, pravastatin 40 mg, and 
rosuvastatin 10 mg in 2 statin drug-drug interaction studies (Studies 1002-007 and 1002-012).  
This increase was generally less pronounced when bempedoic acid 180 mg was administered 
with high dose statins (atorvastatin 80 mg, simvastatin 40 mg, pravastatin 80 mg, and 
rosuvastatin 40 mg) in Study 1002-037, suggesting that the combination is unlikely to alter 
safety profile of statins.  No drug interaction occurred between daily bempedoic acid 180 mg and 
metformin in patients with type 2 diabetes mellitus (T2DM).  A Phase 2 study evaluated and 
showed no effect of ezetimibe 10 mg on steady-state trough bempedoic acid plasma 
concentrations in 40 patients with hypercholesterolemia randomized to receive bempedoic acid 
plus ezetimibe (Study 1002-008).  Results of a drug interaction study in 19 patients (16 evaluable 
for pharmacokinetics [PK]) with the oral contraceptive Ortho-Novum 1/35 in healthy women 
demonstrate no effect of daily bempedoic acid 180 mg on ethinyl estradiol or norethindrone 
exposure (Study 1002-017). 
The results of the thorough QT/QTc (TQT) study (1002-022) showed no significant change in 
QTc.  Following daily bempedoic acid 240 mg for 9 days, bempedoic acid does not prolong QT 
interval duration and has no clinically significant effect on heart rate and PR and QRS intervals. 


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4.2.3. 
Dose Selection 
4.3. 
Nonclinical Experience 
4.4. 
Clinical Experience 


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
• To assess the 12-week efficacy of bempedoic acid 180 mg/day versus placebo in 
decreasing LDL-C in statin intolerant patients with elevated LDL-C 
5.1.2. 
Secondary Objectives 
• To evaluate the effect of 24-week treatment with bempedoic acid 180 mg/day versus 
placebo on LDL-C 
• To evaluate the effect of bempedoic acid 180 mg/day versus placebo on non-high-
density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), hs-CRP, and 
apolipoprotein B (apoB) after 12 weeks of treatment  
• To evaluate the 24-week safety and tolerability of bempedoic acid 180 mg/day 
compared to placebo 
5.1.3. 
Tertiary Objective 
5.2. 
Study Endpoints 
5.2.1. 
Primary Endpoint 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in 
LDL-C 
5.2.2. 
Secondary Endpoints 
1. Percent change from baseline to Week 24 in LDL-C 
2. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP  
3. Absolute change from baseline to Weeks 12 and 24 in LDL-C 
5.2.3. 
Tertiary Endpoints 


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Approximately 300 patients with a history of SI will be stratified based on patient type (primary 
prevention; secondary prevention) and randomized at Week 0 (Visit T1) in a 2:1 ratio to receive 
either bempedoic acid 180 mg (n = 200) or matching placebo (n = 100) once daily for 24 weeks.  
Randomized patients will return for clinic visits at Week 4 (Visit T2), Week 12 (Visit T4), and 
Week 24 (Visit T5).  A phone visit will occur at Week 8 (Visit T3).   
An independent expert Data Monitoring Committee (DMC) will formally review accumulating 
unblinded safety data from this and other ongoing Phase 3 studies of bempedoic acid.  All 
clinical endpoints, including all major cardiac events (MACE) and non-MACE endpoints defined 
as: CV death (MACE), non-CV death (non-MACE), nonfatal myocardial infarction (MI) 
(MACE), nonfatal stroke (MACE), hospitalization for unstable angina (MACE), coronary 
revascularization (MACE), non-coronary arterial revascularization (non-MACE), and 
hospitalization for heart failure (non-MACE), will be adjudicated by an independent blinded 
expert Clinical Events Committee (CEC), using standardized definitions.  
For details of study assessments, see the Schedule of Events in Section 8.3. 
6.2.1. 
Inclusion Criteria 
1. Provision of written informed consent must be obtained prior to any study-specific 
procedure. 
2. Men and nonpregnant, nonlactating women.  Women must be either: 
a. Naturally postmenopausal defined as ≥1 year without menses and:  
− ≥55 years, or  
− <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or 
b. Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal 
ligation; or 
c. Women of childbearing potential must be willing to use 2 acceptable methods of birth 
control (unless they have agreed to follow the definition of true abstinence).  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: 
− oral, implanted, topical, or injectable 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 
subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception). 


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There are no protocol-specific birth control requirements for men with partners who are 
able to become pregnant. 
3. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at 
Week -5 (Visit S1) 
4. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) 
• Primary prevention ≥130 mg/dL (3.4 mmol/L)  
• Secondary prevention and/or heterozygous familial hypercholesterolemia (HeFH) 
≥100 mg/dL (2.6 mmol/L) 
• All patients must have fasting LDL-C ≥70 mg/dL (1.8 mmol/L) at Week -1 (Visit S3) 
In the case of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use, the 
patient must have received 3 stable doses.  It is important that lipid values are measured 
at PCSK9i trough levels.  Therefore, study visits should be scheduled in accordance with 
the patient’s PCSK9i injection regimen so that measurement of lipid values for all visits 
occurs before the PCSK9i injection but not greater than 48 hours before the next 
scheduled PCSK9i injection.  Patients who have discontinued investigational or 
commercial PCSK9 inhibitor must have had their last dose at least 4 months prior to 
Screening Visit S1. 
5. Requiring statin therapy for the purpose of primary or secondary prevention of 
cardiovascular events. 
a. Primary Prevention patients must as a minimum have a history of requiring lipid-
modifying therapy based on local guidelines (for example, American College of 
Cardiology [ACC]/American Heart Association [AHA] guidelines, European Society 
of Cardiology [ESC]/European Atherosclerosis Society [EAS] guidelines, Canadian 
Cardiovascular Society guidelines). 
b. Secondary prevention and/or HeFH patients must include those with a history of: 
− HeFH, defined by: 
− Genotyping or by clinical assessment using either the World Health Organization 
(WHO) criteria/Dutch Lipid Clinical Network Criteria with a score that is 
>8 points (see Appendix 5) or the Simon Broome Register Diagnostic Criteria 
with an assessment of ‘Definite HeFH’ (see Appendix 6).  
and/or 
− Coronary artery disease, defined by: 
○ MI (either ST-elevation MI or non-ST-elevation MI) occurring greater than 
90 days prior to screening (Week -5 Visit S1), or 
○ Percutaneous coronary or surgical coronary revascularization, occurring 
greater than 90 days prior to screening (Week -5 Visit S1), or 
○ Angiographic stenosis of >50% in a least 1 major coronary artery (native or 
graft vessel), as documented by selective coronary angiography or computed 
tomography angiography (CTA), or 


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− Symptomatic peripheral arterial disease (PAD), defined by: 
○ Peripheral vascular disease with symptoms of claudication or resting limb 
ischemia with either ankle brachial index ≤0.9 performed by a vascular lab or 
angiogram (including CTA) showing ≥50% stenosis, or 
○ Peripheral arterial revascularization (surgical or percutaneous), occurring 
greater than 90 days prior to screening (Week -5, Visit S1), or 
○ Abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair, 
occurring greater than 90 days prior to screening (Week -5, Visit S1), or 
○ Lower extremity amputation due to peripheral vascular disease, occurring 
greater than 90 days prior to screening (Week -5, Visit S1), or 
− Cerebrovascular atherosclerotic disease defined by: 
○ Ischemic stroke occurring greater than 90 days prior to screening (Week -5 
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 screening (Week -5 Visit S1). 
6. Patient-reported SI defined as an inability to tolerate 2 or more statins, one at a low dose, 
due to an adverse safety effect that started or increased during statin therapy and resolved 
or improved when statin therapy was discontinued.  
Low-dose statin therapy is defined as an average daily dose of rosuvastatin 5 mg, 
atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 
40 mg, or pitavastatin 2 mg.  
Please note that patients currently tolerating very-low-dose statin therapy (an average 
daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin 
<20 mg, pravastatin <40 mg, fluvastatin <40 mg, or pitavastatin <2 mg) are considered to 
be intolerant to that low-dose statin. Patients may continue taking very-low-dose statin 
therapy throughout the study provided that it is stable (used for at least 4 weeks prior to 
screening, S1) and are taken at a consistent time each day. 
7. Written confirmation by both patient and principal investigator that the patient is statin 
intolerant as defined above and aware of the benefit of statin use to reduce the risk of 
MACE including cardiovascular death. 
6.2.2. 
Exclusion Criteria 
1. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L at Week -5 (Visit S1). 
Note:  A single repeat, fasting (minimum of 10 hours) of TG may be completed prior to 
initiation of the single-blind Run-in period.  For those patients who have a repeat TG, the 
repeat value will be used to determine eligibility. 


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2. Renal dysfunction or a glomerulonephropathy, 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 -5 (Visit S1). 
Note:  A single repeat of eGFR may be completed between Visits S1 and S2.  For those 
patients who have a repeat eGFR, the repeat value will be used to determine eligibility. 
3. Body mass index (BMI) ≥50 kg/m2 
4. Recent (within 3 months prior to the screening visit [Week -5 (Visit S1)] or between 
screening and randomization visits) 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), coronary artery bypass graft 
(CABG), percutaneous coronary intervention (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 (eg, 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/or diastolic blood pressure (DBP) ≥100 mmHg measured according to local 
standards. 
Note:  At the discretion of the investigator, the time between Visits S1 and S2 can be 
extended by 4 weeks for adjustments in blood pressure (BP) medications and/or 
additional assessment of BP, with the repeat assessment value used to determine 
eligibility.  Alternatively, patients can be rescreened if BP status has changed. 
6. Hemoglobin A1C (HbA1C) ≥10% at Week -5 (Visit S1). 
7. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the 
upper limit of normal (ULN) at Week -5 (Visit S1). Patients stabilized on thyroid 
replacement therapy for at least 6 weeks prior to randomization are allowed.  
8. Liver disease or dysfunction, including: 
• Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C 
antibodies (HCV-ABVivi) at Week -5 (Visit S1). 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, 
and/or total bilirubin (TB) ≥1.2 × ULN at Week -5 (Visit S1).  If TB ≥1.2 × ULN, a 
reflex indirect (unconjugated) bilirubin will be obtained and if consistent with 
Gilbert’s disease or if the patient has a history of Gilbert’s Disease, the patient may be 
enrolled in the study.  
Note:  At the discretion of the investigator, a single repeat of ALT, AST, and/or TB may 
be completed prior to randomization.  For those patients who have a repeat ALT and/or 
AST, 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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9. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® 
or gastric bypass) that may affect drug absorption. 
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10 g/dL at Week -5 
(Visit S1) 
11. Persistent poor compliance or lack of tolerance with single-blind, placebo study drug (ie, 
ingesting <80% average of planned doses) assessed at the T1 visit prior to randomization. 
12. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in 
the past 5 years.  Non-metastatic basal or squamous cell carcinoma of the skin and 
cervical carcinoma in situ are allowed. 
13. 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.   
14. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine 
abuse.  Patients taking amphetamine derivatives for medical reasons such as attention 
deficit disorder or taking prescription opioids or other meds for chronic pain that have 
been stable, without evidence of abuse, and prescribed by and under the care of a health 
care practitioner can be enrolled after evaluation by the Investigator. 
15. Blood donation, participation in a clinical study with multiple blood draws, major trauma, 
blood transfusion, or major surgery with or without blood loss within 30 days prior to 
randomization. 
16. Use of any experimental or investigational drugs within 30 days.   
17. Previous enrollment in an Esperion bempedoic acid clinical study.   
18. Use of, or a plan to initiate, these prohibited therapies/supplements during the study: 
• Mipomersen (must be stopped at least 6 months prior to Week -5 [Visit S1]), 
• Lomitapide or apheresis therapy (must be stopped at least 3 months prior to Week -5 
[Visit S1]),  
• Red yeast rice extract and berberine-containing products must be stopped at least 
2 weeks prior to Week -5 [Visit S1]),  
• Use of an investigational cholesterol ester transfer protein (CETP-I) within the last 
2 years (except evacetrapib within the last 3 months). 
• Statins are prohibited at average daily doses of rosuvastatin ≥5 mg, atorvastatin 
≥10 mg, simvastatin ≥10 mg, lovastatin ≥20 mg, pravastatin ≥40 mg, fluvastatin 
≥40 mg, or pitavastatin ≥2 mg. 
Note:  Patients can be on any available lipid-modifying therapy with the exception of the 
exclusions listed above as long as they have been stable on oral medications for 4 weeks 
prior to Screening Visit S1 and are taken at a consistent time each day.  


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19. Planned initiation or changes to the following drugs:  
• Hormone replacement (6 weeks prior to randomization) 
• Thyroid replacement (6 weeks prior to randomization) 
• Diabetes medications (4 weeks prior to randomization) 
• Obesity medication (4 weeks prior to randomization) 
• PCSK9 inhibitors:  Patients who are currently on a stable commercially available 
PCSK9 inhibitor (alirocumab or evolocumab) must have had at least 3 doses prior to 
Visit S1.  Patients who were previously (either investigational or commercial) on a 
PCSK9 inhibitor, must wait at least 4 months after last dose prior to screening 
(Week -5, Visit S1). 
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. 
22. Pregnant, breastfeeding, or intending to become pregnant within 30 days after last dose of 
study drug. 
23. Patients who have enrolled in a study of an experimental small interfering RNA (siRNA) 
inhibitor of PCSK9 are excluded. 
24. In patients taking very low dose statins, gemfibrozil is excluded per the co-administration 
prescribing instructions.   
6.3. 
Patient Identification, Randomization, and Blinding 
Patient identification numbers will be assigned sequentially by interactive web response system 
(IWRS) at the time of informed consent during the screening module transaction.  
For patients who satisfy all entry criteria and complete the 5-week screening period, 
randomization will occur at Week 0 (Visit T1).  Patients will be stratified on primary prevention 
or secondary prevention and randomized in a ratio of 2:1 to receive 1 of the 2 following 
treatments in a double-blind fashion: 
• bempedoic acid 180 mg or 
• matching placebo 
The Sponsor, all clinical site personnel (Investigator, pharmacist, etc), and other vendor 
personnel will be blinded to the treatment group for each patient.  Patients will also be blinded to 
the treatment they receive.   
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.   
Limited vendors (ie, the bioanalytical laboratory and other vendor personnel, if any, that are 
responsible for PK analysis) will have access to the randomization codes to facilitate PK 
analytical work, and will be instructed to not communicate in any manner information associated 
with treatment assignment to any personnel at the clinical site, the Sponsor, or contract research 
organization (CRO).  
Post-randomization values for individual laboratory measures for LDL-C, TG, TC, HDL-C, 
non-HDL, apoB, and hs-CRP, including any plasma concentration of bempedoic acid and its 
metabolite that may inadvertently suggest treatment assignment will not be available to 
personnel from the clinical site, the patient, the Sponsor, and CRO. 


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7. 
INVESTIGATIONAL MEDICINAL PRODUCT  
7.1. 
Investigational Medicinal Product Supply and Control 
The Sponsor will supply the investigational medicinal product (IMP) for this study.  The IMP for 
this study includes bempedoic acid (180-mg film-coated tablets) and matching placebo (film-
coated tablets).  IMP will be distributed and released in accordance with regional and local 
requirements during the conduct of the study. 
The medication identification (MED ID) number (an identifier on the study drug packaging) will 
be obtained via IWRS and used to select placebo study drug for the single-blind placebo run-in 
period and double-blind IMP for the treatment period from available clinical supplies at the 
clinical site.  
A 35-day supply of single-blind placebo drug will be dispensed one time at Week -4 (Visit S2) 
for the 4-week placebo run-in period of the study.  Double-blind IMP will be dispensed in 
100 day supply increments (one 100-day supply bottle) to patients by appropriate clinical site 
personnel at Week 0 (Visit T1), and Week 12 (Visit T4). 
Please see Pharmacy Manual for detailed storage requirements and management instructions. 
7.2. 
Administration of Investigational Medicinal Product 
Patients will be instructed to ingest, placebo study drug starting at Visit S2 for the duration the 
placebo run-in period and the IMP starting at Visit T1 for the duration of treatment period orally 
once daily (once every 24 hours) at approximately the same time each day with water.  IMP may 
be taken with or without food.  On clinic visit days, patients will be instructed to delay ingestion 
of IMP until all study procedures have been completed.   
If the patient fails to take IMP, details describing the reasons for nondosing should be 
documented in the patient’s medical records and eCRF.  Extra IMP (7 extra days per bottle) is 
provided and can be used, if needed, prior to the next visit or to replace a dose of IMP that 
cannot be used because it is lost or damaged. 


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Table 1: 
Investigational Product 
 
Investigational Medicinal Product 
Product Name: 
Bempedoic acid  
Placebo 
Dosage Form: 
Film-coated tablets 
Film-coated tablets 
Unit Dose: 
180 mg 
Not applicable 
Container/Closurea: 
100-count bottle with screw on, 
child-proof cap 
35- or 100-count bottle 
(depending upon visit) with 
screw on, child-proof cap 
Route of Administration: 
Oral, once per day, with or 
without food 
Oral, once per day, with or 
without food 
Physical Description: 
a A 100-day supply of study drug will be included in the 100-count bottle and a 35-day supply of single blind 
placebo will be included in the 35-count bottle. 
7.3. 
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 electronic case report form (eCRF) will be used to record medications, 
herbal remedies, vitamins, other supplements, and over-the-counter medications taken within 
3 months prior to screening (Week -5 Visit S1) and during the study.  
7.3.1. 
Lipid-Regulating Medications and Supplements 
Patients are allowed to continue their background lipid-lowering therapy during this study as 
long as the drugs and doses are stable for 4 weeks prior to screening (at least 3 doses are required 
for PCSK9 inhibitors).  Use of fibrates must be stable at least 6 weeks prior to screening 
(Week -5 Visit S1).  Stable lipid-modifying therapy(s) includes, but is not limited to, 
monotherapies or combination therapies and include: 
Statins 
Patients currently tolerating very-low-dose statin therapy are also considered to be statin 
intolerant and may continue taking that statin/dose throughout the study provided that it is stable 
(used for at least 4 weeks prior to screening) and well tolerated. 
Average daily dose: 
• rosuvastatin <5 mg,  
• atorvastatin <10 mg, 
• simvastatin <10 mg, 


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• lovastatin <20 mg,  
• pravastatin <40 mg,  
• fluvastatin <40 mg, or 
• pitavastatin <2 mg)  
Selective cholesterol and/or bile acid absorption inhibitors 
• Cholestyramine/Colestryamine (Questran®, Questran Light®, Prevalite®, Locholest®, 
Locholest® Light) 
• Colestipol (Colestid®) 
• Colesevelam hydrochloride (Welchol®,Cholestagel®) 
• Ezetimibe (Zetia®, Ezetrol®) 
Fibrates 
• Fenofibrate (Antara®, Lofibra®, Tricor®, Triglide™, Lipantil®, Supralip®)*  
• Bezafibrate (Bezalip®) 
• Ciprofibrate (Modalim®) 
* Note that gemfibrozil (lopid®) is exclusionary in patients taking a very low dose statin as per 
co-administration prescribing instructions.   
PCSK9 inhibitors  
• Alirocumab (Praluent®) 
• Evolocumab (Repatha®) 
Other 
• Niacin (Niaspan®, Niacor®, Slo-Niacin®) 
• Combination statin products must be at or below the above listed average daily statin 
dose. 
7.3.2. 
Prohibited Medications 
The use of the following medications and/or supplements are prohibited during the study.  
• Statins at average daily doses of rosuvastatin ≥5 mg, atorvastatin ≥10 mg, simvastatin 
≥10 mg, lovastatin ≥20 mg, pravastatin ≥40 mg, fluvastatin ≥40 mg, or pitavastatin 
≥2 mg  
• New or planned dose changes of systemic corticosteroids.   
Note:  Stable doses of systemic corticosteroids at screening are allowed (≥4 weeks 
from Visit S1).  Topical and inhaled steroids are allowed. 
• Red yeast rice (monacolin K) extract and Berberine-containing products must be 
discontinued 2 weeks prior to screening (Week -5, Visit S1). 


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• Lomitapide or apheresis therapy within 3 months to screening (Week -5, Visit S1). 
• Mipomersen within 6 months to screening (Week -5, Visit S1). 
• CETP-I within the last 2 years to screening (Week -5, Visit S1) except for 
Evaceptrapib within the last 3 months to screening (Week -5, Visit S1). 
• New or planned anti-arrhythmia medication(s) within 3 months to screening 
(Week -5, Visit S1). 
• Previous enrollment into a study of an experimental siRNA of PCSK9 or use of any 
other experimental or investigational drugs within 30 days to screening (Week -5, 
Visit S1). 
• Gemfibrozil in patients taking a very low dose statin as per co-administration 
prescribing instructions.   
7.3.3. 
Allowable Medications 
Patients must be on stable concomitant medication regimen(s) for the following medications 
and/or supplements:  
• Hormone replacement therapy within 6 weeks of randomization 
• Thyroid replacement therapy within 6 weeks of randomization.  Diabetic 
medication(s) within 4 weeks of randomization. 
• Obesity medication(s) within 4 weeks of randomization.  
• Oral lipid-modifying therapy within 4 weeks to screening (Week -5, Visit S1). 
• PCSK9 inhibitors (alirocumab or evolocumab) if at least 3 doses prior to Visit S1.  
Patients who were previously (either investigational or commercial) on a PCSK9 
inhibitor, must have discontinued 4 months prior to screening (Week -5, Visit S1) 
• Hypertensive medication(s) within 2 weeks prior to randomization.  
• Hypertriglyceridemia medication(s) within 4 weeks prior to screening (Week -5, 
Visit S1) with the exception of fibrates that are within 6 weeks prior to screening 
(Week -5, Visit S1) 
7.4. 
Patient Lifestyle and Dietary Guidelines 
Patients will be counseled to follow a lipid-lowering diet as per local or regional guidelines and 
should be encouraged (as able) to participate in a regular exercise program throughout the study. 
7.5. 
Treatment Compliance 
Screening Compliance 
No study medication treatment will be given during the Screening period; therefore, compliance 
will not be assessed.   


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Placebo Run-In Adherence to Study Medication 
At visits Week -1 (S3) and Week 0 (T1), designated clinical site staff will assess patient study 
drug compliance by counting the number of tablets that are returned as unused and by querying 
the patient with regards to daily intake.  If at the Week -1 (S3) visit the patient has not taken all 
doses of study drug(s) 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.  If at the T1 visit, the average study drug compliance from the placebo run-in period is 
<80%, or if the patient experiences an adverse event related to the run-in single blind placebo, 
the patient will not go onto randomization.   
Treatment Period Adherence to Study Medication and Procedures 
At each patient visit during the treatment period, designated clinical site staff will assess patient 
study drug compliance 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 all doses of study 
drug(s) 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 will continue to be counseled on the importance of carefully 
following all dosing instructions, but will not be removed from the study.   


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8. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
8.1. 
Informed Consent 
The patient must be adequately informed of the nature and risks of the study and understand the 
informed consent document (ICD).  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) or Independent Ethics Committee (IEC).   
8.2. 
Confirmation of Statin Intolerance (SI) 
The investigator is responsible for reviewing the patient’s available medical records and 
assessing the patient for SI.  This will include a review of statin use history.   
Both the patient and the investigator will sign a form confirming that that the patient is statin 
intolerant.  Within this form, the patient will acknowledge an understanding that they are at high 
risk for experiencing a heart attack or stroke and death and that using a statin would reduce that 
risk; however, they are not taking a statin because of intolerable side effects that started or 
increased during statin therapy and resolved or improved when statin therapy was discontinued.  
Within the same form, the investigator will confirm that the patient is unable to tolerate statin 
therapy (except possibly at very low average daily doses of atorvastatin <10 mg, fluvastatin 
<40 mg, lovastatin <20 mg, pravastatin <40 mg, pitavastatin <2 mg, rosuvastatin <5 mg, or 
simvastatin <10 mg) based on review of the medical history and discussion with the patient. 
Documentation of prior statin use will be based on patient recall and copies of relevant medical 
records and pharmacy records if readily available.  If investigator is unable to assess prior statin 
use due to poor patient recall and/or lack of relevant medical records, and if appropriate 
according to local medical practice, documentation of contact with primary care physician 
regarding prior statin use should be obtained.  At minimum, there will need to be documentation 
for the name of 2 statins and the dose of at least 1 statin attempted at low dose to ensure 
inclusion criteria is met.  All available prior statin use history will be recorded in the eCRF.  
Additionally, the basis for the investigator’s confirmation of the patient’s SI will be noted in the 
eCRF. 
8.3. 
Procedures and Schedule of Assessments 
The study will be conducted as outlined in the following sections.  Table 2 summarizes the study 
assessments at each study visit for patients enrolled in this study, followed by an overview of 
assessments by visit in Sections 8.3.1-8.3.8 .  Further details of the assessments are provided in 
the Study Operations Manual. 


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Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 


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Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
HbA1C 
X 
 
 
X 
 
 
X 
X 
PK sample 
 
 
 
 
X 
 
X 
X 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact13 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 
NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to clinic for these visits, the visits will occur according 
to the protocol schedule.  Safety assessments should include clinical safety and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical 
examination (PE), vital signs, and electrocardiograms (ECGs).   
1 An optional fasting (minimum of 10 hours) TG assessment MAY be completed between Visits S1and S2 (prior to starting single-blind medication) if patient fails to meet TG 
criterion at Visit S1.  The repeat value will be used to determine eligibility.  
2 A recheck of blood pressure may be completed between Visits S1 and S2 if the patient’s DBP and/or SBP meet the exclusion criteria levels.  Patients may randomize after blood 
pressure medications have been adjusted, the patients have been on stable doses of blood pressure medications for at least 2 weeks, and the repeat blood pressure values (diastolic 
blood pressure [DBP] and/or systolic blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed between Visit S1 and Visit S2 to determine 
eligibility if the patient’s estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate aminotransferase (AST) or other labs meet exclusion criteria 
levels.  If this optional lab is completed, the repeated value will be used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest for 5 minutes prior to assessments. 


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7 Serology for HbsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without menses and <55 years; 
9 Urine pregnancy test completed in women of child-bearing potential only just prior to randomization.  
10 Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for all patients at Week -5 (Visit S1).  A coagulation 
panel will be completed only for patients on vitamin K antagonists at Day 1 (Visit T1) and 3 to 5 days later.  For these visits, the sample may be analyzed at either the central or a 
local lab.  Please refer to laboratory manual for detailed schedule of tests. 
11 Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-
HDL-C, and triglycerides.   
12 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
13 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation visit date. 


