Conditions: Cardiovascular Diseases Statin Adverse Reaction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13970
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if treatment with bempedoic acid (ETC-1002) versus placebo decreases the risk of cardiovascular events in participants who have or are at high risk for cardiovascular disease and are statin intolerant.

Detailed description:

Arms:
arm 1: Bempedoic acid 180 mg tablet taken orally, once daily. arm 2: Matching placebo tablet taken orally, once daily

Interventions: intervention 1: Bempedoic acid 180 mg tablet intervention 2: Matching placebo tablet
Intervention descriptions: intervention 1: Patients take bempedoic acid 180 mg tablet orally once daily intervention 2: Patients take matching placebo tablet orally once daily

Protocol document:
Prot_000.pdf: 
Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Clinical Study Protocol 1002-043 
Amendment 5, 24 September 2020 
Confidential 
Page 1 of 316 
 
 
 
BEMPEDOIC ACID (ETC-1002) 
1002-043 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO ASSESS THE EFFECTS OF BEMPEDOIC ACID (ETC-1002) ON THE 
OCCURRENCE OF MAJOR CARDIOVASCULAR EVENTS IN 
PATIENTS WITH, OR AT HIGH RISK FOR, CARDIOVASCULAR 
DISEASE WHO ARE STATIN INTOLERANT 
Study Phase: 
3 
IND Number: 
106,654 
EudraCT Number: 
2016-003485-11 
Indication: 
Reduction of cardiovascular disease risk 
Investigators: 
Approximately 1200 sites located in 32 countries 
Sponsor: 
Esperion Therapeutics, Inc. 
3891 Ranchero Drive, Suite 150 
Ann Arbor, MI 48108 
Phone: 1-734-887-3903 
Fax: 1-734-913-5344 
Sponsor Contact: 
, MD, MPH, MSc  
Head of Clinical Development, Medical Affairs, and 
Pharmacovigilance 
Version 
Date 
Original Protocol: 
24 June 2016 
Amendment 1: 
08 February 2017 
Amendment 2: 
15 November 2017 
Amendment 3*: 
17 July 2018 
Amendment 3.1*: 
30 July 2018 
Amendment 4 
19 December 2019 
Amendment 5  
24 September 2020 
* Amendments 3 and 3.1 are identical in content but are versioned separately for administrative reasons.  Amendment 3 applies
to all participating sites in all countries except the United States.  Amendment 3.1 applies to sites from the United States.
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: NCT02993406
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Bempedoic Acid (ETC-1002) 
Clinical Study Protocol 1002-043 
APPENDIX 2. SPONSOR'S SIGNATURES 
Esperion Therapeutics, Inc. 
Amendment 5, 24 September 2020 
Study Title: 
A Randomized, Double-blind, Placebo-Controlled Study to Assess the 
Effects ofBempedoic Acid (ETC-1002) on the Occurrence of Major 
Cardiovascular Events in Patients with, or at High Risk for, 
Cardiovascular Disease who are Statin Intolerant 
Study Number: 
1002-043 
Final Date: 
24 September 2020 
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: 
Drrector, Chmcal Development 
Esperion Therapeutics, Inc. 
Confidential 
Date 
Page 104 of316 


Bempedoic Acid (ETC- I 002) 
Clinical Study Protocol I 002-043 
Esperion Therapeutics, Inc. 
Amendment 5, 24 September 2020 
Study Title: 
Study Number: 
Final Date: 
A Randomized, Double-blind, Placebo-Controlled Study to Assess the 
Effects of Bempedoic Acid (ETC- I 002) on the Occurrence of Major 
Cardiovascular Events in Patients with, or at High Risk for, 
Cardiovascular Disease who are Statin Intolerant 
1002-043 
24 September 2020 
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: 
Director, Biostatistics 
Esperion Therapeutics, Inc. 
Confidential 
Page I 05 of 31 6 


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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 (ETC-1002) 
Title of Study: 
A Randomized, Double-blind, Placebo-controlled Study to Assess the Effects of Bempedoic Acid 
(ETC-1002) on the Occurrence of Major Cardiovascular Events in Patients with, or at high risk for, 
Cardiovascular Disease who are Statin Intolerant 
Study Number:  1002-043 
Phase of Development:  3 
Clinical Sites:  Approximately 1200 sites located in 32 countries 
Objectives: 
Primary: 
• 
To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus placebo 
reduces the risk of major adverse cardiovascular events (MACE) in patients with, or at high 
risk for, cardiovascular disease (CVD) who are statin intolerant.  This will be assessed with a 
composite primary efficacy endpoint that includes time to first occurrence of cardiovascular 
(CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary 
revascularization 
Secondary: 
• 
To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus placebo 
reduces the risk of other clinical endpoints of CV morbidity and mortality and all-cause 
mortality 
• 
To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive 
protein (hs-CRP) 
• 
To evaluate the long-term safety and tolerability of bempedoic acid 180 mg/day compared to 
placebo 
• 
To evaluate the 12-month efficacy of treatment with bempedoic acid 180 mg/day versus 
placebo on absolute change in hemoglobin A1C (HbA1C) in the Inadequately Controlled 
Diabetes Efficacy Population (patients with type 2 diabetes mellitus and having an HbA1C of 
7% or greater at baseline) 
• 
To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus placebo 
reduces the risk of new-onset diabetes 
Tertiary: 
• 
To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), 
high-density-lipoprotein cholesterol (HDL-C), triglycerides (TG), HbA1C and fasting glucose 


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Study Hypotheses: 
This superiority study will test the hypothesis that bempedoic acid, compared to placebo, will reduce 
the risk of CV events in patients with, or at high risk for, CVD who are statin intolerant. 
In addition, it will test the hypothesis that bempedoic acid, compared to placebo, will delay time to 
first occurrence of new-onset diabetes in patients in the prediabetes subpopulation.  It will also test 
the hypothesis that bempedoic acid, compared to placebo, will reduce absolute change from baseline 
to Month 12 in HbA1C in patients in the inadequately controlled diabetes subpopulation. 
Endpoints: 
The following endpoints will be used to evaluate the objectives of the study. 
Primary efficacy endpoint: 
• 
Time to first occurrence of MACE, where MACE is defined as the composite endpoint of CV 
death, nonfatal MI, nonfatal stroke, or coronary revascularization 
Key secondary efficacy time-to-event endpoints: 
• 
Time to first occurrence of the composite endpoint of CV death, nonfatal MI, or nonfatal 
stroke 
• 
Time to first occurrence of (fatal + nonfatal) MI 
• 
Time to first occurrence of coronary revascularization 
• 
Time to first occurrence of (fatal + nonfatal) stroke 
• 
Time to CV death 
• 
Time to all-cause mortality 
Secondary efficacy time-to-event endpoints: 
• 
Time to first occurrence of the composite endpoint of all-cause mortality, nonfatal MI, 
nonfatal stroke, or coronary revascularization 
• 
Time to first occurrence of nonfatal MI 
• 
Time to fatal MI 
• 
Time to first occurrence of nonfatal stroke 
• 
Time to fatal stroke 
• 
Time to first occurrence of (fatal + nonfatal) hemorrhagic stroke 
• 
Time to first occurrence of (fatal + nonfatal) nonhemorrhagic stroke 
• 
Time to hospitalization for unstable angina 
• 
Time to first occurrence of new-onset type 2 diabetes mellitus defined by one or more of the 
following criteria according to the current American Diabetes Association (ADA) guidelines 
(ADA, 2014): 
1. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L).  Fasting is defined as no caloric 
intake for at least 8 hours;* or 
2. Two-hour post-prandial glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose 
tolerance test as defined in the ADA guidelines;* or 
3. HbA1C measurement ≥6.5% (48 mmol/mol);* or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L).  
*Note:  In the absence of unequivocal hyperglycemia, diagnosis requires 2 abnormal test 
results from the same sample or in the 2 separate test results. 


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Secondary efficacy lipid and biomarker endpoints: 
• 
Percent change from baseline to Month 6 in LDL-C 
• 
Percent change from baseline to Month 6 in hs-CRP 
• 
Absolute change from baseline to Month 12 in HbA1C in patients in the inadequately 
controlled diabetes efficacy population (patients with type 2 diabetes mellitus and an HbA1C 
of 7% or greater at baseline) 
Tertiary lipid and biomarker endpoints: 
• 
Percent change from baseline to Months 3, 12, 24, and end-of-study in LDL-C; percent 
change from baseline to Months 3, 6, 12, 24, and end-of-study in HDL-C, non-HDL-C, TC, 
and TG 
• 
Absolute change from baseline to Months 3, 6, 12, 24, and end-of-study in LDL-C 
• 
Percent change from baseline to Month 12 and end-of-study in hs-CRP 
• 
Absolute change from baseline to Month 3, 6, every 6 months following Month 12, and 
end-of-study in HbA1C in patients in the Inadequately Controlled Diabetes Efficacy 
Population (patients with type 2 diabetes mellitus and an HbA1C of 7% or greater at baseline) 
• 
Absolute change from baseline to Month 3, 6, 12, every 6 months following Month 12, and 
end-of-study in fasting glucose in patients in the Normoglycemia Efficacy Population, 
Prediabetes Efficacy Population, No Diabetes Efficacy Population, and Diabetes Efficacy 
Population 
Safety endpoints: 
• 
Adverse events (AEs; including adverse events of special interest [AESI]), vital signs (eg, 
heart rate, weight, blood pressure [BP]), and clinical laboratory measures 
Study Design: 
 
 
 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.  
Screening (Visit S1) will occur approximately 5 weeks prior to Day 1 (Visit T1) but can be extended 
for an additional 5 weeks if needed to adjust background medical therapy or for other reasons.  All 
eligible patients will return at Week -4 (Visit S2) to initiate a 4-week Run-in Period with single-blind 
(blinded to patient only) placebo once daily that will include assessment of tolerability and 
investigational medicinal product (IMP) adherence.  On Day 1 (Visit T1), approximately 
14,000 eligible patients will be randomized 1:1 to receive either double-blind bempedoic acid 180 mg 
(n = 7000) or placebo (n = 7000) once daily. 
Randomized patients will return for clinic visits at Month 1 (Visit T2), Month 3 (Visit T3), and 
Month 6 (Visit T4).  Following Month 6, patients will be contacted every 3 months (alternating with a 
phone visit and a clinic visit) for the remainder of the study.  The study will continue until all of the 


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following have occurred:  1) at least 1620 patients have experienced an adjudicated primary 
4-component MACE [CV death, nonfatal MI, nonfatal stroke, or coronary revascularization], 2) at 
least 810 patients have experienced an adjudicated 3-component MACE [CV death, nonfatal MI, or 
nonfatal stroke] and 3) 24 months have elapsed since the last patient was randomized.  It is estimated 
that median treatment duration for all randomized patients will be approximately 3.5 years.  For each 
patient, the last treatment visit will be a clinic visit, with a follow-up phone call approximately 
30 days after study treatment completion.  Patients who discontinue IMP for any reason will remain 
in the study to be evaluated for efficacy and safety endpoints and will be expected to continue study 
visits (preferred) or agree to some other form of contact with the site for the remainder of the study.  
For details of study assessments, see the Schedule of Events in Appendix 1. 
This study will include several independent and expert committees.  An Executive Committee (EC) 
will oversee the design and conduct of the study and the interpretation of study results.  A Clinical 
Events Committee (CEC) will adjudicate blinded clinical endpoints, including MACE endpoints, as 
well as non-CV deaths using standardized definitions.  An adjudicated clinical endpoint will not be 
reported as a serious adverse event (SAE).  A Diabetes Committee (DC) will verify diagnosis of 
new-onset diabetes.  A Tendon Rupture Adjudication Committee (TRAC) will adjudicate events of 
tendon rupture using standardized definitions.  An independent Data Monitoring Committee (DMC) 
will review accumulating blinded and unblinded safety data from this and other ongoing studies of 
bempedoic acid approximately 4 times per year.  Safety data reviewed by the DMC will include AEs, 
clinical endpoints, and lipids.  Each of these committees has a charter that includes additional details. 
Number of Patients (Planned):  Approximately 14,000 adult male and female patients. 
Duration of Treatment:  It is estimated the median treatment duration will be approximately 
42 months (3.5 years), with all patients remaining in the study for a minimum of 24 months (2 years) 
and some patients remaining in the study for up to approximately 72 months (6 years). For each 
patient, the actual duration of treatment will depend on time of randomization versus when the ‘End 
of Study’ conditions below have been met.  
End of Study:  The study will end when all of the following have occurred: 1) at least 1620 patients 
have experienced an adjudicated primary 4-component MACE, 2) at least 810 patients have 
experienced an adjudicated 3-component MACE (CV death, nonfatal MI, nonfatal stroke), and 3) at 
least 24 months (2 years) have elapsed since the last patient was randomized. The estimated overall 
duration of the study (first patient first visit to last patient last visit) is approximately up to 72 months 
(6 years). 
Inclusion and Exclusion Criteria: 
Each patient must meet the following criteria to be eligible for this study. 
Subject Inclusion Criteria: 
1. Provision of signed informed consent prior to any study-specific procedure. 
2. Patient-reported statin intolerance (SI) due to an adverse safety effect that started or increased 
during statin therapy and resolved or improved when statin therapy was discontinued 
resulting in an inability to tolerate: 
• 
2 or more statins at any dose, or 
• 
1 statin at any dose and unwilling to attempt a second statin or advised by a physician 
to not attempt a second statin. 
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 


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the study provided that it is stable (used for at least 4 weeks prior to screening) and well 
tolerated. 
3. Written confirmation by both patient and investigator that the patient is statin intolerant as 
defined above, aware of the benefit of statin use to reduce the risk of MACE including death, 
and also aware that many other patients who are unable to tolerate a statin are able to tolerate 
a different statin or dose. 
4. Age ≥18 years or legal age of majority based on regional law, whichever is greater, and 
≤85 years at Week -5 (Visit S1). 
5. Men and nonpregnant, nonlactating women.  Women must be one of the following: 
• 
Naturally postmenopausal defined as ≥1 year without menses and: 
o ≥55 years, or 
o <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 willing to use an acceptable method(s) of birth 
control during the study and for 30 days after the end of treatment, including: 
o oral, topical, injectable, or implantable birth control medications, 
o placement of an intrauterine device with or without hormones, 
o barrier methods including condom or occlusive cap with spermicidal foam or 
spermicidal jelly, 
o vasectomized male partner who is the sole partner for this patient, 
o true abstinence that is in line with the preferred and usual lifestyle of the patient 
(periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], declaration of abstinence for the duration of the study or withdrawal 
are not acceptable methods of true abstinence). 
There are no protocol-specific birth control requirements for men with partners who are able 
to become pregnant. 
6. Fasting LDL-C ≥100 mg/dL (2.6 mmol/L) at Week -5 (Visit S1) while taking stable (4 weeks 
prior to Visit S1) and optimized background LDL-C-lowering therapies that may include very 
low dose statin (see definition above), ezetimibe, niacin, bile acid resins, fibrates, and/or 
proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. 
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 repeat value will be used to 
determine eligibility. 
7. History of, or at high risk for, CVD including documented evidence of one or more of the 
following: 
a. Documented history of CVD (ie, secondary prevention) 
• 
Coronary artery disease, defined by: 
o MI (either ST-elevation MI or non-ST-elevation MI) occurring greater than 
90 days prior to screening, or 
o Percutaneous coronary or surgical coronary revascularization, occurring greater 
than 90 days prior to screening, or 
o 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: 
o Peripheral vascular disease with symptoms of claudication or resting limb 
ischemia with either ankle brachial index <0.9 or angiogram (including CTA) 
showing ≥50% stenosis (ankle brachial index will be measured after a period of 
rest and with the patient in the supine position using a Doppler device), or 
o Peripheral arterial revascularization (surgical or percutaneous), occurring greater 
than 90 days prior to screening, or 
o Abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair, 
occurring greater than 90 days prior to screening, or 
o Lower extremity amputation due to peripheral vascular disease, occurring greater 
than 90 days prior to screening, or 
• 
Cerebrovascular atherosclerotic disease defined by: 
o Ischemic stroke occurring greater than 90 days prior to screening, or 
o Carotid endarterectomy, carotid stenting, or more than 70% stenosis in a carotid 
artery determined by carotid ultrasound or angiogram (Note:  If stenosis assessed 
by carotid ultrasound is reported as range between 60%-79%, patient may 
qualify only if internal carotid artery peak systolic velocity is ≥230 cm/sec), 
occurring greater than 90 days prior to screening, or 
b. High risk for a CVD event (ie, high-risk primary prevention) 
• 
Reynolds Risk score >30% or a SCORE Risk score >7.5% over 10 years (see 
Appendix 3 and Appendix 4 for additional details), or 
• 
Coronary artery calcium score >400 Agatston units (AU) at any time in the past, or 
• 
Patients with type 1 or type 2 diabetes, aged >65 years (women) or >60 years (men). 
Subject Exclusion Criteria: 
Patients who meet any of the following criteria will not be eligible to participate: 
1. Total fasting TG >500 mg/dL (5.6 mmol/L) at Week -5 (Visit S1). 
Note:  A single repeat 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 defined as either nephritic or nephrotic 
syndrome, 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. 
3. Forms of CVD that include any of the following: 
a. Recent (within 90 days prior to or during screening) acute CVD events including, but not 
only, transient ischemic attack (TIA), MI, coronary revascularization, peripheral arterial 
revascularization, ischemic stroke, carotid endarterectomy, carotid stenting.  
b. Recent (within 90 days of screening) unstable or symptomatic cardiac arrhythmia 
(including any associated medication changes).  Patients with stable well-controlled 
atrial arrhythmias will be allowed to participate in the study. 
c. Patients with implantable pacemakers or automatic implantable cardioverter 
defibrillators may be considered if deemed by the investigator to be stable for greater 
than 90 days prior to screening, 


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d. New York Heart Association (NYHA) Functional Classification Class IV heart failure, 
e. Uncontrolled hypertension, defined as mean sitting systolic blood pressure (SBP) 
≥180 mmHg and/or diastolic blood pressure (DBP) ≥110 mmHg, 
Note:  At the discretion of the investigator, 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. 
f. Planned coronary revascularization (patient may rescreen 3 months post-procedure). 
4. HbA1C ≥10% at Week -5 (Visit S1). 
5. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper 
limit of normal (ULN) at Week -5 (Visit S1).  Note:  At the discretion of the Investigator, 
thyroid replacement therapy can be adjusted and/or additional measurement of TSH may be 
completed prior to randomization, with the repeat TSH value used to determine eligibility. 
6. Liver disease or dysfunction, including: 
a) Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies 
(HCV-ABVivi) at Week -4 (Visit S2), or 
b) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 × ULN at 
Week -5 (Visit S1). 
Note:  At the discretion of the investigator, a single repeat of ALT and/or AST 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 RNA is negative, patient can be enrolled. 
7. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® or 
gastric bypass) that may affect drug absorption. 
8. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10 g/dL at Week -5 
(Visit S1). 
9. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the 
past 5 years.  Nonmetastatic basal or squamous cell carcinoma of the skin and cervical 
carcinoma in situ are allowed. 
10. Unexplained creatine kinase (CK) >3 × ULN at Week -5 (Visit S1) (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. 
11. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine 
abuse.  Patients with amphetamine derivatives prescribed by and under the care of a health 
care practitioner can be enrolled after evaluation by the investigator. 
12. Blood transfusion for any reason within 30 days prior to randomization. 
13. Use of any experimental or investigational drugs within 30 days prior to screening or 
5 half-lives, whichever is longer. 
14. Randomization into another Phase 3 bempedoic acid clinical study. 
15. 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 (must be stopped at least 2 weeks prior to Week -5 [Visit S1]), 


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• 
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. 
16. Planned initiation or dose adjustments of these allowed drugs prior to screening and during 
the clinical trial (stable use of these drugs is permitted): 
• 
Statins are allowed only 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 (must be stable at least 4 weeks prior to Week -5 
[Visit S1]), 
• 
Other lipid-regulating drugs or supplements (must be stable at least 4 weeks prior to 
Week -5 [Visit S1]) 
• 
PCSK9 inhibitors (must be stable at least 12 weeks prior to Week -5 [Visit S1]). 
17. Lack of adherence (ie, less than 80% of planned doses) with IMP (single-blind placebo) 
during the Run-in Period. 
18. Lack of tolerance with IMP (single-blind placebo) during the Run-in Period. 
19. 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. 
20. An employee or contractor of the facility conducting the study, or a family member of the 
Principal Investigator, Co-Investigator, or Sponsor. 
21. Pregnant, breastfeeding, or intending to become pregnant within 30 days after study 
completion or last dose of IMP. 
Investigational Medicinal Product, Dosage and Mode of Administration:  
• 
Bempedoic acid 180 mg film-coated tablets 
• 
Matching placebo tablets 
All IMP will be ingested once daily at similar time with or without food. 
Non-Investigational Medicinal Product  
Background therapy for all patients will include a wide range of concomitant medications, according 
to local standard of care.  Patients will be permitted to take any concomitant medications or therapies 
except mipomersen, lomitapide, apheresis therapy, red yeast rice, or any statin at a dose greater than 
those noted below.  Background therapy to lower LDL-C may include nonstatin drugs and 
supplements such as ezetimibe, niacin, bile acid resins, fibrates, PCSK9 inhibitors, plant sterols, and 
plant stanols.  Statin use will be limited to 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.  Additionally, patients may use any TG-lowering drugs and supplements. 


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Safety and Monitoring: 
Monitoring and Management of Elevated LDL-C: 
Postrandomization, LDL-C results will be masked in order to maintain the blind.  Beginning at 
Month 6 (Visit T4) and for the remaining duration of the study, the central laboratory will notify the 
investigator if the patient’s LDL-C level is ≥25% higher than baseline LDL-C. The patients will be 
counseled on healthy dietary guidelines and reminded to take all lipid-regulating medications.  The 
patient will return to the clinic for a repeat fasting blood lipid sample to confirm that the LDL-C value 
meets the threshold criteria.  If confirmed, the patient’s LDL-C-lowering treatment regimen may be 
adjusted, if possible, per standard of care and local practice.  Any initiation and/or dose change of 
LDL-C-lowering medications will be documented on the electronic case report form (eCRF) and will 
not be provided by the Sponsor. 
Investigators will not measure LDL-C at a local lab during the study. 
Monitoring and Managements of Elevated TG: 
Postrandomization, TG results will be masked in order to maintain the blind.  Beginning at Month 3 
(Visit T3) and for the remaining duration of the study, the central laboratory will notify the 
investigator if a patient’s TG level is >1000 mg/dL (11.3 mmol/L).  The patient will be counseled on 
healthy dietary guidelines and reminded to take all lipid-regulating medications.  The patient will 
return to the clinic for a repeat fasting blood lipid sample to confirm that the TG value meets the 
threshold criteria.  If confirmed, the patient’s TG-lowering treatment regimen may be adjusted, if 
possible, per standard of care and local practice.  Any initiation and/or dose change of TG 
medications will be documented on the eCRF and will not be provided by the Sponsor.  If, despite 
adjustment of TG-lowering therapies, the TG level remains >1000 mg/dL (11.3 mmol/L), the patient 
will discontinue study medication but will remain in the study.  
Statistical Methods: 
Sample Size 
This event-driven trial is designed to provide at least 90% power to detect an approximate 15% 
relative risk reduction in the primary 4-component MACE endpoint (CV death, nonfatal MI, nonfatal 
stroke, or coronary revascularization) at an overall study significance level (alpha) of 0.05.  Assuming 
a 3.59% annual event rate in the placebo group, a minimum of 1620 patients experiencing an 
adjudicated primary MACE endpoint will be required.  The median treatment duration for all patients 
was assumed to be approximately 42 months (3.5 years), with minimum treatment duration of 
36 months (~3 years) and a lost-to-follow-up (LTFU) rate of 1% per year.  In addition, the trial is 
designed to provide more than 95% power to detect an approximately 17% relative risk reduction in 
the primary 4-component MACE endpoint.  A two-sided log-rank test (with the assumption of 
exponential distribution of survival times) was used to calculate the sample size. 
Approximately 14,000 patients (approximately 7000 in the bempedoic acid group and 7000 in the 
placebo group) will be randomized into the study to achieve the 1620 patients experiencing an 
adjudicated primary endpoint event. 
It is expected that 50% of the 1620 patients experiencing an adjudicated primary 4-component MACE 
(810 patients) will experience an adjudicated 3-component MACE (CV death, nonfatal MI, or 
nonfatal stroke).  Additionally, the median treatment duration for the sample size calculation was 
assumed to be 42 months (~3.5 years) when the annual placebo event rate was 3.59%.  Therefore, the 
study will not stop until at least 1620 patients have experienced an adjudicated primary MACE 
endpoint, with 50% of the patients experiencing an adjudicated 3-component MACE, and a minimum 
of 24 months (2 years) have elapsed since the last patient was randomized. 