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8.3.1. 
Screening Week -5 (Visit S1; Day -35 ± 7 days) 
The screening period will begin with a screening visit that will occur approximately 5 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 8.1), the patient will 
undergo the following assessments and procedures at Visit S1: 
1. Demographics 
2. Clinically relevant medical history  
3. Confirmation of statin intolerance and completion of confirmation forms 
4. Prior and concomitant medication review 
5. Review of all inclusion/exclusion criteria that can be assessed at this time 
6. Height (cm), and weight (kg) 
7. BMI 
8. Vital signs  
9. Diet and exercise counseling 
10. Central clinical laboratory evaluations:  
• TSH  
• Coagulation 
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• HbA1C 
• Serology (including HbsAg, hepatitis C virus [HCV] antibody 
• Serum pregnancy test in women of child-bearing potential only  
• FSH when required  
11. Contact IWRS to register the patient which includes entering whether the patient fits the 
definition of primary prevention or secondary prevention.  The IWRS system will be 
designed to ensure correct definitions of primary and secondary prevention are applied 
for purposes of stratification. 
Patients who meet all enrollment criteria that can be assessed at Visit S1 will be instructed to 
continue their allowed therapy(s) for lipid regulation and to maintain consistent diet and exercise 
patterns throughout the study.  Patients who fail to meet any entry criterion, other than those that 
can be repeated, 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). 
The screening period (between Visits S1 and S2) can be extended an additional 4 weeks if 
needed to adjust background therapy or other reasons. 


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Patients who are considered to be screen failures due to not meeting stability requirements for a 
condition or concurrent medication may be considered for rescreening after consultation with the 
Sponsor (or designee).  These patients must be re-consented, re-registered in the IWRS, and will 
have a new patient ID number assigned.  
8.3.2. 
Screening Week -4 (Visit S2; Day -28 ±3) 
The single-blind run-in period for placebo begins at this visit. After the patient’s eligibility is 
established, the patient will undergo the following assessments and procedures at Visit S2: 
1. Concomitant medication review (ongoing) 
2. Assess AEs, serious adverse events (SAEs), and potential clinical endpoints (starting 
from signing the informed consent document) 
3. Physical examination (PE) 
4. Vital signs 
5. Diet and exercise counseling 
6. Dispense single-blind placebo and ingestion of first dose.  Provide dosing and storage 
instructions 
7. IWRS Contact 
8.3.3. 
Screening Week -1 (Visit S3; Day -7 ±3) 
The patient will undergo the following assessments and procedures at Visit S3: 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints (starting from signing the informed 
consent document) 
3. 12-lead electrocardiogram (ECG) 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG).  LDL-C 
value must be ≥70 mg/dL 
6. Diet and exercise counseling 
7. Study drug compliance assessment 
8.3.4. 
Week 0 (Visit T1; Day 1) 
Prior to scheduling Visit T1, review the screening clinical results to determine whether the 
patient continues to meet lab eligibility criteria.  At Visit T1, determine whether the patient was 
adherent with placebo treatment during the run-in period (average of ≥80% adherence required) 


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and had no issues with tolerability of run-in period study medication.  Patients with intolerable 
side effects, including but not limited to muscular skeletal pain, will be run-in failures. 
If the patient has met all inclusion criteria and none of the exclusion criteria, the patient may be 
randomized into the double-blind treatment period.  Patients who fail to meet all entry criteria 
after initiation of single-blind placebo run-in are considered to be run-in failures and will not be 
randomized.  
Patients are considered randomized once all eligibility criteria are confirmed and IWRS is 
contacted with confirmation of patient randomization on the day of first dose.  
The patient will undergo the following assessments and procedures at Day 1 (Visit T1): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints  
3. Return of unused single-blind placebo and assessment of dosing adherence 
4. Review inclusion/exclusion criteria to establish patient eligibility 
5. Weight 
6. Vital signs 
7. Central clinical laboratory evaluations:  
• Coagulation in patients on vitamin K antagonists (return 3-5 days after Visit T1 for 
repeat coagulation).  Coagulation samples for this visit may be analyzed at the central 
or local lab. 
• Hematology, blood chemistry, and urinalysis 
• apoB 
• hs-CRP 
• HbA1C 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
8. Urine pregnancy in women of childbearing potential only prior to randomization. 
9. Diet and exercise counseling 
10. IWRS contact to randomize patient and assign bottle number(s) for double-blind study 
drug 
11. Dispense double-blind study drug and ingestion of first dose and provide dosing and 
storage instructions 
8.3.5. 
Treatment Week 4 (Visit T2; Day 29 ±3 days) 
Patients will undergo the following assessments and procedures at Week 4 (Visit T2): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints 


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3. Weight 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
• PK Sample prior to dose 
6. Return of study drug; assessment and recording of dosing adherence 
7. Re-dispense IMP container from Visit T1 to patient for continued dosing and provide 
dosing and storage instruction.   
Note: If the patient discontinues at any scheduled visit after T1, or between study visits, please 
proceed to Section 8.4.1 for detailed instructions. 
8.3.6. 
Treatment Week 8 Phone Call (Visit T3; Day 57 ±3 days) 
Patients will undergo the following assessments via telephone at Week 8 (Visit T3): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints 
3. Diet and exercise counseling 
4. Assessment of study drug dosing adherence 
Note: If the patient discontinues at or between study visits, please proceed to Section 8.4.1 for 
detailed instructions.  
8.3.7. 
Treatment Week 12 (Visit T4; Day 85 ±3 days) 
Patients will undergo the following assessments and procedures at Week 12 (Visit T4): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints (ongoing) 
3. Weight 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• apoB 
• hs-CRP 
• HbA1C 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• PK Sample before dose 


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6. Diet and exercise counseling 
7. Return of study drug; assessment and recording of dosing adherence 
8. IWRS contact to obtain new MED ID numbers for double-blind study drug 
9. Dispense double-blind study drug and provide dosing instruction 
Note: If the patient discontinues at any scheduled visit after T1, or between study visits, please 
proceed to Section 8.4.1 for detailed instructions.  
8.3.8. 
Treatment Week 24/EOS (Visit T5; Day 169 ±7 days) 
Patients will undergo the following assessments and procedures at Week 24 (Visit T5): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints (ongoing) 
3. Weight 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• apoB 
• hs-CRP 
• HbA1C 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• PK Sample before dose 
6. Return of study drug; assessment and recording of dosing adherence 
7. IWRS contact to terminate the subject or register completion   
8. Physical Exam 
9. 12-Lead ECG 
8.4. 
Early Withdrawal from Study or Treatment 
Patients who withdraw from study drug prior to Week 24 (Visit T5) for any reason will be asked 
to continue to be followed for safety assessments, including basic fasting lipids, at clinic visit 
following the protocol-specified visit schedule (see Section 8.3). 
Patients who temporarily withdraw from study drug prior to Week 24 (Visit T5) for any reason 
may restart study drug providing that 1) the patient and the investigator are in agreement 
regarding this course of action, 2) the patient has been off of study drug for 4 weeks or less; and 
3) study drug can be started as soon as possible.  For cases where the patient has been off of 
study drug for more than 4 weeks, the investigator must contact the medical monitor for approval 
prior to restarting study drug. 


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Patients who do not wish to continue to return to the clinic for safety assessments will be asked 
to participate in phone calls from the site at protocol-specified visits (see Section 8.3), or at a 
minimum at 24 weeks, to collect information on AEs, concomitant medications, and current 
health status.  
The patient’s decision to participate in the clinical study is voluntary.  Patients may refuse to 
continue in the study and/or withdraw from participation in this study at any time, for any reason, 
specified or unspecified, and without penalty or loss of benefits to which the patient is otherwise 
entitled.  
It is the right and duty of the Investigator to interrupt the treatment of any patient whose health or 
well-being may be threatened by continuation in this study.  Such patients should be withdrawn 
from the study and should not be continued under a modified regimen. 
Patients who are withdrawn from the study may not re-enter.  The reasons for withdrawal from 
this study or treatment may include: 
• Patient’s withdrawal of consent 
• Failure to comply with the protocol 
• Lost to follow-up 
• Illness, condition, or procedural complication (including AEs) affecting the patient’s 
ability to participate or requiring prohibited medication 
• The Sponsor or Investigator terminates the study  
• In the Investigator’s judgment, it is deemed in the best interest of the patient to 
discontinue his/her participation in the study 
• Any other reason 
If a patient is lost to follow-up, every reasonable effort must be made by the clinical site 
personnel to contact the patient and determine the reason for discontinuation/withdrawal.  The 
measures taken to follow-up must be documented. 
8.4.1. 
Procedures for Early Withdrawal 
If a patient withdraws or is removed from the study for any reason, all “End of Study” 
procedures should be completed.  Reason for withdrawal, date of the discontinuation, and date of 
the last dose of study drug should be recorded in the appropriate section of the eCRF.  
Additionally, the discontinuation visit date must be registered in IWRS.  Study drug assigned to 
the withdrawn patient may not be assigned to another patient. 
All effort should be made to have each patient complete all study visits on schedule according to 
the protocol.  Accommodations for early or late visits in special circumstances will be considered 
by the Sponsor to prevent early withdrawal.  Written notice (regardless of cause) is to be 
provided within 48 hours of the withdrawal to the Sponsor personnel or the Medical Monitor.  At 
the time of discontinuation, every effort should be made to ensure all relevant procedures and 
evaluations scheduled for the final study visit are performed.  


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Patients choosing to withdraw from the study early should be encouraged to return for all study 
scheduled clinic visits even if they are no longer taking IMP.  Patients who withdraw from all 
aspects of the study will be asked to consent to clinical visits or phone calls for safety 
assessments, including AEs, concomitant medication, and current health status through Week 24 
(Visit T5).  Subjects who are unwilling to return for clinic visits should return for an end of study 
visit (Visit T5). 
8.4.2. 
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 
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.  Refer to the Retention Guide for additional 
details.  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. 
8.4.3. 
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 in consultation with the Executive Committee (EC) Chair 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). 
Discontinuation of the study may be based on a recommendation from the DMC.  The criteria 
that the DMC will follow to recommend early termination the study will be described in the 
DMC Charter. 
8.5. 
Overdose 
There is no specific antidote for an overdose of bempedoic acid.  Management of an overdose 
should be focused on the treatment of symptoms.  These symptoms should be managed 
according to current standards of care with appropriate supportive measures.  Also 
discontinuation of study drug should be considered, based on medical judgement. 


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9. 
ASSESSMENT OF EFFICACY 
9.1. 
Efficacy Parameters 
After randomization, patients will return to clinic/or have phone contact with the clinic every 4 to 
12 weeks for a total of 24 weeks.  Clinical laboratory samples will be collected and analyzed for 
basic lipid parameters at each visit. 
9.2. 
Clinical Efficacy Laboratory Tests 
Blood draws for efficacy (not safety) must meet the criteria below.  If these criteria have not 
been met, efficacy blood samples will NOT be collected.  If these criteria can be met by 
rescheduling the clinic visit (within 3 days), efficacy blood samples will be collected at the 
rescheduled clinic visit only. 
• Blood samples will be drawn after a minimum 10-hour fast (water is allowed), and 
• Patients will be in a seated position during the blood collection.  Clinical laboratory 
parameters and tests will include those listed in Table 3.  Collection schedule and 
instructions are provided in the 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 10.1.6. 
When ECG, vital signs, and laboratory samples are to be collected at the same time point, ECG 
and vital sign measurements will precede laboratory sample collection. 
Table 3: 
Clinical Efficacy Laboratory Tests 
Clinical Laboratory Test  
Clinical Laboratory Test 
Basic Lipid Parameters 
Other Parameters 
• 
Total cholesterol (TC) 
• 
low-density lipoprotein cholesterol 
(LDL-C) and non-HDL-C 
• 
High-sensitivity C-reactive protein 
(hs-CRP) 
• 
Apolipoprotein B (apoB) 


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10. 
ASSESSMENT OF SAFETY 
10.1. 
Safety Parameters 
At all clinic visits, investigators will review all safety information including vital signs, AEs, 
concomitant medications, and ECG reports and will ensure that the collected data are recorded 
into the appropriate eCRF.  Additionally, 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.   
10.1.1. 
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.   
10.1.2. 
Vital Signs 
Vital signs will include DBP and SBP as well as heart rate. 
The patient should sit quietly for 5 minutes prior to collection of vital signs.  At all time points, 
vitals will be collected prior to blood collection.  Blood pressure and heart rate will be measured 
using a calibrated, fully automated machine with a cuff that is appropriate to the size of the upper 
arm.  If a fully automated machine is not available, BP may be measured manually.  The same 
method (either automated or manual) and the same arm (right or left) must be used throughout 
the study.  The patient should be in a seated position with feet touching the floor.  Patients should 
be seated quietly for at least 5 minutes in a chair with their backs supported, their feet flat on the 
ground, and their arms bared and supported at heart level.  At each clinic visit, 2 BP 
measurements will be collected at least 5 minutes apart.  
10.1.3. 
Weight, Height, and Body Mass Index 
Weight will be measured on a calibrated scale while fasted, using consistent scales, after voiding, 
and without shoes and outerwear (eg, coats).   
Height will be measured using standard clinic procedures.   
BMI will be calculated using the formula:   
BMI (kg/m2) = weight in kg / (height in meters)2 


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10.1.4. 
Physical Examination 
PEs will include an assessment of the following: 
• General appearance 
• Skin 
• Eyes, ears, nose, and throat 
• Head and neck 
• Extremities 
• Musculoskeletal examination 
• Respiratory examination 
• Cardiovascular assessment, including rhythm and presence of cardiac abnormalities 
• Abdominal examination 
• Neurologic examination including documentation of the presence of abnormalities in 
mental status and motor and sensory function 
• Any additional assessments necessary to establish baseline status or evaluate 
symptoms or adverse experiences 
Documentation of the PE findings will be included in the source documentation at the clinical 
site.  Significant findings noted at Visit S2 will be recorded on the Medical History/Current 
Medical Conditions page of the eCRF.  Only changes from Visit S2 physical examination 
findings (or other unscheduled physical exams performed after informed consent but prior to 
randomization) that meet the definition of an AE will be recorded on the AE page of the eCRF. 
Note:  Additional information will be collected regarding muscle-related AEs.  See 
Section 10.2.11.3.3. 
10.1.5. 
Electrocardiogram 
ECG collection will be preceded by a 10-minute rest time during which the patient will remain in 
the supine position.  ECGs will be collected prior to blood collection.  ECGs will be assessed 
using machine readings and physician review. 
10.1.5.1. 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. 


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10.1.6. 
Clinical Laboratory Tests 
10.1.6.1. 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 3-Table 4.  Collection schedule, schedule of 
laboratory parameters by visit, and instructions are in the Clinical Laboratory Manual provided 
by Central Laboratory. 
Table 4: 
Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Hematology 
Blood Chemistry (serum, fasting) 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood (RBC) cell count 
• 
White blood (WBC) cell count with 
differential (absolute and %) 
• 
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 
• 
Urine Pregnancy in females of child 
bearing potential 


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Table 4: 
Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Urinalysis (Microscopic)-only if urine dipstick 
abnormal 
• 
Bacteria 
• 
Casts 
• 
Crystals 
• 
Epithelial cells 
• 
Red blood cell (RBC) 
• 
WBC 
Coagulation – all patients at Visit S1;  only in 
patients receiving vitamin K antagonists  at 
Visit T1 and 3 to 5 days post Visit T1 using local or 
central lab 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
Other Screening Labs 
Additional samples 
• 
Hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) 
• 
Serum pregnancy test (only for females 
of childbearing potential) 
• 
Follicle-stimulating hormone (FSH; 
Females <55 years and >1 year without 
menses) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Hemoglobin A1C (HbA1C) 
10.1.6.2. Clinical Laboratory Tests (PK) 
A PK blood sample will be collected prior to dosing at Visits  T2, T4, and T5. 
Patients will be in a seated position during the blood collection.  Collection schedule and 
instructions are provided in the Clinical Laboratory Manual.  A description of the sample 
collection, storage, and shipping are described in Section 10.1.6.3. 
10.1.6.3. Sample Collection, Storage, and Shipping 
Clinical laboratory and PK 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, and PK samples will be forwarded to the 
Bioanalytical Laboratory for analysis.   
10.1.6.4. 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. 


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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.  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.  Adverse events of special interest (AESI) 
monitored by clinical laboratories are discuss in the section on AESI (Section 10.2.11). 
10.1.6.5. Total Blood Volume of 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 monitoring, efficacy, biomarker assessment, and genetic 
analysis.  Total whole blood volume collected over the study duration is not to exceed 
approximately 250 mL for each patient. 
10.2. 
Adverse and Serious Adverse Events 
10.2.1. 
Definition of Adverse Event 
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 (eg, 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 10.2.2) 
10.2.2. 
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 


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between a medicinal product and an AE is at least a reasonable possibility (ie, the relationship 
cannot be ruled out). 
An unexpected ADR is defined as an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg, IB for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). 
10.2.3. 
Reporting  
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 
the last dose of study drug.  Beginning with Visit S2 (Week -4), 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 ICF through 30 days following the last dose of study drug should be 
reported to the Sponsor per Section 10.2.7.4. 
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, 
the condition that led to a medical or surgical procedure (eg, 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 (eg, 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 (eg, headache) 
• Date of onset 
• Date of resolution (or that the event is continuing) 
• Action taken as a result of the event 
• Seriousness of the event 
• Severity of the event 
• Outcome of the event 


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• 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 (eg, 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.  
10.2.4. 
Severity of Adverse Events 
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. 
10.2.5. 
Relationship  
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, dechallenge or rechallenge.   
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.  


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• 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. 
10.2.6. 
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. 
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 (see Section 8.3). 
10.2.7. 
Treatment-Emergent Adverse Event  
TEAE are defined as AEs that begin or worsen after the first dose of study drug. 
10.2.7.1. 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, nor will hospitalization for an elective or outpatient procedure scheduled or 
planned before signing of informed consent.  However, unexpected complications that occur 


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during elective or outpatient surgery should be recorded as AEs and assessed for seriousness.  
Admission to the hospital for social or situational reasons (eg, no place to stay, live too far away 
to come for hospital visits) will not be considered inpatient hospitalizations.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Any clinical endpoints that meet SAE criteria will be reported as SAEs.  The CEC will 
adjudicate clinical endpoints in a blinded fashion, but the DMC will review clinical endpoints 
and SAEs in an unblinded fashion. 
10.2.7.2. Definition of Serious Adverse Event Events or Outcomes not Qualifying as 
Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• Preplanned or elective hospitalization including social and/or convenience situations 
(eg, due to inclement weather) 
• Overdose of either Esperion study drug or concomitant medication unless the event 
meets SAE criteria (eg, hospitalization).  However, the event should still be captured 
as a nonserious AE on the appropriate eCRF page 
10.2.7.3. 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 10.1.6.4. 
10.2.7.4. Reporting of Serious Adverse Events  
All SAEs, regardless of relationship to study drug, occurring from the time of informed consent 
until 30 days following last dose of study drug, must be reported by the Principal Investigator or 
designee to the Safety designee within 24 hours of the Principal Investigator or the clinical site 
becoming aware of the occurrence.  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 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 


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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 (eg, patient discharge summary or autopsy reports) to 
the safety contact information provided on the SAE report form.  
10.2.7.5. 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 10.2.7.4.  However, these events will not be submitted to the 
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 
10.2.7.6. Reports of Pregnancy 
If a patient becomes pregnant during the study or within 30 days of 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 SAE; however, it must be reported to the 
Sponsor/SAE designee using the paper Pregnancy Report Form within the same timelines as an 
SAE.   


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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 Investigational Medicinal Product (IMP) 
immediately and complete the end of study evaluations. 
10.2.8. 
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 an SAE to the Sponsor/SAE 
designee 
10.2.9. 
Recording of Adverse Events and Serious Adverse Events 
Any AE that occurs following signing of the ICF through 30 days after completing the last study 
visit will be recorded on the AE eCRF.   
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words.  Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate.  For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
SAEs that occur during the study or within 30 days completing the last study visit, whether or 
not related to study drug, must be immediately reported to the Sponsor/SAE designee.  The 
contact information for reporting of SAEs can be found on the SAE Reporting Form.  After the 
30-day reporting window, only SAEs assessed as related to study drug need to be reported. 
10.2.10. 
Follow-Up of Adverse Events and Serious Adverse Events 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until resolved; judged no longer clinically significant; or, if a chronic condition, until 
fully characterized through 30 days after the last dose of study drug.  Any SAEs must be 
followed until resolution or stabilization, or until lost to follow-up.  After the 30-day window, 
only treatment-related SAEs need to be reported.   
10.2.11. 
Adverse Events of Special Interest (AESI) 


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10.2.11.1. Potential Adverse Events Based on Findings in Bempedoic Acid Clinical Studies 
Across clinical studies to date, the most frequently reported TEAEs included musculoskeletal 
and connective tissue disorders (back pain, pain in extremity, myalgia, arthralgia, and muscle 
spasms), nervous system disorders (headache), gastrointestinal (GI) disorders (nausea and 
diarrhea), and infections and infestations.  Overall, AEs were generally reported with similar 
incidence between those patients treated with bempedoic acid, bempedoic acid in combination 
with ezetimibe or statin therapy, ezetimibe, statins, or placebo; however, the incidence of 
headache was higher with bempedoic acid than placebo. 
In general, laboratory results showed no clinically significant trends at the data cut-off for End-of 
Phase 2.  A total of 7 patients receiving bempedoic acid monotherapy or in combination with a 
statin or ezetimibe experienced repeated and confirmed ALT and/or AST >3 × the ULN; in 1 of 
these patients receiving bempedoic acid 80 mg the elevation was assessed by Investigator as not 
related to study drug because the patient tested positive for acute cytomegalovirus (CMV) 
infection.  One patient receiving ezetimibe monotherapy experienced repeated and confirmed 
ALT and/or AST >3 × ULN.  All liver function test (LFT) abnormalities were considered mild to 
moderate and improved upon removal of the study drug.  Small group mean increases in uric 
acid and homocysteine, and decreases in hemoglobin have been observed, but in general, these 
shifts have not been associated with clinical symptoms.  Changes in vital signs, ECG, PE, and 
other physical findings presented no safety issues in any of the clinical studies.   
Monitoring and Management of Elevated Serum Creatinine 
If at any time after randomization, a patient experiences a decrease in eGFR to the level of 
15 mL/min/1.73 m2) or if the patient experiences acute renal failure, the patient should be 
withdrawn from IMP treatment but will be asked to continue to be followed for safety using the 
protocol-specified visit schedule (see Section 8.3). 
Monitoring and Management of Hemoglobin Change 
If at any time after randomization a patient experiences a decrease >2.0 g/dL (20 g/L) from 
baseline (Week 0 [Visit T1]), the patient will undergo repeat confirmatory hematology testing as 
soon as is reasonably possible, preferably within 3 to 7 days of the laboratory result becoming 
available.   
Repeat hematology assessment will include:  1) measurement of Hgb, hematocrit (Hct), mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular 
volume, platelet count, reticulocyte count (percent and absolute), red blood cell count (RBC), 
and white blood cell count (WBC) with differential (absolute values only); 2) history of 
concomitant medication use; and 3) query for related symptoms.  Additionally, further testing 


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may be warranted to rule out additional pathology depending on clinical presentation, and should 
be discussed with Esperion Therapeutics personnel or the authorized Medical Monitor.   
• If repeat Hgb assessment confirms a decrease >2.0 g/dL (20 g/L) from baseline, the 
patient should be monitored carefully during the study and return at 2 week intervals 
after study completion for additional Hgb measurement until the level returns to 
baseline or reaches a stable level.   
• If repeat Hgb assessment confirms Hgb <8 g/dL (80 g/L), the patient should be 
withdrawn from treatment with study drug.  The patient will return at 1-week 
intervals after withdrawing from study drug treatment for additional Hgb 
measurement until the level returns to baseline or reaches a satisfactory conclusion. 
• If the patient is withdrawn from study drug treatment, the patient should be asked to 
continue being followed for safety using the protocol-specified visit schedule (see 
Section 8.3). 
At any time, the investigator may choose to consult with a specialist to further evaluate the cause 
of the alteration in hemoglobin. 
10.2.11.2. Potential Adverse Events Based on Findings in Nonclinical Models 
10.2.11.3. Adverse Events Associated with Other Lipid-Lowering Therapies 
Adverse events that are currently monitored for all experimental lipid-lowering therapies and 
have been associated with previous lipid-lowering therapies and monitoring approach are listed 
below. 


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10.2.11.3.1. 
Cardiovascular Events 
The occurrence of clinical endpoints (major adverse cardiovascular events) will be monitored 
and adjudicated by an independent blinded CEC throughout the bempedoic acid program.  The 
details of the monitoring program can be found in the charter of the CEC.  Standard monitoring 
will include occurrence of CV AEs, SAEs, including those as adjudicated by the CEC, standard 
vital signs, and ECGs.   
10.2.11.3.2. 
Hepatic Function 
Hepatic function will be monitored throughout with the clinical safety labs.  More detailed 
investigation will occur if the safety clinical laboratory results are 3 times or more than the 
ULN).   
If at any time after randomization a patient experiences a new ALT and/or AST >3 × ULN, the 
patient will undergo repeat confirmatory 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, antihepatitis A virus (total), HBsAg (confirmation of screening measurement), HCV 
(confirmation of screening measurement), and anti-cytomegalovirus/immunoglobulin M; 
2) history of concomitant medication use; 3) history of exposure to environmental chemical 
agents, including ethanol; and 4) query for related symptoms.  Additionally, further testing such 
as liver ultrasound or magnetic resonance imaging (MRI) scanning may be warranted to rule out 
additional pathology depending on clinical presentation and should be discussed with the 
Sponsor personnel or the authorized Medical Monitor.   
• If repeat LFT assessment confirms ALT and/or AST >3 × ULN, consideration should 
be given to withdrawing the patient and administering no further doses of study drug.  
At the investigator’s discretion, study drug may be interrupted and the patient 
rechallenged with study drug after LFTs have returned to baseline levels.   
• If repeat LFT assessment confirms ALT and/or AST >5 × ULN, patient should be 
withdrawn from study drug treatment, but will be asked to continue to be followed for 
safety using the protocol-specified visit schedule (see Section 8.3) or more frequently 
if deemed appropriate by the Investigator. 
• If repeat LFT assessment confirms ALT and/or AST >3 × ULN in addition to any of 
the following, the patient should be given no further treatment with study drug, but 
will be asked to continue to be followed for safety using the protocol-specified visit 
schedule (see Section 8.3) or more frequently if deemed appropriate by the 
Investigator: 
− TB >2 × ULN (will be fractionated if >2 × ULN and for those with Gilbert’s 
Disease 2 × ULN conjugated (direct) bilirubin will be evaluated) 
− INR >1.5 × ULN (unless the patient is on stable dose of anticoagulation 
medication) 


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− Appearance or worsening of right upper abdominal discomfort, anorexia, fatigue, 
nausea, vomiting, fever, rash, or eosinophilia 
10.2.11.3.3. 
Muscle-Related Events 
Muscle:  Muscle events have been associated with statins and other lipid-lowering therapies and 
are mentioned in the product information for those products.  The exact mechanism in the 
development of muscle events is unclear.  Bempedoic acid is a prodrug which needs to be 
converted by an acyl-CoA synthetase (ACS) to a coenzyme A (CoA) ester (ETC-1002-CoA).  
The specific ACS known to convert bempedoic acid into its active form is not present in skeletal 
muscle.  This suggests that bempedoic acid may not lead to an increase in muscular side effects 
when given in conjunction with statins.  Nonetheless, muscle symptoms through AE review, CK 
elevations, and symptoms of potential myopathy will be closely monitored and will be recorded 
on eCRFs, including a muscle-specific AE eCRF.  More detailed investigation will occur if 
laboratory CK results exceed 5 × ULN.   
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.   
Repeat CK assessment will include query for related symptoms.   
• 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 symptomatic, the following should be completed: 
− Hold study drug 
− Clarification of the nature, duration, and intensity of muscle symptoms 
− Review possible predisposing factors, such as unaccustomed exercise, heavy 
alcohol intake, viral illness (consider performing serology)  
− Evaluation for additional diagnoses or other conditions which can cause 
myopathy including muscle tenderness (by PE), weakness, rash, measurement of 
serum creatinine, dipstick urinalysis with microscopy if indicated 
− Obtain clinical chemistries to assess the possibility of lactic acidosis 
− Follow symptoms and CK until the abnormality has resolved 
− If based on the above evaluation an alternative explanation is suspected, 
consideration can be given to resuming study drug once CK returns to baseline 
levels 
− If no alternative explanation exists, consideration should be given to withdrawing 
the patient from study drug treatment.   


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• If the repeat CK assessment confirms an unexplained (ie, not associated with recent 
trauma or physically strenuous activity) CK abnormality as listed below, the patient 
should be withdrawn and given no further doses of study drug:   
− >10 × ULN, even in the absence of symptoms.  For CK elevations >10 × ULN, 
hold study drug treatment until the repeat value returns, is evaluated, and is 
<10 × ULN before restarting study medication. 
− In all cases, evaluate the signs/symptoms and laboratory evaluations as outlined 
above. 
• If the patient is withdrawn from study drug treatment, the patient should be asked to 
continue being followed for safety using the protocol-specified visit schedule (see 
Section 8.3). 
10.2.11.3.4. 
Diabetes and Hyperglycemia 
Diabetes and Hyperglycemia:  New onset diabetes has been associated with the use of statins and 
is dose related.  The product information for statins mentions hyperglycemia increased HbA1C 
and increases in fasting glucose as potential adverse reactions.  Hyperglycemia occurred in 
10.8% (n = 10) of the placebo treated patients vs none of the bempedoic acid 180 mg treated 
patients in the Phase 2 program.  Regardless, new onset diabetes through AE monitoring will be 
captured and summarized for this study and across all of the bempedoic acid studies.  Clinical 
safety laboratories will also be evaluated during the studies including HbA1C, and fasting 
glucose.   
10.2.11.3.5. 
Renal 
Nonclinical studies have demonstrated nephrotoxic effects on tubular cells of some lipid-
modifying agents.  In the Phase 2 program, creatinine elevations >25% over baseline occurred in 
1 subject in the bempedoic acid 80 mg, 2 in the 180 mg, 1 in the 180 mg + ezetimibe, 1 in the 
240 mg, and 3 in the 240 mg + baseline statin.  In most cases, this elevation occurred at the end 
of the study and the values were not repeated and the events were not considered related.  In 
1 case, repeat values were obtained and the subject’s creatinine was returning to baseline by 
Week 12.  None exceeded a serum creatinine >1.8 mg/dL.  No subjects withdrew due an AE of 
increased creatinine.  Patients will be monitored beyond the conclusion of the study if necessary 
to follow abnormal renal laboratory values until resolution or stabilization.   
If at any time after randomization, a patient experiences a decrease in eGFR to the level of 
15 mL/min/1.73 m2) or if the patient experiences acute renal failure, the patient should be 
withdrawn from study drug treatment but will be asked to continue to be followed for safety 
using the protocol-specified visit schedule (see Section 8.3) 
10.2.11.3.6. 
Neurocognitive Events 
Theoretically, it is possible that lipid-lowering agents that disrupt cholesterol homeostasis in the 
brain could impact neurological function, and there have been reports of cognitive impairment 
(eg, memory loss) associated with the use of statin drugs (Food and Drug Administration 2012).  
The human brain has a significant requirement for cholesterol (Dietschy 2001; Dietschy 2004) 


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and dysregulation of brain cholesterol homeostasis has been linked to chronic neurodegenerative 
disorders, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Niemann–
Pick type C disease and Smith-Lemli-Opitz syndrome (Goedeke 2014).  In the Phase 2 program, 
the only disorder in this system organ class (SOC) that occurred more commonly in the 
bempedoic acid treated group was headache.  For the ongoing program, neurocognitive events 
will be evaluated by standard PE and adverse monitoring.  Summarization of events will occur 
using prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. 
10.2.12. 
Monitoring and Management of Elevated Triglycerides 
Patients may continue to use stable doses of TG-lowering medications during the study.  An 
adjunctive therapy plan is in place for those patients whose TG values meet the protocol-defined 
threshold criteria.  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.  Beginning at Week 4 (Visit T2), 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.  The investigator will initiate the following plan: 
• Any patient with TG >1000 mg/dL (11.3 mmol/L), will be reminded to fast for at 
least 10 hours and will return to clinic within 1 week for a repeat, fasting TG sample 
to confirm the TG value meets the threshold criteria  
• Any patient with a confirmed TG >1000 mg/dL (11.3 mmol/L) may initiate standard-
of-care therapy to lower TG using a patient-specific prescription.  The initiation of 
this medication will be documented on the case report form as a concomitant 
medication with the associated start date.  These medications will not be provided by 
the sponsor. 
• Patients continuing to exceed the TG threshold after maximizing the standard-of-care 
triglyceride-lowering therapy will be discontinued from study drug treatment and will 
be asked to continue to be followed for safety using the protocol-specified visit 
schedule (see Section 8.3). 
• Please see the Clinical Laboratory Manual for sample collection and instructions. 
10.3. 
Data Monitoring Committee (DMC) 
An independent DMC will monitor unblinded accumulating patient safety and efficacy data until 
the last patient has completed study treatment.  In addition, data on SAEs and deaths, including 
clinical endpoints, will be monitored by the DMC during this period.  At each DMC review, 
relevant unblinded safety and efficacy information from ongoing studies of bempedoic acid will 
be provided to the DMC by an independent unblinded statistician and programmer.  Additional 
details will be provided in a DMC Charter. 
10.4. 
Clinical Event Committee (CEC) 
A blinded independent expert CEC will adjudicate clinical endpoints including all MACE and 
non-MACE endpoints defined as:  CV death (MACE), non-CV death (non-MACE), nonfatal MI 


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(MACE), nonfatal stroke (MACE), hospitalization for unstable angina (MACE), coronary 
revascularization (MACE), non-coronary arterial revascularization (non-MACE), and 
hospitalization for heart failure (non-MACE) using standardized definitions.  Any clinical 
endpoints that meet SAE criteria will be reported as SAEs.  Additional details regarding clinical 
endpoints and clinical endpoint definitions are outlined below and will be included in the CEC 
charter.  The charter will also outline the committee’s composition, meeting timelines, and 
members’ roles and responsibilities.  Clinical endpoints from this study and other studies within 
the bempedoic acid Phase 3 development program will be aggregated to allow for a safety 
assessment across the entire development program. 


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11. 
STATISTICS 
11.1. 
General Considerations 
The statistical analyses described in this section will be performed as further outlined in a 
separate Statistical Analysis Plan (SAP).  The SAP will supersede the protocol in the event of 
any differences between the 2 documents in relation to 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. 
11.2. 
Sample Size 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in 
LDL-C.   
 
11.3. 
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 the treatment they 
actually 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 study medication.  Patients in the SP will be included in 
the treatment group that they actually received, regardless of their randomized treatment.   
11.4. 
Disposition, Demographics and Baseline Characteristics 
Disposition, including reason for withdrawal from the study, will be summarized by treatment 
group.  Demographic information and patient characteristics including, but not limited to, 
gender, race, age, and baseline vital signs will also be summarized by treatment group. 
11.5. 
Primary Endpoint 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 values from Week -1 (Visit S3) and predose 
Day 1/Week 0 (Visit T1).   
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with 
treatment group and patient type (primary prevention; secondary prevention) as factors and 


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baseline LDL-C as a covariate.  The ANCOVA will be performed using the FAS, with patients 
included in their randomized treatment group regardless of the treatment they actually received.  
The details of the ANCOVA model and options to account for unequal variances and group size 
will be described in the SAP. 
Missing data for the primary endpoint will be imputed using a multiple imputation method that 
accounts for treatment adherence.  A pattern mixture model (PMM) will be used to specify 
different imputation strategies depending on whether the patient is still on study treatment.  
Patients with missing LDL-C data at Week 12 who are no longer taking study treatment can be 
assumed no longer to be benefitting from study medication, and their missing value(s) can be 
assumed to be similar to those from placebo patients.  In this instance, it is reasonable to impute 
LDL-C values in a model including placebo patients’ data only.  Patients with missing LDL-C 
data at Week 12 who are still taking study treatment can be assumed to continue to benefit from 
study medication, and their missing value(s) can be assumed to be similar to those who remain 
on study treatment and have data.  In this instance, it is reasonable to impute LDL-C values 
based on the observed values in their randomized treatment group at Week 12.  Details for the 
PMM will be described in the SAP.  
To account for uncertainty, missing values will be imputed using multiple imputation. Imputed 
datasets will be analyzed using an ANCOVA model with the treatment and patient type (primary 
prevention; secondary prevention) as factors and baseline LDL-C as a covariate.  Approximately 
200 imputed datasets will be created, with results from the analysis of each imputed dataset 
combined using Rubin’s method.  For each type of ANCOVA (observed case; imputation via 
PMM), the least squares mean (LSM) and standard error (SE) will be provided for both treatment 
groups, along with the placebo-corrected LSM, its 95% confidence interval (CI) and associated 
p-value. 
11.6. 
Secondary and Tertiary Endpoint Analysis 
Secondary efficacy endpoints are also of interest for this study, in terms of controlling the overall 
Type I error rate, a gatekeeping or stepdown approach will be used to test the primary efficacy 
endpoint and then specific secondary efficacy endpoints sequentially in order to preserve the 
study-wise Type I error rate.  The sequence for the stepdown procedure in this study is as 
follows: 
1. Test the primary efficacy endpoint: percent change from baseline to Week 12 in LDL-C  
2. Test the percent change from baseline to Week 24 in LDL-C 
3. Test the percent change from baseline to Week 12 in non-HDL-C 
4. Test the percent change from baseline to Week 12 in TC 
5. Test the percent change from baseline to Week 12 in apoB 
6. Test the percent change from baseline to Week 12 in hs-CRP   
In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, two-
sided.  Statistical significance at each step is required in order to test the next hypothesis.  If the 
primary endpoint meets the criteria for statistical significance, then the percent change from 
baseline to Week 24 in LDL-C will be tested; and so forth. 


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For the remaining secondary efficacy endpoints and the tertiary efficacy endpoints, a 
significance level of 0.05 will be used; given the large number of remaining endpoints, the 
p-values for those endpoints will be considered descriptive. 
In general, change or percent change in lipid parameters at a given time point will be analyzed 
using similar ANCOVA model for the primary endpoint with treatment group and patient type 
(primary prevention; secondary prevention) as factors and the relevant baseline as a covariate.   
Baseline for 
non-HDL-C,
 and TC is defined as the mean of the values from 
Week -1 (Visit S3) and predose Day 1/Week 0 (Visit T1).  Baseline for apoB and hs-CRP is 
defined as the predose Day 1/Week 0 (Visit T1) value.   
Each ANCOVA will be performed using the FAS, with patients included in their randomized 
treatment group regardless of the treatment they actually received.  Same imputation method 
described for the primary endpoint will be used for those secondary endpoints included in the 
step-down procedure, while only observed data analysis will be used for other secondary and 
tertiary endpoints.  For each lipid parameter and analysis time point, the LSM and SE will be 
provided for both treatment groups, along with the placebo-corrected LSM, its 95% CI and 
associated p-value. 
The ANCOVA assumption of normality will be assessed.  If severe non-normality of the data is 
found at any time point for any parameter, either the data will be transformed so that it is 
normally distributed or a nonparametric test will be considered instead of the planned ANCOVA. 
Finally, the number and percent of patients in each treatment group requiring additional (post-
randomization) TG-lowering therapy will be summarized.  The medications will be summarized 
by treatment group.  
11.7. 
Safety Analysis 
The summarization of AEs will include TEAEs, defined as any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the investigational product, whether 
or not related to the product.  TEAEs and SAEs will be summarized by SOC, severity, and 
relationship to study drug for each treatment group.  These AE summaries will include 
cumulative incidence (percent of patients experiencing the AE) and patient-year adjusted 
incidence rates.  If appropriate, absolute and relative risk differences will be calculated using 
both cumulative incidence and incidence rates.  Deaths, withdrawal from study treatment due to 
AEs, and withdrawal from the study due to AEs 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 from baseline in the value (where appropriate) at each post baseline 
time point. 
Hepatic Safety 
For liver-associated enzymes and TB, the number and percent of patients with abnormal values 
for ALT, AST, and TB will be summarized.  Hy’s law criteria (≥3 × ULN for either ALT or 
AST, with accompanying TB >2 × ULN (conjugated [direct] if Gilbert’s Disease) in the absence 


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of other known causes) will also be applied to the data; any potential Hy’s law cases will be 
listed separately. 
Musculoskeletal Safety 
AEs of muscle-related symptoms will be summarized by treatment group.  In addition, the 
number and percent of patients with abnormal CK values will be summarized.   
Diabetes/Glycemia 
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. 
Renal Safety 
Baseline eGFR and values of CK will be summarized by treatment group and by baseline eGFR 
categories.  Shift tables of eGFR category from baseline over the study, will be provided by 
treatment group.  Finally, muscle-related AEs will be summarized by treatment group and by 
baseline eGFR category. 
Neurocognitive Events 
Neurocognitive events will be identified and evaluated by routine safety monitoring of PE 
findings and AEs.  Summarization of neurocognitive events will occur using prespecified 
MedDRA terms and will be performed by treatment group. 
Clinical endpoints 
Clinical endpoints will be monitored and adjudicated by an independent blinded expert CEC for 
this study and other ongoing studies the bempedoic acid program.  Adjudicated clinical 
endpoints will be summarized by event type and treatment group.  Additional details regarding 
clinical endpoints and clinical endpoint definitions will be included in CEC charter.   
11.8. 
Pharmacokinetics 
Three plasma PK samples for analysis will be collected.  Plasma concentrations of bempedoic 
acid and optionally, one or more of its metabolites, will be determined in patients who are 
receiving bempedoic acid.  All patients, site personnel, and study personnel will remain blinded 
to treatment assignment throughout the duration of the study.  Personnel performing the 
bioanalytical analysis of bempedoic acid concentrations will be unblinded in order to assay the 
appropriate samples during the study.  Plasma concentrations of bempedoic acid and any 
measured metabolite will be included in the listings, but population PK analysis will be reported 
separately will be descriptive by time point. 
11.9. 
Interim Analysis and Data Monitoring Committee 
There are no planned interim analyses for this study.  An independent DMC will review 
accumulating unblinded safety data from this study and other ongoing studies of bempedoic acid.  
Additional details regarding the DMC will be included in the DMC Charter. 


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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Study Monitoring 
The Sponsor (or its authorized representative) has the obligation to follow this study closely to 
ensure that the study is conducted in accordance with the protocol, International Conference on 
Harmonisation (ICH) and GCP guidelines, national 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 
(eg, 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 details 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. 
12.2. 
Audits and Inspections 
Representatives of the Sponsor or its authorized clinical quality assurance group may visit a 
clinical site at any time during the study to conduct an audit of the study in compliance with 
regulatory guidelines and company policy.  These audits will require access to all study records, 
including source documents, for inspection and comparison with the eCRFs.  Patient privacy 
must be respected.  The Investigator and clinical site personnel are responsible for being present 
and available for consultation during routinely scheduled site audit visits conducted by the 
Sponsor or its authorized representative.   
The clinical study may also be inspected by the FDA 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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13. 
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 12.2 for more details 
regarding the audit process. 


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14. 
ETHICS 
14.1. 
Institutional Review Board/Independent Ethics Committee 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 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. 
14.2. 
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. 
14.3. 
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, but 
will be encouraged to continue in the study for safety follow-up (see Section 8.4).  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. 
The Principal Investigator(s) must maintain the original, signed ICD.  A copy of the signed ICD 
must be given to the patient. 
14.4. 
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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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
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. 
15.2. 
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. 
15.3. 
Case Report Forms and Study Records 
Access to eCRFs will be provided to the clinical site.  As part of the responsibilities assumed by 
participating in the study, the Investigator agrees to maintain adequate case histories for the 
patients treated as part of the research under this protocol.  The Investigator agrees to maintain 
accurate source documentation and eCRFs as part of the case histories.   
Study records are comprised of source documents, eCRFs, and all other administrative 
documents (eg, IRB 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 hand-written or computer-generated document that 
contains medical information or test results that have been collected for or in support of the 
protocol specifications (eg, laboratory reports, clinic notes, 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 (eg, faxed and hard copy of laboratory reports, faxed and hard copy of initial 
results, and final report).   
The Investigator agrees to allow direct access to all essential clinical study documents for the 
purpose of monitoring and/or auditing by the Sponsor or its authorized representatives and 
inspection by the appropriate regulatory authorities. 
Data reflecting the patient’s participation with the 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 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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16. 
ADMINISTRATIVE CONSIDERATIONS 
16.1. 
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 
16.2. 
Study Administrative Structure 
Investigational medicinal product supply chain details can be found in the pharmacy manual. 
Central Laboratory: 
Bioanalytical Laboratory: 
Randomization, IWRS, Statistical Analysis, Study Management and Monitoring, Data 
Management, Medical and Safety Services including Medical Monitoring (see Medical and 
Safety Services below), Programming, and Medical Writing: 
Medical and Safety Services: 
Global Medical Monitor 
16.3. 
Amendments 
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 
any departure from the protocol and the source documents will describe the departure and the 
circumstances requiring it. 
16.4. 
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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17. 
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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18. 
REFERENCES 
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, 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. 
Bikdeli B. C-reactive protein, statins and the risk of vascular events: a better understanding. 
cardiovasc Drugs Ther. 2011;25:545-9. 
DeFilippis AP, Blaha MJ, Ndumele CE, Budoff MJ, Lloyd-Jones DM, McClelland, et al. The 
association of Framingham and Reynolds risk scores with incidence and progression of coronary 
artery calcification in MESA (Multi-Ethnic Study of Atherosclerosis). Am J Coll Cardiol. 
2011;58:2076–83. 
Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 
2001(12):105-12. 
Dietschy JM, Turley SD. Cholesterol metabolism in the central nervous system during early 
development and in the mature animal. J Lipid Res. 2004(45):1375-97. 
Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab. 
2010;95(5):2015-22. 
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. 
Goedeke L, Fernandez-Hernando C. microRNAs: A connection between cholesterol metabolism 
and neurodegeneration. Neurobiol Dis. 2014(72):48-53. 
Jacobson TA for the NLA Task Force on Statin Safety - 2014 update. J Clin Lipidol. 
2014;8:S1-4.  
Joy TR, Hegele RA. Narrative review: statin-related myopathy. Annals of Int Med. 
2009;150;858-69. 
Mozffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al, for the writing 
group Members. Heart Disease and Stroke Statistics—2015 Update. A Report from the 
American Heart Association. Circ. 2015;131:e29-322. 
Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein 
levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8. 
Ridker PM, C-reactive protein and the risks and the prediction of cardiovascular events among 
those at intermediate risk. Am J Cardiol. 2007;49:2129–38. 
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merc CN, Blum CB, Eckel RH, et al. 
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic 
cardiovascular risk in adults: a report of the American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. 
doi: 10.1161/01.cir.0000437738.63853.7a. 


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Vidula H, Tian L, Liu K, Criqui MH, Ferrucci L, Pearce WH, et al. Biomarkers of inflammation 
and thrombosis as predictors of near-term mortality in patients with peripheral arterial disease: a 
cohort study. Ann Intern Med. 2008;15;148(2):85–93. 
World Health Organization (WHO) Fact Sheet No 317 Updated January 2015. 
 


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19. 
APPENDICES 
Appendix 1: Schedule of Assessments 
Appendix 2: Sponsor’s Signature 
Appendix 3: Investigator’s Signature 
Appendix 4: Statin Intolerance Confirmation Form 
Appendix 5: Dutch Lipid Clinic Network Criteria for Familial Hypercholesterolemia 
Appendix 6: Simon Broome Diagnostic Criteria for Familial Hypercholesterolemia 
Appendix 7: Summary of Changes Amendment 1  


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-35±7 
Day 
-28±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy/FSH8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
 
X 
 
 
X 
X 
PK Sample 
 
 
 
 
X 
 
X 
X 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact13 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 
 


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NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to 
clinic for these visits, the visits will occur according to the protocol schedule.  Safety assessments should include clinical safety 
and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical examination (PE), vital signs, and 
electrocardiograms (ECGs). 
1 An optional fasting (minimum of 10 hours) TG assessment MAY be completed between Visit S1 and Visit S2 (prior to starting 
single-blind medication) if patient fails to meet TG entry criterion at Visit S1.  If this optional TG is completed, the repeat value 
will be used to determine eligibility.  
2 A recheck of blood pressure may be completed between Visits S1 and S2 if the patient’s DBP and/or SBP meet the exclusion 
criteria levels.  Patients may randomize after blood pressure medications have been adjusted, the patients have been on stable 
doses of blood pressure medications for at least 2 weeks, and the repeat blood pressure values (diastolic blood pressure [DBP] 
and/or systolic blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed at Visit S2 to determine 
eligibility if the patient’s estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) or other labs meet exclusion criteria levels.  If this optional lab is completed, the repeated value will be 
used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest 
for 5 minutes prior to assessments. 
7 Serology for HBsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without 
menses and <55 years; 
9 Urine pregnancy test completed in women of child-bearing potential only just prior to randomization.  
10 Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for 
all patients at Week -5 (Visit S1).  A coagulation panel will be completed only for patients on anti-coagulant therapy at Day 1 
(Visit T1) and 3 to 5 days later.  For these visits, the sample may be analyzed at either the central or a local lab.  Please refer to 
laboratory manual for detailed schedule of tests. 
11 Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides.  
12 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
13 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation 
visit date. 
 


Bempedoic Acid 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
Amendment 1, 10 April 2017 
APPENDIX 2. SPONSOR'S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Evaluate the Efficacy and Safety ofBempedoic Acid (ETC-1002) 180 mg 
Compared to Placebo Added to Background Lipid-Modifying Therapy in 
Patients with Elevated LDL-C Who are Statin Intolerant 
Study Number: 
1002-046 
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: 
J 1-.kp= LO I~ 
Confidential 
Page 92of153 


Bempedoic Acid 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
Amendment 1, 10 April 2017 
Study Title: 
Study Number: 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-I 002) 180 mg 
Compared to Placebo Added to Background Lipid-Modifying Therapy in 
Patients with Elevated LDL-C Who are Statin Intolerant 
1002-046 
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: ( 1 Apv; / J.-cJ 17 
Confidential 
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Bempedoic Acid
Esperion Therapeutics, Inc.
Clinical Study Protocol 1002-046
Amendment 1, 10 April 2017
Confidential
Page 94 of 153
Study Title:
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-1002) 180 mg 
Compared to Placebo Added to Background Lipid-Modifying Therapy in 
Patients with Elevated LDL-C Who are Statin Intolerant
Study Number:
1002-046
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:


Bempedoic Acid 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
Amendment 1, 10 Apri I 2017 
Study Title: 
Study Number: 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-I 002) 180 mg 
Compared to Placebo Added to Background Lipid-Modifying Therapy in 
Patients with Elevated LDL-C Who are Statin Intolerant 
1002-046 
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: _~_,fr---t_?-+-/1-'+ ___ _ 
Confidential 
Page 95 of 153 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 96 of 153 
 
APPENDIX 3. INVESTIGATOR’S SIGNATURE 
Study Title: 
A Randomized, Double-Blind, Parallel Group, Multicenter Study to 
Evaluate the Efficacy and Safety of Bempedoic Acid (ETC-1002) 180 mg 
Compared to Placebo Added to Background Lipid-Modifying Therapy in 
Patients with Elevated LDL-C Who are Statin Intolerant 
 
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:  
 
 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 97 of 153 
 
APPENDIX 4. STATIN INTOLERANCE CONFIRMATION FORM 
Patient Identification (Please Print or Type) 
Name: 
 
Initials: 
 
Screening Number: 
 
 
Patient  
My doctor has recommended that I take a medication (called a statin) to reduce the bad 
cholesterol (fats) in my blood.  My doctor has told me that a statin would reduce my risk of a 
heart attack or stroke and the risk of death.  However, I am not taking a statin (or I am taking a 
statin only at a very low dose) because of side effects.  These side effects began or became 
worse when I was taking the statin and then went away or improved when I stopped taking it or 
decreased the dose.  I can’t tolerate these medications (called statins) even though I know they 
would reduce my risk of a heart attack or stroke or death.  
 
 
Date 
Signature of Patient 
 
Principal Investigator   
For the purposes of the 1002-046 clinical study, in my opinion, this patient is unable to tolerate 
statin therapy (except possibly at very low average daily doses of atorvastatin <10 mg, 
fluvastatin <40 mg, lovastatin <20 mg, pravastatin <40 mg, pitavastatin <2 mg, rosuvastatin 
<5 mg or simvastatin <10 mg) based on my review of the medical and medication histories and 
discussion with the patient.  
 