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Interim Analyses 
There will be no interim efficacy analyses in this study.  The study may be altered or terminated 
based upon recommendations from the DMC as described in Section 14.2. 
Statistical Adjustment for Testing Hypotheses Corresponding to the Primary and Key Secondary 
Efficacy Parameters 
The following 7 hypotheses of no difference between bempedoic acid and placebo, based on the 
primary and key secondary efficacy endpoints, will be tested sequentially.  This gatekeeping or 
stepdown testing approach will preserve the study-wise (family-wise) Type I error rate at 5%.  The 
sequence for the stepdown procedure in this study is as follows: 
1. Testing the hypothesis of no difference between bempedoic acid and placebo in time to first 
occurrence of MACE (CV death, nonfatal MI, nonfatal stroke, or coronary revascularization; 
primary 4-component MACE) 
2. Testing the hypothesis of no difference between bempedoic acid and placebo in time to first 
occurrence of the composite endpoint of CV death, nonfatal MI, or nonfatal stroke 
(3-component MACE) 
3. Testing the hypothesis of no difference between bempedoic acid and placebo in time to first 
occurrence of fatal or nonfatal MI 
4. Testing the hypothesis of no difference between bempedoic acid and placebo in time to first 
occurrence of coronary revascularization 
5. Testing the hypothesis of no difference between bempedoic acid and placebo in time to first 
occurrence of fatal or nonfatal stroke 
6. Testing the hypothesis of no difference between bempedoic acid and placebo in time to CV 
death 
7. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
all-cause mortality 
For the final analysis about the differences between bempedoic acid and placebo at the end of the 
study, each hypothesis in this hierarchical testing structure will be tested at a significance level of 
0.05, two-sided.  Statistical significance at each step is required in order to test the next hypothesis.  
For other efficacy endpoints, a significance level of 0.05 will be used. 
Analysis Populations 
The Full Analysis Set (FAS), used for all of the efficacy analyses and summaries, is defined as all 
randomized patients and 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 Diabetes Efficacy Population, used for efficacy analyses of HbA1C and fasting glucose, is defined 
as the subset of patients in the FAS fulfilling one or more of the following criteria at baseline captured 
by information recorded as medical history, prior medication, and/or laboratory data: 
• 
Medical history indicating type 2 diabetes 
• 
Prior glucose-lowering medication with confirmation of diagnosis of diabetes by a DC 
(Section 14.4) if prior medication is the only criteria met for diagnosis of diabetes 
• 
HbA1C measurement ≥6.5% 
• 
Two or more measurements of fasting glucose ≥126 mg/dL (7.0 mmol/L) 
The Inadequately Controlled Diabetes Efficacy Population, is defined as the subset of patients in the 
Diabetes Efficacy Population with an HbA1C of 7% or greater at baseline.  This efficacy population 
will be used for the corresponding diabetes secondary and tertiary endpoints. 


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The Prediabetes Efficacy Population, used for efficacy analyses of time to new-onset diabetes and for 
efficacy analyses of HbA1C and fasting glucose, is defined the subset of patients in the FAS fulfilling 
all of the following criteria captured at baseline by information recorded as medical history, prior 
medication, and/or laboratory data: 
• 
Having no medical history indicating type 2 diabetes 
• 
Having no prior glucose-lowering medication unless verified by the DC that there is no 
diagnosis of diabetes (Section 14.4) if prior medication is the only criteria assessed for the 
diagnosis of diabetes 
• 
HbA1C measurement of 5.7% to 6.4% or 1 or more measurements of fasting glucose of 
100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L), but not more than 1 value of fasting 
glucose ≥126 mg/dL (7.0 mmol/L) 
The Normoglycemia Efficacy Population, used for efficacy analyses of HbA1C and fasting glucose, is 
defined as the subset of patients not fulfilling the criteria at baseline for the Diabetes Population or 
Prediabetes Efficacy Population. 
The No Diabetes Efficacy Population used for efficacy analyses of HbA1C and fasting glucose, is 
defined as the subset of patients not fulfilling the criteria at baseline for the Diabetes Efficacy 
Population. 
The Safety Population (SP), used for all of the safety analyses, is defined as all randomized patients 
who received at least 1 dose of study medication (investigational product).  Patients in the SP will be 
included in the treatment group that they actually received, regardless of their randomized treatment. 
The Diabetes, Prediabetes, Normoglycemia and the Inadequately Controlled Diabetes Safety 
Populations are used for safety analyses as needed, and defined similarly as Diabetes, Prediabetes, 
Normoglycemia, and the Inadequately Controlled Diabetes Efficacy Populations but using patients 
from Safety Population instead. 
Disposition and Baseline Characteristics: 
Disposition, including reason for withdrawal from the study, will be summarized by treatment group.  
Demographic information and patient characteristics will also be summarized by treatment group. 
Primary Endpoint: 
The primary endpoint of this study is time to first occurrence of a confirmed (adjudicated) MACE, 
where MACE is defined as a composite primary efficacy endpoint that includes CV death, nonfatal 
MI, nonfatal stroke, or coronary revascularization. 
The primary efficacy endpoint will be analyzed using Cox proportional hazards (PH) model with 
treatment as a factor.  The Cox PH analysis will be performed using the FAS, with patients included 
in their randomized treatment group, regardless of the treatment they actually received.  Note that the 
FAS includes patients who permanently discontinue treatment but remain in the study (patients are 
included regardless of their adherence to treatment).  For this analysis, patients who are LTFU 
without experiencing a MACE will be censored at the time they are last known to be event-free.  
Patients who withdraw consent (withdraw from the study and refuse further contact) without 
experiencing a MACE will be censored at the time of consent withdrawal.  Additionally, taking into 
account the period for CV event monitoring is every 3 months, when a patient who is LTFU or 
withdraws consent without experiencing a MACE is known to have later experienced a non-CV 
death, if the death was within 3 months of last contact, the patient will be censored at the time of 
death.  If the death occurs more than 3 months after last contact, then the patient will be censored at 
the time of last contact.  The hazard ratio (HR) and its 95% confidence interval (CI) and associated 
p-value will be provided. 
In addition, Kaplan-Meier (K-M) curves will be provided, to provide a graphical description of the 
time to first occurrence of MACE. 


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Each individual component of the primary efficacy endpoint (CV death, nonfatal MI, nonfatal stroke, 
and coronary revascularization; each of the individual components are secondary time-to-event 
endpoints) will also be analyzed using Cox PH model, to ensure consistency of the treatment effect 
across the components that comprise the composite endpoint.  Each Cox PH model will include 
treatment as a factor and will be performed on the FAS with patients included in their randomized 
treatment group.  The HR and its 95% CI will be provided for each individual component of the 
primary efficacy endpoint. 
Secondary Efficacy Time-to-Event Endpoints: 
Secondary efficacy MACE endpoints related to time-to-events will be analyzed in a manner 
analogous to that used for the primary efficacy analysis, using Cox PH model and with similar 
censoring definitions.  K-M curves will also be provided for each endpoint. 
The time to first occurrence of new onset of diabetes during the treatment period will be analyzed by 
a Cox model in the Prediabetes Efficacy Population.  The date of new onset of diabetes will be the 
earliest date of the event observed during the treatment period.  For this analysis, patients who are 
LTFU and discontinue the study drug early without experiencing a new onset of diabetes will be 
censored at 30 days after the last date of the treatment. 
Secondary Efficacy Lipid and Other Biomarker Endpoints: 
Percent change from baseline to Month 6 in LDL-C and change from baseline to Month 12 in HbA1C 
will be analyzed using analysis of covariance (ANCOVA), with treatment group as a factor and the 
relevant baseline as a covariate.  The ANCOVA for LDL-C will be performed using the FAS.  The 
ANCOVA for HbA1C will be performed in the Inadequately Controlled Diabetes Efficacy Population.  
Two methods for data handling will be used:  the first (primary) will involve specification of the 
missing data mechanism using a pattern mixture model (PMM), while the second (supportive) will be 
observed case data only.  For each analysis, the least squares mean (LSM) and standard error (SE) 
will be provided for each treatment group, along with the placebo-corrected LSM, its 95% CI, and 
associated p-value. 
A nonparametric analysis based on Wilcoxon rank sum test and Hodges-Lehmann (H-L) estimate of 
location shift will be performed in the FAS for percent change from baseline to Month 6 in hs-CRP.  
No imputation will be performed for the hs-CRP endpoint due to the extreme skewed distribution. 
Tertiary Lipid and Biomarker Endpoints: 
Tertiary lipid and HbA1C-related endpoints will be summarized and analyzed as needed.  For each 
parameter at each time point, the value of the parameter, change and the percent change from baseline 
will be summarized by treatment group.  The Mixed Model Repeated Measure (MMRM) analysis 
including factors of treatment group, time point (as a categorical variable), baseline value, and 
treatment group-by-time point interaction will be performed in the observed FAS data.  The LSM and 
SE will be provided for each treatment group, along with the placebo-corrected LSM, its 95% CI, and 
associated p-value, as needed.  A nonparametric analysis based on Wilcoxon rank sum test and H-L 
estimate of location shift will be performed in observed FAS data for percent change from baseline to 
Month 12 and end-of study in hs-CRP. 
Safety Endpoints: 
General safety data in this study include AEs, clinical safety laboratories, physical examinations 
(PEs), vital signs, and electrocardiograms (ECGs).  The summarization of AEs will include only 
treatment-emergent AEs (TEAEs), defined as AEs that begin or worsen after randomization and 
ingestion of the first dose of randomized IMP.  TEAEs and SAEs will be summarized by system 
organ class (SOC), severity, and relationship to IMP for each treatment group.  Deaths, withdrawal 
from study treatment due to AEs, and withdrawal from the study due to AEs will each be summarized 
by treatment group. 


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Clinical safety laboratories, including hematology, blood chemistry, 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 postbaseline time point. 
AESI: 
All AESI will be identified and evaluated by routine safety monitoring of AEs and laboratory values 
(where appropriate) and will be summarized by severity and relationship to IMP for each treatment 
group 
The following are considered AESI categories for this study: 
• 
Hepatic Safety, including liver-associated enzymes, total bilirubin (TB), and any Hy’s law 
cases (≥3 × ULN for either ALT or AST, with accompanying TB >2 × ULN in the setting of 
no known other cause) 
• 
Musculoskeletal Safety, including creatinine phosphokinase (CK) 
• 
Diabetes and Glycemia, including new onset of diabetes and worsening of diabetes  
• 
Hypoglycemia Associated with Metabolic Acidosis 
• 
Renal Impairment, including lab measures of renal function 
• 
Neurocognitive Events 
• 
Atrial Fibrillation 
• 
Tendon Rupture/Tendinopathy.  The TRAC will adjudicate events of tendon rupture per the 
Tendon Rupture Independent Adjudicator Charter (TRIAC), and adjudicated events will be 
summarized. 
• 
Malignancies 
Additional postrandomization adjunctive lipid-modifying therapy: 
The number and percent of patients in each treatment group requiring additional (postrandomization) 
adjunctive lipid-modifying therapy will be summarized by treatment and by lipid-lowering therapy 
class.  The reasons for their additional treatment (hyperlipidemia versus hypertriglyceridemia) will be 
summarized.  Medications will be summarized by treatment group. 
 


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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
TABLE OF CONTENTS ...............................................................................................................15 
LIST OF TABLES .........................................................................................................................20 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
4. 
INTRODUCTION ......................................................................................................25 
4.1. 
Cardiovascular Disease, LDL-C-Lowering Drugs, and Statin Intolerance ................25 
4.2. 
Background on Bempedoic Acid ................................................................................27 
4.2.1. 
Mechanism of Action .................................................................................................27 
4.2.2. 
Nonclinical Experience ...............................................................................................27 
4.2.3. 
Previous Human Experience .......................................................................................28 
4.2.4. 
Dose Selection ............................................................................................................28 
4.3. 
Risk Benefit Summary ................................................................................................28 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................30 
5.1. 
Objectives ...................................................................................................................30 
5.1.1. 
Primary Objective .......................................................................................................30 
5.1.2. 
Secondary Objectives .................................................................................................30 
5.1.3. 
Tertiary Objective .......................................................................................................30 
5.2. 
Study Endpoints ..........................................................................................................30 
5.2.1. 
Primary Efficacy Endpoint .........................................................................................30 
5.2.2. 
Secondary Efficacy Time-to-Event Endpoints ...........................................................31 
5.2.3. 
Secondary Efficacy Lipid and Biomarker Endpoints .................................................32 
5.2.4. 
Tertiary Efficacy Lipid and Other Biomarker Endpoints ...........................................32 
5.2.5. 
Safety Endpoints .........................................................................................................32 
6. 
INVESTIGATIONAL PLAN .....................................................................................33 
6.1. 
Overall Study Design ..................................................................................................33 
6.2. 
Study Hypotheses .......................................................................................................34 
6.3. 
Estimated Study Duration and Period.........................................................................34 
6.4. 
Number of Centers ......................................................................................................34 
6.5. 
End of Study ...............................................................................................................35 
6.6. 
Number of Patients .....................................................................................................35 


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7. 
SELECTION OF PATIENTS.....................................................................................36 
7.1. 
Subject Inclusion Criteria ...........................................................................................36 
7.2. 
Subject Exclusion Criteria ..........................................................................................38 
7.3. 
Patient Lifestyle and Dietary Guidelines ....................................................................40 
8. 
TREATMENT OF PATIENTS ..................................................................................42 
8.1. 
Administration of Investigational Medicinal Product ................................................42 
8.2. 
Prior and Concomitant Medications ...........................................................................42 
8.2.1. 
Prohibited Medications and Dietary Supplement .......................................................42 
8.2.2. 
Permitted Medications ................................................................................................43 
8.3. 
Treatment Assignment, Randomization, and Blinding...............................................44 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................46 
9.1. 
Description of Investigational Medicinal Product ......................................................46 
9.2. 
Investigational Medicinal Product Supply and Control ..............................................46 
9.3. 
Packaging and Labeling ..............................................................................................46 
9.4. 
Investigational Medicinal Product Adherence ............................................................47 
9.5. 
Investigational Medicinal Product Accountability .....................................................47 
9.6. 
Investigational Medicinal Product Handling, Storage, and Disposal .........................48 
10. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS .........................49 
10.1. 
Informed Consent .......................................................................................................49 
10.2. 
Confirmation of Statin Intolerance .............................................................................49 
10.3. 
Interactive Web Response System and eCRFs ...........................................................49 
10.4. 
Patient Identification Numbers ...................................................................................50 
10.5. 
Rescreening .................................................................................................................50 
10.6. 
Procedures and Schedule of Assessments ..................................................................50 
10.6.1. 
Screening Week -5 (Visit S1; Day -35) ......................................................................50 
10.6.2. 
Screening Week -4 (Visit S2; Day -31 to -25) ...........................................................52 
10.6.3. 
Treatment Week 0 (Visit T1; Day 1) ..........................................................................52 
10.6.4. 
Treatment Month 1 (Visit T2; ± 3 days) .....................................................................53 
10.6.5. 
Treatment Month 3 (Visit T3; ± 5 days) .....................................................................53 
10.6.6. 
Treatment Month 6 (Visit T4; ± 5 days) .....................................................................54 
10.6.7. 
Treatment Month 9 (Phone Visit; Visit T5 ± 10 days), Month 15 (Phone 
Visit; Visit T7 ± 10 days), Month 21 (Phone Visit; Visit T9 ± 10 days), and 


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Additional Telephone Visits Until Study Conclusion Every 6 Months 
Thereafter ....................................................................................................................55 
10.6.8. 
Treatment Month 12 (Visit T6 ± 10 days), Month 18 (Visit T8 ± 10 days), 
and Additional Clinic Visits Until Study Conclusion Every 6 Month 
Thereafter ....................................................................................................................55 
10.6.9. 
End of Study ...............................................................................................................57 
10.6.10. 
Post-treatment Visit (Phone Visit; Visit PT1, 30 days ± 10 days After End of 
Study) ..........................................................................................................................58 
10.7. 
Discontinuations .........................................................................................................58 
10.7.1. 
Patients Inadvertently Enrolled ...................................................................................58 
10.7.2. 
Temporary Discontinuation of Investigational Medicinal Product ............................58 
10.7.3. 
Permanent Discontinuation of Investigational Medicinal Product .............................59 
10.7.4. 
Patient Discontinuation from the Study ......................................................................59 
10.7.5. 
Patients Lost to Follow-Up .........................................................................................60 
10.7.6. 
Discontinuation of Study Sites or the Study ...............................................................60 
11. 
ASSESSMENT OF EFFICACY ................................................................................61 
11.1. 
Reporting of Clinical Endpoints .................................................................................61 
11.2. 
Major Adverse Cardiovascular Events .......................................................................62 
11.3. 
Assessment of Diabetes ..............................................................................................62 
11.4. 
Assessments of Lipids and hs-CRP ............................................................................62 
12. 
ASSESSMENT OF SAFETY .....................................................................................64 
12.1. 
Safety Parameters .......................................................................................................64 
12.1.1. 
Demographic/Medical History ...................................................................................64 
12.1.2. 
Vital Signs ..................................................................................................................64 
12.1.3. 
Weight and Height ......................................................................................................64 
12.1.4. 
Physical Examination .................................................................................................65 
12.1.5. 
Electrocardiogram .......................................................................................................65 
12.1.6. 
Central Clinical Laboratory Tests ...............................................................................65 
12.1.6.1. 
Central Clinical Laboratory Parameters (Safety) .......................................................65 
12.1.6.2. 
Sample Collection, Storage, and Shipping .................................................................67 
12.1.6.3. 
General Monitoring and Management of Abnormal Clinical Labs ............................67 
12.1.6.4. 
Total Blood Volume of Central Clinical Laboratory Samples ...................................70 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................71 


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13.1. 
Adverse Events ...........................................................................................................71 
13.1.1. 
Definition of Adverse Events .....................................................................................71 
13.1.2. 
Adverse Drug Reaction ...............................................................................................71 
13.1.3. 
Reporting for Adverse Events ....................................................................................71 
13.1.4. 
Severity .......................................................................................................................73 
13.1.5. 
Relationship ................................................................................................................73 
13.1.6. 
Monitoring and Follow-up of Adverse Events ...........................................................73 
13.1.7. 
Treatment-Emergent Adverse Events .........................................................................74 
13.2. 
Serious Adverse Events ..............................................................................................74 
13.2.1. 
Definition of Serious Adverse Event ..........................................................................74 
13.2.2. 
Events or Outcomes Not Qualifying as Serious Adverse Events ...............................75 
13.2.3. 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .........................................................................................................................75 
13.2.4. 
Reporting Serious Adverse Events .............................................................................75 
13.2.5. 
Events Exempt from (Serious) Adverse Event Reporting ..........................................76 
13.2.6. 
Reporting of Patient Death .........................................................................................77 
13.2.7. 
Reports of Pregnancy and Lactation ...........................................................................77 
13.3. 
Adverse Events of Special Interest .............................................................................77 
14. 
STUDY COMMITTEES ............................................................................................79 
14.1. 
Executive Committee (EC) .........................................................................................79 
14.2. 
Data Monitoring Committee (DMC) ..........................................................................79 
14.3. 
Clinical Event Committee (CEC) ...............................................................................79 
14.4. 
Diabetes Committee (DC) ..........................................................................................79 
14.5. 
Tendon Rupture Adjudication Committee (TRAC) ...................................................79 
15. 
STATISTICS ..............................................................................................................80 
15.1. 
General Considerations ...............................................................................................80 
15.2. 
Determination of Sample Size ....................................................................................80 
15.3. 
Interim Analysis and Stopping Rules .........................................................................80 
15.4. 
Analysis Populations ..................................................................................................81 
15.5. 
Disposition, Demographics, and Baseline Characteristics .........................................82 
15.6. 
Primary Endpoint Analysis .........................................................................................82 
15.7. 
Secondary Efficacy Endpoint Analyses ......................................................................83 


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15.7.1. 
Secondary Efficacy Time-to-Event Endpoints ...........................................................83 
15.7.2. 
Secondary Efficacy Lipid and Other Biomarker Endpoints .......................................84 
15.7.3. 
Tertiary Lipid and Biomarker Efficacy Endpoints .....................................................84 
15.8. 
Safety Endpoints .........................................................................................................84 
15.8.1. 
Adverse Events of Special Interest (AESI) ................................................................85 
15.9. 
Additional Postrandomization Adjunctive Lipid-Modifying Therapy .......................85 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................86 
16.1. 
Study Monitoring ........................................................................................................86 
16.2. 
Audits and Inspections ................................................................................................86 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................88 
18. 
ETHICS ......................................................................................................................89 
18.1. 
Institutional Review Board/Independent Ethics Committee Approval ......................89 
18.2. 
Ethical Conduct of the Study ......................................................................................89 
18.3. 
Written Informed Consent ..........................................................................................90 
18.4. 
Patient Confidentiality ................................................................................................90 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
19.1. 
Inspection of Records .................................................................................................91 
19.2. 
Retention of Records ..................................................................................................91 
19.3. 
Case Report Forms and Study Records ......................................................................91 
20. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................93 
20.1. 
Investigators ................................................................................................................93 
20.2. 
Study Administrative Structure ..................................................................................94 
20.3. 
Amendments and Study Termination .........................................................................95 
20.4. 
Financial Disclosure ...................................................................................................95 
21. 
PUBLICATION AND DISCLOSURE POLICY .......................................................96 
22. 
LIST OF REFERENCES ............................................................................................97 
23. 
APPENDICES ..........................................................................................................100 
APPENDIX 1. SCHEDULE OF EVENTS (SUBJECT VISIT SCHEDULE) .........................101 
APPENDIX 2. SPONSOR’S SIGNATURES ...........................................................................104 
APPENDIX 3. CALCULATING REYNOLDS RISK SCORE ...............................................106 
APPENDIX 4. CALCULATING SCORE RISK ......................................................................107 
APPENDIX 5. INVESTIGATOR’S SIGNATURE..................................................................110 