 
Date 
Signature of Principal Investigator 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 98 of 153 
 
APPENDIX 5. 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 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 99 of 153 
 
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. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 100 of 153 
 
APPENDIX 6. SIMON BROOM 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 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 101 of 153 
 
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. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 102 of 153 
 
APPENDIX 7. SUMMARY OF CHANGES AMENDMENT 1 
 
SUMMARY OF CHANGES 
CLINICAL STUDY PROTOCOL 
Study Number: 
1002-046 
Study Title: 
A Randomized, Double-Blind, Parallel Group, 
Multicenter Study to Evaluate the Efficacy and Safety of 
Bempedoic Acid (ETC-1002) 180 mg Compared to 
Placebo Added to Background Lipid-Modifying Therapy 
in Patients with Elevated LDL-C Who are Statin 
Intolerant 
Protocol Version Incorporating 
Current Summary of Changes: 
Amendment 1:  10 April 2017 
Preceding Protocol Version: 
Original Protocol:  25 August 2016 
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 bolded and 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: 
• Updated Sponsor details on the title page and in the Sponsor signature section 
• Added a line for Amendment 1 version and date to reflect amendment version details. 
• Revised secondary and tertiary endpoints as well as added safety endpoints to more 
accurately describe statistical testing and analysis. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 103 of 153 
 
• Under inclusion criteria 
− Added topical method to allowable forms of hormonal contraception.  
− Added requirement that women use 2 rather than 1 form of acceptable 
contraception based on a request from the European Heads of Medicines 
Agency’s Voluntary Harmonization Procedure review of another Esperion 
sponsored protocol.  In addition, specified the period that contraception should be 
followed.  This amendment is to maintain consistency across protocols and is not 
based on any new data with bempedoic acid. 
− Added expanded definition of ‘true abstinence. 
− Added an additional fasting LDL-C assessment (Week -1 (Visit S3) ≥70 mg/dL 
(1.8 mmol/L) after the Run-in period to inclusion criteria.  Removed the 
allowance of repeating a screening LDL-C measurement after Visit S1. 
− Clarified the timing of the collection of lipid values with reference to PCSK9 
inhibitor injections in order to ensure lipid values are obtained at trough levels of 
PCSK9. 
• Under exclusion criteria 
− Revised exclusionary blood pressure to systolic blood pressure (SBP) 
≥160 mmHg and diastolic blood pressure (DBP) ≥100 mmHg based on a request 
by Health Canada.  Instructions regarding repeat measures of blood pressure were 
further clarified.   
− Shortened the window that obesity medications should not be initiated or changed 
before randomization from 3 months to 4 weeks. 
− Clarified language around PCSK9 inhibitor use prior to screening. 
− Added an exclusion for women who are pregnant, breastfeeding or intending to 
become pregnant within 30 days after the last dose of study drug.   
− Based on the extremely long half-lives of experimental siRNA inhibitors, eg, 
Inclisiran, excluded patients who have enrolled in a study of an experimental 
siRNA inhibitor of PCSK9. 
− Excluded gemfibrozil in patients taking very low dose statins per the co-
administration prescribing instructions.   
• Removed collection of optional genetic sampling. 
• Removed collection of reserve samples. 
• Removed collection of pharmacokinetic (PK) sample collection on Day 1 and 
clarified that collection needs to be prior to dosing at visits where PK samples are 
collected. 
• Updated text pertaining to bempedoic acid mechanism of action based on new 
information. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 104 of 153 
 
• Removed manufacturing contact details from the protocol and indicated the details 
will be described in the pharmacy manual. 
• Updated the sections on prohibited and allowed medications to reflect the following: 
− Added inhaled steroids to allowable stable systemic corticosteroids at screening.  
− Noted that fibrates could not be used within 6 weeks prior to screening versus 
within 4 weeks for other hypertriglyceridemia medications. 
• Specified that documentation for the name of two statins and dose of at least one 
statin attempted at a low dose is required.   
• Added a section on overdose management based on a request from Health Canada. 
• Based on a request from the FDA, the monitoring and management of CK values for 
asymptomatic patients was modified.   
• Updated text around reporting of Adverse Events and Pregnancies. 
• Added the following sections to the protocol: 
Definition of Serious Adverse Event Events or Outcomes not qualifying as 
Serious Adverse Events 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events 
• Revised statistical sections regarding 
− methods for imputation of missing data for primary, secondary, and tertiary 
endpoints. 
− how ANCOVA model will be applied to primary, secondary, and tertiary 
endpoints. 
• Made administrative changes throughout the protocol where required to correct 
inconsistencies, add clarification, or correct errors. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 105 of 153 
 
CHANGE 1 
REVISION OF TITLE PAGE INFORMATION 
Location: 
Title Page  
Original Text: 
Sponsor Contact: 
 
 
Version 
Date 
 
 
Original Protocol: 
25 August 2016 
 
 
New Text: 
Sponsor Contact: 
 
 
Version 
Date 
 
 
Original Protocol: 
25 August 2016 
 
 
Amendment 1: 
10 April 2017 
 
 
CHANGE 2 
MECHANISM OF ACTION REVISION 
Location: 
Section 4.2.1, Mechanism of Action 
Original Text: 
An important differentiating feature of bempedoic acid is that it does not inhibit cholesterol 
synthesis in skeletal muscle.  In addition to preliminary data suggesting that only minor amounts 
of bempedoic acid enters skeletal muscle (<5% of systemic exposure), skeletal muscle does not 
express the enzyme required to activate bempedoic acid to ETC-1002-CoA and inhibit ACL.  
Therefore, bempedoic acid is not anticipated to mediate the adverse effects associated with 
inhibition of biological intermediates within the cholesterol biosynthesis pathway in skeletal 
muscle. 
New Text: 
An important differentiating feature of bempedoic acid is that, unlike statins, it does not inhibit 
cholesterol synthesis in skeletal muscle.  The enzyme required to convert bempedoic acid to 
ETC-1002-CoA is not present in skeletal muscle.  In addition to preliminary data suggesting 
that only minor amounts of bempedoic acid enters skeletal muscle (<5% of systemic exposure), 
skeletal muscle does not express the enzyme required to activate bempedoic acid to ETC-1002-


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 106 of 153 
 
CoA and inhibit ACL.  Therefore, bempedoic acid is not anticipated to mediate the adverse 
effects associated with inhibition of biological intermediates within the cholesterol biosynthesis 
pathway in skeletal muscle; however, the safety of bempedoic acid and its metabolites 
regarding human skeletal muscle is not yet established. 
 
CHANGE 3 
EFFICACY AND SAFETY ENDPOINT REVISIONS 
Location: 
Section 2, Synopsis; Section 5.2, Study Endpoints 
Original Text: 
5.2.1. 
Primary Endpoint 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in 
LDL-C 
5.2.2 
Secondary Endpoints 
1. Percent change from baseline to Week 24 in LDL-C 
2. Change from baseline to Weeks 12 and 24 in LDL-C 
3. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP  
5.2.3. 
Tertiary Endpoints 
New Text: 
5.2.1. 
Primary Endpoint 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in 
LDL-C 
5.2.2 
Secondary Endpoints 
1. Percent change from baseline to Week 24 in LDL-C 
2. Change from baseline to Weeks 12 and 24 in LDL-CPercent change from baseline to 
Week 12 in non-HDL-C, TC, apoB, and hs-CRP 
3. Absolute change from baseline to Weeks 12 and 24 in LDL-C 
5.2.3. 
Tertiary Endpoints 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
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5.2.4 
Safety Endpoints 
1. Patient incidence to TEAE 
2. Safety laboratory values and vital signs 
3. Cardiovascular event rates 
 
CHANGE 4 
STUDY METHODOLOGY REVISIONS 
Location: 
Section 2, Synopsis; Section 6.2, Study Population and Selection 
Original Text: 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group multicenter study 
that will be conducted at approximately 71 clinical sites in North America.  Screening Week -5 
(Visit S1) will be approximately 5 weeks prior to randomization but can be extended for an 
additional 4 weeks if needed to adjust background medical therapy or for other reasons.  Eligible 
patients will return to the clinical site at Week -4 (Visit S2) to initiate administration of single-
blind (patient only) placebo study drug.  Eligible patients will return at Week -1 (Visit S3) for 
lipid and safety laboratories and an assessment of tolerability and study drug adherence.  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.  As 
necessary, for reasons of safety if a patient begins the run-in period but screen fails prior to 
randomization, the patient may be asked to return to the clinical site for further evaluation and 
follow-up of AEs. 
New Text: 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group multicenter study 
that will be conducted at approximately 71 clinical sites in North America.  Screening Week -5 
(Visit S1) will be approximately 5 weeks prior to randomization.  The time period between 
Visits S1 and S2but can be extended for an additional 4 weeks if needed to adjust background 
medical therapy or for other reasons.  Eligible patients will return to the clinical site at Week -4 
(Visit S2) to initiate administration of single-blind (patient only) placebo study drug.  Eligible 
patients will return at Week -1 (Visit S3) for lipid and safety laboratories and an assessment of 
tolerability and study drug adherence.  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.  As necessary, for reasons of safety if a patient begins the 
run-in period but screen fails prior to randomization, the patient may be asked to return to the 
clinical site for further evaluation and follow-up of AEs. 
 


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Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
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CHANGE 5 
SUBJECT INCLUSION CRITERIA REVISIONS 
Location: 
Section 2, Synopsis; Section 6.2.1, Subject Inclusion Criteria 
Original Text: 
2. Men and nonpregnant, nonlactating women.  Women must be either: 
a. Naturally postmenopausal defined as ≥1 year without menses and:  
− ≥55 years, or  
− <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or 
b. Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal 
ligation; or 
c. Women of childbearing potential willing to use 1 acceptable method of birth control 
including: 
− oral, implanted, or injectable 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 (not including periodic abstinence such as calendar, ovulation, 
symptothermal, postovulation methods, or withdrawal) 
There are no protocol-specific birth control requirements for men with partners who are 
able to become pregnant. 
3. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at 
Week -5 (Visit S1) 
4. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) 
• Primary prevention ≥130 mg/dL (3.4 mmol/L)  
• Secondary prevention and/or heterozygous familial hypercholesterolemia (HeFH) 
≥100 mg/dL (2.6 mmol/L) 
Note:  A single repeat of LDL-C may be completed prior to initiation of the single-blind 
Run–in period.  For those patients who have a repeat LDL-C, the mean of the first value 
and the repeat value will be used to determine eligibility.  
For patients taking proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, 
alirocumab and evolocumab), doses must be administered on a consistent schedule and 
the study lipid values must be obtained within 24-48 hours prior to the next planned dose 
of the PCSK9 inhibitor.  


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 109 of 153 
 
New Text: 
2. Men and nonpregnant, nonlactating women.  Women must be either: 
a. Naturally postmenopausal defined as ≥1 year without menses and:  
− ≥55 years, or  
− <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L; or 
b. Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal 
ligation; or 
c. Women of childbearing potential must be willing to use 1 2 acceptable methods of 
birth control including (unless they have agreed to follow the definition of true 
abstinence).  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: 
− oral, implanted, topical, or injectable 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 
subject.  (not including pPeriodic abstinence [eg, such as calendar, ovulation, 
symptothermal, postovulation methods], declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of contraception 
or withdrawal). 
There are no protocol-specific birth control requirements for men with partners who are 
able to become pregnant. 
3. Age ≥18 years or legal age of majority depending on regional law, whichever is greater at 
Week -5 (Visit S1) 
4. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) 
• Primary prevention ≥130 mg/dL (3.4 mmol/L)  
• Secondary prevention and/or heterozygous familial hypercholesterolemia (HeFH) 
≥100 mg/dL (2.6 mmol/L) 
• All patients must have fasting LDL-C ≥70 mg/dL (1.8 mmol/L) at Week -1 
(Visit S3) 
Note:  A single repeat of LDL-C may be completed prior to initiation of the single-blind 
Run–in period.  For those patients who have a repeat LDL-C, the mean of the first value 
and the repeat value will be used to determine eligibility.  
For patients taking proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, 
alirocumab and evolocumab), doses must be administered on a consistent schedule and 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 110 of 153 
 
the study lipid values must be obtained within 24-48 hours prior to the next planned dose 
of the PCSK9 inhibitor.  
In the case of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use, the 
patient must have received 3 stable doses.  It is important that lipid values are 
measured at PCSK9i trough levels.  Therefore, study visits should be scheduled in 
accordance with the patient’s PCSK9i injection regimen so that measurement of lipid 
values for all visits occurs before the PCSK9i injection but not greater than 48 hours 
before the next scheduled PCSK9i injection.  Patients who have discontinued 
investigational or commercial PCSK9 inhibitor must have had their last dose at least 
4 months prior to Screening Visit S1. 
 
CHANGE 6 
SUBJECT EXCLUSION CRITERIA REVISIONS 
Location:  
Section 2, Synopsis; Section 6.2.2, Subject Exclusion Criteria 
Original Text: 
2. Renal dysfunction or a glomerulonephropathy, 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 -5 (Visit S1). 
Note: A single repeat of eGFR may be completed prior to randomization.  For those 
patients who have a repeat eGFR, the repeat value will be used to determine eligibility. 
New Text: 
2. Renal dysfunction or a glomerulonephropathy, 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 -5 (Visit S1). 
Note: A single repeat of eGFR may be completed prior to randomization between 
Visits S1 and S2.  For those patients who have a repeat eGFR, the repeat value will be 
used to determine eligibility. 
Original Text: 
5. Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) ≥180 mmHg 
and/or diastolic blood pressure (DBP) ≥110 mmHg measured according to local 
standards. 
Note: At the discretion of the investigator, blood pressure (BP) medications can be 
adjusted and/or additional assessment of BP may be completed prior to randomization, 
with the repeat assessment value used to determine eligibility.  Alternatively, patients can 
be rescreened if BP status has changed. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
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New Text 
5. Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) ≥180 
160 mmHg and/or diastolic blood pressure (DBP) ≥110 100 mmHg measured according 
to local standards. 
Note:  At the discretion of the investigator, the time between Visits S1 and S2 can be 
extended by 4 weeks for adjustments in blood pressure (BP) medications can be adjusted 
and/or additional assessment of BP may be completed prior to randomization, with the 
repeat assessment value used to determine eligibility.  Alternatively, patients can be 
rescreened if BP status has changed. 
Original Text: 
19. Planned initiation or changes to the following drugs:  
• Hormone replacement (6 weeks prior to randomization) 
• Thyroid replacement (6 weeks prior to randomization) 
• Diabetes medications (4 weeks prior to randomization) 
• Obesity medication (3 months prior to randomization) 
• PCSK9:  Patients who are currently on a stable inhibitor (alirocumab or evolocumab) 
for at least 3 doses will be included in this study (all lipid values must be obtained 
1-2 days prior to the next PCSK9 inhibitor dose to evaluate eligibility and on 
treatment lipid values). Patients who were previously (either investigational or 
commercial) on a PCSK9 inhibitor, must have discontinued 4 months prior to 
screening (Week -5, Visit S1). 
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. 
New Text:  
19. Planned initiation or changes to the following drugs:  
• Hormone replacement (6 weeks prior to randomization) 
• Thyroid replacement (6 weeks prior to randomization) 
• Diabetes medications (4 weeks prior to randomization) 
• Obesity medication (3 months4 weeks prior to randomization) 
• PCSK9 inhibitors:  Patients who are currently on a stable commercially available 
PCSK9 inhibitor (alirocumab or evolocumab) for must have had at least 3 doses 
prior to Visit S1.will be included in this study (all lipid values must be obtained 
1-2 days prior to the next PCSK9 inhibitor dose to evaluate eligibility and on 
treatment lipid values).  Patients who were previously (either investigational or 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 112 of 153 
 
commercial) on a PCSK9 inhibitor, must have discontinued wait at least 4 months 
after last dose prior to screening (Week -5, Visit S1). 
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. 
22. Pregnant, breastfeeding, or intending to become pregnant within 30 days after last 
dose of study drug. 
23. Patients who have enrolled in a study of an experimental small interfering RNA 
(siRNA) inhibitor of PCSK9 are excluded. 
24. In patients taking very low dose statins, gemfibrozil is excluded per the co-
administration prescribing instructions 
 
CHANGE 7 
PATIENT IDENTIFICATION, RANDOMIZATION, AND BLINDING 
REVISION 
Location:  
Section 6.3, Patient Identification, Randomization, and Blinding 
Original Text: 
Patient identification numbers will be assigned sequentially by interactive web response system 
(IWRS) at the time of informed consent during the screening module transaction.  The patient 
numbers will be an
 
   
For patients who satisfy all entry criteria and complete the 5-week screening period, 
randomization will occur at Week 0 (Visit T1), and their randomization number will be assigned 
via IWRS.  Patients will be stratified on primary prevention or secondary prevention and 
randomized in a ratio of 2:1 to receive 1 of the 2 following treatments in a double-blind fashion: 
• bempedoic acid 180 mg or 
• matching placebo 
New Text: 
Patient identification numbers will be assigned sequentially by interactive web response system 
(IWRS) at the time of informed consent during the screening module transaction.  The patient 
numbers will be an
 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 113 of 153 
 
For patients who satisfy all entry criteria and complete the 5-week screening period, 
randomization will occur at Week 0 (Visit T1) and their randomization number will be assigned 
via IWRS.  Patients will be stratified on primary prevention or secondary prevention and 
randomized in a ratio of 2:1 to receive 1 of the 2 following treatments in a double-blind fashion: 
• bempedoic acid 180 mg or 
• matching placebo 
 
CHANGE 8 
ADMINISTRATION OF INVESTIGATIONAL MEDICINAL 
PRODUCT 
Location:  
Section 7.2, Administration of Investigational Medicinal Product 
Original Text: 
Table 1: 
Investigational Product 
 
Investigational Medicinal Product 
Product Name: 
Bempedoic acid  
Placebo 
Dosage Form: 
Film-coated tablets 
Film-coated tablets 
Unit Dose: 
180 mg 
Not applicable 
Container/Closurea: 
100-count bottle with screw on, 
child proof cap 
35- or 100-count bottle 
(depending upon visit) with 
screw on, child proof cap 
Route of Administration: 
Oral, once per day, with or 
without food 
Oral, once per day, with or 
without food 
Physical Description: 
Manufacturer (Fill/Finish): 
a A 100-day supply of study drug will be included in the 100-count bottle and a 35-day supply of single blind 
placebo will be included in the 35-count bottle. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 114 of 153 
 
New Text: 
Table 1: 
Investigational Product 
 
Investigational Medicinal Product 
Product Name: 
Bempedoic acid  
Placebo 
Dosage Form: 
Film-coated tablets 
Film-coated tablets 
Unit Dose: 
180 mg 
Not applicable 
Container/Closurea: 
100-count bottle with screw on, 
child-proof cap 
35- or 100-count bottle 
(depending upon visit) with 
screw on, child-proof cap 
Route of Administration: 
Oral, once per day, with or 
without food 
Oral, once per day, with or 
without food 
Physical Description: 
Manufacturer (Fill/Finish): 
a A 100-day supply of study drug will be included in the 100-count bottle and a 35-day supply of single blind 
placebo will be included in the 35-count bottle. 
 
CHANGE 9 
LIPID-REGULATING MEDICATIONS AND SUPPLEMENTS 
REVISIONS 
Location:  
Section 7.3.1, Lipid-Regulating Medications and Supplements 
Original Text: 
Patients are allowed to continue their background lipid-lowering therapy during this study as 
long as the drugs and doses are stable for 4 weeks prior to screening.  Use of fibrates must be 
stable at least 6 weeks prior to screening (Week -5 Visit S1).  Screening lipid values and other 
assessments of lipids must be within 24-48 hours of the next dose if a patient is taking a PCSK9 
inhibitor.  Stable lipid-modifying therapy(s) includes, but is not limited to, monotherapies or 
combination therapies and include: 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 115 of 153 
 
New Text: 
Patients are allowed to continue their background lipid-lowering therapy during this study as 
long as the drugs and doses are stable for 4 weeks prior to screening (at least 3 doses are 
required for PCSK9 inhibitors).  Use of fibrates must be stable at least 6 weeks prior to 
screening (Week -5 Visit S1).  Screening lipid values and other assessments of lipids must be 
within 24-48 hours of the next dose if a patient is taking a PCSK9 inhibitor.  Stable lipid-
modifying therapy(s) includes, but is not limited to, monotherapies or combination therapies and 
include: 
Original Text: 
Fibrates 
• Fenofibrate (Antara®, Lofibra®, Tricor®, Triglide™, Lipantil®, Supralip®)  
• Bezafibrate (Bezalip®) 
• Ciprofibrate (Modalim®) 
• Gemfibrozil (Lopid®) 
New Text: 
Fibrates 
• Fenofibrate (Antara®, Lofibra®, Tricor®, Triglide™, Lipantil®, Supralip®)*  
• Bezafibrate (Bezalip®) 
• Ciprofibrate (Modalim®) 
• Gemfibrozil (Lopid®) 
* Note that gemfibrozil (lopid®) is exclusionary in patients taking a very low dose statin as per 
co-administration prescribing instructions. 
 
CHANGE 10 
PROHIBITED MEDICATIONS REVISIONS 
Location: 
Section 7.3.2, Prohibited Medications 
Original Text: 
The use of the following medications and/or supplements are prohibited during the study.  
• Statins at average daily doses of rosuvastatin ≥5 mg, atorvastatin ≥10 mg, simvastatin 
≥10 mg, lovastatin ≥20 mg, pravastatin ≥40 mg, fluvastatin ≥40 mg, or pitavastatin 
≥2 mg  
• New or planned dose changes of systemic corticosteroids.   
Note:  Stable doses of systemic corticosteroids at screening are allowed (≥4 weeks 
from Visit S1).  Topical steroids are allowed. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 116 of 153 
 
• Red yeast rice (monacolin K) extract and Berberine-containing products must be 
discontinued 2 weeks prior to screening (Week -5, Visit S1). 
• Lomitapide or apheresis therapy within 3 months to screening (Week -5, Visit S1). 
• Mipomersen within 6 months to screening (Week -5, Visit S1). 
• CETP-I within the last 2 years to screening (Week -5, Visit S1) except for 
Evaceptrapib within the last 3 months to screening (Week -5, Visit S1). 
• New or planned anti-arrhythmia medication(s) within 3 months to screening 
(Week -5, Visit S1). 
• Any experimental or investigational drugs within 30 days to screening (Week -5, 
Visit S1). 
New Text: 
The use of the following medications and/or supplements are prohibited during the study.  
• Statins at average daily doses of rosuvastatin ≥5 mg, atorvastatin ≥10 mg, simvastatin 
≥10 mg, lovastatin ≥20 mg, pravastatin ≥40 mg, fluvastatin ≥40 mg, or pitavastatin 
≥2 mg  
• New or planned dose changes of systemic corticosteroids.   
Note:  Stable doses of systemic corticosteroids at screening are allowed (≥4 weeks 
from Visit S1).  Topical and inhaled steroids are allowed. 
• Red yeast rice (monacolin K) extract and Berberine-containing products must be 
discontinued 2 weeks prior to screening (Week -5, Visit S1). 
• Lomitapide or apheresis therapy within 3 months to screening (Week -5, Visit S1). 
• Mipomersen within 6 months to screening (Week -5, Visit S1). 
• CETP-I within the last 2 years to screening (Week -5, Visit S1) except for 
Evaceptrapib within the last 3 months to screening (Week -5, Visit S1). 
• New or planned anti-arrhythmia medication(s) within 3 months to screening 
(Week -5, Visit S1). 
• Previous enrollment into a study of an experimental siRNA of PCSK9 or use of 
aAny experimental or investigational drugs within 30 days to screening (Week -5, 
Visit S1). 
• Gemfibrozil in patients taking a very low dose statin as per co-administration 
prescribing instructions.  
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 117 of 153 
 
CHANGE 11 
ALLOWABLE MEDICATIONS REVISIONS 
Location:  
Section 7.3.3, Allowable Medications 
Original Text: 
Patients must be on stable concomitant medication regimen(s) for the following medications 
and/or supplements:  
• Hormone replacement therapy within 6 weeks of randomization 
• Thyroid replacement therapy within 6 weeks of randomization.  Diabetic 
medication(s) within 4 weeks of randomization. 
• Obesity medication(s) within 3 months of randomization.  
• Oral lipid-modifying therapy within 4 weeks to screening (Week -5, Visit S1). 
• PCSK9 inhibitors (alirocumab or evolocumab) for at least 3 doses will be included in 
this study (all lipid values must be obtained 1-2 days prior to the next PCSK9 
inhibitor dose to evaluate eligibility and on treatment lipid values).  Patients who 
were previously (either investigational or commercial) on a PCSK9 inhibitor, must 
have discontinued 4 months prior to screening (Week -5, Visit S1) 
• Hypertensive medication(s) within 2 weeks prior to randomization.  
• Hypertriglyceridemia medication(s) within 4 weeks prior to screening (Week -5, 
Visit S1) 
New Text: 
Patients must be on stable concomitant medication regimen(s) for the following medications 
and/or supplements:  
• Hormone replacement therapy within 6 weeks of randomization 
• Thyroid replacement therapy within 6 weeks of randomization.  Diabetic 
medication(s) within 4 weeks of randomization. 
• Obesity medication(s) within 3 months4 weeks of randomization.  
• Oral lipid-modifying therapy within 4 weeks to screening (Week -5, Visit S1). 
• PCSK9 inhibitors (alirocumab or evolocumab) for if at least 3 doses will be included 
in this study (all lipid values must be obtained 1-2 days prior to Visit S1the next 
PCSK9 inhibitor dose to evaluate eligibility and on treatment lipid values).  Patients 
who were previously (either investigational or commercial) on a PCSK9 inhibitor, 
must have discontinued 4 months prior to screening (Week -5, Visit S1) 
• Hypertensive medication(s) within 2 weeks prior to randomization.  
• Hypertriglyceridemia medication(s) within 4 weeks prior to screening (Week -5, 
Visit S1) with the exception of fibrates that are within 6 weeks prior to screening 
(Week -5, Visit S1) 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 118 of 153 
 
 
CHANGE 12 
TREATMENT COMPLIANCE REVISION 
Location:  
Section 7.5, Treatment Compliance 
Original Text: 
Placebo Run-In Adherence to Study Medication 
At visits Week -1 (S1) and Week 0 (T1), designated clinical site staff will assess patient study 
drug compliance by counting the number of tablets that are returned as unused and by querying 
the patient with regards to daily intake.  If at the Week -1 (S1) visit the patient has not taken all 
doses of study drug(s) 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.  If at the T1 visit, the average study drug compliance from the placebo run-in period is 
<80%, or if the patient experiences an adverse event related to the run-in single blind placebo, 
the patient will not go onto randomization. 
New Text: 
Placebo Run-In Adherence to Study Medication 
At visits Week -1 (S1S3) and Week 0 (T1), designated clinical site staff will assess patient study 
drug compliance by counting the number of tablets that are returned as unused and by querying 
the patient with regards to daily intake.  If at the Week -1 (S1S3) visit the patient has not taken 
all doses of study drug(s) 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.  If at the T1 visit, the average study drug compliance from the placebo run-in period is 
<80%, or if the patient experiences an adverse event related to the run-in single blind placebo, 
the patient will not go onto randomization. 
 