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APPENDIX 6. SUMMARY OF CHANGES IN AMENDMENT 1 ........................................111 
APPENDIX 7. SUMMARY OF CHANGES IN AMENDMENT 2 ........................................115 
APPENDIX 8. SUMMARY OF CHANGES IN AMENDMENT 3.1 .....................................168 
APPENDIX 9. SUMMARY OF CHANGES IN AMENDMENT 4 ........................................174 
APPENDIX 10. SUMMARY OF CHANGES IN AMENDMENT 5 ......................................248 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................21 
Table 2: 
Investigational Medicinal Products ............................................................................46 
Table 3: 
Central Clinical Laboratory Parameters (Lipids and hs-CRP) ...................................63 
Table 4: 
Central Clinical Laboratory Parameters (Safety) .......................................................66 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ACL 
adenosine triphosphate-citrate lyase 
ACS 
acyl-CoA synthetase 
ACSVL1 
very long-chain acyl-CoA synthetase 1 
ADA 
American Diabetes Association 
ADR(s) 
adverse drug reaction(s) 
AE(s) 
adverse event(s) 
AESI 
adverse events of special interest 
Alb 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AU 
Agatston units 
AUC0-24 
area under the curve during 24 hours 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C5Research 
Cleveland Clinic Coordinating Center for Clinical Research 
Ca 
calcium 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CI(s) 
confidence interval(s) 
CK 
creatine kinase 
COVID-19 
Coronavirus disease of 2019 
CPK 
creatine phosphokinase 
Cl 
chloride 
CNS 
central nervous system 
CoA 
acetyl-coenzyme A 
CO2 
carbon dioxide 
CRO(s) 
contract research organization(s) 
CTA 
computed tomography angiography 
CV 
cardiovascular 


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Abbreviation or Specialist Term 
Explanation 
CVD 
cardiovascular disease 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DC 
Diabetes Committee 
DHA 
docosahexaenoic acid 
DMC 
Data Monitoring Committee 
EC 
Executive Committee 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
eGFR 
estimated glomerular filtration rate 
EPA 
eicosapentaenoic acid 
ESP15228 
metabolite of bempedoic acid 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1C 
glycosylated hemoglobin, Type A1C 
HBsAg 
hepatitis B surface antigen 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HCV-Ab 
hepatitis C antibodies 
HDL-C 
high-density lipoprotein cholesterol 
Hgb 
hemoglobin 
H-L 
Hodges-Lehmann 
HMG-CoA 
3-hydroxy-3-methylglutaryl coenzyme A 
HR 
hazard ratio 
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 


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Abbreviation or Specialist Term 
Explanation 
IRB 
Institutional Review Board 
ITT 
intention-to-treat 
IWRS 
interactive web response system 
K 
potassium 
K-M 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
LFT 
liver function test 
LS 
least square 
LSM 
least squares mean 
LTFU 
lost-to-follow-up 
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 
MMRM 
mixed model repeated measure 
MRI 
magnetic resonance imaging 
Na 
sodium 
NOAEL 
no-observed-adverse-effect level 
non-HDL-C 
non-high-density lipoprotein cholesterol 
NYHA 
New York Heart Association 
PAD 
peripheral arterial disease 
PCSK9 
proprotein convertase subtilisin kexin type 9 
PE 
physical exam 
PH 
proportional hazards 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model 
PT 
prothrombin time 
RBC 
red blood cell 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 


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Abbreviation or Specialist Term 
Explanation 
SE 
standard error 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SI 
statin intolerance 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP(s) 
standard operating procedure(s) 
SP 
Safety Population 
SUSAR(s) 
suspected and unexpected serious adverse reaction(s) 
TB 
total bilirubin 
TC 
total cholesterol 
TEAE(s) 
treatment-emergent adverse event(s) 
TG(s) 
triglyceride(s) 
TIA(s) 
transient ischemic attack(s) 
TRAC 
Tendon Rupture Adjudication Committee 
TRIAC 
Tendon Rupture Independent Adjudicator Charter 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
WBC 
white blood cell 
WHO 
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4. 
INTRODUCTION 
Bempedoic acid (ETC-1002) is an oral, first-in class, small molecule designed to lower low-
density lipoprotein cholesterol (LDL-C).  It inhibits adenosine triphosphate-citrate lyase (ACL), 
an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the 
cholesterol biosynthesis pathway.  Bempedoic acid, like statins, inhibits cholesterol synthesis and 
up-regulates LDL-C receptors.  However, unlike statins, bempedoic acid does not inhibit 
cholesterol synthesis in muscle tissue, therefore it is anticipated that negative muscle-related 
adverse effects associated with statin use may be avoided by use of bempedoic acid. 
Bempedoic acid and bempedoic acid and ezetimibe, under the marketed names of Nexletol® and 
NexlizetTM respectively, have been approved by the United States (US) Food and Drug 
Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy for the 
treatment of heterozygous familial hypercholesterolemia or established atherosclerotic 
cardiovascular disease in adults who require additional lowering of LDL-C (Nexletol, 2020; 
Nexlizet, 2020).  In the European Union (EU) bempedoic acid and bempedoic acid and ezetimibe 
have been approved by the European Commission and are marketed under the names Nilemdo® 
and Nustendi®, respectively, for the treatment of primary hypercholesterolemia (heterozygous 
familial and non-familial) or mixed dyslipidemia as an adjunct to diet:  in combination with a 
statin or statin with other lipid-lowering therapies in adults unable to reach LDL-C goals with the 
maximum tolerated dose of statin, or alone or in combination with other lipid-lowering therapies 
in patients who are statin-intolerant or for whom a statin is contraindicated.  Additionally, 
Nustendi® is indicated in patients already being treated with the combination of bempedoic acid 
and ezetimibe as separate tablets with or without statin (Nilemdo, 2020; Nustendi, 2020).  
Patients who are statin intolerant have an unmet medical need for therapeutic options to lower 
LDL-C and reduce their risk of cardiovascular disease (CVD).  Recent mechanistic and clinical 
data suggest that bempedoic acid may meet this medical need with a once-daily, nonstatin 
alternative.  This Phase 3 study is being conducted as a part of a comprehensive Phase 3 program 
to determine whether bempedoic acid will reduce the risk of major adverse cardiovascular events 
(MACE) in patients with, or at high risk for, CVD who are unable to tolerate statins. 
4.1. 
Cardiovascular Disease, LDL-C-Lowering Drugs, and Statin 
Intolerance 
Despite aggressive interventional and pharmacologic therapies, CVD is the number 1 cause of 
death globally (World Health Organization [WHO], 2015).  The Global Burden of Disease study 
estimated that 29.6% of all deaths worldwide (approximately 15.6 million deaths) were caused 
by CVD in 2010, more than all communicable, maternal, neonatal, and nutritional disorders 
combined, and double the number of deaths caused by cancers (Nichols, 2014).  In the US, based 
on 2011 death rate data, more than 2150 Americans die from CVD daily, an average of 1 death 
every 40 seconds (Mozffarian, 2015).  Of great concern, approximately 155,000 Americans 
dying from CVD are less than 65 years of age (Mozffarian, 2015).  In Europe, CVD remains the 
most common cause of deaths, resulting in almost 2 times as many deaths as cancer 
(Townsend, 2015). 
Elevated LDL-C is a major modifiable risk factor for the development of atherosclerosis and 
CVD (Sharrett, 2001).  Evidence supporting LDL-C as a therapeutic target and surrogate for 


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cardiovascular (CV) outcomes comes from interventional studies with LDL-C-lowering 
therapies, epidemiological studies, and genetic variants (both gain of function and loss of 
function).  Large randomized clinical studies aimed at lowering LDL-C show a consistent, 
log-linear relationship between LDL-C reduction and CV risk reduction, independent of the 
mechanism for LDL-C lowering (Kathiresan, 2008; Baigent, 2010; Robinson, 2005; 
Stamler, 1986).  A published patient-level meta-analysis including 26 trials and more than 
160,000 participants, showed a consistent relationship between LDL-C reduction and CV 
outcomes (Baigent, 2010).  This analysis showed that a 1 mmol/L (~39 mg/dL) reduction in 
LDL-C was associated with a 22% reduction in the 5-year incidence of major coronary events, 
revascularizations, and ischemic strokes.  Thus, LDL-C is largely accepted as a valid surrogate 
endpoint of CV events by clinicians and regulatory authorities (Stone, 2013). 
Statins are central to the LDL-C-lowering strategy and are supported by a large body of data 
demonstrating robust effectiveness in lowering LDL-C and reducing the risk of CVD 
(Waters, 2006; Grundy, 2004).  However, there is increasing awareness of the limitations and 
risks of statin use.  Many individuals at risk for CVD fail to achieve LDL-C goals (Martin, 2013; 
Virani, 2011).  In 2011, the FDA mandated safety-labeling changes limiting the use of high dose 
(80 mg) simvastatin due to safety concerns of muscle injury or myopathy (Egan, 2011).  
Although myopathy events are rare, a more widespread problem is various muscle side effects 
such as pain and weakness, particularly at high doses, leading to poor tolerability and lack of 
persistence on statin therapy (Cohen, 2012).  It is estimated that approximately 10% of patients 
who are prescribed statins are considered statin intolerant (Bruckert, 2005).  Statin intolerance 
(SI) in patients most frequently manifests as muscle soreness and aching, but a range of signs 
and symptoms may be present, including elevated liver enzymes, gastric upset, diarrhea, 
constipation, rash, headache, dizziness, mental confusion, forgetfulness, or erectile dysfunction 
(Eckel, 2010).  Given the importance of statin treatment for lowering CVD risk, statin 
discontinuation can have a marked adverse impact on CV outcomes in this population 
(Stroes, 2015).  A study found that SI patients who discontinued therapy demonstrated a 
nonsignificant trend toward increased 8-year all-cause mortality compared with those who 
remained on statin therapy (Mampuya, 2013). 
Other than statins, only a few drugs are approved to lower LDL-C, none of which are approved 
in the US to treat patients with SI.  Currently, there are no approved drugs or studies that 
demonstrate CV risk reduction in the SI population.  In the EU there are lipid-lowering therapies 
approved for SI patients such as the proprotein convertase subtilisin kexin type 9 (PCSK9) 
inhibitors, ezetimibe, bempedoic acid, and bempedoic acid and ezetimibe.  Although LDL-C 
lowering is robust with PCSK9 inhibitors, use of these drugs is limited by mode of 
administration and other accessibility issues.  Ezetimibe is an intestinal cholesterol absorption 
inhibitor that lowers LDL-C by 18% in patients with primary hyperlipidemia (Knopp, 2003).  
Other LDL-C-lowering therapies include colesevelam, a bile acid sequestrant that lowers LDL-C 
by up to 18% but is limited by considerable gastrointestinal side effects (Insull, 2001), while 
extended-release niacin in doses up to 2 g lowers LDL-C by up to 17% (Goldberg, 1998).  
Finally, fenofibrate, an activator of peroxisome proliferator-activated receptor alpha, lowers 
LDL-C by approximately 20% in patients with hypercholesterolemia (Knopp, 1987), but may 
substantially increase LDL-C in patients with hypertriglyceridemia. 


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Statin intolerance is a significant barrier to successful cholesterol management, particularly in 
CVD patients (Harris, 2011).  Therefore, a once-daily oral therapy demonstrated to reduce CV 
events in patients who are statin intolerant can fulfill an unmet medical need. 
4.2. 
Background on Bempedoic Acid  
4.2.1. 
Mechanism of Action 
Bempedoic acid is a first-in-class small molecule that decreases cholesterol synthesis in the liver. 
Bempedoic acid is a prodrug that requires coenzyme A (CoA) activation by very long-chain 
acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA.  ETC-1002-CoA inhibits ACL, an enzyme 
upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway.  Like statins, 
bempedoic acid decreases liver cholesterol synthesis which results in increased LDL receptor 
activity and LDL particle clearance from the blood.  
Both ETC-1002-CoA (via ACL inhibition) and statins (via HMG-CoA reductase inhibition) 
inhibit cholesterol synthesis in the liver, but an important differentiating feature is that unlike 
statins, bempedoic acid is inactive in skeletal muscle.  This is consistent with the absence of 
ACSVL1 (the synthetase required to activate bempedoic acid to ETC-1002-CoA and inhibit 
ACL) expression in muscle tissue.  Evidence suggests that muscle-related adverse effects 
associated with statin use is a result of HMG-CoA reductase inhibition directly in skeletal muscle 
leading to a reduction of several downstream biological intermediates within the cholesterol 
synthesis pathway important for muscle cell function.  Since bempedoic acid is not activated to 
ETC-1002-CoA and does not inhibit cholesterol synthesis in muscle tissue, it is anticipated that 
negative muscle-related adverse effects associated with statin use may be avoided by use of 
bempedoic acid. 
Due to the position of ATP-ACL in the lipid biosynthesis pathway upstream of HMG-CoA 
reductase, its inhibition also results in concomitant suppression of fatty acid synthesis and 
potential improvement in glycemic control (Ference, 2019).  In nonclinical disease models where 
elevated hepatic fatty acid synthesis promotes the accumulation of lipotoxic metabolites, 
inflammatory signaling, and insulin resistance; treatment with bempedoic acid improves 
inflammatory status and insulin sensitivity (Pinkosky, 2013; Samsoondar, 2017).  Therefore, the 
impact of bempedoic acid on fatty acid synthesis in the liver provides a mechanistic basis for 
improvements in glycemic control. 
4.2.2. 
Nonclinical Experience 
The primary pharmacology of bempedoic acid was evaluated in several well-characterized and 
predictive rodent models of dyslipidemia.  In these studies, bempedoic acid lowered LDL-C and 
triglycerides (TGs) and increased high-density lipoprotein cholesterol (HDL-C).  In a study of 
cholesterol-fed LDL receptor-deficient mice, bempedoic acid substantially slowed the 
progression of atherosclerosis in a dose-related manner. 
Results of the nonclinical safety pharmacology studies did not identify any significant risks for 
subjects over the mean range of bempedoic acid exposures in clinical studies. 
In toxicology studies, evaluations of bempedoic acid in mice, rats, and monkeys in oral studies 
up to 52 weeks in duration have been completed.  No significant central nervous system (CNS), 


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respiratory, or CV liabilities were identified.  Target organs identified in repeat-dose studies 
were liver in rats, and liver and kidney in monkeys, and changes were reversible following 
cessation of treatment.  Changes in clinical laboratory parameters indicative of hepatic and renal 
function were observed in animals at doses lower than those associated with frank toxicity. 
Bempedoic acid is nonmutagenic and nonclastogenic in both in vitro and in vivo genetic 
toxicology assays.  
In the pivotal 26-week rat study, the no-observed-adverse-effect level (NOAEL) dose was 
30 mg/kg/day in rats and the corresponding area under the curve during 24 hours (AUC0-24) 
values of the sum of bempedoic acid and its metabolite ESP15228 were up to 528 µghr/mL.  In 
the pivotal 52-week monkey study, the NOAEL dose was 60 mg/kg/day and the corresponding 
AUC0-24 values of the sum of bempedoic acid and ESP15228 were up to 4760 µghr/mL. 
In vitro studies indicated that bempedoic acid is neither an inhibitor nor inducer of major 
cytochrome P450 (CYP) enzymes at clinically relevant plasma concentrations.  In addition, 
bempedoic acid does not appear to inhibit major drug transporters. 
Please refer to the most recent Investigator’s Brochure (IB) for additional information regarding 
pharmacology, pharmacokinetics (PK), and nonclinical safety studies. 
4.2.3. 
Previous Human Experience 
Detailed information on the clinical effects of bempedoic acid in indicated patient populations 
are provided in the country-specific prescribing information within the current United States 
Prescribing Information (USPI) and the EU Summary of Product Characteristics (SmPC). 
Please refer to the most recent IB for information regarding previous human experience. 
4.2.4. 
Dose Selection 
Doses of bempedoic acid ranging from 40 to 240 mg/day have been evaluated in the Phase 2 
program.  Based on data from the integrated analysis of safety and efficacy, observed values and 
percent change from baseline in the primary efficacy endpoint, LDL-C, together with a positive 
safety profile, support the choice of the 180 mg dose for the Phase 3 studies.  An integrated 
analysis of six Phase 2 studies resulted in placebo-adjusted LS means for percent change from 
baseline of approximately 32% with bempedoic acid 180 mg monotherapy, 50% with bempedoic 
acid 180 mg + ezetimibe 10 mg, and 22% for 180 mg on top of stable statin therapy.  The 
180 mg dose was noted to have an excellent safety profile.  Overall, balancing efficacy and 
safety the 180 mg dose was chosen for the Phase 3 program. 
4.3. 
Risk Benefit Summary 
To date, the nonclinical and clinical data indicate that bempedoic acid 180 mg has a favorable 
risk-benefit profile.  The ability of bempedoic acid to achieve clinically meaningful LDL-C 
lowering while demonstrating a favorable tolerability profile in a variety of patient populations 
supports continued development of bempedoic acid. 
Two Phase 2 clinical studies have assessed bempedoic acid in patients unable to tolerate statins 
due to muscle related side effects (1002-006 and 1002-008).  These studies have demonstrated 
that the magnitude of LDL-C lowering due to bempedoic acid treatment in patients with SI is 


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similar to that occurring in patients who tolerate statins.  Additionally, in patients with SI, the 
safety and tolerability profile of bempedoic acid was similar to either ezetimibe (1002-008) or 
placebo (1002-006). 
Although a large body of data has shown that LDL-C lowering, particularly via inhibition of 
cholesterol synthesis and up-regulation of LDL receptors, results in reduced CV risk, the direct 
effect of bempedoic acid on reducing CV risk has not previously been assessed.  That is the 
purpose of this study. 
Please refer to the most recent IB for additional information regarding previous human 
experience. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Objectives 
5.1.1. 
Primary Objective 
The primary objective is to evaluate whether administration of bempedoic acid 180 mg/day 
versus placebo reduces the risk of MACE in patients with, or at high risk for, CVD who are 
statin intolerant.  This will be assessed with a composite primary efficacy endpoint that includes 
time to first occurrence of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or 
coronary revascularization. 
5.1.2. 
Secondary Objectives  
• To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus 
placebo reduces the risk of other clinical endpoints of CV morbidity and mortality 
and all-cause mortality 
• To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on LDL-C and high-sensitivity C-reactive protein (hs-CRP) 
• To evaluate the long-term safety and tolerability of bempedoic acid 180 mg/day 
compared to placebo 
• To evaluate the 12-month efficacy of treatment with bempedoic acid 180 mg/day 
versus placebo on absolute change in hemoglobin A1C (HbA1C) in the Inadequately 
Controlled Diabetes Efficacy Population (patients with type 2 diabetes mellitus and 
having an HbA1C of 7% or greater at baseline) 
• To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus 
placebo reduces the risk of new-onset diabetes  
5.1.3. 
Tertiary Objective 
• To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol 
(TC), HDL-C, TG, HbA1C, and fasting glucose 
5.2. 
Study Endpoints 
The following endpoints will be used to evaluate the objectives of the study. 
5.2.1. 
Primary Efficacy Endpoint 
• Time to first occurrence of a MACE, where MACE is defined as the composite 
endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization 


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5.2.2. 
Secondary Efficacy Time-to-Event Endpoints 
Key secondary efficacy time-to-event endpoints: 
• Time to first occurrence of the composite endpoint of CV death, nonfatal MI, or 
nonfatal stroke 
• Time to first occurrence of (fatal + nonfatal) MI 
• Time to first occurrence of coronary revascularization 
• Time to first occurrence of (fatal + nonfatal) stroke 
• Time to CV death 
• Time to all-cause mortality 
Secondary efficacy time-to-event endpoints: 
• Time to first occurrence of the composite endpoint of all-cause mortality, nonfatal 
MI, nonfatal stroke, or coronary revascularization 
• Time to first occurrence of nonfatal MI 
• Time to fatal MI 
• Time to first occurrence of nonfatal stroke 
• Time to fatal stroke 
• Time to first occurrence of (fatal + nonfatal) hemorrhagic stroke 
• Time to first occurrence of (fatal + nonfatal) nonhemorrhagic stroke  
• Time to hospitalization for unstable angina 
• Time to first occurrence of new-onset type 2 diabetes mellitus defined by one or more 
of the following criteria according to the current American Diabetes Association 
(ADA) guidelines (ADA, 2014): 
1. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L).  Fasting is defined as no caloric 
intake for at least 8 hours;* or 
2. Two-hour post-prandial glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose 
tolerance test as defined in the ADA guidelines;* or 
3. HbA1C measurement ≥6.5% (48 mmol/mol);* or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
*Note:  In the absence of unequivocal hyperglycemia, diagnosis requires 2 abnormal test results 
from the same sample or in 2 separate test results. 


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5.2.3. 
Secondary Efficacy Lipid and Biomarker Endpoints 
• Percent change from baseline to Month 6 in LDL-C  
• Percent change from baseline to Month 6 in hs-CRP 
• Absolute change from baseline to Month 12 in HbA1C in patients in the inadequately 
controlled diabetes efficacy population (patients with type 2 diabetes mellitus and an 
HbA1C of 7% or greater at baseline) 
5.2.4. 
Tertiary Efficacy Lipid and Other Biomarker Endpoints 
• Percent change from baseline to Months 3, 12, 24, and end-of-study in LDL-C; 
percent change from baseline to Months 3, 6, 12, 24, and end-of-study in HDL-C, 
non-HDL-C, TC, and TG 
• Absolute change from baseline to Months 3, 6, 12, 24, and end-of-study in LDL-C  
• Percent change from baseline to Month 12 and end-of-study in hs-CRP 
• Absolute change from baseline to Month 3, 6, every 6 months following Month 12, 
and end-of-study in HbA1C in patients in the Inadequately Controlled Diabetes 
Efficacy Population (patients with type 2 diabetes mellitus and HbA1C of 7% or 
greater at baseline) 
• Absolute change from baseline to Month 3, 6, 12, every 6 months following 
Month 12, and end-of-study in fasting glucose in patients in the Normoglycemia 
Efficacy Population, Prediabetes Efficacy Population, No Diabetes Efficacy 
Population, and Diabetes Efficacy Population 
5.2.5. 
Safety Endpoints 
• Adverse events (AEs including adverse events of special interest [AESI]), vital signs 
(eg, heart rate, weight, blood pressure [BP]), and clinical laboratory measures 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study assessing the occurrence of MACE in patients with, or at high risk for, CVD who are 
unable to tolerate statin therapy.  The study will be conducted at approximately 1200 clinical 
sites in 32 countries. 
Following signing of an informed consent document (ICD) prior to any study procedures, 
screening (Visit S1) will occur approximately 5 weeks prior to Day 1 (Visit T1) (Note:  the 
screening period can be extended for an additional 5 weeks if needed to adjust background 
therapy or for other reasons).  All eligible patients in stable condition and who meet all the entry 
criteria will return for Week -4 (Visit S2) to initiate a 4-week Run-in Period with single-blind 
(blinded to patient only) daily placebo treatment.  At Day 1 (Visit T1), assessment of tolerability 
and adherence to IMP (single-blind placebo) during run-in, laboratory results, and other 
screening assessments will be reviewed to confirm eligibility prior to randomization.  Patients 
who meet all entry criteria will be eligible for randomization into the study. 
Randomization numbers will be assigned via interactive web response system (IWRS) at Day 1 
(Visit T1).  Approximately 14,000 eligible patients will be randomized in a ratio of 1:1 to receive 
1 of the 2 following treatments in a double-blind fashion: 
• Bempedoic acid 180 mg tablet once daily (n = 7000) 
• Matching placebo tablet once daily (n = 7000) 
Please note that among other qualifying events, patients may meet the CVD inclusion criterion 
by being part of the group identified as “at high risk for a CVD event” based on Reynolds risk, 
SCORE risk, or coronary artery calcium score.  It is anticipated that less than 30% of total 
patients will fall into this group by meeting the CVD inclusion criterion based solely on the 
events listed above.  If, during the randomization period, more than 30% of the overall 
14,000 patients are part of this group (more than 4200 randomized patients), then recruitment 
into this group may be capped. 
Treatment with randomized, double-blind IMP will begin at Visit T1 and continue daily.  
Randomized patients will return for clinic visits at Month 1 (Visit T2), Month 3 (Visit T3), and 
Month 6 (Visit T4).  Following Month 6, patients will be contacted every 3 months (alternating 
phone visits and clinic visits) for the remainder of the study.  The study will continue until the 
following 3 conditions are met:  1) at least 1620 patients have experienced an adjudicated 
primary 4-component MACE (CV death, nonfatal MI, nonfatal stroke, or coronary 
revascularization), 2) at least 810 patients have experienced an adjudicated 3-component MACE 
(CV death, nonfatal MI, or nonfatal stroke), and 3) 24 months (2 years) have elapsed since the 
last patient was randomized.  It is estimated that average treatment duration for all randomized 
patients will be approximately 3.5 years.  For each patient, the last treatment visit will be a clinic 
visit, with a follow-up phone call approximately 30 days after study treatment completion.  
Patients who discontinue IMP for any reason will remain in the study to be evaluated for efficacy 
and safety endpoints and will be expected to continue study visits (preferred) or agree to some 


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other form of contact with the site for the remainder of the study.  For details of study 
assessments, see the Schedule of Events in Appendix 1. 
This study will include several independent and expert committees.  An Executive Committee 
(EC) will oversee the design and conduct of the study and the interpretation of study results.  A 
Clinical Events Committee (CEC) will adjudicate blinded clinical endpoints, including MACE 
endpoints, as well as non-CV deaths using standardized definitions.  An adjudicated clinical 
endpoint will not be reported as a serious adverse event (SAE).  A Diabetes Committee (DC) 
will verify diagnosis of new onset diabetes.  A Tendon Rupture Adjudication Committee 
(TRAC) will adjudicate AEs of tendon rupture using standardized definitions.  An independent 
Data Monitoring Committee (DMC) will review accumulating blinded and unblinded safety data 
from this and other ongoing studies of bempedoic acid approximately 4 times per year.  Safety 
data reviewed by the DMC will include AEs, clinical endpoints, and lipids.  Each of these 
committees has a charter that includes additional details. 
6.2. 
Study Hypotheses 
This superiority study will test the hypothesis that bempedoic acid, compared to placebo, will 
reduce the risk of CV events in patients with, or at high risk for, CVD who are statin intolerant. 
In addition, it will test the hypothesis that bempedoic acid, compared to placebo, will delay time 
to first occurrence of new-onset diabetes in patients in the prediabetes subpopulation.  It will also 
test the hypothesis that bempedoic acid, compared to placebo, will reduce absolute change from 
baseline to Month 12 in HbA1C in patients in the inadequately controlled diabetes subpopulation. 
6.3. 
Estimated Study Duration and Period 
The estimated enrollment period is approximately 33 months.  It is estimated the median 
treatment duration will be approximately 42 months (3.5 years), with all patients remaining in 
the study for a minimum of 24 months (2 years) and some patients remaining in the study for up 
to approximately up to 72 months (6 years).  The study will continue until all 3 criteria for study 
end described in Section 6.5 have been met.  Depending on the rates of accumulating endpoints 
in this study, the study duration may be shorter or longer.  The estimated overall duration of the 
study (first patient first visit to last patient last visit) is approximately 72 months (6 years). 
For each patient, the actual duration of treatment will depend on time of randomization versus 
when the ‘End of Study’ conditions have been met.  All patients will be followed from 
randomization through the date of study termination unless the patient has withdrawn consent, 
irrespective of whether the patient is continuing to receive study treatment.  
6.4. 
Number of Centers 
Up to approximately 1200 centers will participate in this study worldwide.  Additional sites may 
be invited to participate to ensure study timelines are met.  Sites that do not enroll patients within 
3 to 6 months of being open for enrollment may be closed. 


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6.5. 
End of Study 
This study is event-driven.  The study will end when all of the following have occurred: 1) at 
least 1620 patients have experienced an adjudicated primary 4-component MACE, 2) at least 
810 patients have experienced an adjudicated 3-component MACE (CV death, nonfatal MI, 
nonfatal stroke), and 3) at least 24 months (2 years) have elapsed since the last patient was 
randomized. 
6.6. 
Number of Patients 
The study will enroll approximately 14,000 adult male and female patients. 


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7. 
SELECTION OF PATIENTS 
Please note that among other qualifying events, patients may meet the CVD inclusion criterion 
by being part of the group identified as “at high risk for a CVD event” based on Reynolds risk, 
SCORE risk, or coronary artery calcium score.  It is anticipated that less than 30% of total 
patients will meet the CVD inclusion criterion based solely on Reynolds risk, SCORE risk, or 
coronary artery calcium score.  If, during the randomization period, more than 30% of the overall 
14,000 patients are part of this group (more than 4200 randomized patients), then recruitment 
into this group may be capped. 
7.1. 
Subject Inclusion Criteria 
Each patient must meet the following criteria to be eligible for this study. 
1. Provision of signed informed consent prior to any study-specific procedure. 
2. Patient-reported SI due to an adverse safety effect that started or increased during statin 
therapy and resolved or improved when statin therapy was discontinued resulting in an 
inability to tolerate: 
• 2 or more statins at any dose, or  
• 1 statin at any dose and unwilling to attempt a second statin or advised by a physician 
to not attempt a second statin.  
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) and well tolerated.  
3. Written confirmation by both patient and investigator that the patient is statin intolerant 
as defined above, aware of the benefit of statin use to reduce the risk of MACE including 
death, and also aware that many other patients who are unable to tolerate a statin are able 
to tolerate a different statin or dose. 
4. Age ≥18 years or legal age of majority based on regional law, whichever is greater, and 
≤85 years at Week -5 (Visit S1). 
5. Men and nonpregnant, nonlactating women.  Women must be one of the following: 
• 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 


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• Women of childbearing potential willing to use an acceptable method(s) of birth 
control during the study and for 30 days after the end of treatment, including: 
− oral, topical, injectable, or implantable 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 that is in line with the preferred and usual lifestyle of the patient 
(periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], declaration of abstinence for the duration of the study or withdrawal are 
not acceptable methods of true abstinence). 
There are no protocol-specific birth control requirements for men with partners who are 
able to become pregnant. 
6. Fasting LDL-C ≥100 mg/dL (2.6 mmol/L) at Week -5 (Visit S1) while taking stable 
(4 weeks prior to Visit S1) and optimized background LDL-C-lowering therapies that 
may include very low dose statin (see definition above), ezetimibe, niacin, bile acid 
resins, fibrates, and/or PCSK9 inhibitors. 
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 repeat value will be 
used to determine eligibility. 
7. History of, or at high risk for, CVD including documented evidence of one or more of the 
following: 
a. Documented history of CVD (ie, secondary prevention) 
− Coronary artery disease, defined by: 
○ MI (either ST-elevation MI or non-ST-elevation MI) occurring greater than 
90 days prior to screening, or 
○ Percutaneous coronary or surgical coronary revascularization, occurring 
greater than 90 days prior to screening, 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 or angiogram (including CTA) 
showing ≥50% stenosis (ankle brachial index will be measured after a period 
of rest and with the patient in the supine position using a Doppler device), or 
○ Peripheral arterial revascularization (surgical or percutaneous), occurring 
greater than 90 days prior to screening, or 


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○ Abdominal aortic aneurysm confirmed by imaging or aortic aneurysm repair, 
occurring greater than 90 days prior to screening, or 
○ Lower extremity amputation due to peripheral vascular disease, occurring 
greater than 90 days prior to screening, or 
− Cerebrovascular atherosclerotic disease defined by: 
○ Ischemic stroke occurring greater than 90 days prior to screening, or 
○ Carotid endarterectomy, carotid stenting, or more than 70% stenosis in a 
carotid artery determined by carotid ultrasound or angiogram (Note:  If 
stenosis assessed by carotid ultrasound is reported as range between 
60%-79%, patient may qualify only if internal carotid artery peak systolic 
velocity is >230 cm/sec), occurring greater than 90 days prior to screening, or 
b. High risk for a CVD event (ie, high-risk primary prevention) 
− Reynolds Risk score >30% or a SCORE Risk score >7.5% over 10 years (see 
Appendix 3 and Appendix 4 for additional details), or 
− Coronary artery calcium score >400 Agatston units (AU) at any time in the past, 
or 
− Patients with type 1 or type 2 diabetes, aged >65 years (women) or >60 years 
(men). 
7.2. 
Subject Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible to participate: 
1. Total fasting TG >500 mg/dL (5.6 mmol/L) at Week -5 (Visit S1). 
Note:  A single repeat 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 defined as either nephritic or nephrotic 
syndrome, 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. 
3. Forms of CVD that include any of the following: 
a. Recent (within 90 days prior to or during screening) acute CVD events including, but 
not only transient ischemic attack (TIA), MI, coronary revascularization, peripheral 
arterial revascularization, ischemic stroke, carotid endarterectomy, carotid stenting,  
b. Recent (within 90 days of screening) unstable or symptomatic cardiac arrhythmia 
(including any associated medication changes).  Patients with stable well-controlled 
atrial arrhythmias will be allowed to participate in the study. 


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c. Patients with implantable pacemakers or automatic implantable cardioverter 
defibrillators may be considered if deemed by the investigator to be stable for greater 
than 90 days prior to screening, 
d. New York Heart Association (NYHA) Functional Classification Class IV heart 
failure, 
e. Uncontrolled hypertension, defined as mean sitting systolic blood pressure (SBP) 
≥180 mmHg and/or diastolic blood pressure (DBP) ≥110 mmHg, 
Note:  At the discretion of the investigator, 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. 
f. Planned coronary revascularization (patient may rescreen 3 months post-procedure). 
4. HbA1C ≥10% at Week -5 (Visit S1). 
5. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the 
upper limit of normal (ULN) at Week -5 (Visit S1).  Note:  At the discretion of the 
investigator, thyroid replacement therapy can be adjusted and/or additional measurement 
of TSH may be completed prior to randomization, with the repeat TSH value used to 
determine eligibility. 
6. Liver disease or dysfunction, including: 
a. Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C 
antibodies (HCV-ABVivi) at Week -4 (Visit S2), or 
b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 × 
ULN at Week -5 (Visit S1). 
Note:  At the discretion of the investigator, a single repeat of ALT and/or AST 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 RNA is negative, patient 
can be enrolled. 
7. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® 
or gastric bypass) that may affect drug absorption. 
8. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10 g/dL at Week -5 
(Visit S1). 
9. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in 
the past 5 years.  Nonmetastatic basal or squamous cell carcinoma of the skin and 
cervical carcinoma in situ are allowed. 
10. Unexplained creatine kinase (CK) >3 × ULN at Week -5 (Visit S1) (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. 


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11. History within the last 2 years of drug, alcohol, amphetamine and derivatives, or cocaine 
abuse.  Patients with amphetamine derivatives prescribed by and under the care of a 
health care practitioner can be enrolled after evaluation by the investigator. 
12. Blood transfusion for any reason within 30 days prior to randomization. 
13. Use of any experimental or investigational drugs within 30 days prior to screening or 
5 half-lives, whichever is longer. 
14. Randomization into another Phase 3 bempedoic acid clinical study. 
15. 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 (must be stopped at least 2 weeks prior to Week -5 [Visit S1]), 
• 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. 
16. Planned initiation or dose adjustments of these allowed drugs prior to screening and 
during the clinical trial (stable use of these drugs is permitted): 
• Statins are allowed only 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 (must be stable at least 4 weeks prior to Week -5 
[Visit S1]) , 
• Other lipid-regulating drugs or supplements must be stable at least 4 weeks prior to 
Week -5 [Visit S1]), 
• PCSK9 inhibitors (must be stable at least 12 weeks prior to Week -5 [Visit S1]). 
17. Lack of adherence (ie, less than 80% of planned doses) with IMP (single-blind placebo) 
during the Run-in Period. 
18. Lack of tolerance with IMP (single-blind placebo) during the Run-in Period. 
19. 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. 
20. An employee or contractor of the facility conducting the study, or a family member of the 
Principal Investigator, Co-Investigator, or Sponsor. 
21. Pregnant, breastfeeding, or intending to become pregnant within 30 days after study 
completion or last dose of IMP. 
7.3. 
Patient Lifestyle and Dietary Guidelines 
Patients will fast for a minimum of 10 hours prior to collection of all laboratory samples (water 
and concomitant medications are permitted). 


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Patients will be counseled to follow a heart-healthy diet as per local or regional guidelines and 
should be encouraged (as able) to participate in a regular exercise program throughout the study. 
Women of childbearing potential must use an acceptable method(s) of birth control during the 
study and for 30 days after the end of treatment.  Acceptable method(s) of birth control are 
defined in Section 7.1. 


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8. 
TREATMENT OF PATIENTS 
8.1. 
Administration of Investigational Medicinal Product 
During the Run-in Period, all patients will receive single-blind placebo (once daily tablets).  
During the Treatment Period, patients will be randomized to receive IMP of either bempedoic 
acid 180 mg or placebo once daily.  Each dose of IMP is comprised of 1 tablet from 1 bottle.  
The IMP will be dispensed at most, but not all, scheduled clinic visits.  Patients will be instructed 
to ingest IMP orally once daily at a similar time with or without food. 
If the patient forgets to take IMP on nonclinic visit days, it may be taken up to 12 hours later the 
same day.  After that time, the patient should not take IMP that day and should resume ingestion 
of IMP the following day.  Details describing the reasons for nondosing should be documented in 
the patient’s medical records and electronic case report form (eCRF).  Extra IMP is provided and 
can be used, if needed, prior to the next visit or to replace a dose of IMP that cannot be used 
because it is lost or damaged. 
Other details regarding IMP, including description, supply and control, accountability, handling, 
and disposal are provided in Section 9. 
8.2. 
Prior and Concomitant Medications 
Patients will be questioned about their concomitant medication use at each clinic visit. 
Patients in this study may be using a wide range of concomitant medications, according to local 
standard of care for their medical conditions.  Patients will be permitted to take any concomitant 
medications required except those listed in Section 8.2.1.  Therapies to lower LDL-C may 
include nonstatin drugs and supplements such as ezetimibe, niacin, bile acid resins, fibrates, 
PCSK9 inhibitors, plant sterols, and plant stanols, but not red yeast rice.  Statin use will be 
limited to the doses listed below and must be currently well tolerated.  Additionally, patients may 
use any TG-lowering drugs and supplements. 
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 Nonstatin Medications eCRF will be used to record nonstatin 
medications, herbal remedies, vitamins, other supplements, and over-the-counter medications 
taken within 3 months prior to screening and during the study. 
The Prior and Concomitant Statin Therapy for Dyslipidemia eCRF will be used to record statin 
medications taken at any point in the past in order to document patient’s efforts to utilize statins.  
In addition to statin type, dose, and frequency of use, information about start dates, stop dates, 
and reason for discontinuation will be collected when available. 
8.2.1. 
Prohibited Medications and Dietary Supplement 
Patients may not have used medications (monotherapies or combination therapies) listed below 
within the time periods indicated, and may not use these drugs during the study: 
• Mipomersen (within the last 6 months prior to Week -5 [Visit S1]), lomitapide, or 
apheresis therapy (within the last 3 months prior to Week -5 [Visit S1]) 


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• Red yeast rice, also known as monascus purpureus extract or Cholestin, (within the 
last 2 weeks prior to Week -5 [Visit S1]) 
• If approved and commercially available, bempedoic acid or the fixed dose 
combination of bempedoic acid and ezetimibe 
• Any statin taken within the first 6 months at average daily doses greater than those 
listed in Section 8.2.2 below.  However, beginning at Month 6, if the threshold for 
elevated LDL-C levels has been met and confirmed as described in the monitoring 
and management section of the protocol (Section 12.1.6.3.3), average daily doses of 
statins greater than those listed in Section 8.2.2 below may be used in accordance 
with the standard of care and local practice.  Simvastatin at average daily doses 
greater than or equal to 40 mg and pravastatin at average daily doses greater than or 
equal to 80 mg may not be used while the patient is taking IMP. 
8.2.2. 
Permitted Medications 
Permitted medications must be stable for at least 2 weeks prior to Visit S1 (Week -5) with the 
exception of PCSK9 inhibitors, which must be stable for 12 weeks prior to screening and other 
lipid-regulating medications that must be stable for 4 weeks prior to screening and during the 
study.  Stable is defined as no addition or cessation of a drug or change in the dose of a drug. 
Lipid-regulating medications and dietary supplements including but not limited to: 
Statins – permitted only at average daily doses defined below provided these statin/doses 
are currently well tolerated.  However, beginning at Month 6, if the threshold for elevated 
LDL-C levels has been met and confirmed as described in the monitoring and management 
section of the protocol (Section 12.1.6.3.3), average daily doses of statins greater than those 
listed below may be used in accordance with the standard of care and local practice.  Simvastatin 
at average daily doses greater than or equal to 40 mg and pravastatin at average daily doses 
greater than or equal to 80 mg may not be used while the patient is taking IMP. 
• Atorvastatin <10 mg 
• Fluvastatin <40 mg  
• Lovastatin <20 mg 
• Pravastatin <40 mg 
• Pitavastatin <2 mg 
• Rosuvastatin <5 mg 
• Simvastatin <10 mg 
Selective cholesterol and/or bile acid absorption inhibitors 
• Cholestyramine/Colestipol/Colesevelam hydrochloride  
• Ezetimibe 


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Fibrates 
• Fenofibrate 
• Bezafibrate 
• Ciprofibrate 
• Gemfibrozil 
PCSK9 inhibitors 
• Evolocumab 
• Alirocumab 
• Other PCSK9 inhibitors that may become commercially available 
Niacin derivatives 
Other TG-lowering agents containing 
• Eicosapentaenoic acid (EPA) and/or  
• Docosahexaenoic acid (DHA) 
8.3. 
Treatment Assignment, Randomization, and Blinding 
During the Run-in Period, all patients will receive single-blind (blinded to patient only) daily 
placebo.  Sponsor and site personnel will be aware that this single-blind IMP is placebo, and will 
ensure that this information is not in any manner provided to the patient. 
During the Treatment Period, patients will receive double-blind IMP.  At Day 1 (Visit T1), 
patients will be randomized to receive either bempedoic acid 180 mg/day or placebo.  The 
investigator or designee will utilize IWRS during the visit to obtain a randomization number and 
the appropriate IMP container via medication identification numbers (MED ID).  A patient is 
considered to be randomized when they have been assigned a randomization number by IWRS. 
The randomization number will be determined by a computer-generated random code and will 
correspond to a treatment group according to patient’s sequential entrance into the study.  The 
randomization schedule for blinding of treatment assignment will be generated by the contract 
research organization (CRO), provided to IWRS, and released only after the study is complete 
and the database is locked. 
During the Treatment Period, Sponsor, site personnel, CRO, and patient will all be unaware of 
patient’s treatment assignment. 
Blinding of treatment must be maintained for all patients unless, in the opinion of the 
investigator, the safety of the patient may be at risk.  Only under the rarest of circumstances 
should the investigator consider breaking the blind and only when medical/supportive care 
cannot be provided without determining if the patient is receiving active drug treatment.  In the 
event that the blind needs to be broken prior to completion of the study, the investigator should 
contact the appropriate Medical Monitor by telephone.  If the blind must be broken prior to 
consultation with the Medical Monitor, contact must be made within 24 hours of breaking the 
blind. 


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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.  Unblinding of IMP will NOT automatically discontinue the patient from the 
study.  Any patient for whom the blind is broken will be permanently discontinued from IMP but 
should continue in the study per Section 10.7.3. 
Postrandomization values for individual laboratory measures for LDL-C, non-HDL-C, TC, TG, 
and hs-CRP that may inadvertently suggest treatment assignment will not be available to 
personnel from the clinical site, the patient, the Sponsor, or the CRO.  While knowledge of these 
values does not truly ‘unblind,’ the completion of these lab assessments by the investigator, all 
collaborating physicians, or the patients locally (outside the study visits) is strongly discouraged.  
Investigators should not perform testing of these analytes at the local lab during the conduct of 
the study, except for TG levels that may be measured for some safety reasons. 
During the study, an independent DMC will monitor accumulating unblinded patient safety data 
summaries and an unblinded independent CRO programmer and statistician will provide data to 
the DMC.  Additional details will be provided in a DMC Charter. 


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9. 
INVESTIGATIONAL MEDICINAL PRODUCT  
9.1. 
Description of Investigational Medicinal Product 
Table 2: 
Investigational Medicinal Products 
Product Name: 
Investigational Medicinal Product 
Bempedoic acid 
Placebo 
Dosage Form: 
Film-coated tablets 
Film-coated tablets 
Unit Dose: 
180 mg 
Not applicable 
Container/Closure: 
100-count bottle with screw-on, 
non-childproof cap 
35- and 100-count bottle 
(depending upon visit) with 
screw-on, non-childproof cap 
Route of Administration: 
Oral, daily at similar time, with 
or without food 
Oral, daily at similar time, with 
or without food 
Physical Description: 
Oval, white to off-white 
film-coated tablet debossed with 
“ABC” on one face and 
debossed with “000” on the 
opposite face 
Oval, white to off-white 
film-coated tablet debossed with 
“ABC” on one face and 
debossed with “000” on the 
opposite face 
Please see Pharmacy Manual for detailed storage requirements and instructions. 
9.2. 
Investigational Medicinal Product Supply and Control 
The Sponsor will supply the IMP for this study.  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 MED ID number (an identifier on the IMP packaging) will be obtained via IWRS and used 
to select single- and double-blind IMP from available clinical supplies at the clinical site. 
IMP will be dispensed by the investigator or other qualified site personnel only to appropriate 
patients who have provided written informed consent. 
9.3. 
Packaging and Labeling 
Single-blind IMP will be packaged in bottles containing 35 tablets.  Double-blind IMP will be 
packaged in bottles containing 100 tablets. 
The IMP bottle labels will include protocol number, MED ID number, patient identification 
number, lot number, site number, and investigator name in addition to standard language 
regarding warnings and regulations, administration, and storage of the product. 