CHANGE 13 
INFORMED CONSENT  
Location: 
Section 8.1, Informed Consent 
Original Text: 
The patient must be adequately informed of the nature and risks of the study and understand the 
informed consent document (ICD).  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) or Independent Ethics Committee (IEC).  Participation in banking of 
samples for genetic analysis is optional for all patients, and consent for this must be documented 
in the patient’s written informed consent. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 119 of 153 
 
New Text: 
The patient must be adequately informed of the nature and risks of the study and understand the 
informed consent document (ICD).  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) or Independent Ethics Committee (IEC).  Participation in banking of 
samples for genetic analysis is optional for all patients, and consent for this must be documented 
in the patient’s written informed consent. 
 
CHANGE 14 
CONFIRMATION OF STATIN INTOLERANCE REVISIONS 
Location: 
Section 8.2, Confirmation of Statin Intolerance (SI) 
Original Text: 
Documentation of prior statin use will be based on patient recall and copies of relevant medical 
records and pharmacy records if readily available.  If investigator is unable to assess prior statin 
use due to poor patient recall and/or lack of relevant medical records, and if appropriate 
according to local medical practice, documentation of contact with primary care physician 
regarding prior statin use should be obtained.  All available prior statin use history will be 
recorded in the eCRF.  Additionally, the basis for the investigator’s confirmation of the patient’s 
SI will be noted in the eCRF. 
New Text: 
Documentation of prior statin use will be based on patient recall and copies of relevant medical 
records and pharmacy records if readily available.  If investigator is unable to assess prior statin 
use due to poor patient recall and/or lack of relevant medical records, and if appropriate 
according to local medical practice, documentation of contact with primary care physician 
regarding prior statin use should be obtained.  At minimum, there will need to be documentation 
for the name of 2 statins and low dose of at least 1 statin to ensure inclusion criteria is met.  
All available prior statin use history will be recorded in the eCRF.  Additionally, the basis for the 
investigator’s confirmation of the patient’s SI will be noted in the eCRF. 
 
CHANGE 15 
PROCEDURE AND SCHEDULE OF ASSESSMENTS REVISIONS 
Location: 
Section 8.3, Procedure and Schedule of Assessments 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 120 of 153 
Original Text: 
Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 121 of 153 
Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
 
X 
 
 
X 
X 
10 mL reserve sample 
 
 
 
X 
 
 
 
X 
PK sample 
 
 
 
X 
X 
 
X 
X 
Pharmacogenomic sample 
(optional) 
 
 
 
X 
 
 
 
 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact13 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 
NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to clinic for these visits, the visits will occur according 
to the protocol schedule.  Safety assessments should include clinical safety and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical 
examination (PE), vital signs, and electrocardiograms (ECGs).  For patients who withdraw from study drug treatment, but consent to be followed for safety assessments by 
phone, the telephone contacts will occur according the protocol schedule with information regarding current health status and to collect information on AEs (eg, recent 
procedures, hospitalizations, and if the patient has died, the cause of death).  If a patient does not provide consent to be followed for safety assessments per the protocol (either by 
returning to clinic or by phone), Visit T5 will be considered the End of Study (EOS)/Early Withdrawal from study and no further visits will be scheduled. 
1 An optional basic fasting (minimum of 10 hours) lipid MAY be completed at Visit S2 (prior to starting single-blind medication) if patient fails to meet lipid entry criterion at 
Visit S1,The mean of the first value and the repeat value will be used to determine eligibility.  


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 122 of 153 
2 A recheck of blood pressure may be completed at Visit S2 if the patient’s DBP and/or SBP meet the exclusion criteria levels.  Patients may randomize after blood pressure 
medications have been adjusted, the patients have been on stable doses of blood pressure medications for at least 2 weeks, and the repeat blood pressure values (diastolic blood 
pressure [DBP] and/or systolic blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed at Visit S2 to determine eligibility if the patient’s 
estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate aminotransferase (AST) or other labs meet exclusion criteria levels.  If this optional lab is 
completed, the repeated value will be used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest for 5 minutes prior to assessments. 
7 Serology for HbsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without menses and <55 years; 
9 Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for all patients at Week -5 (Visit S1).  A coagulation 
panel will be completed only for patients on vitamin K antagonists at Day 1 (Visit T1) and 3 to 5 days later.  Please refer to laboratory manual for detailed schedule of tests. 
10Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-
HDL-C, and triglycerides.  Repeat within 1 week if exceed protocol-specified criteria. 
11 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
12 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation visit date. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 123 of 153 
New Text: 
Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 124 of 153 
Table 2: 
Schedule of Events (Subject Visit Schedule) 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28 ±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169 ±7 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
 
X 
 
 
X 
X 
 10 ml reserve sample 
 
 
 
X 
 
 
 
X 
PK sample 
 
 
 
X 
X 
 
X 
X 
Pharmacogenomic sample 
(optional) 
 
 
 
X 
 
 
 
 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact13 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 
NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to clinic for these visits, the visits will occur according 
to the protocol schedule.  Safety assessments should include clinical safety and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical 
examination (PE), vital signs, and electrocardiograms (ECGs). For patients who withdraw from study drug treatment, but consent to be followed for safety assessments by phone, 
the telephone contacts will occur according the protocol schedule with information regarding  current health status and to collect information on AE (eg, rcent procedures, 
hospitalizations, and if the patient has died, the cause of death).  If a patient does not provide consent to be followed for safety assessments per the protocol (either by returning 
to the clinic or by phone), Visit T5 will be considered the End of Study (EOS)/Earthly Withdrawal from study and no further visits will be scheduled. 
1 An optional basic fasting (minimum of 10 hours) lipid TG assessment MAY be completed between Visits S1and at visit S2 (prior to starting single-blind medication) if patient 
fails to meet lipid only TG criterion at Visit S1.  The mean of the first repeat value and the repeat value will be used to determine eligibility.  


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 125 of 153 
2 A recheck of blood pressure may be completed at between Visits S1 and Visit S2 if the patient’s DBP and/or SBP meet the exclusion criteria levels.  Patients may randomize 
after blood pressure medications have been adjusted, the patients have been on stable doses of blood pressure medications for at least 2 weeks, and the repeat blood pressure 
values (diastolic blood pressure [DBP] and/or systolic blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed between Visit S1 and Visit S2 to 
determine eligibility if the patient’s estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate aminotransferase (AST) or other labs meet exclusion 
criteria levels.  If this optional lab is completed, the repeated value will be used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest for 5 minutes prior to assessments. 
7 Serology for HbsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without menses and <55 years; 
9 Urine pregnancy test completed in women of child-bearing potential only just prior to randomization.  
10 9Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for all patients at Week -5 (Visit S1).  A 
coagulation panel will be completed only for patients on vitamin K antagonists at Day 1 (Visit T1) and 3 to 5 days later.  For these visits, the sample may be analyzed at either 
the central or a local lab.  Please refer to laboratory manual for detailed schedule of tests. 
11Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-
HDL-C, and triglycerides.  Repeat within 1 week if exceed protocol specified criteria.  
12 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
13 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation visit date. 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 126 of 153 
CHANGE 16 
SCREENING WEEK -5 REVISIONS 
Location: 
Section 8.3.1, Screening Week -5 
Original Text: 
8.3.1. 
Screening Week -5 (Visit S1; Day -63 to -29) 
New Text: 
8.3.1. 
Screening Week -5 (Visit S1; Day -63 to -29 -35 ±7 days) 
Original Text: 
The screening period can be extended an additional 4 weeks if needed to adjust background 
therapy or other reasons. 
New Text: 
The screening period (between Visits S1 and S2) can be extended an additional 4 weeks if 
needed to adjust background therapy or other reasons. 
Patients who are considered to be screen failures due to not meeting stability requirements for 
a condition or concurrent medication may be considered for rescreening after consultation 
with the Sponsor (or designee).  These patients must be re-consented, re-registered in the 
IWRS, and will have a new patient ID number assigned.  
 
CHANGE 17 
SCREENING VISITS REVISIONS 
Location:  
Section 8.3.3, Screening Week -1 (Visit S3; Day -7 ±3) 
Original Text: 
The patient will undergo the following assessments and procedures at Visit S3: 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints (starting from signing the informed 
consent document) 
3. 12-lead electrocardiogram (ECG) 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
6. Diet and exercise counseling 
7. Study drug compliance assessment 


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New Text: 
The patient will undergo the following assessments and procedures at Visit S3: 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints (starting from signing the informed 
consent document) 
3. 12-lead electrocardiogram (ECG) 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG).  LDL-C 
value must be ≥70 mg/dL. 
6. Diet and exercise counseling 
7. Study drug compliance assessment 
 
CHANGE 18 
WEEK 0 VISIT REVISION 
Location: 
Section 8.3.4, Week 0 (Visit T1; Day 1) 
Original Text: 
Prior to scheduling Visit T1, review the screening clinical results to determine whether the 
patient continues to meet lab eligibility criteria.  At Visit T1, determine whether the patient was 
adherent with placebo treatment during the run-in period (average of ≥80% adherence required) 
and had no issues with tolerability of run-in period study medication.  Patients with intolerable 
side effects, including but not limited to muscular skeletal pain, will be run-in failures. 
If the patient has met all inclusion criteria and none of the exclusion criteria, the patient may be 
randomized into the double-blind treatment period.  Patients who fail to meet all entry criteria 
after initiation of single-blind placebo run-in are considered to be run-in failures and will not be 
randomized.  
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.  
 
7. Central clinical laboratory evaluations:  
• Coagulation in patients on vitamin K antagonists 
• Hematology, blood chemistry, and urinalysis 
• 10-mL reserve sample  
• apoB 


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• hs-CRP 
• HbA1C 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• Predose PK sample 
8. Urine pregnancy in women of childbearing potential only prior to randomization. 
9. Diet and exercise counseling 
10. IWRS contact to obtain the patient randomization number and MED ID number for 
double-blind study drug 
11. Dispense double-blind study drug and ingestion of first dose and provide dosing and 
storage instructions 
New Text: 
Prior to scheduling Visit T1, review the screening clinical results to determine whether the 
patient continues to meet lab eligibility criteria.  At Visit T1, determine whether the patient was 
adherent with placebo treatment during the run-in period (average of ≥80% adherence required) 
and had no issues with tolerability of run-in period study medication.  Patients with intolerable 
side effects, including but not limited to muscular skeletal pain, will be run-in failures. 
If the patient has met all inclusion criteria and none of the exclusion criteria, the patient may be 
randomized into the double-blind treatment period.  Patients who fail to meet all entry criteria 
after initiation of single-blind placebo run-in are considered to be run-in failures and will not be 
randomized.  
Patients are considered randomized once all eligibility criteria are confirmed and a 
randomization number is obtained by the IWRS IWRS is contacted with confirmation of patient 
randomization on the day of first dose.  
 
7. Central clinical laboratory evaluations:  
• Coagulation in patients on vitamin K antagonists (return 3-5 days after Visit T1 for 
repeat coagulation).  Coagulation samples for this visit may be analyzed at the 
central or local lab. 
• Hematology, blood chemistry, and urinalysis 
• 10-mL reserve sample 
• apoB 
• hs-CRP 
• HbA1C 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• Predose PK sample 
8. Urine pregnancy in women of childbearing potential only prior to randomization. 


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9. Diet and exercise counseling 
10. IWRS contact to obtain the patient randomization number and MED ID number contact 
to randomize patient and assign bottle number(s) for double-blind study drug 
11. Dispense double-blind study drug and ingestion of first dose and provide dosing and 
storage instructions 
 
CHANGE 19 
TREATMENT WEEK 4 AND 12 REVISIONS 
Location: 
Section 8.3.5, Treatment Week 4 (Visit T2; Day 29 ±3 days);  
Section 8.3.7 Treatment Week 12 (Visit T4; Day 85 ±3 days) 
Original Text: 
Patients will undergo the following assessments and procedures at Week 4 (Visit T2): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints 
3. Weight 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
• PK Sample 
New Text: 
Patients will undergo the following assessments and procedures at Week 4 (Visit T2): 
1. Concomitant medication review (ongoing) 
2. Assess AEs, SAEs, and potential clinical endpoints 
3. Weight 
4. Vital signs 
5. Central clinical laboratory evaluations:  
• Hematology, blood chemistry, and urinalysis 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
• PK Sample prior to dose 
 


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CHANGE 20 
WEEK 24/EOS REVISION 
Location: 
Section 8.3.8, Treatment Week 24/EOS (Visit T5; Day 169 ±7 days) 
Original Text: 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• PK Sample 
• Reserve Sample 
New Text: 
• Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG)  
• PK Sample before dose 
• Reserve Sample 
 
CHANGE 21 
EARLY WITHDRAWAL REVISION 
Location: 
Section 8.4, Early Withdrawal from Study or Treatment 
Original Text: 
Patients who withdraw from study drug prior to Week 24 (Visit T5) for any reason will be asked 
to continue to be followed for safety assessments, including basic fasting lipids, at clinic visit 
following the protocol-specified visit schedule (see Section 8.3).  Protocol procedures to be 
completed for patients who consent will include those specified at each visit as noted in Schedule 
of Events (see Section 8.3).  
New Text: 
Patients who withdraw from study drug prior to Week 24 (Visit T5) for any reason will be asked 
to continue to be followed for safety assessments, including basic fasting lipids, at clinic visit 
following the protocol-specified visit schedule (see Section 8.3).  Protocol procedures to be 
completed for patients who consent will include those specified at each visit as noted in Schedule 
of Events (see Section 8.3) 
 
CHANGE 22 
OVERDOSE INFORMATION ADDED 
Location: 
New section 
Original Text: 
Not applicable. 


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New Text: 
8.5.  
Overdose 
There is no specific antidote for an overdose of bempedoic acid.  Management of an overdose 
should be focused on the treatment of symptoms.  These symptoms should be managed 
according to current standards of care with appropriate supportive measures.  Also 
discontinuation of study drug should be considered, based on medical judgement. 
 
CHANGE 23 
PHYSICAL EXAMINATION REVISIONS 
Location: 
Section 10.1.4, Physical Examination 
Original Text: 
Documentation of the PE findings will be included in the source documentation at the clinical 
site.  Significant findings prior to the start of study drug 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. 
New Text: 
Documentation of the PE findings will be included in the source documentation at the clinical 
site.  Significant findings prior to the start of study drug noted at Visit S2 will be recorded on the 
Medical History/Current Medical Conditions page of the eCRF.  Only changes from Visit S2 
baseline physical examination findings (or other unscheduled physical exams performed after 
informed consent but prior to randomization) that meet the definition of an AE will be recorded 
on the AE page of the eCRF. 
 
CHANGE 24 
CLINICAL LABORATORY TESTS REVISIONS 
Location: 
Section 10.1.6.1, Laboratory Parameters (Safety) 
Original Text: 
Table 4: 
Clinical Laboratory Parameters (Safety) 


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Clinical Laboratory Test 
Clinical Laboratory Test 
Hematology 
Blood Chemistry (serum, fasting) 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood (RBC) cell count 
• 
White blood (WBC) cell count with 
differential (absolute and %) 
• 
Albumin (Alb) 
• 
Alkaline phosphatase (Alk-P) 
• 
Alanine aminotransferase (ALT; SGPT) 
• 
Aspartate aminotransferase (AST; SGOT) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine kinase (CK) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total and direct bilirubin (TB) 
• 
Total protein 
• 
Uric acid 
Urinalysis (Dipstick) 
• 
Clarity 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Urine Pregnancy in females of child 
bearing potential 
Urinalysis (Microscopic)-only if urine dipstick 
abnormal 
• 
Bacteria 
• 
Casts 
• 
Crystals 
• 
Epithelial cells 
• 
Red blood cell (RBC) 
• 
WBC 
Coagulation – all patients at Visit S1;  only in 
patients receiving vitamin K antagonists  at 
Visit T1 and 3 to 5 days post Visit T1 using local or 
central lab 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 


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Table 4: 
Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Other Screening Labs 
Additional samples 
• 
Hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) 
• 
Serum pregnancy test (only for females of 
childbearing potential) 
• 
Follicle-stimulating hormone (FSH; 
Females <55 years and >1 year without 
menses) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Hemoglobin A1C (HbA1C) 
• 
Reserve blood samples for potential future 
measurement of bempedoic acid safety or 
pharmacodynamic biomarkers 
• 
Reserve genetic blood sample (optional) 
 


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New text 
Table 4: 
Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Hematology 
Blood Chemistry (serum, fasting) 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood (RBC) cell count 
• 
White blood (WBC) cell count with 
differential (absolute and %) 
• 
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 
• 
Urine Pregnancy in females of child 
bearing potential 


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Table 4: 
Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Urinalysis (Microscopic)-only if urine dipstick 
abnormal 
• 
Bacteria 
• 
Casts 
• 
Crystals 
• 
Epithelial cells 
• 
Red blood cell (RBC) 
• 
WBC 
Coagulation – all patients at Visit S1;  only in 
patients receiving vitamin K antagonists  at 
Visit T1 and 3 to 5 days post Visit T1 using local or 
central lab 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
Other Screening Labs 
Additional samples 
• 
Hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) 
• 
Serum pregnancy test (only for females of 
childbearing potential) 
• 
Follicle-stimulating hormone (FSH; 
Females <55 years and >1 year without 
menses) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Hemoglobin A1C (HbA1C) 
• 
Reserve blood samples for potential future 
measurement of bempedoic acid safety or 
pharmacodynamic biomarkers 
• 
Reserve genetic blood sample (optional) 
Location: 
Section 10.1.6.2, Clinical Laboratory Tests (PK) 
Original Text: 
A PK blood sample will be collected prior to dosing at Visits T1, T2, T4, and T5. 
Patients will be in a seated position during the blood collection.  Collection schedule and 
instructions are provided in the Clinical Laboratory Manual.  A description of the sample 
collection, storage, and shipping are described in Section 10.1.6.3. 
New Text: 
A PK blood sample will be collected prior to dosing at Visits T1, T2, T4, and T5. 
Patients will be in a seated position during the blood collection.  Collection schedule and 
instructions are provided in the Clinical Laboratory Manual.  A description of the sample 
collection, storage, and shipping are described in Section 10.1.6.3. 
Location: 
Section 10.1.6.3, Sample Collection, Storage, and Shipping 
Original Text: 
Clinical laboratory and PK samples will be collected by appropriate clinical site personnel and 
then shipped according to a separate laboratory manual provided by the Central Laboratory.  


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Samples will be processed by the Central Laboratory, and PK samples will be forwarded to the 
Bioanalytical Laboratory for analysis.  Reserve samples will be stored frozen for potential future 
measurement of additional bempedoic acid safety and efficacy biomarkers.  A reserve genetic 
blood sample (optional) will also be stored frozen for potential future bempedoic acid genetic 
analyses.   
New Text: 
Clinical laboratory and PK 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, and PK samples will be forwarded to the 
Bioanalytical Laboratory for analysis.  Reserve samples will be stored frozen for potential future 
measurement of additional bempedoic acid safety and efficacy biomarkers.  A reserve genetic 
blood sample (optional) will also be stored frozen for potential future bempedoic acid genetic 
analyses.   
Location: 
Section 10.1.6.5, Exploratory Biomarker Measurement; Section 10.1.6.6, Genetic Testing 
Original Text: 
10.1.6.5 
Exploratory Biomarker Measurement 
Additional exploratory safety, efficacy, PK, or potential biomarkers may be assayed from reserve 
samples. 
10.1.6.6 
Genetic Testing 
As part of this study, all patients will be invited to provide a blood sample to be banked for 
potential future genetic analyses.  Participation in this portion of the study is optional and a 
sample will only be obtained if consent is provided.  Those who choose not to provide a sample 
for genetic analysis may still participate in the main portion of the study.  Samples will be 
anonymized before testing to assure that the results cannot be traced back to an individual 
patient.   
New Text: 
10.1.6.5 
Exploratory Biomarker Measurement 
Additional exploratory safety, efficacy, PK, or potential biomarkers may be assayed from reserve 
samples. 
10.1.6.6 
Genetic Testing 
As part of this study, all patients will be invited to provide a blood sample to be banked for 
potential future genetic analyses.  Participation in this portion of the study is optional and a 
sample will only be obtained if consent is provided.  Those who choose not to provide a sample 
for genetic analysis may still participate in the main portion of the study.  Samples will be 
anonymized before testing to assure that the results cannot be traced back to an individual 
patient. 
 


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CHANGE 25 
ADVERSE EVENT REPORTING REVISIONS 
Location: 
Section 10.2.3, Reporting 
Original Text: 
All AEs occurring during the course of the study (starting from signing informed consent to 
study completion) will be collected on the AE eCRF.  Patients should be instructed to report any 
AE that they experience to the Investigator.  Beginning with Visit S2 (Week -4), Investigators 
should make an assessment for AEs at each visit and record the event on the appropriate AE 
eCRF.  
New Text: 
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 
the last dose of study drug.  Beginning with Visit S2 (Week -4), 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 ICF through 30 days following the last dose of study drug should 
be reported to the Sponsor per Section 10.2.7.4. 
 
CHANGE 26 
DEFINITION OF SAE REVISIONS 
Location: 
New sections 
Original Text: 
Not applicable. 
New Text: 
10.2.7.2 
Definition of Serious Adverse Events or Outcomes not Qualifying as Serious 
Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• Preplanned or elective hospitalization including social and/or convenience 
situations (eg, due to inclement weather) 
• Overdose of either Esperion study drug or concomitant medication unless the event 
meets SAE criteria (eg, hospitalization).  However, the event should still be 
captured as a non-serious AE on the appropriate eCRF page 
10.2.7.3 
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 10.1.6.4. 


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Location: 
10.2.7.2, Reporting of Serious Adverse Events 
Original Text: 
10.2.7.2 
Reporting of Serious Adverse Events 
All SAEs, regardless of relationship to study drug, occurring from the time of informed consent 
until 30 days following study completion or study discontinuation, must be reported by the 
Principal Investigator or designee to the Safety designee within 24 hours of the Principal 
Investigator or the clinical site becoming aware of the occurrence.  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.  
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. 
10.2.7.210.2.7.4 
Reporting of Serious Adverse Events  
All SAEs, regardless of relationship to study drug, occurring from the time of informed consent 
until 30 days following study completion or study discontinuation last dose of study drug, must 
be reported by the Principal Investigator or designee to the Safety designee within 24 hours of 
the Principal Investigator or the clinical site becoming aware of the occurrence.  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 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. 
 
CHANGE 27 
REPORTS OF PREGNANCY REVISIONS 
Location: 
Section 10.2.7.4, Reports of Pregnancy 
Original Text: 
10.2.7.4. 
Reports of Pregnancy 
If a patient becomes pregnant during the study the investigator is to stop dosing with study 
drug(s) immediately. 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to the 
Sponsor/SAE designee using the Pregnancy Report Form within the same timelines as an SAE.   


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A pregnancy should be followed through to outcome, whenever possible.  Once the outcome of 
the pregnancy is known, the 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 or SAE forms.   
Patients who become pregnant will discontinue Investigational Medicinal Product (IMP) 
immediately and complete the end of study evaluations. 
New Text: 
10.2.7.410.2.7.6. 
Reports of Pregnancy 
If a patient becomes pregnant during the study or within 30 days of 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 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 AEor SAE forms CRF.   
Patients who become pregnant will discontinue Investigational Medicinal Product (IMP) 
immediately and complete the end of study evaluations. 
 
CHANGE 28 
HEPATIC FUNCTION REVISIONS 
Location: 
Section 10.2.11.3.2, Hepatic Function 
Original Text: 
• If repeat LFT assessment confirms ALT and/or AST >5 × ULN, patient should be 
withdrawn from study drug treatment, but will be asked to continue to be followed for 
safety using the protocol-specified visit schedule (see Section 8.3) 
• If repeat LFT assessment confirms ALT and/or AST >3 × ULN in addition to any of 
the following, the patient should be given no further treatment with study drug, but 
will be asked to continue to be followed for safety using the protocol-specified visit 
schedule (see Section 8.3): 
New Text: 
• If repeat LFT assessment confirms ALT and/or AST >5 × ULN, patient should be 
withdrawn from study drug treatment, but will be asked to continue to be followed for 
safety using the protocol-specified visit schedule (see Section 8.3) or more frequently 
if deemed appropriate by the Investigator. 


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• If repeat LFT assessment confirms ALT and/or AST >3 × ULN in addition to any of 
the following, the patient should be given no further treatment with study drug, but 
will be asked to continue to be followed for safety using the protocol-specified visit 
schedule (see Section 8.3) or more frequently if deemed appropriate by the 
Investigator. 
 
CHANGE 29 
MUSCLE-RELATED EVENTS REVISIONS 
Location: 
Section 10.2.11.3.3, Muscle-Related Events 
Original Text: 
Repeat CK assessment will include query for related symptoms.   
• If the repeat CK assessment confirms an unexplained (ie, not associated with recent 
trauma or physically strenuous activity) CK abnormality >5 × ULN, if asymptomatic 
the investigator with input from the Sponsor may consider continuing study 
medication with continued CK assessments every 1-2 weeks.   
New Text: 
Repeat CK assessment will include query for related symptoms.   
• 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.  investigator with input from the Sponsor may consider 
continuing study medication with continued CK assessments every 1-2 weeks.   
 
CHANGE 30 
STATISTICAL METHODS REVISIONS 
Location: 
Section 2, Synopsis; Section 11.1, General Considerations 
Original Text: 
The statistical analyses described in this section will be performed as further outlined in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to the first time that the 
DMC reviews data for this study.  The SAP will supersede the protocol in the event of any 
differences between the 2 documents in relation to 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. 
New Text: 
The statistical analyses described in this section will be performed as further outlined in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to the first time that the 


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DMC reviews data for this study.  The SAP will supersede the protocol in the event of any 
differences between the 2 documents in relation to 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. 
 