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9.4. 
Investigational Medicinal Product Adherence 
IMP Adherence during the Run-in Period 
In order to reduce the burden of unnecessary procedures on patients who may not be appropriate 
for this study, all patients will receive daily placebo during the 4-week Run-in Period to assess 
their adherence and ability to tolerate the single-blind treatment.  IMP (placebo) will be 
dispensed at Week -4 (Visit S2).  At Day 1 (Visit T1), designated clinical site staff will assess 
patient IMP intake adherence by counting the number of tablets that are returned as unused and 
by querying the patient with regards to daily intake.  If the patient has not taken all doses of IMP 
as instructed, the patient will be queried for a reason and findings will be documented.  Patients 
with adherence <80% will not be eligible for randomization. 
IMP Adherence during the Randomization Period 
At each clinic visit during the Treatment Period, designated clinical site staff will assess patient 
IMP intake adherence by counting the number of tablets that are returned as unused and by 
querying the patient with regards to daily intake.  If the patient has not taken multiple 
consecutive doses (ie, more than 5 consecutive doses) of IMP as instructed, the patient will be 
queried for a reason, findings will be documented, and the patient will be counseled on the 
importance of carefully following all dosing instructions.  Factors contributing to poor adherence 
will be determined and, if possible, remedied.  Patients demonstrating poor adherence during the 
Treatment Period will continue to be counseled on the importance of carefully following all 
dosing instructions but will not be removed from the study. 
9.5. 
Investigational Medicinal Product Accountability 
Patients will be instructed to return all packaging and unused IMP at every visit for assessment 
of adherence and drug accountability. 
Accurate records of the receipt of all IMP shipped by the Sponsor (or designee) and the 
disposition of that IMP must be maintained. 
IMP records or logs must comply with applicable regulations, local law, and guidelines, and 
should include: 
• Amount received/placed in storage area 
• Amount currently in storage area 
• MED ID number for all IMP 
• Dates and initials of person(s) responsible for IMP inventory (including 
entry/movement/disposition) 
• Date and amount of IMP dispensed to each patient, including unique patient 
identifiers 
• Date that IMP was returned by patient, assessment of adherence, and relevant 
documentation of discrepancies 
• Nonstudy disposition (eg, lost, broken, wasted) 


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• Amount returned to Sponsor (or designee)/destroyed or amount destroyed per local 
standard operating procedure (SOP) following accountability by site monitor. 
9.6. 
Investigational Medicinal Product Handling, Storage, and Disposal 
The Principal Investigator will ensure that all IMP is stored in a secured area, under 
recommended storage conditions (at room temperature [15°C/59°F to 30°C/86°F] protected from 
any extreme conditions of temperature, light, or humidity) in accordance with applicable 
regulatory requirements for investigational drugs.  Access to IMP will be limited to those clinical 
site personnel authorized by the investigator.  Upon completion or termination of the study, all 
IMP and used and unused IMP packaging must be returned to the Sponsor (or designee) for 
eventual destruction unless otherwise authorized by the Sponsor.  All IMP returns must be 
accompanied by the appropriate documentation. 


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10. 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
10.1. 
Informed Consent 
The patient must be adequately informed of the nature and risks of the study and understand the 
ICD.  It is the investigator’s responsibility that no study-related procedure will be performed 
until the patient has been completely informed of the study, has freely consented to take part in 
the study, and has signed and dated an ICD approved by the Sponsor (or designee) and the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  The written ICD 
should be prepared in the local language(s) of the potential patient population. 
10.2. 
Confirmation of Statin Intolerance 
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 and a discussion with 
the patient about the patient’s high risk of experiencing MACE, the ability of a statin to reduce 
that risk, and the patient’s experience using a statin.  For patients who are unwilling to attempt a 
second statin or a low dose despite physician encouragement, the investigator will explain that 
many patients unable to tolerate a single statin are able to tolerate a different statin or a lower 
dose. 
Both the patient and the investigator will sign a form confirming that the patient is statin 
intolerant.  Within this form, the patient will confirm an understanding that he/she is at high risk 
for experiencing a heart attack, stroke, or death and that using a statin would reduce that risk and 
also that many other patients who are unable to tolerate a single statin are able to tolerate a 
different statin or dose; however, he/she is 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 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. 
10.3. 
Interactive Web Response System and eCRFs 
Data will be captured on eCRFs.  Randomization, IMP (re)ordering, IMP distribution, and 
patient status tracking will occur via IWRS.  Instructions for these systems and additional contact 
time points for IWRS will be provided separately. 


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10.4. 
Patient Identification Numbers 
A unique patient identification number will be assigned to each patient to identify each patient 
throughout the study.  Patient identification numbers will be assigned sequentially by IWRS at 
the time of informed consent during the screening module transaction.  The 10-digit number is 
comprised of protocol, country, site, and patient-specific numbers (ie, 43 01 002 003 identifies 
Protocol 43, Country 01, Site 002, and Patient 003). 
10.5. 
Rescreening 
Patients who are screen or run-in failures due to stability requirements for a condition or 
concurrent medication or other reason may be considered for rescreening after consultation with 
the Sponsor (or designee).  If rescreened, these patients must also be re-consented and screening 
procedures must be repeated.  If a patient is a screen failure or a run-in failure, or if a patient 
discontinues from the study, their patient ID number will not be assigned to another patient. 
10.6. 
Procedures and Schedule of Assessments 
The study is comprised of 3 distinct periods: screening, run-in, and double-blind treatment. 
The schedule of study events is provided in Appendix 1.  However, a patient can be seen at any 
time for reasons of safety. 
Note:  If the patient discontinues IMP at any time after T1, please proceed to Section 10.7 for 
detailed instructions. 
• If the patient agrees to clinical visits after withdrawing from IMP at any time after 
Visit T1, the visit will include all procedures and assessments except for those 
pertaining to IMP management (IMP dispensing, adherence, and accountability). 
• If the patient agrees to telephone or other form of contact after withdrawing from IMP 
at any time after Visit T1, the contact will include collection of patient-reported 
information to complete the eCRF including concomitant medication use, AEs, SAEs, 
and potential clinical endpoints. 
• Patient is expected to continue to receive IMP and complete study visits following a 
clinical endpoint unless, for some reason, this is no longer clinically appropriate. 
10.6.1. 
Screening Week -5 (Visit S1; Day -35) 
The screening period will begin with a screening visit that will occur 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 10.1), the patient will undergo 
the following assessments and procedures at Visit S1: 
• Assess AEs, SAEs, and potential clinical endpoints (starting from signing the 
informed consent document) 
• Demographics 
• Clinically relevant medical history 


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• Prior and concomitant medication review 
• Review of all inclusion/exclusion criteria that can be assessed at this time 
• Height (cm), and weight (kg) 
• Vital signs 
• Central clinical laboratory evaluations: 
− TSH 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs) 
− hs-CRP (optional assessment to be completed only if patient qualifies based on 
Reynolds Risk Score and local hs-CRP value is not available) 
− HbA1C 
− Serum pregnancy test (in female patients of childbearing potential) or FSH (on 
postmenopausal women <55 years of age) 
• Contact IWRS to register the patient 
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 that can be assessed 
at Visit S1 are considered to be screen failures and are not required to return for additional visits 
(although a patient can be seen at any time for safety reasons). 
Note: 
• The number of days between Week -5 (Visit S1) and Week -4 (Visit S2) may be less 
than 7, and the number of days between Week -5 (Visit S1) and randomization may 
be less than 35 as long as eligibility can be determined. 
• The screening period can be extended for an additional 5 weeks without repeat of all 
screening procedures if needed to adjust background therapy or for other reason. 
• An additional visit prior to Visit S2 MAY be completed if patient fails to meet 
LDL-C and/or TG entry criterion.  If this optional visit is completed, the value from 
the repeat visit will be used to determine eligibility. 
• An additional visit and/or assessment between Visits S1 and T1 MAY be completed 
if the patient fails to meet DBP, SBP, TSH, eGFR, ALT, AST, and CK entry criteria.  
Patients may qualify for randomization after any associated medications have been 
adjusted, they have been on stable doses for at least 2 weeks, and the repeat 
assessment meets entry criteria. 


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10.6.2. 
Screening Week -4 (Visit S2; Day -31 to -25) 
• The single-blind Run-in Period for placebo begins at this visit.  The patient will 
undergo the following assessments and procedures at Visit S2:Concomitant 
medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Physical examination (PE) 
• 12-lead electrocardiogram (ECG) 
• Central clinical laboratory evaluations: 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) 
• Serology (including HBsAg, hepatitis C virus [HCV] antibody)  
• Dispense single-blind IMP (placebo) and dosing and storage instructions 
• Diet and exercise counselling 
10.6.3. 
Treatment Week 0 (Visit T1; Day 1) 
Prior to scheduling Visit T1, screening clinical results will be reviewed to determine whether the 
patient continues to meet lab eligibility criteria.  At Visit T1, adherence to and tolerability with 
placebo IMP during the Run-in Period (≥80% adherence required) will be assessed.  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 run-in IMP 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. 
The patient will undergo the following assessments and procedures at Day 1 (Visit T1): 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Return of unused single-blind IMP and assessment of IMP dosing adherence 
• Assessment of tolerability of IMP and continued interest in study participation 
• Review inclusion/exclusion criteria to establish patient eligibility 
• Weight 
• Vital signs 


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• Central clinical laboratory evaluations: 
- Hematology, blood chemistry, and urinalysis 
- Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TG) and 
hs-CRP 
• Urine pregnancy test (in female patients of childbearing potential) 
• IWRS contact to obtain the patient randomization number and MED ID number for 
double-blind IMP 
• Dispense double-blind IMP and provide dosing and storage instructions 
• Diet and exercise counselling 
• Schedule next visit 
10.6.4. 
Treatment Month 1 (Visit T2; ± 3 days) 
Patients will undergo the following assessments and procedures at Month 1 (Visit T2): 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Weight 
• Vital signs 
• Central clinical laboratory evaluations: 
- Limited blood chemistry safety panel (ALT, AST, total bilirubin [TB], and CK) 
• Return of IMP; assessment and recording of IMP dosing adherence 
• Re-dispense IMP container from Visit T1 to patient for continued dosing and provide 
dosing and storage instruction 
• Diet and exercise counselling 
• Schedule next visit 
Note:  If the patient discontinues at any scheduled visit after T1, or between study visits, please 
proceed to Section 10.7 for detailed instructions. 
10.6.5. 
Treatment Month 3 (Visit T3; ± 5 days) 
Patients will undergo the following assessments and procedures at Month 3 (Visit T3): 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Weight 
• Vital signs 


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• Central clinical laboratory evaluations: 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs)  
− HbA1C 
• Return of IMP; assessment and recording of IMP adherence 
• IWRS contact to obtain new MED ID number for double-blind IMP 
• Dispense double-blind IMP and provide dosing and storage instruction 
• Diet and exercise counselling 
• Schedule next visit 
Note:  If the patient discontinues at or between study visits, please proceed to Section 10.7 for 
detailed instructions.  
10.6.6. 
Treatment Month 6 (Visit T4; ± 5 days) 
Patients will undergo the following assessments and procedures at Month 6 (Visit T4): 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints (ongoing) 
• Weight 
• Vital signs 
• Central clinical laboratory evaluations: 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs) and 
hs-CRP 
− HbA1C 
• Return of IMP; assessment and recording of IMP adherence 
• IWRS contact to obtain new MED ID numbers for double-blind IMP 
• Dispense double-blind IMP (with amount sufficient until next clinic visit, typically 
2 bottles) and provide dosing instruction 
• Diet and exercise counselling 
• Schedule next visit 
Note:  If the patient discontinues at any scheduled visit after T1, or between study visits, please 
proceed to Section 10.7 for detailed instructions. 
The conduct of this visit may be altered to ensure patient safety during the global coronavirus 
disease of 2019 (COVID-19) pandemic.  If permitted and approved by regional regulatory 
authorities and the appropriate IRB/IEC, this visit may be converted to a remote visit (telephone, 


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telemedicine, etc.) or conducted within the patient’s home by a qualified visiting nurse.  After 
obtaining either written or verbal consent from the patient, verifying the correct shipping address 
and patient availability to receive the shipment, IMP dispensation may be completed by utilizing 
an appropriate courier service.  IMP may also be dispensed utilizing curbside pick-up at the site 
by the patient or patient representative.  The procedures and data collected will be dependent 
upon the type of visit that is conducted.  However, at a minimum, it is expected that the 
following data be collected regardless of whether the visit is conducted by phone or by visiting 
nurse:  concomitant medications, assessment of AEs, SAEs, and clinical endpoints, and IMP 
adherence.  When visits are conducted in the patient’s home by a qualified visiting nurse, it is 
also expected, if logistically possible, that weight, vital signs, and samples for central laboratory 
evaluations will also be collected.  Alterations to study visits and procedures during the 
pandemic will be recorded on a COVID-19-specific case report form. 
Local laboratories may be utilized during the pandemic at the investigator’s discretion with the 
following requirements: 
• Lipids should not be assessed by local laboratories during the study.  However, if lipids 
are included in a local laboratory report, care must be taken to ensure that the values 
remain masked for study site personnel, the patient, CRO, and Sponsor. 
• A copy of the lab results and reference ranges, with lipid results redacted, must be filed 
within the patient records. 
10.6.7. 
Treatment Month 9 (Phone Visit; Visit T5 ± 10 days), Month 15 (Phone Visit; 
Visit T7 ± 10 days), Month 21 (Phone Visit; Visit T9 ± 10 days), and Additional 
Telephone Visits Until Study Conclusion Every 6 Months Thereafter 
Patients will undergo the following assessments via telephone at Month 9 (Visit T5), and every 
6 months thereafter as long as the patient remains on study: 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Diet and exercise counselling 
Note:  If the patient discontinues at or between study visits, please proceed to Section 10.7 for 
detailed instructions. 
10.6.8. 
Treatment Month 12 (Visit T6 ± 10 days), Month 18 (Visit T8 ± 10 days), and 
Additional Clinic Visits Until Study Conclusion Every 6 Month Thereafter 
Patients will undergo the following assessments and procedures at Month 12 (Visit T6), and 
every 6 months thereafter as long as the patient remains on study: 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints 
• Weight 
• Vital signs 


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• Central clinical laboratory evaluations: 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs)  
− hs-CRP (Month 12 only) 
− HbA1C  
• Return of IMP; assessment and recording of IMP adherence 
• IWRS contact to obtain new MED ID numbers for double-blind IMP 
• Dispense double-blind IMP (with amount sufficient until next clinic visit, typically 
2 bottles) and provide dosing instruction 
• Diet and exercise counselling 
• Schedule next visit 
Note:  If the patient discontinues at or between study visits, please proceed to Section 10.7 for 
detailed instructions. 
The conduct of this visit may be altered to ensure patient safety during the global COVID-19 
pandemic.  If permitted and approved by regional regulatory authorities and the appropriate 
IRB/IEC, this visit may be converted to a remote visit (telephone, telemedicine, etc.) or 
conducted within the patient’s home by a qualified visiting nurse.  After obtaining either written 
or verbal consent from the patient, verifying the correct shipping address and patient availability 
to receive the shipment, IMP dispensation may be completed by utilizing an appropriate courier 
service.  IMP may also be dispensed utilizing curbside pick-up at the site by the patient or patient 
representative.  The procedures and data collected will be dependent upon the type of visit that is 
conducted.  However, at a minimum, it is expected that the following data be collected regardless 
of whether the visits is conducted by phone or by visiting nurse:  concomitant medications, 
assessment of AEs, SAEs, and clinical endpoints, and IMP adherence.  When visits are 
conducted in the patient’s home by a qualified visiting nurse, it is also expected, if logistically 
possible, that weight, vital signs, and samples for central laboratory evaluations will also be 
collected.  Alterations to study visits and procedures during the pandemic will be recorded on a 
COVID-19-specific case report form. 
Local laboratories may be utilized during the pandemic at the investigator’s discretion with the 
following requirements: 
• Lipids should not be assessed by local laboratories during the study.  However, if 
lipids are included in a local laboratory report, care must be taken to ensure that the 
values remain masked for study site personnel, the patient, CRO, and Sponsor. 
• A copy of the lab results and reference ranges, with lipid results redacted, must be 
filed within the patient records. 
In individual cases after the pandemic has been determined to be over and if permitted and 
approved by regional regulatory authorities and the appropriate IRB/IEC, these visits may 
continue to be conducted within the patient’s home by a qualified visiting nurse.  In instances 


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where it is identified as necessary, IMP dispensation may be completed utilizing either an 
appropriate courier service (after obtaining consent and verification of shipping address and 
patient availability) or curbside pick-up at the site. 
10.6.9. 
End of Study 
Patients will undergo the following assessments and procedures at End of Study: 
• Concomitant medication review (ongoing) 
• Assess AEs, SAEs, and potential clinical endpoints (ongoing) 
• Weight 
• Vital signs 
• 12-lead ECG 
• PE 
• Central clinical laboratory evaluations: 
− Hematology, blood chemistry, and urinalysis 
− Basic fasting lipids (TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs) 
− hs-CRP 
− HbA1C 
• Return of IMP; assessment and recording of IMP adherence 
• Diet and exercise counselling 
Note:  The conduct of this visit may be altered to ensure patient safety during the global 
COVID-19 pandemic.  If permitted and approved by regional regulatory authorities and the 
appropriate IRB/IEC, this visit may be converted to a remote visit (telephone, telemedicine, etc.) 
or conducted within the patient’s home by a qualified visiting nurse.  However, at a minimum, it 
is expected that the following data be collected regardless of whether the visits is conducted by 
phone or by visiting nurse: concomitant medications, assessment of AEs, SAEs, and clinical 
endpoints, and IMP adherence.  When visits are conducted in the patient’s home by a qualified 
visiting nurse, it is also expected, if logistically possible, that weight, vital signs, and samples for 
central laboratory evaluations will also be collected.  Alterations to study visits and procedures 
during the pandemic will be recorded on a COVID-19-specific case report form. 
Local laboratories may be utilized during the pandemic at the investigator’s discretion with the 
following requirements: 
• Lipids should not be assessed by local laboratories during the study.  However, if 
lipids are included in a local laboratory report, care must be taken to ensure that the 
values remain masked for study site personnel, the patient, CRO, and Sponsor. 
• A copy of the lab results and reference ranges, with lipid results redacted, must be 
filed within the patient records. 


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In individual cases after the pandemic has been determined to be over and if permitted and 
approved by regional regulatory authorities and the appropriate IRB/IEC, this visit may be 
conducted within the patient’s home by a qualified visiting nurse. 
10.6.10. 
Post-treatment Visit (Phone Visit; Visit PT1, 30 days ± 10 days After End of 
Study) 
Patients will undergo the following assessments via telephone 30 days after the end of study: 
• Assess AEs, SAEs, and potential clinical endpoints 
10.7. 
Discontinuations 
10.7.1. 
Patients Inadvertently Enrolled 
The inclusion and exclusion criteria for enrollment must be followed exactly and completely.  If 
a patient who does not meet enrollment criteria is inadvertently enrolled, the Medical Monitor 
should be contacted within 24 hours of identification.  If it is determined after discussion with 
the Medical Monitor that, in considering patient safety, it is appropriate to continue IMP 
(documentation of this is necessary), the patient will continue on IMP and be monitored for all 
visits and testing (including laboratory measures) for the duration of the study.  If, after 
discussion with the Medical Monitor, it is determined that the patient should not continue IMP, 
IMP will be discontinued, but the patient will remain in the study to be evaluated for 
concomitant medications, and efficacy and safety endpoints until the end of the study visit. 
Patients inadvertently enrolled under the following criteria should be discontinued from IMP (but 
remain in the study): 
• Female patients who are pregnant or are breastfeeding or who do not agree to use an 
acceptable method(s) of birth control during the study 
• Any clinically significant medical condition that according to the investigator could 
interfere with participation in the study 
• Unable or unwilling to comply with protocol requirements, or deemed by the 
investigator to be unfit for the study 
• Have a history of drug, alcohol, or substance abuse within the past 6 months, as 
assessed by the investigator 
If a patient stops IMP for any of the above exclusion criteria following discussion with the 
Medical Monitor, then investigators should notify the Sponsor (or designee).  The reason for the 
patient’s inadvertent enrollment should be documented in the patient’s record. 
10.7.2. 
Temporary Discontinuation of Investigational Medicinal Product 
There may be situations in which IMP is temporarily discontinued at the discretion of the 
investigator.  IMP should be restarted as soon as possible based on investigator judgment.  The 
number of days the IMP was not taken and the reason for temporary discontinuation should be 
documented in the patient’s record.  There is no limit to the amount of time patient can be off 
IMP prior to restarting. 


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Investigators should contact the Medical Monitor if IMP is temporarily discontinued and this 
should occur prior to IMP discontinuation if possible. 
10.7.3. 
Permanent Discontinuation of Investigational Medicinal Product 
There may be situations where it may be necessary for a patient to permanently discontinue IMP. 
Investigators should contact the Medical Monitor prior to permanent IMP discontinuation to 
discuss the situation.  If IMP is permanently discontinued, the patient will remain in the 
study to be evaluated for concomitant medications, efficacy and safety endpoints until the 
final study visit.  If the patient is unwilling or unable to return for follow-up visits in person, 
alternatives such as telephone contact visits per the Schedule of Events, or telephone follow up 
bi-annually, annually or at the end of the study will be offered.  The follow-up frequency will be 
documented in the eCRF. 
The reason for permanent discontinuation of IMP should be documented in the eCRF.  If the 
discontinuation of IMP is due to an AE, the event should be documented in the eCRF.  Some 
possible reasons that must lead to permanent early IMP discontinuation include: 
• Female patients who become pregnant or are breastfeeding or who do not agree to use 
an acceptable method(s) of birth control during the study will be permanently 
discontinued from IMP 
• The patient requests to stop IMP permanently 
• The patient study blind is broken 
• Patient moves away and it is impossible to come to this or any other trial site for 
visits as required by protocol. 
Some possible reasons that may lead to permanent early IMP discontinuation include: 
• In the opinion of the investigator, any AE or a significant change in a laboratory value 
that warrants permanent discontinuation of IMP therapy.  Investigators are advised to 
call the Medical Monitor prior to making such a decision. 
• Illness, condition, or procedural complication (including AEs) affecting the patient’s 
ability to participate or requiring prohibited medication.  Investigators are advised to 
call the Medical Monitor prior to making such a decision. 
• Enrollment in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.  If, after discussion with the study Medical 
Monitor, it is determined that the patient should not continue IMP, IMP will be 
discontinued. 
10.7.4. 
Patient Discontinuation from the Study 
Patient discontinuation prior to the patient’s completion of the study is expected to be 
uncommon, occurring only if the patient explicitly withdraws consent.  At the time of 
discontinuing from the study, the Medical Monitor should be contacted, and, if possible, an early 
discontinuation visit should be conducted, per the Study Schedule.  The patient will be 


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permanently discontinued both from the IMP and from the study at that time.  During the study 
closeout period, survival (vital) status will be collected within legal and ethical boundaries for all 
patients randomized who withdrew their participation from the study. 
10.7.5. 
Patients Lost to Follow-Up 
A patient would be considered potentially lost to follow-up if he or she repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.  Site personnel are expected 
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. 
10.7.6. 
Discontinuation of Study Sites or the Study 
The Sponsor may suspend enrollment or discontinue a site at any time.  A written statement will 
be provided to the investigator, the IRB or IEC, and regulatory authorities, if required.  
Possible reasons for site discontinuation include, but are not limited to: 
• Unsatisfactory enrollment with respect to quantity or quality 
• Inaccurate or incomplete data collection on a chronic basis 
• Falsification of records 
• Failure to adhere to the protocol 
• Lack of study oversight by the Principal Investigator and/or designee 
If any serious or nonserious AEs have occurred at such a clinical site, all documentation relating 
to the event(s) must be obtained. 
The Sponsor in consultation with the 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. 


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11. 
ASSESSMENT OF EFFICACY  
11.1. 
Reporting of Clinical Endpoints  
All clinical endpoints occurring at any point from signing the ICD until 30 days after completion 
of the study will be reported by the site and adjudicated by the CEC according to guidelines 
detailed in the CEC Charter.  Study sites will complete the relevant clinical endpoint eCRFs and 
obtain other required source documents in a timely fashion as per study-specific instructions 
contained in the Endpoint Manual.  
Clinical endpoints include any of the following: 
• CV Death (MACE) 
• Non-CV Death (non-MACE clinical endpoint) 
• Nonfatal MI (MACE) 
• Nonfatal stroke (MACE) 
• Hospitalization for unstable angina (non-MACE clinical endpoint)  
• Coronary revascularization (MACE) 
Detailed definitions of these clinical endpoints are included in the CEC Charter and the Endpoint 
Manual.  Please note that the Sponsor will also review blinded AE and SAE reports on a routine 
basis in order to identify potential additional clinical endpoints.  AEs and SAEs that are 
identified by the Sponsor as potential clinical endpoints will be reviewed by the CEC and may 
result in a request to the site that additional source documentation be obtained or adjustments to 
reporting in the eCRF be completed. 
An adjudicated clinical endpoint will not be reported as an AE nor, if appropriate, as an SAE in 
the eCRF.  Additionally, it will NOT be reported in an expedited manner as an SAE since these 
events are expected to occur in this patient population. 
A clinical endpoint that is reported by the site but, upon subsequent review by the CEC is 
adjudicated to NOT meet all of the clinical endpoint criteria as defined by the CEC Charter, will 
be reclassified as an AE, SAE, or procedure as appropriate.  If that reclassified event meets one 
or more of the seriousness criteria for AEs, the event must be reported (within 24 hours of 
notification of investigator) as an SAE in the same manner as other SAEs.  In this instance, 
Day 1 for SAE reporting purposes will be the day that the investigator is informed that the 
reported clinical endpoint did not meet clinical endpoint criteria adjudicated by the CEC.  At the 
time that a clinical endpoint is reported, information will also be collected that would be required 
if, in the future, it is determined to be an SAE.  This information will include AE term, severity, 
action taken with IMP, relatedness, etc. 
Any clinical endpoint occurring after the 30-day follow-up period that the investigator becomes 
aware of and considers related to IMP must be reported to the Sponsor as an SAE. 
Please contact your monitor regarding any questions about the reporting of clinical endpoints and 
whether these clinical endpoints should be reported as AEs and/or SAEs. 


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11.2. 
Major Adverse Cardiovascular Events 
The following MACE are included in the primary efficacy endpoint: 
• CV death 
• Nonfatal MI 
• Nonfatal stroke 
• Coronary revascularization 
Also additional clinical endpoints include: 
• Non-CV death (assessed as a secondary efficacy endpoint) 
• Hospitalization for unstable angina (assessed as a secondary efficacy endpoint) 
The CEC will adjudicate all reported MACE and additional clinical endpoints to determine 
which events meet the criteria detailed in the CEC Charter. 
11.3. 
Assessment of Diabetes 
The DC will review and utilize data that is recorded in the eCRF and is available in the clinical 
laboratory database to verify potential events of new-onset diabetes.  The verification will occur 
beginning from the point where the patient signs the informed consent through 30 days after the 
patient’s last study visit.  Verification will be completed according to the guidelines detailed in 
the DC charter.  Sites will continue to follow study procedures for recording diabetes and 
diabetes-related diagnoses as medical history, AEs, or SAEs. 
Criteria for a diagnosis of diabetes for inclusion in the diabetes efficacy and safety populations 
are described in Section 15.4. 
11.4. 
Assessments of Lipids and hs-CRP 
Central clinical laboratory samples will be collected and analyzed for the parameters detailed in 
Table 3.  Calculated LDL-C (or measured directly if TGs are >400 mg/dL or LDL-C is 
<50 mg/dL), non-HDL-C, TC, HDL-C, and TG at Week -5 and Week -4, and at Months 0, 3, 6, 
12, 18, 24, and every 6 months until end of study. 
Central clinical laboratory samples will be collected and analyzed for hs-CRP at Months 0, 6, 12, 
and end-of-study.  
Blood draws for lipids (not safety) must meet the criteria below.  If these criteria have not been 
met, these blood samples will NOT be collected.  If these criteria can be met by rescheduling 
a clinic visit to occur within 3 days, these blood samples will be collected at the rescheduled 
clinic visit only. 
• Blood samples will be drawn after a minimum 10-hour fast (water and concomitant 
medications is allowed).  If the patient has fasted but IMP was taken the morning of a 
clinic visit, blood samples may be drawn, and the clinic visit does not need to be 
rescheduled. 


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Patients are to be in a seated position during the blood collection.  Collection schedule and 
instructions are provided in the Central Clinical Laboratory Manual.  A description of the sample 
collection, storage, and shipping, as well as monitoring and management of abnormal 
laboratories, are described in Section 12.1.6. 
When vital signs and laboratory samples are to be collected at the same time point, vital signs 
measurements will precede laboratory sample collection. 
Table 3: 
Central Clinical Laboratory Parameters (Lipids and hs-CRP) 
Clinical Laboratory Test  
Clinical Laboratory Test 
Basic Lipid Parameters 
Other Parameters 
• 
Total cholesterol (TC) 
• 
Calculated low-density lipoprotein 
cholesterol (LDL-C) and non-HDL-C 
• 
High-density lipoprotein cholesterol 
(HDL-C) 
• 
Triglycerides (TG) 
• 
High-sensitivity C-reactive protein (hs-CRP) 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
At all clinic visits, investigators will review all safety information including vital signs, AEs, 
SAEs, potential endpoints, concomitant medications, and ECG reports and will ensure that the 
collected data are recorded into the appropriate eCRF.  Additionally, central clinical laboratory 
samples will be collected and sent for analysis and the investigator will review the results to 
ensure continued patient safety while participating in the study. 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee if appropriate. 
The investigator is responsible for the appropriate medical care of patients during the study. 
The investigator is responsible for following AEs that are serious or that caused the patient to 
discontinue before completing the study until the event is resolved or explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator. 
12.1.1. 
Demographic/Medical History 
Demographic data and a complete medical history will be obtained from the patient. For medical 
history, conditions and surgeries 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.  In 
particular, a careful medical history for diabetes, neurocognitive conditions, statin-associated 
muscle effects, and other statin-associated adverse effects should be collected. 
12.1.2. 
Vital Signs 
Vital signs will include DBP and SBP as well as heart rate. 
Vitals will be collected prior to blood collection.  Blood pressure 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 several 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.  Each BP measure must be recorded within ±2 mmHg. 
12.1.3. 
Weight and Height 
Body weight will be measured on a calibrated scale in the morning while fasted and after 
voiding. 
Height will be measured using standard clinic procedures. 
Body mass index (BMI) will be calculated systematically using the formula:  
BMI (kg/m2) = weight in kg/(height in meters)2 


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12.1.4. 
Physical Examination 
Physical examinations will include an assessment of the following: 
• General appearance 
• Skin 
• Eyes, ears, nose, and throat 
• Head and neck 
• Extremities 
• Musculoskeletal examination 
• Respiratory examination 
• Cardiovascular assessment, including rhythm and presence of cardiac abnormalities 
• Abdominal examination 
• Neurologic examination including documentation of the presence of abnormalities in 
mental status and motor and sensory function 
• Any additional assessments necessary to establish baseline status or evaluate 
symptoms or adverse experiences 
Documentation of the PE findings will be included in the source documentation at the clinical 
site.  Significant findings prior to the start of IMP will be recorded on the Medical 
History/Current Medical Conditions page of the eCRF.  Only changes from baseline physical 
examination findings that meet the definition of an AE will be recorded on the AE page of the 
eCRF. 
Note: Additional information will be collected regarding muscle-related AEs.  See 
Section 13.1.3. 
12.1.5. 
Electrocardiogram 
ECG collection will be collected in the supine position. ECGs will be assessed using machine 
readings and physician review. 
Unscheduled ECG assessments will be completed at the discretion of the investigator. 
12.1.6. 
Central Clinical Laboratory Tests 
12.1.6.1. Central Clinical Laboratory Parameters (Safety) 
Patients will be in a seated position during the blood collection.  Clinical laboratory parameters 
and tests will include those listed in Table 4.  Collection schedule, schedule of laboratory 
parameters by visit, and instructions are in the Clinical Laboratory Manual provided by Central 
Laboratory. 


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Table 4: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Hematology 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count with 
differential (absolute values only) 
Blood Chemistry (serum, fasting) 
• 
Albumin (Alb) 
• 
Alkaline phosphatase (Alk-P) 
• 
Alanine aminotransferase (ALT; SGPT) 
• 
Aspartate aminotransferase (AST; 
SGOT) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine kinase (CK) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total and direct bilirubin (TB) 
• 
Total protein 
• 
Uric acid 
Urinalysis (Dipstick) 
• 
Clarity 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Urinalysis (Microscopic) – only if urine dipstick 
abnormal 
• 
Bacteria 
• 
Casts 
• 
Crystals 
• 
Epithelial cells 
• 
Red blood cells (RBC) 
• 
White blood cells (WBC) 
Coagulation – only in patients receiving 
anti-coagulant therapy that in the investigator’s 
judgement require monitoring 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: 
Central Clinical Laboratory Parameters (Safety) 
Clinical Laboratory Test 
Clinical Laboratory Test 
Other Screening Labs 
Additional samples 
• 
Hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV), optional 
reflexive Hepatitis C RNA only if HCV 
is positive 
• 
Serum or urine pregnancy test (only for 
females of childbearing potential) 
• 
Follicle-stimulating hormone (FSH; only 
for postmenopausal females <55 years 
old) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Hemoglobin A1C (HbA1C) 
• 
hs-CRP 
12.1.6.2. Sample Collection, Storage, and Shipping 
Central clinical laboratory samples will be collected by appropriate clinical site personnel and 
then shipped according to a separate Laboratory Manual provided by the Central Laboratory.  
Samples will be processed by the Central Laboratory. 
12.1.6.3. General Monitoring and Management of Abnormal Clinical Labs 
It is the investigator’s responsibility to review the results of all laboratory tests as they become 
available and to sign and date the review.  For each laboratory test outside of the laboratory 
normal range, the investigator needs to ascertain if this is a clinically significant change from 
baseline for the individual patient, with baseline defined as the last value or observation before 
the first dose of double-blind IMP.  The investigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory test. 
If a laboratory value is determined to be an abnormal and a clinically significant change from 
baseline for the patient, the investigator should determine if it qualifies as an AE (please see 
Section 13.2.3), and if yes, an appropriate eCRF will be completed. All clinically significant 
laboratory abnormalities occurring during the study that were not present at baseline should be 
followed and evaluated with additional tests if necessary, until diagnosis of the underlying cause 
or resolution.  Specific monitoring and management guidelines for laboratories of special interest 
are outlined in the sections below. 
12.1.6.3.1. Monitoring and Management of Elevated Liver Function Tests 
If at any time after randomization a patient experiences a new ALT and/or AST >3 × ULN, the 
patient will undergo repeat confirmatory liver function test (LFT) assessment as soon as is 
reasonably possible, preferably within 3 to 7 days of the laboratory result becoming available. 
Repeat LFT assessment will include: 1) measurement of ALT, AST, alkaline phosphatase, total 
and direct bilirubin, prothrombin time (PT)/international normalized ratio (INR), eosinophil 
count, CK; 2) history of concomitant medication use; 3) history of exposure to environmental 
chemical agents, including ethanol; and 4) query for related symptoms.  Additionally, further 


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


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the investigator with input from the Sponsor may consider continuing IMP with 
continued CK assessments every 1-2 weeks. 
• 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 discontinued from IMP treatment:  
− >5 × ULN that is associated with symptoms of muscle pain, muscle weakness, or 
dark urine; or  
− >10 × ULN, even in the absence of symptoms. 
• If the patient is discontinued from IMP treatment, the patient should continue being 
followed for safety using the protocol-specified visit schedule (see Appendix 1). At 
the investigator’s discretion, IMP may be interrupted and the patient rechallenged 
with IMP after creatine phosphokinase (CPK) has returned to the baseline level. 
12.1.6.3.3. Monitoring and Management of Elevated LDL-C  
Postrandomization, LDL-C results will be masked to investigators in order to maintain the blind.  
Beginning at Month 6 and for the remaining duration of the study, the central laboratory will 
notify the investigator if the patient’s LDL-C level is ≥25% higher than baseline (mean of values 
at S2 and T1).  The patient will return to the clinic for a repeat fasting blood lipid sample to 
confirm that the LDL-C value meets the threshold criteria.  The patient will be counseled on 
healthy dietary guidelines and reminded to take all lipid-regulating medications.  If confirmed, 
the patient’s LDL-C-lowering treatment regimen may be adjusted, if possible, per standard of 
care and local practice.  Any initiation and/or dose change of LDL-C-lowering medications will 
be documented on the eCRF.  Additional LDL-C-lowering medications initiated will not be 
provided by the Sponsor. 
Investigators will not measure LDL-C at a local lab during the study. 
12.1.6.3.4. Monitoring and Management of Elevated TG 
Post-randomization, TG results will be masked to investigators in order to maintain the blind.  
Beginning at Month 3 (Visit T3) and for the remaining duration of the study, the central 
laboratory will notify the investigator if patient’s TG level is >1000 mg/dL (11.3 mmol/L).  The 
patient will be counseled on healthy dietary guidelines and reminded to take all lipid-regulating 
medications.  The patient will return to the clinic for a repeat fasting blood lipid sample to 
confirm that the TG value meets the threshold criteria.  If confirmed, the patient’s TG- lowering 
treatment regimen may be adjusted, if possible, per standard of care and local practice.  Any 
initiation and/or dose change of TG medications will be documented on the eCRF.  Additional 
TG-lowering medications initiated will not be provided by the Sponsor.  If, despite adjustment of 
TG-lowering therapies, the TG level remains >1000 mg/dL, the patient will discontinue study 
medication but will remain in the study.  


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12.1.6.3.5. Monitoring and Management of Potential Hypoglycemia with Associated 
Metabolic Acidosis 
Patients will be educated on the signs and symptoms of hypoglycemia.  If such signs and 
symptoms are experienced, patients will be advised to report them to the study site (see 
Section 13.3 for additional details). 
Clinical laboratories (bicarbonate levels) will be assessed to determine the possible occurrence of 
metabolic acidosis.  If the laboratories are consistent with metabolic acidosis, immediate follow 
up with the patient for further medical evaluation will occur (see Section 13.3 for additional 
details). This event should be captured as an AE. 
12.1.6.4. Total Blood Volume of Central Clinical Laboratory Samples 
The total number of venipunctures and total volume of whole blood collected during the study 
will be limited to that needed for safety, efficacy, and biomarker assessment.  Total whole blood 
volume collected over the study duration is not to exceed approximately 200 mL for each patient. 


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13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1. 
Adverse Events 
13.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, including control, and which does not necessarily have a 
causal relationship with treatment.  The investigator is responsible for ensuring that any AEs 
observed by the investigator or reported by the patient are recorded in the patient’s medical 
record. 
An AE can be: 
• Any unfavorable and unintended sign (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 IMP 
• Treatment-emergent AEs (TEAEs) are defined as AEs that begin or worsen after 
randomization and the first dose of double-blind IMP 
• Adverse Drug Reaction (see Section 13.1.2) 
13.1.2. 
Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction (ADR).  “Responses” to a medicinal product means that a 
causal relationship 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). 
13.1.3. 
Reporting for Adverse Events 
All AEs occurring during the course of the study (starting from signing informed consent to the 
end of study) will be collected on the AE eCRF.  Patients should be instructed to report any AE 
that they experience to the investigator.  Investigators should make an assessment for AEs at 
each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the eCRF.  However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the eCRF.  Additionally, 


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the condition that led to a medical or surgical procedure (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 
• Investigator’s assessment of relationship to IMP. 
A cluster of signs and symptoms that results from a single cause should be reported as a single 
AE (eg, fever, elevated white blood cells [WBC], cough, abnormal chest x-ray, etc, can all be 
reported as “pneumonia”). 
The investigator will carefully evaluate the comments of the patient and the response to 
treatment in order that he/she may judge the true nature and severity of the AE.  The question of 
the relationship of AEs to IMP administration should be determined by the investigator or study 
physician after thorough consideration of all facts that are available. 
Additional information may be collected regarding muscle-related AEs including type of 
muscle-related symptoms, location of the muscle-related AE, and potential cause of the 
muscle-related AE. 
Additional information may be collected regarding malignancy AEs including patient risk 
factors, diagnostic details, organ and tissue type, staging, test results, and treatment approach. 


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


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Patients with AEs related to IMP that are ongoing at study discontinuation or completion must be 
followed until resolution or for 30 days after study completion, whichever comes first, with the 
exception of patients reporting SAEs (see Section 13.2.4). 
13.1.7. 
Treatment-Emergent Adverse Events 
TEAE are defined as AEs that begin or worsen after randomization and the first dose of 
double-blind IMP. 
13.2. 
Serious Adverse Events 
13.2.1. 
Definition of Serious Adverse Event  
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:  
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital anomaly/birth defect 
• An important medical event 
NOTE:  An emergency room visit without hospital admission 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 and/or 
prolongation of hospitalization that occur during elective or outpatient surgery should be 
recorded as AEs and assessed for seriousness.  Admission to the hospital for social or situational 
reasons (eg, no place to stay, live too far away to come for hospital visits) will not be considered 
inpatient hospitalizations. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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13.2.2. 
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. 
13.2.3. 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the corresponding laboratory.  In some cases, 
significant changes in lab values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically 
significant 
13.2.4. 
Reporting Serious Adverse Events 
All SAEs occurring from the time of informed consent until 30 days following completion or 
discontinuation of study must be reported by the Principal Investigator or designee to the 
designated Safety contact within 24 hours of the Principal Investigator or the clinical site 
becoming aware of the occurrence.  All SAEs that the investigator considers related to IMP that 
occur after the 30-day follow-up period of the study period must be reported to the Sponsor.  As 
a reminder, adjudicated clinical endpoints will NOT be reported as SAEs in the eCRF and will 
NOT be reported in an expedited manner as an SAE since these events are known to occur in this 
patient population. 
To report the SAE, the SAE information should be entered into the EDC RAVE database within 
24 hours of becoming aware of the occurrence.  Additional documentation, such as laboratory or 
diagnostic test results or discharge summaries may be sent separately via email 
  If you have questions, please call the 
designated Safety contact for assistance.  All contact information is provided on the SAE report 
form for this study. 
Detailed instructions and contact information for the Global and Regional Safety and Medical 
Monitor(s) will be provided in the SAE Completion Guidelines. 
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. 


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All SAEs should be recorded on the eCRF and source documents.  Criteria for documenting the 
relationship to IMP and severity will be the same as those previously described. 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of follow-up information, the investigator must update the SAE form 
and submit any supporting documentation (eg, patient discharge summary or autopsy reports) to 
the designated Safety contact. 
The Sponsor (and/or legally transferred designee) will report SAEs and suspected and 
unexpected serious adverse reactions (SUSARs) as required by global regulatory authorities, 
IECs/IRBs, investigators/institutions in compliance with all reporting requirements according to 
local regulations, laws, and GCPs.  The investigator should notify the appropriate IEC/IRB of 
SAEs occurring at the site and other AE reports received from the Sponsor, in accordance with 
local procedures and statutes. 
13.2.5. 
Events Exempt from (Serious) Adverse Event Reporting 
Adjudicated clinical endpoints will NOT be reported as AEs or SAEs and will NOT be reported 
in an expedited manner as an SAE to the designated Safety contact since these events are known 
to occur in this patient population. 
All SAEs that occur during the course of the study, whether or not causally related to the IMP, 
must be reported immediately (within 24 hours of the investigator becoming aware of the event), 
except for clinical endpoints defined as the following: 
• CV Death 
• Non-CV Death 
• Nonfatal MI 
• Nonfatal stroke 
• Hospitalization for unstable angina  
• Coronary revascularization 
A clinical endpoint that is reported by the site but, upon subsequent review by the CEC, is 
adjudicated to NOT meet all of the clinical endpoint criteria as defined by the CEC Charter will 
be reclassified as an AE, SAE, or procedure as appropriate.  If that reclassified event meets one 
or more of the seriousness criteria for AEs, the event must be reported in an expedited manner 
(within 24 hours of notification of investigator) as an SAE to the designated Safety contact in the 
same manner as other SAEs.  In this instance, the date of awareness of the event for SAE 
reporting purposes will be the day that the investigator is informed that the reported clinical 
endpoint did not meet clinical endpoint criteria adjudicated by the CEC.  At the time that a 
clinical endpoint is reported, information will also be collected that would be required if, in the 
future, it is determined to be an SAE.  This information will include AE term, severity, action 
taken with IMP, relatedness, etc. 


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13.2.6. 
Reporting of Patient Death 
The death of any patient during the study or within 30 days after study discontinuation or 
completion must be treated as a clinical endpoint for adjudication.  This event will not be 
reported as an SAE. 
13.2.7. 
Reports of Pregnancy and Lactation 
Although not considered an SAE (unless an event occurs with a serious outcome), pregnancy and 
lactation information on female patients will be collected by the designated Safety contact.  If a 
female patient should become pregnant during the course of the study, the Principal Investigator 
or designee must contact the designated Safety contact within 24 hours of the Principal 
Investigator or designee first becoming aware of the pregnancy. 
To report a pregnancy, the pregnancy information should be recorded on the Clinical Pregnancy 
Report Form and sent to the Safety contact within 24 hours of becoming aware of the pregnancy 
via email 
  Additionally, the patient’s 
pregnancy should be followed through to its conclusion with the final outcome recorded on the 
Pregnancy Outcome Form and sent to the safety contact using either the email or fax noted 
previously.  If you have questions, please call the designated Safety contact for assistance. 
Patients who become pregnant will discontinue study medication immediately and will continue 
to be followed until the pregnancy is completed.  Patients who lactate during the study may be 
required to discontinue study medication. 
13.3. 
Adverse Events of Special Interest 
Hepatic Safety:  
 
 
 
Musculoskeletal Safety:  
 
  
 
 
Diabetes and Glycemia:  
 
 
 
 
 
 
Hypoglycemia Associated with Metabolic Acidosis:  
 
  
 


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Renal Impairment:  
 
 
 
 
 
 
Neurocognitive Events:  
 
 
 
 
 
Atrial Fibrillation:  
 
 
 
 
 
Tendon Rupture/Tendinopathy:  
 
 
 
 
Malignancy:   
 
 
 
 
 
 
 
 
 
 
 
 


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14. 
STUDY COMMITTEES 
14.1. 
Executive Committee (EC) 
The EC will oversee the design and conduct of the study and the interpretation of study results.  
It is responsible for reviewing, at regular intervals, the progress of the study.  The EC will 
comprise designated representatives from Cleveland Clinic Coordinating Center for Clinical 
Research (C5Research), other institutions, and the Sponsor. 
14.2. 
Data Monitoring Committee (DMC) 
An independent DMC will review accumulating blinded and unblinded safety data from this and 
other ongoing studies of bempedoic acid in regularly scheduled intervals approximately 4 times 
per year to ensure there is no avoidable increased risk of harm to patients.  Safety data reviewed 
by the DMC will include AEs, including AESI, clinical endpoints, and lipids.  The DMC is 
responsible for making recommendations about alteration or early termination of the study based 
upon their review of the blinded and unblinded data.  The DMC will be chaired by an external 
academic cardiologist who is an expert in this therapeutic area and who has no conflicts of 
interest.  Analysis for the DMC will be provided by an independent Statistical Analysis Data 
Center, which is external to the Sponsor.  Additional details will be provided in a DMC Charter. 
14.3. 
Clinical Event Committee (CEC) 
A blinded independent expert CEC will adjudicate designated clinical endpoints, including all 
MACE endpoints, as well as all non-CV deaths.  Additional details regarding clinical endpoint 
definitions are included in the CEC charter.  The charter will also outline the committee’s 
composition, timelines, members’ roles and responsibilities and the operational aspects.  The 
CEC of C5Research will provide adjudication services. 
14.4. 
Diabetes Committee (DC) 
A blinded independent DC will verify diagnoses of new-onset diabetes.  Additional details 
regarding clinical endpoint definitions are included in the DC charter.  The charter will also 
outline the committee’s composition, timelines, members’ roles and responsibilities, and the 
operational aspects. 
14.5. 
Tendon Rupture Adjudication Committee (TRAC) 
A blinded independent expert TRAC will adjudicate events of tendon rupture.  Additional details 
regarding event definitions are included in the TRIAC.  The TRIAC will also outline the 
committee’s composition, timelines, members’ roles and responsibilities, and the operational 
aspects. 