CHANGE 31 
PRIMARY AND SECONDARY ENDPOINT AND SAFETY 
ANALYSES 
Location: 
Section 2, Synopsis; Section 11.5, Primary Endpoint Analysis; Section 11.6, Secondary and 
Tertiary Endpoint Analysis; Section 11.7, Safety Analysis 
Original Text: 
11.5 
Primary Endpoint 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 values from Week -1 (Visit S3) and predose 
Day 1/Week 0 (Visit T1).   
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with 
treatment group and patient type (primary prevention; secondary prevention) as factors and 
baseline LDL-C as a covariate.  The ANCOVA will be performed using the FAS, with patients 
included in their randomized treatment group regardless of the treatment they actually received.   
Two methods for data handling will be used: the first is observed case data only, while the 
second will involve specification of the missing data mechanism using a pattern mixture model 
(PMM).  The primary analysis will be that from the PMM, while the observed case analysis will 
be confirmatory.  The PMM will be used to specify different imputation strategies depending on 
whether the patient is still on study treatment.  Patients with missing LDL-C data at Week 12 
who are no longer taking study treatment can be assumed to no longer be benefitting from study 
medication, and their missing value(s) can be assumed to be returning toward their baseline 
value.  In this instance, it is reasonable to impute LDL-C values based on the patients’ baseline 
value.  Patients with missing LDL-C data at Week 12 who are still taking study treatment can be 
assumed to continue to benefit from study medication, and their missing value(s) can be assumed 
to be similar to those who remain on study treatment and have data.  In this instance, it is 
reasonable to impute LDL-C values based on the observed values in their randomized treatment 
group at Week 12.  To account for uncertainty, missing values will be imputed using multiple 
imputation. Imputed datasets will be analyzed using an ANCOVA model with the treatment and 
patient type (primary prevention; secondary prevention) as factors and baseline LDL-C as a 
covariate.  Approximately 100 imputed datasets will be created, with results from the analysis of 
each imputed dataset combined using Rubin’s method.  For each type of ANCOVA (observed 
case; imputation via PMM), the least squares mean (LSM) and standard error (SE) will be 
provided for both treatment groups, along with the placebo-corrected LSM, its 95% confidence 
interval (CI) and associated p-value. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 142 of 153 
11.6 
Secondary and Tertiary Endpoint Analysis 
Secondary efficacy endpoints are also of interest for this study, in terms of controlling the overall 
Type I error rate, a gatekeeping or stepdown approach will be used to test the primary efficacy 
endpoint and then specific secondary efficacy endpoints sequentially in order to preserve the 
study-wise Type I error rate.  The sequence for the stepdown procedure in this study is as 
follows: 
6. Test the primary efficacy endpoint: percent change from baseline to Week 12 in LDL-C  
7. Test the percent change from baseline to Week 24 in LDL-C 
8. Test the percent change from baseline to Week 12 in non-HDL-C 
9. Test the percent change from baseline to Week 12 in TC 
10. Test the percent change from baseline to Week 12 in apoB 
11. Test the percent change from baseline to Week 12 in hs-CRP   
In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, two-
sided.  Statistical significance at each step is required in order to test the next hypothesis.  If the 
primary endpoint meets the criteria for statistical significance, then the percent change from 
baseline to Week 24 in LDL-C will be tested; and so forth. 
For the remaining secondary efficacy endpoints and the tertiary efficacy endpoints, a 
significance level of 0.05 will be used; given the large number of remaining endpoints, the 
p-values for those endpoints will be considered descriptive. 
Percent change from baseline to Week 24 in LDL-C; change from baseline to Weeks 12 and 24 
in LDL-C; percent change from baseline to Weeks 12
in
non-HDL-C,
 and 
TC; and percent change from baseline to Weeks 12
in apoB and hs-CRP will each be 
analyzed using ANCOVA with treatment group and patient type (primary prevention; secondary 
prevention) as factors and the relevant baseline as a covariate.  Baseline for
 non-
HDL-C,
 and TC is defined as the mean of the values from Week -1 (Visit S3) and predose 
Day 1/Week 0 (Visit T1).  Baseline for apoB and hs-CRP is defined as the predose 
Day 1/Week 0 (Visit T1) value.  Each ANCOVA will be performed using the FAS, with patients 
included in their randomized treatment group regardless of the treatment they actually received.  
Only observed case data will be included in each analysis (no imputation will be performed for 
missing data).  For each lipid parameter and analysis time point, the LSM and SE will be 
provided for both treatment groups, along with the placebo-corrected LSM, its 95% CI and 
associated p-value. 
For all continuous efficacy endpoints (percent change from baseline in LDL-C,
 non-
HDL-C, TC,
apoB, and hs-CRP; change from baseline in LDL-C; to Week 12 and 24, as 
appropriate), the ANCOVA assumption of normality will be assessed.  If non-normality of the 
data is found at any time point for any parameter, either the data will be transformed so that it is 
normally distributed or a nonparametric test will be used instead of the planned ANCOVA. 
Finally, the number and percent of patients in each treatment group requiring additional (post-
randomization) TG-lowering therapy will be summarized.  The medications will be summarized 
by treatment group.  


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 143 of 153 
 
11.7 
Safety Analysis 
No statistical analyses will be performed on any of the safety data in this study.   
The summarization of AEs will include TEAEs, defined as any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the investigational product, whether 
or not related to the product.  TEAEs and SAEs will be summarized by SOC, severity, and 
relationship to study drug for each treatment group.  These AE summaries will include 
cumulative incidence (percent of patients experiencing the AE) and patient-year adjusted 
incidence rates.  If appropriate, absolute and relative risk differences will be calculated using 
both cumulative incidence and incidence rates.  Deaths, withdrawal from study treatment due to 
AEs, and withdrawal from the study due to AEs will each be summarized by treatment group. 
New Text: 
11.5 
Primary Endpoint 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 values from Week -1 (Visit S3) and predose 
Day 1/Week 0 (Visit T1).   
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with 
treatment group and patient type (primary prevention; secondary prevention) as factors and 
baseline LDL-C as a covariate.  The ANCOVA will be performed using the FAS, with patients 
included in their randomized treatment group regardless of the treatment they actually received.  
The details of the ANCOVA model and options to account for unequal variances and group 
size will be described in the SAP. 
Missing data for the primary endpoint will be imputed using a multiple imputation method 
that accounts for treatment adherence.  Two methods for data handling will be used: the first is 
observed case data only, while the second will involve specification of the missing data 
mechanism using a pattern mixture model (PMM).  The primary analysis will be that from the 
PMM, while the observed case analysis will be confirmatory.  The A pattern mixture model 
(PMM) will be used to specify different imputation strategies depending on whether the patient 
is still on study treatment.  Patients with missing LDL-C data at Week 12 who are no longer 
taking study treatment can be assumed to no longer to be benefitting from study medication, and 
their missing value(s) can be assumed to be returning toward their baseline value similar to those 
from placebo patients.  In this instance, it is reasonable to impute LDL-C values based on the 
patients’ baseline value. in a model including placebo patients’ data only.  Patients with missing 
LDL-C data at Week 12 who are still taking study treatment can be assumed to continue to 
benefit from study medication, and their missing value(s) can be assumed to be similar to those 
who remain on study treatment and have data.  In this instance, it is reasonable to impute LDL-C 
values based on the observed values in their randomized treatment group at Week 12.  Details 
for the PMM will be described in the SAP.  
To account for uncertainty, missing values will be imputed using multiple imputation.  Imputed 
datasets will be analyzed using an ANCOVA model with the treatment and patient type (primary 
prevention; secondary prevention) as factors and baseline LDL-C as a covariate.  Approximately 
100 200 imputed datasets will be created, with results from the analysis of each imputed dataset 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 144 of 153 
combined using Rubin’s method.  For each type of ANCOVA (observed case; imputation via 
PMM), the least squares mean (LSM) and standard error (SE) will be provided for both treatment 
groups, along with the placebo-corrected LSM, its 95% confidence interval (CI) and associated 
p-value. 
11.6 
Secondary and Tertiary Endpoint Analysis 
Secondary efficacy endpoints are also of interest for this study, in terms of controlling the overall 
Type I error rate, a gatekeeping or stepdown approach will be used to test the primary efficacy 
endpoint and then specific secondary efficacy endpoints sequentially in order to preserve the 
study-wise Type I error rate.  The sequence for the stepdown procedure in this study is as 
follows: 
1. Test the primary efficacy endpoint: percent change from baseline to Week 12 in LDL-C  
2. Test the percent change from baseline to Week 24 in LDL-C 
3. Test the percent change from baseline to Week 12 in non-HDL-C 
4. Test the percent change from baseline to Week 12 in TC 
5. Test the percent change from baseline to Week 12 in apoB 
6. Test the percent change from baseline to Week 12 in hs-CRP   
In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, two-
sided.  Statistical significance at each step is required in order to test the next hypothesis.  If the 
primary endpoint meets the criteria for statistical significance, then the percent change from 
baseline to Week 24 in LDL-C will be tested; and so forth. 
For the remaining secondary efficacy endpoints and the tertiary efficacy endpoints, a 
significance level of 0.05 will be used; given the large number of remaining endpoints, the 
p-values for those endpoints will be considered descriptive. 
In general, change or percent change in lipid parameters at a given time point will be analyzed 
using similar ANCOVA model for the primary endpoint with treatment group Percent change 
from baseline to Week 24 in LDL-C; change from baseline to Weeks 12 and 24 in LDL-C; 
percent change from baseline to Weeks 12
in
 non-HDL-C,
 and TC; and 
percent change from baseline to Weeks 12and 24 in apoB and hs-CRP will each be analyzed 
using ANCOVA with treatment group and patient type (primary prevention; secondary 
prevention) as factors and the relevant baseline as a covariate.   
Baseline for
 non-HDL-C,
 and TC is defined as the mean of the values from 
Week -1 (Visit S3) and predose Day 1/Week 0 (Visit T1).  Baseline for apoB and hs-CRP is 
defined as the predose Day 1/Week 0 (Visit T1) value.   
Each ANCOVA will be performed using the FAS, with patients included in their randomized 
treatment group regardless of the treatment they actually received.  Same imputation method 
described for the primary endpoint will be used for those secondary endpoints included in the 
step-down procedure, while only observed data analysis will be used for other secondary and 
tertiary endpoints.  Only observed case data will be included in each analysis (no imputation will 
be performed for missing data).  For each lipid parameter and analysis time point, the LSM and 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 145 of 153 
SE will be provided for both treatment groups, along with the placebo-corrected LSM, its 95% 
CI and associated p-value. 
For all continuous efficacy endpoints (percent change from baseline in LDL-C, HDL-C, non-
 TC,
apoB, and hs-CRP; change from baseline in LDL-C; to Week 12 and 24, as 
appropriate), tThe ANCOVA assumption of normality will be assessed.  If severe non-normality 
of the data is found at any time point for any parameter, either the data will be transformed so 
that it is normally distributed or a nonparametric test will be used considered instead of the 
planned ANCOVA. 
Finally, the number and percent of patients in each treatment group requiring additional (post-
randomization) TG-lowering therapy will be summarized.  The medications will be summarized 
by treatment group.  
11.7 
Safety Analysis 
No statistical analyses will be performed on any of the safety data in this study.   
The summarization of AEs will include TEAEs, defined as any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the investigational product, whether 
or not related to the product.  TEAEs and SAEs will be summarized by SOC, severity, and 
relationship to study drug for each treatment group.  These AE summaries will include 
cumulative incidence (percent of patients experiencing the AE) and patient-year adjusted 
incidence rates.  If appropriate, absolute and relative risk differences will be calculated using 
both cumulative incidence and incidence rates.  Deaths, withdrawal from study treatment due to 
AEs, and withdrawal from the study due to AEs will each be summarized by treatment group. 
 
CHANGE 32 
PHARMACOKINETIC SAMPLE REVISION 
Location: 
Section 2, Synopsis; Section 11.8, Pharmacokinetics 
Original Text: 
Four plasma PK samples for analysis will be collected.  Plasma concentrations of bempedoic 
acid and optionally, one or more of its metabolites, will be determined in patients who are 
receiving bempedoic acid.  All patients, site personnel, and study personnel will remain blinded 
to treatment assignment throughout the duration of the study.  Personnel performing the 
bioanalytical analysis of bempedoic acid concentrations will be unblinded in order to assay the 
appropriate samples during the study.  Plasma concentrations of bempedoic acid and any 
measured metabolite will be included in the listings, but population PK analysis will be reported 
separately will be descriptive by time point. 
New Text: 
FourThree plasma PK samples for analysis will be collected.  Plasma concentrations of 
bempedoic acid and optionally, one or more of its metabolites, will be determined in patients 
who are receiving bempedoic acid.  All patients, site personnel, and study personnel will remain 
blinded to treatment assignment throughout the duration of the study.  Personnel performing the 
bioanalytical analysis of bempedoic acid concentrations will be unblinded in order to assay the 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 146 of 153 
appropriate samples during the study.  Plasma concentrations of bempedoic acid and any 
measured metabolite will be included in the listings, but population PK analysis will be reported 
separately will be descriptive by time point. 
CHANGE 33 
INFORMED CONSENT REVISION 
Location: 
Section 14.3, Written Informed Consent 
Original Text: 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
A separate informed consent will be obtained for collecting the genetic blood sample. 
The Principal Investigator(s) must maintain the original, signed ICD.  A copy of the signed ICD 
must be given to the patient. 
New Text: 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
A separate informed consent will be obtained for collecting the genetic blood sample. 
The Principal Investigator(s) must maintain the original, signed ICD.  A copy of the signed ICD 
must be given to the patient. 
 
CHANGE 34 
CASE REPORT FORM COLLECTION REVISION 
Location: 
Section 15.3, Case Report Forms and Study Records 
Original Text: 
It is essential that all dates appearing on the Sponsor’s patient data collection forms for 
laboratory tests, cultures, etc, be the dates on which the specimens were obtained or the 
procedures performed.  The eCRFs will be electronically signed by the Investigator and dated as 
verification of the accuracy of the recorded data.  All data collection forms should be completed 
within 48 hours following the evaluation. 
New Text: 
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 
a timely manner according to the CRF completion guidelines.within 48 hours following the 
evaluation. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 147 of 153 
CHANGE 35 
STUDY ADMINISTRATIVE STRUCTURE REVISION 
Location: 
Section 16.2, Study Administrative Structure 
Original Text: 
Fill/Finish Manufacturing: 
And 
Secondary Packaging/Depot for Clinical Site Drug Shipments:  
New Text: 
Investigational medicinal product supply chain details can be found in the pharmacy manual. 
Fill/Finish Manufacturing: 
And 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 148 of 153 
Secondary Packaging/Depot for Clinical Site Drug Shipments:  
 
CHANGE 36 
SCHEDULE OF EVENTS REVISIONS 
Location: 
Appendix 1, Schedule of Events 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 149 of 153 
Original Text: 
APPENDIX 1.  
SCHEDULE OF ASSESSMENTS 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
-63 to -29 
Day 
-28±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy/FSH8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
 
X 
 
 
X 
X 
10-mL reserve sample 
 
 
 
X 
 
 
 
X 
PK Sample 
 
 
 
X 
X 
 
X 
X 
Pharmacogenomics Sample 
(optional) 
 
 
 
X 
 
 
 
 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact12 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 150 of 153 
NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to 
clinic for these visits, the visits will occur according to the protocol schedule.  Safety assessments should include clinical safety 
and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical examination (PE), vital signs, and 
electrocardiograms (ECGs).  For patients who withdraw from study drug treatment, but consent to be followed for safety 
assessments by phone, the telephone contacts will occur according the protocol schedule with information regarding current 
health status and to collect information on AEs (eg, recent procedures, hospitalizations, and if the patient has died, the cause of 
death).  If a patient does not provide consent to be followed for safety assessments per the protocol (either by returning to clinic 
or by phone), Visit T5 will be considered the End of Study (EOS)/Early Withdrawal from study and no further visits will be 
scheduled. 
1 An optional basic fasting (minimum of 10 hours) lipid MAY be completed at Visit S2 (prior to starting single-blind medication) 
if patient fails to meet lipid entry criterion at Visit S1.  If this optional basic fasting lipid is completed, the mean of the first value 
and the repeat value will be used to determine eligibility.  
2 A recheck of blood pressure may be completed at Visit S2 if the patient’s DBP and/or SBP meet the exclusion criteria levels.  
Patients may randomize after blood pressure medications have been adjusted, the patients have been on stable doses of blood 
pressure medications for at least 2 weeks, and the repeat blood pressure values (diastolic blood pressure [DBP] and/or systolic 
blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed at Visit S2 to determine eligibility if the 
patient’s estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate aminotransferase (AST) or other 
labs meet exclusion criteria levels.  If this optional lab is completed, the repeated value will be used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest 
for 5 minutes prior to assessments. 
7 Serology for HBsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without 
menses and <55 years; 
9 Urine pregnancy test completed in women of child-bearing potential only just prior to randomization.  
10 Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for 
all patients at Week -5 (Visit S1).  A coagulation panel will be completed only for patients on anti-coagulant therapy at Day 1 
(Visit T1) and 3 to 5 days later.  Please refer to laboratory manual for detailed schedule of tests. 
11 Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides.  Repeat within 1 week if exceed protocol-specified 
criteria. 
12 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
13 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation 
visit date. 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 151 of 153 
New Text: 
APPENDIX 1.  
SCHEDULE OF ASSESSMENTS 
Visit 
S11,2 
S2 
S3 
T1 
T2 
T3/phone 
T4 
T5/EOS3 
Week  
Wk -5 
Wk -4 
Wk -1 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 24 
Procedure 
Day 
 -35± 7-63 
to -29 
Day 
-28±3 
Day 
-7±3 
Day 
1 
Day 
29±3 
Day 
57±3 
Day 
85±3 
Day 
169±7 
Informed Consent 
X 
 
 
 
 
 
 
 
Enrollment Criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Statin Intolerance Status 
Determination 
X 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
X 
Weight4 
X 
 
 
X 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
12-Lead ECG5 
 
 
X 
 
 
 
 
X 
Vital Signs6 
X 
X 
X 
X 
X 
 
X 
X 
Serology7 
X 
 
 
 
 
 
 
 
Serum Pregnancy/FSH8  
X 
 
 
 
 
 
 
 
Urine Pregnancy9 
 
 
 
X 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
Clinical Safety Labs10 
X 
 
X 
X 
X 
 
X 
X 
Basic Fasting Lipids11 
X 
 
X 
X 
X 
 
X 
X 
HbA1C 
X 
 
 
X 
 
 
X 
X 
10-mL reserve sample 
 
 
 
X 
 
 
 
X 
PK Sample 
 
 
 
X 
X 
 
X 
X 
Pharmacogenomics Sample 
(optional) 
 
 
 
X 
 
 
 
 
apoB 
 
 
 
X 
 
 
X 
X 
hs-CRP 
 
 
 
X 
 
 
X 
X 
Diet and exercise counseling12 
X 
X 
X 
X 
X 
X 
X 
 
Establish Patient Eligibility 
 
X 
 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
IWRS Contact1213 
X 
X 
 
X 
 
 
X 
X 
Single-blind Drug Dispensing 
 
X 
 
 
 
 
 
 
Double-blind Drug Dispensing 
 
 
 
X 
 
 
X 
 
Drug Return/Compliance 
 
 
X 
X 
X 
 
X 
X 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 152 of 153 
 
NOTE: For patients who withdraw from study drug treatment, but consent to be followed for safety assessments and return to 
clinic for these visits, the visits will occur according to the protocol schedule.  Safety assessments should include clinical safety 
and basic lipid laboratories (except for apoB and hs-CRP), adverse events (AEs), physical examination (PE), vital signs, and 
electrocardiograms (ECGs).  For patients who withdraw from study drug treatment, but consent to be followed for safety 
assessments by phone, the telephone contacts will occur according the protocol schedule with information regarding current 
health status and to collect information on AEs (eg, recent procedures, hospitalizations, and if the patient has died, the cause of 
death).  If a patient does not provide consent to be followed for safety assessments per the protocol (either by returning to clinic 
or by phone), Visit T5 will be considered the End of Study (EOS)/Early Withdrawal from study and no further visits will be 
scheduled. 
1 An optional basic fasting (minimum of 10 hours) lipid TG assessment MAY be completed between Visit S1 and at Visit S2 
(prior to starting single-blind medication) if patient fails to meet lipid TG entry criterion at Visit S1.  If this optional basic fasting 
lipid TG is completed, the mean of the first value and the repeat value will be used to determine eligibility.  
2 A recheck of blood pressure may be completed between Visit S1 and at Visit S2 if the patient’s DBP and/or SBP meet the 
exclusion criteria levels.  Patients may randomize after blood pressure medications have been adjusted, the patients have been on 
stable doses of blood pressure medications for at least 2 weeks, and the repeat blood pressure values (diastolic blood pressure 
[DBP] and/or systolic blood pressure [SBP]) do not meet exclusionary values.  Repeat labs may be completed at Visit S2 to 
determine eligibility if the patient’s estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) or other labs meet exclusion criteria levels.  If this optional lab is completed, the repeated value will be 
used to determine eligibility. 
3 All procedures will be completed for all patients at either EOS if completing the study or early withdrawal. 
4 Body weight will be measured while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).   
5 Single 12-lead ECG will be performed prior to any blood sample collection. 
6 Vital signs will include DBP, SBP, heart rate (HR) and will be collected prior to any blood sample collection.  Patient will rest 
for 5 minutes prior to assessments. 
7 Serology for HBsAg, HCV-ABVivi. 
8 Pregnancy test completed in women of child-bearing potential only. FSH in naturally postmenopausal women ≥1 year without 
menses and <55 years; 
9 Urine pregnancy test completed in women of child-bearing potential only just prior to randomization.  
10 Clinical safety labs include hematology, blood chemistry, and urinalysis at all visits.  A coagulation panel will be completed for 
all patients at Week -5 (Visit S1).  A coagulation panel will be completed only for patients on anti-coagulant therapy at Day 1 
(Visit T1) and 3 to 5 days later.  For these visits, the sample may be analyzed at either the central or a local lab.  Please refer to 
laboratory manual for detailed schedule of tests. 
11 Basic fasting (minimum of 10 hours) lipids include total cholesterol, calculated low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides.  Repeat within 1 week if exceed protocol-specified 
criteria. 
12 Diet and exercise counseling per local and/or regional guidelines for the management of hyperlipidemia. 
13 Interactive web response system (IWRS) contact at either an early withdrawal or an EOS visit to register study discontinuation 
visit date. 
 
CHANGE 37  
REMOVAL OF DATE WITHIN THE BODY OF APPENDIX 2 PAGES 
Location:  
Appendix 2:  Final Date, all pages within Appendix 2 
Original text: 
Final Date: 
25 August 2016 
New text: 
Final Date: 
25 August 2016 
 


Bempedoic Acid 
 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-046 
 
Amendment 1, 10 April 2017 
Confidential 
Page 153 of 153 
CHANGE 38 
SPONSOR’S SIGNATORY CHANGES 
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SAP_001.pdf: 
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ESPERION THERAPEUTICS, INC. 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1002-046 
Page 1 of 48 
STATISTICAL ANALYSIS PLAN 
PROTOCOL 1002-046 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, MULTICENTER STUDY
TO EVALUATE THE EFFICACY AND SAFETY OF BEMPEDOIC ACID (ETC-1002)
180 MG COMPARED TO PLACEBO ADDED TO BACKGROUND LIPID-
MODIFYING THERAPY IN PATIENTS WITH ELEVATED LDL-C WHO ARE STATIN
INTOLERANT 
AUTHOR: 
 
VERSION NUMBER AND DATE: V1.7, 21MAR2018 
Page 1 of 50
NCT number: NCT02988115
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


Page 2 of 50
Author: 
Position: 
. Company: 
-Upon re~iew .of this document, the undersigned approves this version of th~ StatiStical An~ly~IS Plani 
authorizing that the content is acceptable for the reporting of this study. 
Approved· By: 
Position: 
· Company: 
Approved By: 
Position: 
Company: 
Approv~d By: 
Position; 
Company: 
-
or 
designe!! 
Date 


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STATISTICAL ANALYSIS PLAN: PROTOCOL 1002-046 
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Version Number: 
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Version Date: 
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 MODIFICATION HISTORY 
Unique 
Identifier 
for 
this 
Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from 
Previous Authorized Version 
1.0 
07FEB2017 
Not Applicable – First Version 
1.1 
07MAR2017 
Changes requested from client, 
first review.  Added appendices for 
multiple imputation method, AESIs 
and list of TLF for DMC. 
1.2 
14APR2017 
Changes requested from client, 
second review. 
1.3 
24MAY2017 
Changes requested from client, 
added new tables. 
1.4 
10OCT2017 
Make 
relevant 
changes 
from 
reviews of 047 and 048 SAPs and 
shells. 
1.5 
7JAN2018-
28FEB2018 
Make Esperion’s changes resulting 
from review of 048 dry run and 046 
dry run of TLF. 
1.6 
14MAR2018 
Final changes from Esperion 
1.7 
21MAR2018 
Add additional analysis for hsCRP 
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TABLE OF CONTENTS 
1.
INTRODUCTION ...................................................................................................................... 11 
2.
STUDY OBJECTIVES ............................................................................................................... 11 
2.1. 
Primary Objective ...................................................................................................................................... 11 
2.2. 
Secondary Objectives ................................................................................................................................ 11 
2.3. 
Tertiary Objective ...................................................................................................................................... 11 
3.
STUDY DESIGN ........................................................................................................................ 12 
3.1. 
General Description ................................................................................................................................... 12 
3.2. 
Schedule of Events..................................................................................................................................... 12 
4.
PLANNED ANALYSES............................................................................................................. 13 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................... 13 
4.2. 
Final Analysis ............................................................................................................................................. 13 
5.
ANALYSIS SETS ....................................................................................................................... 13 
5.1. 
Safety Analysis Set [SAF] ........................................................................................................................... 13 
5.2. 
Full Analysis Set [FAS] ................................................................................................................................ 13 
5.3. 
Completer Analysis Set [CAS] ..................................................................................................................... 14 
5.4. 
PK Analysis Set [PKS] ................................................................................................................................. 14 
6.
GENERAL CONSIDERATIONS .............................................................................................. 14 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 14 
6.2. 
Baseline ..................................................................................................................................................... 14 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 15 
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6.4. 
Visit Windowing ........................................................................................................................................ 15 
6.5. 
Statistical Tests .......................................................................................................................................... 16 
6.6. 
Common Calculations ................................................................................................................................ 16 
6.7. 
Software Version ....................................................................................................................................... 16 
7.
STATISTICAL CONSIDERATIONS ...................................................................................... 16 
7.1. 
Sample Size................................................................................................................................................ 16 
7.2. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 17 
7.3. 
Multicenter Studies ................................................................................................................................... 17 
7.4. 
Missing data .............................................................................................................................................. 17 
7.5. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 17 
8.
OUTPUT PRESENTATIONS.................................................................................................. 18 
9.
DISPOSITION AND WITHDRAWALS ................................................................................ 18 
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 18 
11.1. 
Derivations ............................................................................................................................................ 19 
12.
MEDICAL AND SURGICAL HISTORY ............................................................................. 19 
13.
CONCOMITANT ILLNESSES ............................................................................................. 19 
14.
CARDIOVASCULAR HISTORY/RISK FACTORS .......................................................... 19 
15.
MEDICATIONS ..................................................................................................................... 20 
15.1. 
Baseline Background Lipid Modifying Therapy ....................................................................................... 20 
16.
ADDITIONAL 
POST-RANDOMIZATION 
ADJUNCTIVE 
LIPID-LOWERING
THERAPY .......................................................................................................................................... 20 
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17.
STUDY MEDICATION COMPLIANCE AND EXPOSURE ............................................. 21 
17.1. 
Derivations ............................................................................................................................................ 21 
18.
EFFICACY OUTCOMES ....................................................................................................... 22 
18.1. 
Primary Efficacy ..................................................................................................................................... 22 
18.1.1. 
Primary Efficacy Variable & Derivation .....................................................................................................22 
18.1.2. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................22 
18.1.3. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................23 
18.2. 
Secondary Efficacy ................................................................................................................................. 23 
18.2.1. 
Key secondary Efficacy Variables & Derivations .......................................................................................24 
18.2.2. 
Other Secondary Efficacy Variables & derivations ...................................................................................24 
18.2.3. 
Sensitivity Analysis of Primary and Key Secondary Efficacy Variables ......................................................24 
18.2.3.1. 
Completer Analysis ...........................................................................................................................24 
18.2.3.2. 
Adjunctive Lipid-modifying Therapy (LMT) Analysis .........................................................................25 
18.2.3.3. 
On-treatment Analysis ......................................................................................................................25 
18.2.3.4. 
Observed Data Analysis ....................................................................................................................25 
18.2.4. 
Subgroup Analysis of Efficacy Variable .....................................................................................................25 
18.3. 
Tertiary Efficacy ..................................................................................................................................... 26 
18.3.1. 
Tertiary Efficacy Variables & Derivations..................................................................................................26 
18.3.2. 
Missing Data Methods for Tertiary Efficacy Variables ..............................................................................26 
18.3.3. 
Analysis of Tertiary Efficacy Variables ......................................................................................................26 
18.3.4. 
Additional analysis ....................................................................................................................................26 
19.
SAFETY OUTCOMES ........................................................................................................... 27 
19.1. 
Adverse Events ...................................................................................................................................... 27 
19.1.1. 
All TEAEs ...................................................................................................................................................27 
19.1.1.1. 
Severity .............................................................................................................................................27 
19.1.1.2. 
Relationship to Study Medication.....................................................................................................27 
19.1.2. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................28 
19.1.3. 
Serious Adverse Events .............................................................................................................................28 
19.1.4. 
Adverse Events Of Special Interest (AESI) .................................................................................................28 
19.1.5. 
Muscle Related Adverse Events ................................................................................................................28 
19.2. 
Deaths ................................................................................................................................................... 28 
19.3. 
Clinical Endpoints .................................................................................................................................. 29 
19.4. 
Laboratory Evaluations .......................................................................................................................... 29 
19.4.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................30 
19.5. 
ECG Evaluations ..................................................................................................................................... 31 
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19.6. 
Vital Signs .............................................................................................................................................. 31 
19.6.1. 
Vital Signs Specific Derivations .................................................................................................................31 
19.7. 
Physical Examination ............................................................................................................................. 31 
19.8. 
Pharmacokinetics .................................................................................................................................. 31 
20.
DATA NOT SUMMARIZED OR PRESENTED ................................................................ 32 
21.
REFERENCES ........................................................................................................................ 32 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUT ........................................... 33 
APPENDIX 2. PARTIAL DATE CONVENTIONS ........................................................................ 40 
APPENDIX 3. LIST OF DMC TABLES, LISTINGS AND FIGURES ......................................... 43 
APPENDIX 4. DETAILS OF MULTIPLE IMPUTATION METHOD ........................................ 45 
APPENDIX 5. LIST OF ADVERSE EVENTS OF SPECIAL INTEREST .................................. 46 
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LIST OF ABBREVIATIONS  
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
apoB 
Apolipoprotein B 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below Limit of Quantification  
Bpm 
Beats per Minute 
C 
Celcius 
CAS 
Completer Analysis Set 
CEC 
Clinical Endpoints Committee 
CI 
Confidence Interval 
cm 
Centimeters 
 