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15. 
STATISTICS 
15.1. 
General Considerations 
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 the plans for data analysis, and the protocol will be 
amended if appropriate.  The SAP will be included as an appendix in the clinical study report for 
this protocol. 
15.2. 
Determination of Sample Size 
This event-driven trial is designed to provide at least 90% power to detect an approximate 15% 
relative risk reduction in HR corresponding to the primary composite MACE endpoint (CV 
death, nonfatal MI, nonfatal stroke, or coronary revascularization) at an overall study 
significance level (alpha) of 0.05.  There are no interim analyses. 
A statistical relationship between on-treatment LDL-C differences between the bempedoic acid 
group and the placebo group and CV event risk reduction is used to derive the postulated 
treatment effect of 15% stated above.  Assuming a 3.59% annual event rate in the placebo group, 
a minimum of 1620 primary composite MACE events are needed. 
The average treatment duration for all patients is estimated to be approximately 42 months 
(3.5 years), with an enrollment phase of approximately 33 months, a minimum treatment 
duration to be approximately 36 months (~3 years) and a lost-to-follow-up (LTFU) rate of 1% 
per year.  Based on these assumptions, approximately 14,000 patients (approximately 7000 in the 
bempedoic acid group and 7000 in the placebo group) will be randomized into the study to 
achieve the 1620 patients experiencing an adjudicated primary endpoint event. 
It is expected that 50% of the 1620 patients experiencing an adjudicated primary 4-component 
MACE (810 patients) will experience an adjudicated 3-component MACE (CV death, nonfatal 
MI, or nonfatal stroke).  Additionally, the median treatment duration for the sample size 
calculation was assumed to be 42 months (~3.5 years) when the annual placebo event rate was 
3.59%.  Therefore, the study will not stop until at least 1620 patients have experienced an 
adjudicated primary MACE endpoint, with 50% of the patients experiencing an adjudicated 
3-component MACE, and a minimum of 24 months (2 years) have elapsed since the last patient 
was randomized. 
Six key secondary efficacy endpoints are also of interest for statistical testing in this study.  To 
preserve the study-wise (family-wise) Type 1 error at 5%, a gatekeeping or stepdown approach 
will be followed and is described in detail in Section 15.7. 
15.3. 
Interim Analysis and Stopping Rules 
There are no interim efficacy analyses during the study.  The study may be altered or terminated 
based upon recommendations from the DMC as described in Section 14.2. 


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15.4. 
Analysis Populations 
The Full Analysis Set (FAS), used for all of the efficacy analyses and summaries, is defined as 
all randomized patients and 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 (investigational product).  Patients in 
the SP will be included in the treatment group that they actually received, regardless of their 
randomized treatment. 
The Diabetes Efficacy Population, used for efficacy analyses of HbA1C and fasting glucose, is 
defined as the subset of patients in the FAS fulfilling one or more of the following criteria at 
baseline captured by information recorded as medical history, prior medication, and/or 
laboratory data: 
• Medical history indicating type 2 diabetes 
• Prior glucose-lowering medication with confirmation of diagnosis of diabetes by a 
DC (Section 14.4) if prior medication is the only criteria met for diagnosis of diabetes 
• HbA1C measurement ≥6.5% 
• Two or more measurements of fasting glucose ≥126 mg/dL (7.0 mmol/L) 
The Inadequately Controlled Diabetes Efficacy Population, is defined as the subset of patients in 
the Diabetes Efficacy Population with an HbA1C of 7% or greater at baseline.  This efficacy 
population will be used for the corresponding diabetes secondary and tertiary endpoints. 
The Prediabetes Efficacy Population, used for efficacy analyses of time to new-onset diabetes 
and for efficacy analyses of HbA1C and fasting glucose, is defined as the subset of patients in the 
FAS fulfilling all of the following criteria at baseline captured by information recorded as 
medical history, prior medication, and/or laboratory data: 
• Having no medical history indicating type 2 diabetes 
• Having no prior glucose-lowering medication unless verified by the DC that there is 
no diagnosis of diabetes (Section 14.4) if prior medication is the only criteria assessed 
for the diagnosis of diabetes 
• HbA1C measurement of 5.7% to 6.4% or 1 or more measurements of fasting glucose 
of 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L), but not more than 1 value of 
fasting glucose ≥126 mg/dL (7.0 mmol/L). 
The Normoglycemia Efficacy Population, used for efficacy analyses of HbA1C and fasting 
glucose, is defined as the subset of patients in the FAS not fulfilling the criteria at baseline for 
the Diabetes Efficacy Population or Prediabetes Efficacy Population. 
The No Diabetes Efficacy Population used for efficacy analyses of HbA1C and fasting glucose, is 
defined as the subset of patients not fulfilling the criteria at baseline for the Diabetes Efficacy 
Population. 


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The Diabetes, Prediabetes, Normoglycemia and the Inadequately Controlled Diabetes Safety 
Populations are used for safety analyses as needed, and defined similarly as Diabetes, 
Prediabetes, Normoglycemia, and the Inadequately Controlled Diabetes Efficacy Populations but 
using patients from Safety Population instead. 
15.5. 
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. 
15.6. 
Primary Endpoint Analysis 
The primary endpoint of this study is time to first occurrence of a confirmed (adjudicated) 
MACE, where MACE is defined as a composite primary efficacy endpoint that includes CV 
death, nonfatal MI, nonfatal stroke, or coronary revascularization. 
The primary efficacy endpoint will be analyzed using Cox proportional hazards (PH) with 
treatment as a factor.  The Cox PH will be performed using the FAS, with patients included in 
their randomized treatment group, regardless of the treatment they actually received.  Note that 
the FAS includes patients who permanently discontinue treatment but remain in the study 
(patients are included regardless of their adherence to treatment).  For this analysis, patients who 
are LTFU without experiencing a MACE will be censored at the time they are last known to be 
event-free.  Patients who withdraw consent (withdraw from the study and refuse further contact) 
without experiencing a MACE will be censored at the time of consent withdrawal.  Additionally, 
taking into account the period for CV event monitoring is every 3 months, when a patient who is 
LTFU or withdraws consent without experiencing a MACE is known to have later experienced a 
non-CV death, if the death was within 3 months of last contact, the patient will be censored at the 
time of death.  If the death occurs more than 3 months after last contact, then the patient will be 
censored at the time of last contact.  The hazards ratio (HR) and its 95% confidence interval (CI) 
and associated p-value will be provided. 
In addition, Kaplan-Meier (K-M) curves will be provided, to provide a graphical description of 
the time to first occurrence of MACE. 
Each individual component of the primary efficacy endpoint (CV death, nonfatal MI, nonfatal 
stroke, and coronary revascularization; each of the individual components are secondary time to 
event endpoints) will also be analyzed using Cox PH, to ensure consistency of the treatment 
effect across the components that comprise the composite endpoint.  Each Cox PH will include 
treatment as a factor, and will be performed on the FAS with patients included in their 
randomized treatment group.  The HR and its 95% CI will be provided for each individual 
component of the primary efficacy endpoint. 
In addition, sensitivity analyses will be performed on the primary efficacy endpoint as needed.  
Additional details on the sensitivity analyses will be included in the SAP. 
Finally, subgroup analyses will also be performed on the primary efficacy endpoint as needed.  
The primary efficacy analysis will be repeated within relevant subgroups including (but not 


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limited to) gender, age categories, and race.  The HR and its 95% CI within each subgroup will 
be provided. 
15.7. 
Secondary Efficacy Endpoint Analyses 
Key secondary efficacy endpoints that are included in the statistical testing hierarchy will be 
analyzed as indicated in Section 15.7.1 and Section 15.7.2 below, and then tested in the hierarchy 
with the primary efficacy endpoint as follows: 
1. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
first occurrence of MACE (CV death, nonfatal MI, nonfatal stroke, or coronary 
revascularization; primary 4-component MACE) 
2. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
first occurrence of the composite endpoint of CV death, nonfatal MI, or nonfatal stroke 
(3-component MACE) 
3. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
first occurrence of fatal or nonfatal MI 
4. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
first occurrence of coronary revascularization 
5. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
first occurrence of fatal or nonfatal stroke 
6. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
CV death 
7. Testing the hypothesis of no difference between bempedoic acid and placebo in time to 
all-cause mortality 
For the final analysis about the differences between bempedoic acid and placebo, each 
hypothesis in this hierarchical order will be tested at a significance level of 0.05, two-sided.  
Statistical significance at each step is required in order to test the next hypothesis.  For other 
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 nominal. 
15.7.1. 
Secondary Efficacy Time-to-Event Endpoints 
Secondary efficacy time-to-event MACE endpoints will each be analyzed in a manner analogous 
to that used for the primary efficacy analysis, using Cox PH model with similar censoring 
definitions and performed on the FAS.  For each endpoint, the HR and its 95% CI and associated 
p-value will be provided.  In addition, K-M curves will be provided for each of the secondary 
efficacy time-to-event endpoints.  Note that for the analyses involving hemorrhagic and 
nonhemorrhagic stroke, any stroke for which the CEC is unable to determine the type will be 
included as an ischemic (nonhemorrhagic) stroke. 
The time to first occurrence of new onset of diabetes during the treatment period will be 
analyzed by a Cox model in the prediabetes efficacy population.  The date of new onset of 
diabetes will be the earliest date of the event observed during the treatment period.  For this 


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analysis, patients who are LTFU discontinue the study drug early without experiencing a new 
onset of diabetes will be censored at 30 days after the last date of the treatment. 
15.7.2. 
Secondary Efficacy Lipid and Other Biomarker Endpoints 
Percent change from baseline to Month 6 in LDL-C and absolute change from baseline to 
Month 12 in HbA1C will be analyzed using analysis of covariance (ANCOVA), with treatment 
group as a factor and the relevant baseline as a covariate.  The ANCOVA for LDL-C will be 
performed in the FAS.  The ANCOVA for HbA1C will be performed in the Inadequately 
Controlled Diabetes Efficacy Population.  Two methods for data handling will be used:  the first 
(primary) will involve specification of the missing data mechanism using a pattern mixture 
model (PMM), while the second (supportive) will be observed case data only.  For each analysis, 
the least squares mean (LSM) and standard error (SE) will be provided for each treatment group, 
along with the placebo-corrected LSM, its 95% CI, and associated p-value.  A nonparametric 
analysis based on Wilcoxon rank sum test and Hodges-Lehmann (H-L) estimate of location shift 
will be performed in FAS for percent change from baseline to Month 6 in hs-CRP.  No 
imputation will be performed for the hs-CRP endpoint due to the extreme skewed distribution. 
15.7.3. 
Tertiary Lipid and Biomarker Efficacy Endpoints 
Tertiary lipid and HbA1C-related endpoints will be summarized and analyzed as needed.  For 
each parameter at each time point, the value of the parameter, change and the percent change 
from baseline will be summarized by treatment group.  The Mixed Model Repeated Measure 
(MMRM) analysis including factors of treatment group, time point (as a categorical variable), 
baseline value, and treatment group-by-time point interaction will be performed in the observed 
FAS data.  The LSM and SE will be provided for each treatment groups, along with the 
placebo-corrected LSM, its 95% CI, and associated p-value as needed.  A nonparametric analysis 
based on Wilcoxon rank sum test and H-L estimate of location shift will be performed in 
observed FAS data for percent change from baseline to Month 12 and end-of study in hs-CRP.  
Changes in HbA1C will be assessed in patients in the Normoglycemia Efficacy Population, 
Prediabetes Efficacy Population, No Diabetes Efficacy Population, Diabetes Efficacy Population, 
and Inadequately Controlled Diabetes Efficacy Population. 
15.8. 
Safety Endpoints 
General safety data in this study includes AEs, clinical safety laboratories, PEs, vital signs, and 
ECGs.  The summarization of AEs will include only TEAEs, defined as AEs that begin or 
worsen after randomization and ingestion of the first dose of IMP.  TEAEs and SAEs will be 
summarized by System Organ Class (SOC), severity, and relationship to IMP for each treatment 
group. 
AE summaries will be provided overall and for subgroups such as gender and age.  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, 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 postbaseline time point. 


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15.8.1. 
Adverse Events of Special Interest (AESI) 
All AESI will be identified and evaluated by routine safety monitoring of AEs and laboratory 
values (where appropriate) and will be summarized by severity and relationship to IMP for each 
treatment group. 
The following are considered AESI categories for this study:  
• Hepatic Safety, including liver-associated enzymes, TB, and any Hy’s law cases 
(≥3 × ULN for either ALT or AST, with accompanying TB >2 × ULN in the setting 
of no known other cause) 
• Musculoskeletal Safety, including CK 
• Diabetes and Glycemia, including new onset of diabetes and worsening of diabetes 
• Hypoglycemia Associated with Metabolic Acidosis 
• Renal Impairment, including lab measures of renal function 
• Neurocognitive Events 
• Atrial Fibrillation 
• Tendon Rupture/Tendinopathy.  The TRAC will adjudicate events of tendon rupture 
per the TRIAC, and adjudicated events will be summarized. 
• Malignancies 
15.9. 
Additional Postrandomization Adjunctive Lipid-Modifying Therapy 
The number and percent of patients in each treatment group requiring additional 
(postrandomization) adjunctive lipid-modifying therapy will be summarized by treatment group 
and by lipid-lowering therapy class.  The reasons for their additional treatment (hyperlipidemia 
versus hypertriglyceridemia) will be summarized by treatment group and by lipid-lowering 
therapy class.  Medications will be summarized by treatment group. 


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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
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, IMP dispensing log, pharmacy records, patient sign-in 
sheets, patient-completed questionnaires, telephone logs, ECGs) required to confirm information 
contained in the eCRFs. 
The monitoring strategy for the study foresees a risk-based monitoring approach, in line with the 
relevant FDA and European Medicines Agency (EMA) recommendations, and will be described 
in detail by the study-specific risk-based-monitoring plan. 
A monitoring visit should include a review of the essential clinical study documents (regulatory 
documents, case report forms, medical records and source documents, drug disposition records, 
patient informed consent forms, etc.) as well as discussion on the conduct of the study with the 
investigator and staff.  The CEC, DC, and TRAC will require that copies of relevant source 
documents be submitted for review by the committees for adjudication or verification as defined 
by their individual charters.  These documents should be redacted by the site in accordance with 
local law. 
The monitor should conduct these visits as frequently as appropriate for the clinical study.  The 
investigator and staff should be available during these visits for discussion of the conduct of the 
study as well as to facilitate the review of the clinical study records and resolve/document any 
discrepancies found during the visit. 
All monitoring activities will be reported and archived.  In addition, monitoring visits will be 
documented at the clinical site by signature and date on the study-specific monitoring log. 
16.2. 
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.  


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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. 
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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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor (or 
designee) may conduct a quality assurance audit.  Please see Section 16.2 for more details 
regarding the audit process. 


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18. 
ETHICS 
18.1. 
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 Code of Federal Regulations (CFR) Part 56, ICH and GCP guidelines, and applicable 
pertinent state and federal requirements.  For locations participating outside of the US, the IRB 
or IEC must comply with the applicable requirements of each participating location, including 
ICH and GCP guidelines, except where a waiver is applicable. 
IRBs and IECs must be constituted according to the applicable laws.  It is the responsibility of 
each clinical site to submit the protocol, IB, patient informed consent, patient recruitment 
materials (if applicable), and other documentation as required by the IRB or IEC for review and 
approval.  A copy of the written approval must be provided to the Sponsor. 
The documentation should clearly mention the approval/favorable opinion of the protocol, the 
patient informed consent form, and patient recruitment materials (if applicable), including 
respective version dates.  The written approval and a list of the voting members, their titles or 
occupations, and their institutional affiliations must be obtained from the IRBs or IECs and 
provided to the Sponsor prior to the release of clinical study supplies to the clinical site and 
commencement of the study.  If any member of the IRB or IEC has direct participation in this 
study, written notification regarding his or her abstinence from voting must also be obtained. 
Clinical sites must adhere to all requirements stipulated by their respective IRB or IEC.  This 
includes notification to the IRB or IEC regarding: protocol amendments, updates to the ICD, 
recruitment materials intended for viewing by patients, aggregate safety reports required by 
regulatory competent authorities, serious and unexpected AEs, reports and updates regarding the 
ongoing review of the study at intervals specified by the respective IRB or IEC, and submission 
of final study reports and summaries to the IRB or IEC. 
It is the responsibility of each clinical site to submit information to the appropriate IRB or EC for 
annual review and annual re-approval. 
The investigator must promptly inform their IRB or IEC of all SAEs or other safety information 
reported from the patient or the Sponsor. 
18.2. 
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 authorized 
designee will be scheduled with the appropriate staff at mutually agreeable times periodically 
throughout the study. 


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The investigator will assure proper implementation and conduct of the study, including those 
study-related duties delegated to other appropriately qualified individuals.  The Investigator will 
assure that study staff cooperates with monitoring and audits, and will demonstrate due diligence 
in recruiting and screening study patients.  The investigator must sign and return to the Sponsor 
the “Investigator’s Signature” page (see Appendix 5) and provide a copy of current curriculum 
vitae.  For this study and all studies conducted under an IND, the investigator must sign and 
return a completed Form FDA 1572 “Statement of Investigator” to the Sponsor (or designee).  
For 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. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Patients must also clearly understand that they are free to discontinue from the study at any time.  
The patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures on the Sponsor-agreed ICD.  Updates to the ICD during the conduct of the study will 
be communicated by written letter from the Sponsor to the investigator.  The ICD should be 
provided in the appropriate language of the patient population. 
The Principal Investigator(s) must maintain the original, signed ICD.  A copy of the signed ICD 
must be given to the patient. 
18.4. 
Patient Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained. 
The names and identities of all research patients will be kept in strict confidence and will not 
appear on eCRFs or other records provided to or retained by the Sponsor (or designee).  If a 
patient’s name appears on any document, it must be redacted and replaced with the patient 
identifier before a copy of the document is supplied to the Sponsor (or designee).  The ICD must 
include appropriate statements explaining that patient data will be confidential and what actions 
will be taken to ensure patient confidentiality. 
Any other confidentiality requirements specified by the site, IRB or IEC, or national or local 
regulations will be adhered to and detailed appropriately in the ICD. 


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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Inspection of Records 
Applicable regulations require the Sponsor (or designee) to inspect all documents and records to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) for the patients in this study.  These regulations also allow the Sponsor’s records to be 
inspected by authorized representatives of the regulatory agencies.  The investigator will permit 
study-related monitoring, audits, IRB 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. 
19.2. 
Retention of Records 
In compliance with the ICH/GCP guidelines, the investigator/Institution agrees to retain and 
maintain all study records that support the data collected from each patient, as well as all study 
documents as specified in ICH/GCP, Section 8 Essential Documents for the Conduct of a 
Clinical Trial.  The investigator agrees to contact the Sponsor before destroying or relocating any 
study documentation and is expected to take measures to prevent accidental or premature 
destruction of these documents. 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept responsibility.  
The Sponsor must be contacted in writing regarding the name and address of the new person 
responsible as well as the disposition of document storage.  Under no circumstances shall the 
Investigator relocate or dispose of any study documents before having obtained written approval 
from the Sponsor. 
Essential records (including eCRFs, source documents, IMP disposition records, signed patient 
ICDs, AE reports, and other regulatory documents) as required by the applicable regulations, 
must be maintained for 2 years after a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after formal discontinuation of 
clinical development of the investigational product. 
It is the responsibility of the Sponsor to inform the investigator/Institution as to when these 
documents no longer need to be retained. 
19.3. 
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, IMP disposition log, pharmacy 
records, patient sign-in sheets, telephone logs, X-rays, and ECGs).  All draft, preliminary, and 
pre/final iterations of a final report are also considered to be source documents (eg, faxed and 
hard copy of laboratory reports, faxed and hard copy of initial results, and final report).  
The investigator agrees to allow direct access to all essential clinical study documents for the 
purpose of monitoring and/or auditing by the Sponsor or its authorized representatives and 
inspection by the appropriate regulatory authorities. 
Data reflecting the patient’s participation with the IMP under investigation are to be reported to 
the Sponsor.  The data are to be recorded on the eCRFs and/or other media provided or approved 
by the Sponsor. 
A completed eCRF must be submitted for each patient who receives IMP, regardless of duration.  
All supportive documentation submitted with the eCRF, such as laboratory or hospital records, 
should be clearly identified with the study and patient number.  Any personal information, 
including patient name, should be removed or rendered illegible to preserve individual 
confidentiality.  The eCRF should not be used as a source document unless otherwise specified 
by the Sponsor.  
Neither the Sponsor nor a service provider contracted to analyze data and complete the study 
report is permitted to interpret a blank answer; therefore, all fields should be completed.  All 
requested information must be entered on the eCRFs.  If an item is not available or is not 
applicable, this fact should be indicated as not available (N/A) or not done (N/D); do not leave a 
field blank.  
Each set of completed eCRFs must be signed and dated by the investigator acknowledging 
review and that the data are accurate and complete.  The completed database is to be returned to 
the Sponsor as soon as practical after completion by the mechanism prescribed for the protocol. 
It is essential that all dates appearing on the Sponsor’s patient data collection forms for 
laboratory tests, cultures, etc., be the dates on which the specimens were obtained or the 
procedures performed.  The eCRFs will be electronically signed by the investigator and dated as 
verification of the accuracy of the recorded data.  All data collection forms should be completed 
in a timely manner as defined in the eCRF Completion Guidelines. 


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20. 
ADMINISTRATIVE CONSIDERATIONS 
20.1. 
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 IMP 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 IMP 
• Ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments 
• Maintain adequate and accurate records and make those records available for 
inspection  
• Ensure that an appropriate IRB/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 
− Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance: 
http://www.fda.gov/cder/guidance/959fnl.pdf 


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20.3. 
Amendments and Study Termination 
Changes to the research covered by this protocol must be implemented by formal protocol 
amendment.  All amendments to the protocol must be initiated by the Sponsor and signed and 
dated by the investigator.  Protocol amendments must not be implemented without prior IRB or 
IEC approval.  Documentation of amendment approval by the investigator and IRB or IEC must 
be provided to the Sponsor or its authorized representative.  When the change(s) involve only 
logistic or administrative aspects of the study, the IRB or IEC only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator will contact the Medical Monitor.  Except in emergency situations, this contact 
should be made before implementing any departure from the protocol.  In all cases, contact with 
the Medical Monitor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action.  The data recorded on the eCRF and source documents will reflect 
any departure from the protocol and the source documents will describe the departure and the 
circumstances requiring it. 
The Sponsor reserves the right to terminate this study at any time. 
20.4. 
Financial Disclosure 
Prior to the start of the study, investigators will release sufficient and accurate financial 
information that permits the Sponsor to demonstrate that an investigator and all study relevant 
assigned personnel have no personal or professional financial incentive regarding the future 
approval or disapproval of the IMP such that his or her research might be biased by such 
incentive. 