CV 
Cardiovascular; coefficient of variation 
CVD 
Cardiovascular Disease 
DBP 
Diastolic Blood Pressure 
dL 
Deciliters 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FAS  
Full Analysis Set 
HDL-C 
High-density Lipoprotein – Calculated 
HR 
Heart Rate 
hsCRP 
High-sensitivity C-reactive Protein 
IMP 
Investigational Medicinal Product 
ITT 
Intention-to-treat 
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LIST OF ABBREVIATIONS (cont’d) 
kg 
kilograms 
LDL-C 
Low-density Lipoprotein – Calculated 
LDL-M 
Low-density Lipoprotein - Measured 
LMT 
Lipid-modifying Therapy 
LSM 
Least Squares Mean 
LTFU 
Lost to Follow-up 
m 
Meters 
MACE 
Major Adverse Cardiac Events 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Myocardial Infarction 
min 
Minutes 
PK 
Pharmacokinetics 
PMM 
Pattern Mixture Model 
PT 
Preferred Term 
SAF  
Safety Analysis Set 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SE 
Standard Error 
SBP  
Systolic Blood Pressure 
SI 
Systeme International 
SOC 
System Organ Class 
STDM 
Study Data Tabulation Model 
TC 
Total Cholesterol 
TEAE 
Treatment-emergent Adverse Event 
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LIST OF ABBREVIATIONS (cont’d) 
TG 
Triglycerides 
ULN 
Upper Limit of Normal 
ULQ 
Upper Limit of Quantification 
US  
United States 
WHO-DDE World Health Organization – Drug Dictionary Enhanced 
Yrs  
Years 
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1. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis of
efficacy and safety data for Protocol 1002-046. It describes the data to be summarized and
analyzed, including specifics of the statistical analyses to be performed.
This statistical analysis plan (SAP) is based on the original protocol version dated August 25, 2016
and amendment 1 dated March 27, 2017.
2. STUDY OBJECTIVES
2.1. PRIMARY OBJECTIVE 
The primary objective is to assess the 12-week efficacy of bempedoic acid 180 mg/day versus 
placebo in decreasing low-density lipoprotein cholesterol (LDL-C) in statin intolerant patients with 
elevated LDL-C.  
2.2. SECONDARY OBJECTIVES 
The secondary objectives are: 
•
To evaluate the effect of 24-week treatment with bempedoic acid 180 mg/day versus placebo on
LDL-C.
•
To evaluate the effect of bempedoic acid 180 mg/day versus placebo on non-high-density
lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), high-sensitivity C-reactive protein (hs-
CRP), and apolipoprotein B (apoB) after 12 weeks of treatment.
•
To evaluate the 24-week safety and tolerability of bempedoic acid 180 mg/day compared to
placebo.
2.3. TERTIARY OBJECTIVE 
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ESPERION THERAPEUTICS, INC. 
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3DJHRI
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


3. STUDY DESIGN
3.1. GENERAL DESCRIPTION
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group multicenter study that 
will be conducted at approximately 71 clinical sites in North America. Screening Week -5 (Visit S1) will be 
approximately 5 weeks prior to randomization. Eligible patients will return to the clinical site at Week -4 
(Visit S2) to initiate administration of single-blind (patient only) placebo study drug. Eligible patients will 
return at Week -1 (Visit S3) for lipid and safety laboratories and an assessment of tolerability and study 
drug adherence.  Approximately 300 patients with a history of statin intolerance (SI) will be stratified 
based on patient type (primary prevention; secondary prevention) and randomized at Week 0 (Visit T1) 
in a 2:1 ratio to receive either bempedoic acid 180 mg (n = 200) or matching placebo (n = 100) once daily 
for 24 weeks. Randomized patients will return for clinic visits at Week 4 (Visit T2), Week 12 (Visit T4), and 
Week 24 (Visit T5). A phone visit will occur at Week 8 (Visit T3).  
Figure A 1002-046 Study Design 
3.2. SCHEDULE OF EVENTS 
The schedule of events can be found in Section 8.3 of the protocol. 
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4. PLANNED ANALYSES
The following analyses will be performed for this study:
•
Safety analyses for Data Monitoring Committee (DMC) meetings
•
Final Analysis
4.1. DATA MONITORING COMMITTEE (DMC) 
The subset of outputs for the DMC is listed in Appendix 3.  Access to results will be provided by 
Quintiles in a separate unblinding plan. 
4.2. FINAL ANALYSIS 
All final, planned analyses identified in this SAP will be performed by Quintiles Biostatistics 
following Sponsor Authorization of this Statistical Analysis Plan, Database Lock, Sponsor 
Authorization of Analysis Sets and Unblinding of Treatment. 
5. ANALYSIS SETS
Agreement and authorization of subjects included/ excluded from each analysis set will be
conducted prior to the unblinding of the study.
5.1. SAFETY ANALYSIS SET [SAF] 
The Safety Analysis Set (SAF), used for all of the safety summaries, is defined as all randomized 
patients who received at least 1 dose of double-blind study medication. Patients in the SAF will be 
included in the treatment group that they actually received, regardless of their randomized 
treatment. 
5.2. FULL ANALYSIS SET [FAS] 
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 the treatment they actually 
received.  
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5.3. COMPLETER ANALYSIS SET [CAS] 
The Completer Analysis Set (CAS), used for all the primary, and secondary efficacy analysis, is 
defined as patients who completed IMP treatment per the end of treatment CRF page and have 
non-missing week 12 LDL-C value. 
5.4. PK ANALYSIS SET [PKS] 
The PK Analysis Set will include all subjects in the safety analysis set who have at least one non-
missing PK assessment.  These subjects will be evaluated for PK concentration summaries unless 
major protocol deviations are identified during the protocol deviation review or if key dosing or 
sampling information is missing. 
6. GENERAL CONSIDERATIONS
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of 
assessments and events.  
Reference start date is defined as the day of the first dose of study medication (Day 1 is the day of the 
first dose of study medication).  In case the first dose date is missing, randomization date will be used 
instead. 
If the date of the event is on or after the reference date then: 
Study Day = (date of event – reference date) + 1. 
If the date of the event is prior to the reference date then: 
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the 
listings, and Study Day, and any corresponding durations will be presented based on the imputations 
specified in Appendix 2: Partial Date Conventions. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
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reference start date (including unscheduled assessments).  In the case where the last non-missing 
measurement and the reference start date coincide, that measurement will be considered as baseline, 
but Adverse Events (AEs) and medications commencing on the reference start date will be considered 
post-baseline. 
Baseline for calculated LDL-C,
 non-HDL-C,
 and TC is defined as the mean of the values from 
Week -1 (Visit S3) and predose 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 predose 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. 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In the event of a missing value at a scheduled visit, and if an unscheduled visit falls within the protocol-
defined window of that visit (see table below), the value from the unscheduled visit will be used for 
that visit.  
In the case of a retest (same visit number assigned), the later available measurement for that visit will 
be used for by-visit summaries.  
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. VISIT WINDOWING 
Protocol-defined assessments will be “slotted” to study weeks based on collection date and applying 
the rules summarized in the following table.  If there is more than one scheduled visit in a visit 
window, the visit closest to the target date will be used.  If there is a tie between the numbers of days 
from the target date, the visit after the target date will be used.  Unscheduled visits that fall within the 
protocol-defined visit windows will be summarized in the by-visit analyses if there is no scheduled visit 
available.  If there is more than one unscheduled visit within the protocol-defined visit window and no 
scheduled visit available, the unscheduled visit closest to the scheduled visit date will be used.  If there 
is a tie between the numbers of days from the target date, the visit after the target date will be used.   
However, exposure data obtained from the drug accountability and administration CRF will be 
summarized and listed according to nominal visit information 
Visit 
S1 
S2 
S3 
T1 
T2 
T3 
T4 
T5, EOS 
Slotted Study Week -5
-4
-1
0 
4 
8 
12 
24 
Target Study Day 
-35
-28
-7
1 
29 
57 
85 
168 
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Visit Windows 
[-∞,-32] [-31,-18] [-17,-1] [1,1] [2,43] [44,71] [72,127] [128,∞] 
6.5. STATISTICAL TESTS 
The default significance level will be (5%); confidence intervals will be 95% and all tests will be two-
sided, unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
•
Test Value at Visit X – Baseline Value
Percent change from baseline will be calculated as: 
•
[(Test Value at Visit X – Baseline Value)/Baseline Value] x 100
6.7. SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher. 
7. STATISTICAL CONSIDERATIONS
7.1. SAMPLE SIZE 
The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in LDL-C. 
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7.2. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED 
IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 
•
treatment group (bempedoic acid 180 mg/day; placebo)
•
baseline laboratory value of interest
•
CVD risk category (primary prevention; secondary prevention)
•
treatment by subgroup interaction term for subgroup analyses of efficacy variables
7.3. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in North America. 
7.4. MISSING DATA 
Missing efficacy data will be handled as described in section 18.1.2 of this analysis plan. 
7.5. MULTIPLE COMPARISONS/ MULTIPLICITY 
In terms of controlling the overall Type I error rate, a gatekeeping or stepdown approach will be used to 
test the primary efficacy endpoint and then specific secondary efficacy endpoints sequentially in order to 
preserve the study-wise Type I error rate. The sequence for the stepdown procedure in this study is as 
follows:  
1. Test the primary efficacy endpoint: percent change from baseline to Week 12 in LDL-C
2. Test the percent change from baseline to Week 24 in LDL-C
3. Test the percent change from baseline to Week 12 in non-HDL-C
4. Test the percent change from baseline to Week 12 in TC
5. Test the percent change from baseline to Week 12 in apoB
6. Test the percent change from baseline to Week 12 in hsCRP
In this hierarchical testing structure, each hypothesis is tested at a significance level of 0.05, two-
sided. Statistical significance at each step is required in order to test the next hypothesis. If the 
primary endpoint meets the criteria for statistical significance, then the percent change from 
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baseline to Week 24 in LDL-C will be tested; and so forth. 
8. OUTPUT PRESENTATIONS
Appendix 1 shows conventions for presentation of data in outputs.
The templates provided with this SAP describe the presentations for this study and therefore the
format and content of the summary tables, figures and listings to be provided by 
Biostatistics.
9. DISPOSITION AND WITHDRAWALS
All patients who were screened will be accounted for in this study.  Reasons for screen failure will
be summarized by pre-defined categories per CRF.  For screen failure due to inclusion and
exclusion criteria, the criteria category will be presented.  Patient disposition and withdrawals
(both from study treatment and the study), will be presented for the FAS.  The number of patients
in each analysis set will be presented for all randomized patients.
10.
PROTOCOL DEVIATIONS
All protocol deviations will be provided in a listing with type and description. Major protocol deviations 
will be summarized by treatment group. The protocol deviations are recorded and tracked in the trial 
monitoring platform CTMS.   
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be presented for the FAS and CAS. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
•
Age (years) - calculated relative to date of randomization
•
Age category (<65 years vs. ≥65 years and < 75 years vs. ≥75 years)
•
Gender
•
Race
•
Ethnicity
•
CVD risk category (primary prevention; secondary prevention)
•
Region (US vs. Canada)
•
Weight (kg)
•
Height (cm)
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•
BMI (kg/m2)
•
BMI category (< 25 vs. 25 - < 30 vs. ≥ 30 kg/ m2)
•
Baseline Laboratory Results (Total Cholesterol, LDL-C, HDL-C, Triglycerides, Non-HDL-C, ApoB,
and hsCRP)
•
Baseline LDL-C category (<130 mg/dL, ≥130 and < 160 mg/dL, or ≥160 mg/dL)
•
Background lipid modifying therapy use (Statin vs. Non-statin vs. None)
•
History of diabetes (Yes vs. No)
•
History of hypertension (Yes vs. No)
•
Baseline Vital Signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate
(HR)
•
Alcohol consumption
•
Tobacco use
11.1. DERIVATIONS 
•
Age (years) = (date of randomization – date of birth)/365.25
•
BMI (kg/ m2) = weight (kg)/ height (m)2
12.
MEDICAL AND SURGICAL HISTORY
Medical and Surgical History information will be presented by MedDRA SOC (System Organ Class) 
and PT (Preferred Term) for the FAS.  Medical History conditions are defined as those conditions 
which stopped prior to or at Screening.  Medical and Surgical History will be coded using MedDRA 
Version 20.1. 
13.
CONCOMITANT ILLNESSES
Concomitant Illnesses will be presented by SOC (System Organ Class) and PT (Preferred Term) for 
the FAS.  Concomitant Illnesses are conditions (other than the indication being studied) which 
started prior to the date of randomization and are ongoing at the date of randomization.  
Concomitant Illnesses will be coded using MedDRA Version 20.1. 
14.
CARDIOVASCULAR HISTORY/RISK FACTORS
Cardiovascular history/risk factors collected at screening will be presented in a table by treatment 
group and in a data listing. 
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15.
MEDICATIONS
Prior and concomitant medications will be presented for the SAF and coded using the September 
2017 version of the World Health Organization Drug Dictionary Enhanced (WHO-DDE).  Tables 
excluding lipid-modifying therapies will be presented.   
Prior and concomitant lipid modifying therapy including statin (less than low dose) and others will 
be tabulated and listed separately.  See protocol section 7.3.1 for the list of LMT allowed in the 
study. 
Medications will be summarized by ATC classification and preferred term by treatment group.  
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior or concomitant to treatment, the medication will be classified by the 
worst case, i.e. concomitant.  
Prior medications are medications which started and stopped prior to the first dose of double-
blind study medication.  
Concomitant medications are medications that patients are taking at the time of first dose of 
double-blind medication or started during the study, which means: started prior to, on or after the 
first dose of double-blind study medication and no later than 30 days following the end of study 
medication, and ended on or after the date of first dose of study medication or were ongoing at 
the end of the study. 
15.1.BASELINE BACKGROUND LIPID MODIFYING THERAPY 
Baseline background Lipid modifying therapy is defined as any lipid modifying agents that are on-
going at the time of randomization.  It will be presented in separate tables and listings by category 
(as defined in protocol section 7.3.1) and coded medication name and by treatment group. 
16.
ADDITIONAL POST-RANDOMIZATION ADJUNCTIVE LIPID-LOWERING THERAPY
The number and percent of patients in each treatment group requiring additional (post-
randomization) lipid-lowering therapy will be summarized by treatment group as well as provided 
in a listing. The lipid-lowering therapy includes all post-randomization concomitant medications 
based on ATC class 2 = lipid-modifying agent.   
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17.
STUDY MEDICATION COMPLIANCE AND EXPOSURE
Compliance to study medication will be presented for the SAF.  At visits Week -1 (S1), Week 0 (T1), and 
each patient visit during the study, clinical site staff will count the number of tablets that are returned as 
unused and query the patient with regards to daily intake.  
17.1. DERIVATIONS 
Compliance with placebo-run in (as an overall group) and double-blind study medication by 
treatment group—based on the drug accountability data—will be calculated as the number of 
tablets taken (total dispensed – total returned) divided by the number of days on treatment within 
each of the 2 periods. 
During the run-in period, the compliance will be summarized as a single overall group and during 
the double-blind period, compliance will be summarized by treatment group (bempedoic acid and 
placebo).  
Compliance will not be computed by visit. 
A 35-day supply of single-blind placebo drug will be dispensed one time at Week -4 (Visit S2) for 
the 4-week placebo run-in period of the study. Double-blind IMP will be dispensed in 100 day 
supply increments to patients by appropriate clinical site personnel. Patients will receive one 100-
day supply bottle at Week 0 (Visit T1)). 
The treatment is taken once daily and it is assumed that the patient takes medication on the visit 
day at which their medication is initially dispensed to the date of last dose as captured on the End 
of Treatment eCRF page.  For example, if the initial dispense date is Day 1 and the last dose is Day 
84, then the patient should have taken the first tablet at Day 1, once a day on Days 2 to 83 and 1 
tablet on Day 84; hence, the total number of prescribed tablets would be 84.   
For subjects who did not return any bottle during the double-blind period, their compliance will be 
set to missing.  
Treatment exposure will be calculated in weeks as (date of last dose of study medication – first 
date of first dose of study medication +1)/7.  Descriptive statistics will be presented for exposure 
as well as categorization into time periods (e.g., <12weeks, >=12 weeks to <24 weeks, >=24 weeks, 
etc.). 
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18.
EFFICACY OUTCOMES
18.1. PRIMARY EFFICACY 
18.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy endpoint is the percent change from baseline to Week 12 in LDL-C.  Baseline LDL-C 
is defined as the mean of the LDL-C values from Week -1 (Visit S3) and predose Day 1/Week 0 (Visit T1). 
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. 
18.1.2. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE
The null hypothesis, H0, will be that there is no difference between bempedoic acid 180 mg/day 
and placebo in mean percent change from baseline to Week 12 in LDL-C. The alternative 
hypothesis, H1, will be that bempedoic acid 180 mg/day is different from placebo: 
H0: µp = µb
H1: µp ≠ µb 
where µp and µb denote the mean percent change from baseline to Week 12 in LDL-C on placebo 
and bempedoic acid 180 mg/day respectively. 
The primary efficacy endpoint will be analyzed using analysis of covariance (ANCOVA), with 
treatment group and stratification factor patient type as factors and baseline LDL-C as a covariate. 
To account for the likelihood of unequal variances between the treatment groups, the ANCOVA 
model will be implemented within mixed model framework and the <repeated/group=> option will 
be used to allow estimating the residual variances separately between the groups.  Model 
assumptions for performing  ANCOVA will be assessed and if the assumptions are severely 
violated, non-parametric methods will be performed. 
In addition, descriptive statistics will be presented for LDL-C at each visit and for change from 
baseline and % change from baseline. 
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18.1.3. MISSING DATA METHODS FOR PRIMARY EFFICACY
VARIABLE 
For the primary endpoint of percent change from baseline to Week 12 in LDL-C values, a pattern 
mixture model (PMM) will be used to specify different imputation strategies depending on 
whether the patient is still on study treatment. Patients with missing lipid data at Week 12 who 
are no longer taking study treatment (defined by date of last dose of study medication is < Week 
12 lab assessment date -7) can be assumed to no longer be benefitting from study medication, and 
their missing value(s) can be assumed to be similar to those in placebo group who remained on 
study and have data. To account for uncertainty, missing values will be imputed using multiple 
imputation via a regression based model including stratification and baseline data from placebo 
subjects only.  In this imputation model, treatment group will not be included as a factor. 
Patients with missing lipid data at Week 12 who are still taking study treatment (date of last dose 
of study medication is ≥ Week 12 lab assessment date -7) can be assumed to continue to benefit 
from study medication, and their missing value(s) can be assumed to be similar to those who 
remain on study treatment and have data and as a result, lipid values will be imputed based on the 
observed values in their randomized treatment group at Week 12. To account for uncertainty, 
missing values will be imputed using multiple imputation via a regression based model including 
treatment, stratification and baseline value.    
Imputed datasets will be analyzed using the same ANCOVA model with treatment and 
stratification as factors and baseline LDL-C as a covariate descried in section 18.1.2. Approximately 
200 imputed datasets will be created, with results from the analysis of each imputed dataset 
combined using Rubin’s method. The least squares mean (LSM) and standard error (SE) will be 
provided for both treatment groups, along with the placebo-corrected LSM, its 95% confidence 
interval (CI) and associated p-value.  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 variance between 
the groups. 
Further information on the multiple imputation method is presented in Appendix 4. 
18.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the full analysis set (FAS). 
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18.2.1. KEY SECONDARY EFFICACY VARIABLES &
DERIVATIONS 
The key secondary endpoints, which are included in the hierarchical analysis described in Section 
7.5, are: 
•
percent change from baseline to Week 24 in LDL-C
•
percent change from baseline to Week 12 in non-HDL-C
•
percent change from baseline to Week 12 in TC
•
percent change from baseline to Week 12 in apoB
•
percent change from baseline to Week 12 in hsCRP.
Key secondary endpoints of LDL-C, non-HDL-C, TC, and apoB will be analyzed using the same 
ANCOVA model described in 18.1.2.   
Similar to the primary endpoint, missing data will be imputed using multiple imputation method as 
described in 18.1.3.   
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.  
Graphic presentations (mean+/-SE) or median (IQR) for efficacy parameters will be provided. 
18.2.2. OTHER SECONDARY EFFICACY VARIABLES &
DERIVATIONS
Other secondary efficacy endpoints are: 
•
Change from baseline to Week 12 in LDL-C
•
Change from baseline to Week 24 in LDL-C.
The absolute change in LDL-C at week 12, 24 will be summarized using descriptive statistics. 
18.2.3. SENSITIVITY ANALYSIS OF PRIMARY AND KEY
SECONDARY EFFICACY VARIABLES 
18.2.3.1. 
 Completer Analysis 
The completer analysis set (CAS) will be used as a sensitivity analysis for all primary and key 
secondary efficacy endpoints.  There will be no imputation for missing data. 
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18.2.3.2. 
Adjunctive Lipid-modifying Therapy (LMT) Analysis 
To explore the potential impact from adjunctive lipid-modifying therapy use during the study, a 
sensitivity analysis will be performed for primary and key secondary endpoints using data prior to 
the change of the post-baseline LMT only, i.e., lab test date <=change date of LMT.  There will be 
no imputation for missing data. 
18.2.3.3. 
On-treatment Analysis 
An on-treatment analysis will also be conducted for primary and key secondary endpoints using 
data collected from the on-treatment period, i.e. lab test date <= of last dose of double-blind 
IMP+7 days.   On-treatment analysis will be based on FAS.  There will be no imputation for missing 
data. 
18.2.3.4. 
Observed Data Analysis 
The observed case data with no imputation for missing data will be used in sensitivity analyses for 
primary and key secondary endpoints. 
18.2.4. SUBGROUP ANALYSIS OF EFFICACY VARIABLE 
The primary endpoint for LDL-C will be analysed within subgroups below using the same analysis 
method previously described.   The treatment and subgroup interaction will be examined by including 
the 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 is 
too small, e.g. less than 5% of the overall population, the analyses may not be performed or the 
subgroup levels may be combined.  Forest plots for the primary efficacy variable will also be 
presented. 
•
CVD risk category (primary prevention; secondary prevention)
•
Baseline LDL category (<130mg/dL, ≥130 mg/dL and < 160 mg/dL, ≥160mg/dL )
•
History of diabetes (yes vs.no)
•
Age (< 65 yrs. vs. ≥65 yrs. and <75 yrs vs. ≥75 yrs)
•
Race (White vs. Non-White))
•
Gender  (male vs. female)
•
BMI category (< 25 vs. 25 - < 30 vs. ≥ 30 kg/ m2)
•
Background lipid modifying therapy (statin vs. non-statin vs. none)
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18.3. TERTIARY EFFICACY 
18.3.1. TERTIARY EFFICACY VARIABLES & DERIVATIONS 
The tertiary efficacy endpoints are: 
18.3.2. MISSING DATA METHODS FOR TERTIARY EFFICACY
VARIABLES 
No missing data imputation will be performed for the tertiary endpoint analyses, only observed 
data will be used. 
18.3.3. ANALYSIS OF TERTIARY EFFICACY VARIABLES 
18.3.4. ADDITIONAL ANALYSIS 
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19.
SAFETY OUTCOMES
All outputs for safety outcomes will be based on the Safety Analysis Set. 
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section.  
19.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA, Version 20.1. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity after the first dose of IMP (double-blind study medication) and prior to the last dose date 
of double-blind study medication + 30 days. AEs that occurred on day 1 will be only be determined 
as TEAE if the site indicated it occurred after first dose on the AE CRF.  
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define 
an AE as treatment emergent or not, the AE will be classified by the worst case, i.e. treatment 
emergent.  
An overall summary of number of subjects within each of the categories described in the sub-
section below, will be provided as specified in the templates.  Listings will include TEAEs and Non-
TEAEs. 
19.1.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and 
also broken down further by maximum severity and relationship to study medication.  Adverse 
events by the subgroups in Section 18.2.4 with the exception of baseline LDL subgroup will also be 
presented. 
19.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first 
dose of IMP with a missing severity will be classified as severe. If a patient reports a TEAE more 
than once within that SOC/ PT, the AE with the worst case severity will be used in the 
corresponding severity summaries. 
19.1.1.2. 
Relationship to Study Medication 
Relationship to IMP, as indicated by the Investigator, is “not related” if the TEAE is “not related” or 
“unlikely”.  A ”related” TEAE is defined as a TEAE with a relationship of ”possibly related”, 
”probably related”, or “definitely related” to study medication. TEAEs with a missing relationship 
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to study medication will be regarded as ”probably related” to study medication. If a patient 
reports the same AE more than once within that SOC/ PT, the AE with the worst case relationship 
to study medication will be used in the corresponding relationship summaries.  
19.1.2. TEAES LEADING TO DISCONTINUATION OF STUDY
MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the 
response of ‘Drug Withdrawn/Permanently discontinued’ on the Action Taken with Study Drug 
Field on the AE eCRF page.  For TEAEs leading to discontinuation of study medication, summaries 
of incidence rates (frequencies and percentages) by SOC and PT will be summarized. 
19.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ‘serious’ on the adverse events page of the 
eCRF.  Summaries of serious TEAEs and serious related TEAEs by SOC and PT will be prepared. 
19.1.4. ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
Adverse events of special interest will be identified by pre-specified MedDRA preferred terms 
provided by Esperion Therapeutics Inc. (see Appendix 5).  These events will be summarized by AESI 
category, SOC and PT. All AESI will be summarized by severity and relationship to study 
medication.  In addition, AESI will be evaluated by monitoring safety labs as detailed in section 
19.4. 
19.1.5. MUSCLE RELATED ADVERSE EVENTS
Muscle related events as reported on the general AE CRF will be summarized by maximum severity 
and SOC and PT.  All muscle related events and details associated with it including cause and 
location will be provided in a listing. 
19.2. DEATHS 
If any patient dies during the study, as recorded on the Death Event page of the eCRF, the 
information will be presented in a data listing.  Deaths will be categorized as cardiovascular (CV) 
death (MACE) or non-CV death (non-MACE).   
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19.3.CLINICAL ENDPOINTS 
Clinical endpoints will be monitored and adjudicated by an independent blinded expert CEC for 
this study.  The following clinical endpoints will be tabulated: 
x
CV death (MACE)
x
Nonfatal myocardial infarction [MI] (MACE)
x
Nonfatal stroke (MACE)
x
Hospitalization for unstable angina (MACE)
x
Coronary revascularization (MACE)
x
Non-coronary arterial revascularization (non-MACE)
x
Hospitalization for heart failure (non-MACE)
x
Non-CV death (non-MACE)
Additional details regarding clinical endpoints and clinical endpoint definitions will be included in 
CEC charter.  The number of incidences and percentage of patients with each positively 
adjudicated outcome will be presented in a table. Only treatment emergent positively adjudicated 
events will be presented in the summary table.  All adjudicated events will be included in a listing. 
19.4.LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, 
Blood Chemistry, Lipids, Coagulation, HbA1c, hsCRP and Urinalysis. A list of laboratory assessments 
to be included in the outputs is included in Protocol, Section 10.1.6.1.  
Presentations will use SI Units and conventional units. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted 
to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or 
“> X” in the listings. 
The formula to calculate eGFR is:  eGFR = 186 x (Creatinine / 88.4)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.210 if black), where creatinine is in mmol/L. 
Summaries for all lab results, including unscheduled visit values, will be included for below 
analyses: 
x
Observed and change/percent change from baseline by visit (for quantitative measurements).
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•
Observed and change/percent change from baseline for HbA1c and glucose by history of
diabetes and visit.
•
Shift from baseline by visit according to normal ranges.
•
Shift from baseline according to normal ranges for HbA1c and glucose by history of diabetes
and visit.
•
eGFR and values of CK will be summarized by treatment group and by baseline eGFR
categories (low, normal, high).
•
Potential Hy’s law cases (>3 × ULN for ALT and/or AST with concurrent Total Bilirubin >2 × ULN)
will be  tabulated listed.
•
Laboratory abnormalities in parameters of interest
ALT or AST (> 3x ULN , >5xULN)
TB (>2x ULN)
CK (> 5x ULN) and (>10x ULN)
Fasting Blood Glucose (≤50 mg/dL,  ≥126 mg/dL) by history of diabetes
HbA1c (≥6.5%) by history of diabetes
Creatinine (change from baseline for >1 mg/dL  )
eGFR (< 15 mL/min/1.73m2, 15 –< 30 mL/min/1.73m2)
Hgb (decrease from baseline for ≥2 g/dL)
Hgb (<8 g/dL)
19.4.1. LABORATORY REFERENCE RANGES AND MARKEDLY
ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as: 
•
Low: Below the lower limit of the laboratory reference range.
•
Normal: Within the laboratory reference range (upper and lower limit included).
•
High: Above the upper limit of the laboratory reference range.
In addition to the high and low quantitative laboratory assignments, Hy’s law criteria (≥3 × ULN for 
either ALT or AST, with accompanying total bilirubin >2 × ULN in the absence of other known 
causes) will be used to identify potential Hy’s law cases. 
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19.5. ECG EVALUATIONS 
The Investigator’s judgment of overall assessment of ECG (Normal, Abnormal, Not Clinically 
Significant [ANCS], and Abnormal, Clinically Significant [ACS]) will be recorded at baseline and end 
of study.  A summary of shift from baseline to end of study in overall assessment will be provided. 
19.6. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
•
Sitting Systolic Blood Pressure (mmHg)
•
Sitting Diastolic Blood Pressure (mmHg)
•
Sitting Heart Rate (bpm)
•
Weight (kg)
•
Height (cm) (at Screening only)
•
BMI (kg/m2) (calculated automatically by the EDC system)
The following summaries will be provided for vital signs data: Observed and change from baseline 
by visit.  
19.6.1. VITAL SIGNS SPECIFIC DERIVATIONS
Blood pressure is taken twice five minutes apart at each vital sign collection.   Blood pressure will be 
analyzed as the average of these two measurements.   If there is only 1 measurement, that 
measurement will be used. 
19.7. PHYSICAL EXAMINATION 
Abnormalities in physical examinations will be presented in a listing. 
19.8. PHARMACOKINETICS 
Descriptive statistics for concentrations of bempedoic acid and its metabolite ESP15228 will be 
presented for each visit weeks 4, 8, and 12 if the PK sample time is within 18-30 hours of the last dose of 
IMP.  All concentration data will also be presented in a listing.  All concentrations below the limit of 
quantification or missing data will be labelled as such in the concentration data listings. Concentrations 
below the lower limit of quantification will be treated as zero in summary statistics. 
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20.
DATA NOT SUMMARIZED OR PRESENTED
The other variables and/or domains not summarized or presented are: 
•
Comments
•
Variables used by the data entry system to direct user to proper page (e.g., patient visit
status, patient health status)
•
Inclusion/Exclusion Criteria that are not violated
•
Normal Physical Examination Results
•
Diet and Exercise Counselling
•
Normal PE findings
These domains and/or variables will not be summarized or presented, but will be available in the 
clinical study database, SDTM and/or ADaM datasets.
21.
REFERENCES
ICH E9. E9 Statistical Principles for Clinical Trials. Federal Register. 1998; 63(179):49583-49598. 
Little, R. & Rubin,  D.(1987) Statistical Analysis with Missing Data, Wiley, New York.  
Ratitch, B. and O’Kelley, M., “Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures,” in Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS Users Group), 
SP04, 
Nashville. 
O'Brien, Peter C., and Thomas R. Fleming. "A multiple testing procedure for clinical trials." 
Biometrics (1979): 549-556. 
Demets, David L., and K. K. Lan. "Interim analysis: the alpha spending function approach." Statistics 
in medicine 13.13‐14 (1994): 1341-1352. 
Brendan M.Everett, TobiasKurth, 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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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUT 
Quintiles Output Conventions 
File names should only consist of uppercase letters, lowercase letters, digits (0 to 9) and underscores. A 
period should only be used to indicate a separator between the file name and the extension. No spaces, 
other special characters or punctuation marks are permitted. 
As far as possible, output files should be in RTF format, although .DOC files are also permitted. 
The program, program log and output file name should reflect the type and number of the statistical 
output. If this is not possible, then the output name should be at least as descriptive as possible. A prefix 
can be used to distinguish between a Table, Listing and Figure document (‘T’ for table, ‘L’ for listing and 
‘F’ for figure). If there is only 1 digit in the number of the table, listing or figure in the place where 2 digits 
are possible, a leading zero should be added in the file name to make sorting consistent with the 
sequence (eg T14_3_01_1.RTF). 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter for the United States, otherwise A4. 
The page orientation should preferably be landscape, but portrait is also permitted. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless 
of the paper size. 
The number of columns per page (linesize) should be 145 for A4 and 134 for Letter. 
The number of rows per page (pagesize) should be 49 for A4 and 51 for Letter. 
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FONTS 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The 
font color should be black. No bolding, underlining italics or subscripting should be permitted. Try to 
avoid using super-scripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times Roman”, “Helvetica”, or “Courier New” . 
This can be achieved by using the following options in SAS: 
goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 
ftext = "TimesRoman" 
htext = 2.5 
device = cgmof97l 
gaccess = gsasfile; 
filename gsasfile "….cgm"; 
HEADER INFORMATION 
Headers should be defined as follows: 
• The header should be placed at the top of the page (same place on each page) regardless of the size or
orientation of the table or listing
• The customer name and protocol number should appear in row 1, left-aligned
• The output identification number should appear in row 2, centered
• The output title should start in row 3, centered
• The output population should appear in row 4, centered. The population should be spelled out in full,
e.g. Intention-to-Treat in preference to ITT.
• Row 5 should be a continuous row of underscores (‘_’) (the number of underscores should equal the
linesize)
• Row 6 should be a blank line
• Mixed case should be used for titles
• The output titles should be designed so that they are arranged consistently through all outputs. For
example, content (eg Vital Signs) followed by metric (eg Change from Baseline) e.g. Vital Signs –
Change from Baseline. 
• Titles should not contain quotation marks or footnote references
• The column headings should be underlined with a row of underscores (‘_’)
• Column headings spanning more than one column should be underlined and have underscores on
either side of the title and should be centered
• Column headings containing numbers should be centered
• Column headings should be in sentence case
• In general, the population count should appear in the column header in the form “(N=XXX)”
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• “Statistic” should be the column header over n, Mean, SE, n (%) etc.
• As a rule, all columns should have column headings.
TABLE AND LISTING OUTPUT CONVENTIONS
General: 
• The first row in the body of the table or listing should be blank
• The left hand column should start in column 1. No indenting or centering of the output should occur.
• Rounding should be done with the SAS function ROUND.
• Numbers in tables should be rounded, not truncated.
• Alphanumeric output should be left aligned.
• Numbers should be decimal point aligned.
• Whole numbers should be right aligned.
• Text values should be left aligned.
• The first letter of a text entry should be capitalized
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in
chronological order, with earliest adverse event, medication or history coming first.
• The study drug should appear first in tables with treatments as columns
• In general, only present totals (across treatment groups) at baseline/randomization, and do not
present them post randomization, unless the customer specifically requests it.
• If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for
percentage calculations.
• All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number).
• Do not use superscripts and subscripts
• Exponentiation will be expressed using a double asterisk, i.e., mm3 will be written as mm**3.
• All variables that are output in the CRF (which have data present) should appear in the listings, along
with all derived data appearing in the corresponding tables
• The width of the entire output should match the linesize
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Q1, Median, Q3,
Minimum, Maximum)
• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points
should line up. If the minimum and maximum are output on one line as Minimum, Maximum then the
comma should line up with the decimal point. 
• If the original data has N decimal places, then the summary statistics should have the following decimal
places:
Minimum and maximum: N 
Mean, median and CV%: N + 1 
SD: N + 2 
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Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with one space between the count and the left
parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a
value and padded with blank space if the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be
presented as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented as
‘<0.1%’ (e.g., 0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. 
Eg ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the 
denominator is relatively small). 
• Where counts are zero, percentages of 0.0% should appear in the output.
Confidence Intervals: 
• As a rule confidence intervals are output to one place more than the raw data, and standard deviations
and standard errors to two places more than the raw data
• Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table
“line up”.
• Boundary values of confidence intervals should be separated by a comma.
• Boundary values should be padded as necessary to accept negative values and to allow alignment of
the decimal place.
• An example is given below:
(-0.12, -0.10)
( 9.54, 12.91) 
P-values:
• P-values should be reported to three decimal places, except values <1.000 but >0.999 will be presented
as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g.,
0.0009 is presented as <0.001). Rounding will be applied after the <0.001 and >0.999 rule 
Ratios: 
• Ratios should be reported to one more decimal place than the original data.
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2)
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Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to
calculate percentages, there should be a row in the table that identifies that number “n”.
• Alternatively, a footnote should be included in each table with percentages to indicate the
denominator for percentages.
Missing values 
• A “0” should be used to indicate a zero frequency.
• A blank will be used to indicate missing data in an end-of-text table or subject listing.
FIGURE OUTPUT CONVENTIONS
• Figures should be provided in RTF files using the SAS Output Delivery System (ODS), as Computer
Graphics Metafile (CGM) formatted graphical output generated by SAS.
• The CGM file itself should contain the title or footer.
• The image should be clear and of high quality when viewed in the Word document, and when printed.
• In general, boxes around the figures should be used.
FOOTNOTE INFORMATION
Footers should be defined as follows: 
• A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes
at the bottom of the page
• Table footnotes should be defined using compute statements in the proc report, and should appear
directly after the body of the table
• The program path and name and version number (if applicable) should appear as footnote 1 at the
bottom of the page
• The date/time stamp should appear as footnote 2 at the bottom of the page
• Footnotes should be left-aligned.
• Footnotes should be in sentence case.
• Only “typewriter” symbols are permitted – eg “*”, “$”, “#”, “@”, “&” and “+”.
• The choice of footnote symbols should be consistent. E.g. if you have the footnote “# indicates last
observation carried forward” for one table, the same symbol and footnote should indicate LOCF for
all tables. 
• If text wraps across more than one line (for a note), the first letter for all lines of text after the first one
will be indented to align beneath the first letter of the text in the first line.
• The page identification in the format Page X of Y (where Y is the total number of pages for the output)
should appear in the first footnote, right aligned
Ordering of footnotes should be as follows: 
1.) Source data listing reference, if necessary 
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2.) Abbreviations and definitions 
3.) Formulae 
4.) P-value significance footnote 
5.) Symbols 
6.) Specific notes 
• Common notes from table to table should appear in the same order.
• The symbols should appear in the same order as what they are defined in the table or listing, from left
to right.
PROGRAMMING INSTRUCTIONS 
Programming instructions must appear in blue font at the end of each table or listing shell. Programming 
instructions, where necessary, should follow the table or listing shells in blue font, beginning with the 
words “Programming Note” followed by a colon. These include notes on the output, reminders of how to 
handle missing values, repeat shells for similar tables etc. 
Dates & Times 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
Presentation of Treatment Groups 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment 
Group 
For Tables and Graphs 
For Listings 
Placebo 
Placebo 
Placebo 
Bempedoic Acid 
180 mg 
Bempedoic Acid 180 mg 
Bempedoic Acid 180 mg 
Not Randomized 
Not Randomized 
Not Randomized 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name 
Week -5 (Visit S1) 
W-5 (VS1)
Week -4 (Visit S2) 
W-4 (VS2)
Week -1 (Visit S3) 
W-2 (VS3)
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Long Name (default) 
Short Name 
Week 0 (Visit T1) 
W0 (VT1) 
Week 4 (Visit T2) 
W4 (VT2) 
Week 8 (Visit T3) 
W8 (VT3) 
Week 12 (Visit T4) 
W12 (VT4) 
Week 24 (Visit T5) 
W24 (VT5) 
Listings 
All listings will be ordered by the following (unless otherwise indicated in the template): 
•
randomized treatment
•
center-subject ID,
•
date (where applicable),
•
For listings where non-randomized subjects are included, these will appear in a category
after the randomized treatment groups labeled ‘Not Randomized’.
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
Algorithm for Treatment Emergence of Adverse Events: 
START DATE 
ACTION 
Known and 
AESTART=study med 
start date 
If AEPRIOR=Y  then not TEAE 
If AEPRIOR=N then TEAE 
Known and AESTART>or 
< study med start date 
If start date < study med start date, then not TEAE 
If start date > study med start date and <=study med 
end date + 30 , then TEAE 
Partial 
If AEPRIOR=Y then not TEAE 
Otherwise, 
If Impute 1st of month if date is missing; impute 1st of 
Jan if both date and month are missing.   
If resulting imputed start date is prior to study med 
start date, set as study med start date.  If imputed 
start date is <= study med end date + 30 days, then 
TEAE; otherwise NOT TEAE 
Missing 
If AEPRIOR=Y then not TEAE 
Otherwise, 
Assumed TEAE 
Algorithm for Prior / Concomitant Medications:  
Please note that the study med start date is the double-blind med start date. 
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post study  
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START 
DATE 
STOP 
DATE 
ACTION 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
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START 
DATE 
STOP 
DATE 
ACTION 
Missing 
Assign as concomitant 
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APPENDIX 3. 
LIST OF DMC TABLES, LISTINGS AND FIGURES 
TABLES 
14.1.1.1 
Patient Disposition – All Patients 
14.1.2.1a 
Demographic and Other Baseline Characteristics – Full Analysis Set 
14.1.3.1 
Medical/Surgical History – Full Analysis Set 
14.1.3.3 
Targeted Cardiovascular History/Risk Factors – Full Analysis Set 
14.1.5.1 
Study Drug Compliance – Safety Analysis Set 
14.3.1.1 
Overview of Treatment-Emergent Adverse Events – Safety Analysis Set 
14.3.1.2 
Treatment-Emergent Adverse Events by Maximum Severity, System Organ Class and 
Preferred Term – Safety Analysis Set 
14.3.1.3 
Serious Treatment-Emergent Adverse Events by Maximum Severity, System Organ Class 
and Preferred Term – Safety Analysis Set 
14.3.1.4 
Related Treatment-Emergent Adverse Events by Maximum Severity, System Organ Class 
and Preferred Term – Safety Analysis Set 
14.3.1.5 
Related Serious Treatment-Emergent Adverse Events by Maximum Severity, System 
Organ Class and Preferred Term – Safety Analysis Set 
14.3.1.6 
Treatment-Emergent Adverse Events That Led to Discontinuation of Study Drug by 
Maximum Severity, System Organ Class and Preferred Term – Safety Analysis Set 
14.3.1.8 
Treatment-Emergent AESIs by Maximum Severity, System Organ Class and Preferred 
Term – Safety Analysis Set 
14.3.1.15 
Investigator-reported Major Cardiac Events (MACE) by Event Type – Safety Analysis Set 
14.3.1.16 
Adjudicated Major Cardiac Events (MACE) by Event Type – Safety Analysis Set 
14.3.2.8 
Laboratory Parameters of Interest:  Observed and Change from Baseline – Safety 
Analysis Set 
14.3.2.9 
Laboratory Parameters of Interest:  Laboratory Abnormalities – Safety Analysis Set 
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14.3.2.10 
Quantitative Clinical Laboratory Evaluations: Lipids – Safety Analysis Set (note that this 
table is produced for DMC only) 
FIGURES 
14.3.1 
Boxplots of Hematology Parameters 
14.3.2 
Boxplots of Chemistry Parameters 
The next 2 listings will created at the same time frame as DMC TLFs above. However, these 2 listings will 
be sent to Esperion Team only for monitoring thresholds for protocol deviations and for evaluable 
patients, but not sent to DMC members. 
Listing 16.2.3 
Patient Inclusion per Analysis Population – All Screened Patients 
Listing 16.2.4 
Screen Failures – All Screened Patients (note that this listing is produced for DMC only) 
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APPENDIX 4. 
DETAILS OF MULTIPLE IMPUTATION METHOD 
Missing Week 12 values will be imputed based on baseline values.  The following table details the possible cohorts 
and which cohorts will be used for imputation.  Missing Week 24 values will be imputed in the same way. 
Treatment 
Week 12 
Value 
On 
Treatment 
at Week 12 
Imputation Cohort(s) 
1 
Placebo 
Missing 
Yes 
Cohort 5: 
Placebo patients with non-missing 
Week 12 
2 
BA 
Missing 
Yes 
Cohorts 6 and 8 
BA patients with non-missing Week 12 
3 
placebo 
Missing 
No 
Cohort 5: 
Placebo patients with non-missing 
Week 12 
4 
BA 
Missing 
No 
Cohorts 5 and 7 
Placebo patients with non-missing Week 12 and not on 
treatment 
5 
placebo 
Non-missing 
Yes 
6 
BA 
Non-missing 
Yes 
7 
placebo 
Non-missing 
No 
8 
BA 
Non-missing 
No 
Imputation code for Cohorts 1-3. 
proc mi; 
where cohort in(1,2,3,5,6,8); 
  class trt01pn strata; 
  monotone regression; 
  var trt01pn strata base aval; 
run; 
Imputation code for Cohort 4. 
proc mi; 
where cohort in(4,5,7);  
class strata; 
monotone regression; 
  var base strata aval; 
run; 
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Two hundred imputed datasets will be created, with results from the analysis of each imputed dataset 
(ANCOVA) combined using Rubin’s method. 
APPENDIX 5. LIST OF ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse Event Terms per Protocol 
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 disorders 
Alanine aminotransferase abnormal 
Hepatic disorders 
Alanine aminotransferase increased 
Hepatic disorders 
Aspartate aminotransferase abnormal 
Hepatic disorders 
Aspartate aminotransferase abnormal 
Hepatic disorders 
Blood bilirubin abnormal 
Hepatic disorders 
Blood bilirubin increased 
Hepatic disorders 
Hepatic enzyme abnormal 
Hepatic disorders 
Hepatic enzyme increased 
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Adverse Event Terms per Protocol 
Associated MedDRA Preferred Terms 
Hepatic disorders 
Hypertransaminaseaemia 
Hepatic disorders 
Liver function test abnormal 
Hepatic disorders 
Liver function test increased 
Hepatic disorders 
Transaminases abnormal 
Hepatic disorders 
Transaminases increased 
Hypoglycemia 
Blood glucose abnormal 
Hypoglycemia 
Blood glucose decreased 
Hypoglycemia 
Hypoglycaemia 
Hypoglycemia 
Hypoglycaemic coma 
Hypoglycemia 
Hypoglycaemic encephalopathy 
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/Neurologic disorders 
Amnesia 
Neurocognitive/Neurologic disorders 
Cognitive disorder 
Neurocognitive/Neurologic disorders 
Confusional state 
Neurocognitive/Neurologic disorders 
Disorientation 
Neurocognitive/Neurologic disorders 
Memory impairment 
Neurocognitive/Neurologic disorders 
Mental status changes 
Renal disorders 
Acute kidney injury 
Renal disorders 
Acute prerenal failure 
Renal disorders 
Blood creatinine abnormal 
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Adverse Event Terms per Protocol 
Associated MedDRA Preferred Terms 
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 
Gout 
Renal disorders 
Oliguria 
Renal disorders 
Prerenal  failure 
Renal disorders 
Renal failure 
Renal disorders 
Renal function test abnormal 
Renal disorders 
Renal impairment 
Page 48 of 50


 
Esperion Therapeutics, Inc. 
Dec 18, 2018 
Protocol: ETC-1002-046 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 1 of 2 
 
 
Addendum to Statistical Analysis Plan 
Title: 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, 
MULTICENTER STUDY TO EVALUATE THE EFFICACY AND 
SAFETY 
OF 
BEMPEDOIC 
ACID 
(ETC-1002) 
180 
MG 
COMPARED TO PLACEBO ADDED TO BACKGROUND LIPID-
MODIFYING THERAPY IN PATIENTS WITH ELEVATED LDL-
C WHO ARE STATIN INTOLERANT 
Protocol: 
ETC-1002-046 
Clinical Phase: 
3 
Product: 
ETC-1002 
Date: 
Dec 18, 2018  
 
 
 
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Esperion Therapeutics, Inc. 
Dec 18, 2018 
Protocol: ETC-1002-046 
Addendum to Statistical Analysis Plan 
 
Confidential 
Page 2 of 2 
 
Addendum to the Statistical Analysis Plan for Study 1002-046 
Post-hoc Analyses 
Esperion completed the planned analysis as described in Study 1002-046 SAP for all data 
collected in the study.   
After unblinding, some issues of clinical interest were identified. To address these issues, 
post-hoc analyses were performed to summarize the following:  statin related adverse 
events prior to study entry, patients experiencing repeated and confirmed abnormal liver 
function tests after randomization, and percent change from baseline in LDL-C over time 
by background lipid modifying therapy (LMT).  Finally, a sensitivity analysis was 
performed for the primary endpoint with Site 1020 excluded, since this was closed 
prematurely based on administrative and site accessibility issues.   
The listing of tables for the post-hoc analyses is provided in the table below. 
Listing of new Tables for Study 1002-046.  
Table 17.1.1.1 
Statin Related Adverse Effect/ 
Full Analysis Set 
Table 17.2.1.1 
Primary Efficacy Post-hoc Analysis: Percent Change from Baseline in 
Low Density Lipoprotein Cholesterol (LDL-C)/ 
Excluding Site 1021/ 
Full Analysis Set 
Table 17.3.1.1 
Primary Efficacy Post-hoc Analysis: Percent Change from Baseline in 
Low Density Lipoprotein Cholesterol (LDL-C)/ 
By Background Lipid Modifying Therapy Lipid Modifying Treatment 
Subgroup/ 
Observed Data/ 
Full Analysis Set 
Table 17.4.1.1 
Primary Efficacy Post-hoc Analysis: Percent Change from Baseline in 
Low Density Lipoprotein Cholesterol (LDL-C)/ 
By Background Lipid Modifying Therapy Lipid Modifying Treatment 
Subgroup/ 
On-Treatment Analysis/ 
Full Analysis Set 
Table 17.5.1.1 
Post-Randomization Abnormal Liver Function Summary/ 
Safety Analysis Set 
  
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