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22. 
LIST OF REFERENCES 
American Diabetes Association, Diagnosis and Classification of Diabetes Mellitus. Diabetes 
Care. 2014;37(Supplement 1):S81-90.  
Baigent C, Blackwell L, Emberson J, et al. Cholesterol Treatment Trialists’ (CTT) Collaboration. 
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 
170 000 participants in 26 randomised trials. Lancet. 2010;376:1670-81. 
Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with 
high-dosage statin therapy in hyperlipidemic patients‒the PRIMO study. Cardiovasc Drugs Ther. 
2005;19(6):403-14. 
Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in America and gaps in 
patient education (USAGE): an internet-based survey of 10,138 current and former statin users. 
Clinical Lipidol. 2012;6:208-15. 
Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab. 
2010;95(5):2015-22. 
Egan A and Colman E. Weighing the benefits of high-dose simvastatin against the risk of 
myopathy. N Engl J Med. 2011;365:285-7. 
Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, et al. Mendelian 
Randomization Study of ACLY and Cardiovascular Disease. N Engl J Med. 2019 Mar 
14;380(11):1033-1042. doi: 10.1056/NEJMoa1806747. 
Food and Drug Administration (2012). FDA announces safety changes in labeling form some 
cholesterol-lowering drugs [Press release]. Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnoucments/ucm293623.htm 
Goldberg AC. Clinical trial experience with extended-release niacin (Niaspan): dose-escalation 
study. Am J Cardiol. 1998;82:35U–8U. 
Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, et al. Implications 
of recent clinical trials for the National Cholesterol Education Program Adult Treatment 
Panel III Guidelines. Circulation. 2004;110:227-39. 
Harris LJ, Thapa R, Brown M, Pabbathi S, Childress RD, Heimberg M, et al. Clinical and 
laboratory phenotype of patients experiencing statin intolerance attributable to myalgia. J Clin 
Lipidol. 2011;5(4):299-307.  
Insull W, Toth P, Mullican W, Hunninghake D, Burke S, Donovan J, et al. Effectiveness of 
colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary 
hypercholesterolemia: a 24-week randomized controlled trial. Mayo Clin Proc. 2001;76:971–82. 
Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, et al. Polymorphisms 
associated with cholesterol and risk of cardiovascular events. New Engl J Med. 
2008:358;12:1240-9. 
Knopp RH, Brown WV, Dujovne CA, Farquhar JW, Feldman EB, Goldberg AC, et al. Effects of 
fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am 
J Med. 1987;83:50–9. 


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Knopp RH, Dujovne CA, LeBeaut A, Lipka LJ, Suresh R, Veltri EP, et al. Evaluation of the 
efficacy, safety and tolerability of ezetimibe in primary hypercholesterolemia: a pooled analysis 
from two controlled phase III clinical studies. Int J Clin Pract. 2003;57:363–8. 
Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, et al. Treatment strategies 
in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J. 
2013;166(3):597-603. 
Martin SS, Gosch K, Kulkarni KR, Spertus JA, Mathews R, Ho PM, et al. Modifiable factors 
associated with failure to attain low-density lipoprotein cholesterol goal at 6 months after acute 
myocardial infarction. Am Heart J. 2013;165:26-33.e3. 
Mozffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al, for the writing 
group Members. Heart Disease and Stroke Statistics—2015 Update. A Report from the 
American Heart Association. Circ. 2015;131:e29-322. 
Nexletol [Highlights of Prescribing Information]. Ann Arbor, MI, Esperion The Lipid 
Management Company: 2020. 
Nexlizet [Highlights of Prescribing Information]. Ann Arbor, MI, Esperion The Lipid 
Management Company: 2020. 
Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: 
epidemiological update. Eur Heart J. 2014; 35:2950-9. 
Nilmendo [Summary of Produce Characteristics]. Pfaffenhofen, Germany, Daiichi Sankyo 
Europe: 2020. 
Nustendi [Summary of Produce Characteristics]. Pfaffenhofen, Germany, Daiichi Sankyo 
Europe: 2020. 
Pinkosky SL, Filippov S, Srivastava RA, Hanselman JC, Bradshaw CD, Hurley TR, et al. AMP-
activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a 
novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013 
Jan;54(1):134-51. 
Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond 
cholesterol reduction: A meta-regression analysis. J Am Coll Cardiol. 2005 Nov 
15;46(10):1855-62. Epub 2005 Oct 24. 
Samsoondar JP, Burke AC, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, et al. 
Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis in 
Ldlr-/- Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic Acid. Arterioscler 
Thromb Vasc Biol. 2017 Apr;37(4):647-656. doi: 10.1161/ATVBAHA.116.308963. Epub 2017 
Feb 2. 
Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, et al. Atherosclerosis 
Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein 
cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density 
subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 
2001;104:1108-13. 


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Stamler J, Wentworth D, Neaton J. Is relationship between serum cholesterol and risk for 
premature death from coronary heart disease continuous and graded? JAMA. 1986;256(20) 
823-8. 
Stone NJ, Robinson J, Lichtenstein AH, et al. for the Heart Association Task Force on Practice 
Guidelines Cardiovascular Risk in Adults. 2013 ACC/AHA Guideline on the Treatment of Blood 
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circ, DOI: 
10.1161/01.cir.0000437738.63853.7a 
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al; European 
Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin 
therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology 
and Management. Eur Heart J. 2015;36(17):1012–22. 
Townsend N, Nichols M, Scarborough P, Rayner M. Cardiovascular disease in Europe – 
epidemiological update 2015. Eur Heart J. 2015;36(40):2696-705. 
Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003:289:1681-90. 
Virani SS, Woodard LD, Chitwood SS, Landrum CR, Urech TH, Wang D, et al. Frequency and 
correlates of treatment intensification for elevated cholesterol levels in patients with 
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Waters DD. What the statin trials have taught us. Am J Cardiol. 2006;98:129-34. 
World Health Organization (WHO) Fact Sheet No 317 Updated January 2015. 
 


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23. 
APPENDICES 
Appendix 1: Schedule of Assessments 
Appendix 2: Sponsor’s Signature 
Appendix 3: Calculating Reynolds Risk Score 
Appendix 4: Calculating SCORE Risk 
Appendix 5: Investigator’s Signature 
Appendix 6: Summary of Changes in Amendment 1 
Appendix 7: Summary of Changes in Amendment 2 
Appendix 8: Summary of Changes in Amendment 3.1 
Appendix 9: Summary of Changes in Amendment 4 
Appendix 10: Summary of Changes in Amendment 5 
 


Bempedoic Acid (ETC-1002) 
Clinical Study Protocol 1002-043 
APPENDIX 1. SCHEDULE OF EVENTS (SUBJECT VISIT SCHEDULE) 
Screen and 
Treatment 
Run-In 
Phone 
Phone 
Phone 
Visit 
Visit 
Visit 
Visit 
s11 
S2 
Tl 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 no8 
Week/Month 
Week 
Week 
Day 1/ Month Month Month Month Month Month Month Month Month 
-5 
-4 
Week0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
Day 
Day 
±3 Days 
±5 
±5 
±10 
±10 
±10 
±10 
±10 
±10 
Procedure 
-35 
-31 to 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
-25 
Infonned Consent 
X 
Enrolhnent C1ite1ia 
X 
X 
X 
Demographics 
X 
Medical History 
X 
Concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medications 
Diet and Exercise 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Counselling 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recording 
Physical Exam 
X 
Weight:2 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
12-Lead ECG 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
Serology4 
X 
Semm or Urine 
X 
X 
Pregnancy/FSH5 
TSH 
X 
Clinical Safety Labs6 
X 
X 
X 
X 
X 
X 
X 
X 
Esperion Therapeutics, Inc. 
Amendment 5, 24 September 2020 
Phone 
Phone 
Phone 
Visit 
Visit 
Visit 
Tl18 
T128 
T138 EOS9•10 
PTl 
Month Month Mont 
30 days 
27 
30 
h 33 
±10 
±10 
±10 
±10 
after 
Days 
Days 
Days 
EOS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Amendment 5, 24 September 2020 
Screen and 
Treatment 
Run-In 
Phone 
Phone 
Phone 
Phone 
Phone 
Phone 
Visit 
Visit 
Visit 
Visit 
Visit 
Visit 
Visit 
s 11 
S2 
Tl 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 
no8 
Tl18 
T128 
T138 EOS9•10 
PTl 
Week/Month 
Week 
Week 
Day 1/ Month Month Month Month Month Month Month Month Month Month Month Mont 
30 days 
-5 
-4 
Week0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
h 33 
±10 
Day 
Day 
±3 Days 
±5 
±5 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
after 
Procedure 
-35 
-31 to 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
Days 
EOS 
-25 
Basic Fasting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipids7 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
hs-CRP 
X 
X 
X 
X 
Randomization 
X 
Single-Blind Drug 
X 
Dispensing 
Single-Blind Drug 
X 
Retrnn 
Double-blind Drug 
X 
X 
X 
X 
X 
X 
X 
Dispensing 
Double-Blind Drug 
X 
X 
X 
X 
X 
X 
X 
Retrnn 
ALT = alanine aminotransferase; AST = aspartate arninotransferase; CK = creatine kinase; DBP = diastolic blood pressure; ECG = electrocardiogram; eGFR = 
estimated glomerular filtration rate; EOS = End of Study; FSH = follicle-stimulating honnone; HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; 
HCV-Ab = hepatitis C antibody; HDL-C = high-density lipoprotein cholesterol; HR = heart rate; hs-CRP = high-sensitivity C-reactive protein; Labs = 
laboratory tests; LDL-C = low-density lipoprotein cholesterol; MACE = major adverse cardiovascular event; SBP = systolic blood pressure; TC = total 
cholesterol; TG(s) = triglyceride(s); TSH = thyroid-stimulating hormone. 
I An additional visit approximately I week after Visit SI and prior to Visit S2 MAY be completed if patient's LDL-C and/or TG level fail to meet entry criteria. Also, an 
additional visit and/or assessment between Visits SI and Tl MAY be completed if the patient's DBP, SBP, TSH, eGFR, ALT, AST, and/or CK fail to meet entiy criteria. If 
this optional visit/assessment is completed, the value from the repeat visit/assessment will be used to detemune eligibility. Also, at Visit SI an optional hs-CRP may be 
measured only if needed for Reynolds Risk Score and local hs-CRP value is not available. Finally, the number of days between Week -5 (Visit SI) and Week -4 (Visit S2) may 
be less than 7, and the number of days between Week -5 (Visit SI) and randomization may be less than 35 as long as eligibility can be detemuned. 
2 Body weight will be measured in the morning while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats). 
3 Vital signs w-ill include DBP, SBP, HR and will be collected prior to any blood sample collection. The patient will rest for several minutes prior to assessments. 
4 Serology for HBsAg and HCV-Ab. 
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Bempedoic Acid (ETC-1 002) 
Clinical Study Protocol 1002-043 
Screen and 
Run-In 
Visit 
s11 
S2 
Week 
Week 
Tl 
Day 1/ 
Week/Month 
-5 
-4 
Week0 
Day 
Day 
Procedure 
-35 
-31 to 
-25 
T2 
T3 
Month Month 
1 
3 
±3 Days 
±5 
Days 
Treatment 
Phone 
Phone 
Visit 
Visit 
T48 
T58 
T68 
T78 
Month Month Month Month 
6 
9 
12 
15 
±5 
±10 
±10 
±10 
Days 
Days 
Days 
Days 
Esperion Therapeutics, Inc. 
Amendment 5, 24 September 2020 
Phone 
Phone 
Phone 
Phone 
Visit 
Visit 
Visit 
Visit 
T88 
T98 
no8 
Tl18 
T128 
T138 EOS9•10 
PTl 
Month Month Month Month Month Mont 
30 days 
18 
21 
24 
27 
30 
h 33 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
after 
Days 
Days 
Days 
Days 
Days 
Days 
EOS 
5 Pregnancy test completed in premenopausal women only, senun test at Week -5 (Visit SI) and urine test at Day I (Visit Tl); FSH competed on postmenopausal women 
<55 years of age. 
6 Clinical safety laboratory tests include hematology, blood chemistry, and urinalysis. Urinalysis includes dipstick measured at the clinic and microscopic, if abnormal, 
completed by the centi·al lab. A limited safety laborato1y assessment (ALT, AST, 1B, and CK) will completed at Visit T2 only. A coagulation panel will be completed only if 
needed for patients on anticoagulant therapy at Day I (Visit Tl) and 3 to 5 days later. 
7 Basic fasting lipids include TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs. 
8 After Visit T4 (Month 6), telephone and clinic visits (alternating every 3 months) will continue until the study is completed. 
9 All procedtu·es will be completed at the End of Study or Early Tennination Visit. 
IO Dtu·ation of treatment for each patient will va1y and is dependent on acctunulation of MACE in the entire study. For individual subjects, treatiuent dtu·ation w-ill be a minimum 
of24 months and mav continue for up to aooroximatelv 57.5 months. 
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SAP_001.pdf: 
Bempedoic Acid (ETC-1002) 
Esperion Therapeutics, Inc. 
Statistical Analysis Plan: Protocol 1002-043 
Version 1.0, 14 November 2022 
Confidential 
Page 1 of 72 
STATISTICAL ANALYSIS PLAN 
PROTOCOL 1002-043 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO ASSESS THE EFFECTS OF BEMPEDOIC ACID 
(ETC-1002) ON THE OCCURRENCE OF MAJOR 
CARDIOVASCULAR EVENTS IN PATIENTS WITH, OR AT 
HIGH RISK FOR, CARDIOVASCULAR DISEASE WHO ARE 
STATIN INTOLERANT 
Version:  1.0 (Final) 
14 November 2022 
Property of Esperion Therapeutics, Inc. 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Esperion Therapeutics, Inc. 
NCT Number: NCT02993406
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Bempedoic Acid (ETC-1002) 
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Statistical Analysis Plan: Protocol 1002-043 
Version 1.0, 14 November 2022 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan vl.0 (14Nov2022) for Protocol 1002-043 Amendment 5 (24Sep2020) 
Prepared by: 
, PhD 
Stu y Stat1sbc1an 
Senior Director, Biostatistics 
Esperion Therapeutics 
Approved by: 
OocuSigned by: 
Vice President, Biometrics 
Esperion Therapeutics 
Executive Director, Clinical Development 
Esperion Therapeutics 
DocuSlgn•d by: 
, MD, MPH, MSc 
Head of Clinical Development and 
Phannacovigilance 
Esperion Therapeutics 
Confidential 
11/14/2022 I 12:04 PM PST 
Date 
11/14/2022 I 11 : 26 AM PST 
Date 
11/14/2022 I 2:24 PM EST 
Date 
11/14/2022 I 1:41 Pl'-1 EST 
Date 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
INTRODUCTION ......................................................................................................12 
2. 
STUDY OBJECTIVES ..............................................................................................13 
2.1. 
Primary Objective .......................................................................................................13 
2.2. 
Secondary Objectives .................................................................................................13 
2.3. 
Tertiary Objective .......................................................................................................13 
3. 
STUDY ENDPOINTS ................................................................................................14 
3.1. 
Primary Efficacy Endpoint .........................................................................................14 
3.2. 
Secondary Efficacy Endpoints ....................................................................................14 
3.2.1. 
Key Secondary Efficacy Endpoints ............................................................................14 
3.2.2. 
Additional Secondary Time-to-Event Endpoints ........................................................14 
3.2.3. 
Secondary Efficacy Lipid and Biomarker Endpoints .................................................15 
3.3. 
Tertiary Lipid and Biomarker Endpoints ....................................................................15 
3.4. 
Safety Endpoints .........................................................................................................15 
4. 
STUDY DESIGN .......................................................................................................15 
4.1. 
General Description ....................................................................................................15 
4.2. 
Maintenance of Blinding ............................................................................................16 
4.3. 
Study Closeout ............................................................................................................16 
4.4. 
Study Committees .......................................................................................................17 
4.5. 
COVID-19 Impact ......................................................................................................17 
4.6. 
Schedule of Events .....................................................................................................18 
5. 
PLANNED ANALYSES ............................................................................................18 
5.1. 
Data Monitoring Committee (DMC) ..........................................................................18 
5.2. 
Interim Analyses .........................................................................................................18 
5.3. 
Final Analyses ............................................................................................................18 
6. 
ANALYSIS SETS ......................................................................................................18 
6.1. 
Patients Irregularities ..................................................................................................18 
6.1.1. 
Patients at Site 18705 ..................................................................................................18 
6.1.2. 
Patients Randomized Multiple Times .........................................................................19 
6.2. 
Full Analysis Set [FAS] ..............................................................................................19 
6.3. 
Safety Analysis Set [SAS] ..........................................................................................20 


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6.4. 
Per-Protocol Analysis Set [PPS] .................................................................................20 
7. 
STUDY DEFINITIONS .............................................................................................20 
7.1. 
Disposition ..................................................................................................................20 
7.2. 
Key Study Dates .........................................................................................................21 
7.2.1. 
Definition and Imputation of Key Event Dates ..........................................................21 
7.2.2. 
Reference Start Date and Study Day ..........................................................................21 
7.2.3. 
Baseline .......................................................................................................................22 
7.2.4. 
Analysis Visit Windows .............................................................................................22 
7.2.5. 
Time to Event and Date of Censoring ........................................................................23 
7.3. 
Prior and Concomitant Medications ...........................................................................23 
7.4. 
Diabetes Related Definitions ......................................................................................23 
7.4.1. 
Baseline Glycemic Status ...........................................................................................23 
7.4.2. 
Antidiabetic Medications ............................................................................................24 
7.4.3. 
NODM as an Efficacy Endpoint .................................................................................24 
7.5. 
Other Baseline Characteristics ....................................................................................25 
7.5.1. 
Region .........................................................................................................................25 
7.5.2. 
History of Hypertension .............................................................................................25 
7.5.3. 
Baseline CVD Risk Category .....................................................................................25 
7.5.4. 
History of Chronic Kidney Disease ............................................................................25 
7.6. 
Lipid-Modifying Therapy (LMT) ...............................................................................26 
7.6.1. 
Definition of LMT ......................................................................................................26 
7.6.2. 
Categorization of Statin Intensity ...............................................................................26 
7.6.3. 
Baseline LMT .............................................................................................................27 
7.6.4. 
Cross-in LMT .............................................................................................................27 
8. 
STATISTICAL CONSIDERATIONS .......................................................................28 
8.1. 
Sample Size ................................................................................................................28 
8.2. 
Multicenter Studies .....................................................................................................28 
8.3. 
Multiplicity .................................................................................................................28 
8.4. 
Coding Dictionaries ....................................................................................................29 
8.5. 
Missing Data Handling ...............................................................................................29 
8.5.1. 
Imputation of Missing Dates ......................................................................................29 
8.5.2. 
Laboratory Data Beyond the Limits of Quantification ...............................................30 


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8.6. 
General Principles .......................................................................................................30 
9. 
DISPOSITION OF STUDY PARTICIPANTS ..........................................................30 
10. 
PROTOCOL DEVIATIONS ......................................................................................30 
11. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................32 
12. 
MEDICAL AND SURGICAL HISTORY .................................................................33 
13. 
MEDICATIONS .........................................................................................................33 
13.1. 
Prior and Concomitant Medications ...........................................................................33 
13.2. 
Antidiabetic Medications ............................................................................................33 
13.3. 
Lipid-Modifying Therapy ...........................................................................................34 
14. 
STUDY MEDICATION COMPLIANCE AND EXPOSURE ..................................35 
15. 
EFFICACY ENDPOINTS ..........................................................................................36 
15.1. 
Adjudicated Clinical Endpoints ..................................................................................36 
15.2. 
Primary Efficacy Endpoint .........................................................................................36 
15.2.1. 
Primary Efficacy Endpoint .........................................................................................36 
15.2.2. 
Primary Analysis Method of Primary Efficacy Endpoint ...........................................36 
15.2.3. 
Primary Efficacy Endpoint Data Censoring Pattern ...................................................37 
15.2.4. 
Sensitivity Analyses of Primary Efficacy Endpoint ...................................................37 
15.3. 
Analyses of Secondary and Other Efficacy Endpoints ...............................................37 
15.3.1. 
Secondary Efficacy Time-to-Event Endpoints ...........................................................37 
15.3.2. 
Secondary Efficacy Endpoint Time to NODM ..........................................................38 
15.3.3. 
Secondary Efficacy Endpoint LDL-C ........................................................................38 
15.3.4. 
Secondary Efficacy Endpoint HbA1C .........................................................................39 
15.3.5. 
Secondary Efficacy Endpoint hs-CRP ........................................................................39 
15.4. 
Sensitivity Analyses for Efficacy Endpoints ..............................................................39 
15.4.1. 
Per-Protocol Analyses ................................................................................................39 
15.4.2. 
On-Treatment Analysis ...............................................................................................39 
15.4.3. 
Adjunctive Cross-in Lipid-Modifying Therapy ..........................................................40 
15.4.4. 
Additional Analyses for Diabetes Endpoints ..............................................................40 
15.5. 
Exploratory and Descriptive Analyses of Efficacy Endpoints ...................................41 
15.5.1. 
Subgroup Analyses .....................................................................................................41 
15.5.2. 
Covariate Analyses .....................................................................................................41 
15.5.3. 
Total Event Analysis ...................................................................................................41 


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15.5.4. 
Incidence Rates of Primary and Key Secondary Endpoints .......................................42 
15.5.5. 
Additional Analysis of Adjudicated Events ...............................................................42 
15.6. 
Tertiary and Exploratory Analyses for Lipid and Biomarkers Endpoints ..................42 
15.6.1. 
Tertiary Lipid and Biomarker Endpoints ....................................................................42 
15.6.2. 
Responder Analyses ....................................................................................................42 
16. 
SAFETY OUTCOMES ..............................................................................................43 
16.1. 
Adverse Events ...........................................................................................................43 
16.1.1. 
Treatment Emergent Adverse Events .........................................................................43 
16.1.2. 
Adverse Events of Special Interest .............................................................................43 
16.1.3. 
Other Adverse Events .................................................................................................44 
16.1.4. 
Exposure Adjusted Incidence Rates (EAIRs) of TEAEs ............................................44 
16.1.5. 
Subgroup Analyses of Adverse Events .......................................................................45 
16.2. 
Death and Major Adverse Cardiac Events ..................................................................45 
16.3. 
Safety Laboratory Evaluations ...................................................................................45 
16.4. 
Electrocardiogram Evaluations ...................................................................................47 
16.5. 
Vital Signs ..................................................................................................................47 
16.6. 
Physical Examination .................................................................................................47 
17. 
COVID-19 IMPACT ASSESSMENT ........................................................................48 
17.1. 
Impact on Study Visits and Procedures ......................................................................48 
17.2. 
Impact on Disposition and Treatment Compliance ....................................................48 
17.3. 
COVID-19 Related Safety Assessments ....................................................................49 
17.4. 
Potential Impact on Efficacy Endpoints .....................................................................49 
18. 
UPDATES AS A RESULT OF UKRAINE CONFLICT...........................................50 
18.1. 
Impact on Study Conduct ...........................................................................................50 
18.2. 
Patient Disposition ......................................................................................................50 
18.3. 
Efficacy Analyses of Clinical Events .........................................................................50 
18.4. 
Sensitivity Analyses of Primary and Key Secondary Efficacy Endpoints .................51 
18.5. 
Other Analyses ............................................................................................................51 
19. 
LIST OF REFERENCES ............................................................................................52 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................53 
APPENDIX 2. PATIENTS WITH MULTIPLE RANDOMIZATIONS ....................................57 
APPENDIX 3. ANALYSIS VISIT WINDOWS ........................................................................58 


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APPENDIX 4. IMPUTATION OF DATES ...............................................................................59 
APPENDIX 5. STATIN INTENSITY CATEGORIZATION ....................................................61 
APPENDIX 6. MULTIPLE IMPUTATION AND TIPPING POINT ANALYSIS ...................62 
APPENDIX 7. ADVERSE EVENTS OF SPECIAL INTEREST ..............................................63 
APPENDIX 8. TYPE 2 DIABETES MEDICAL HISTORY AND PRIOR 
MEDICATION ...........................................................................................................68 
APPENDIX 9. MALIGNANCY CATEGORIZATION BASED ON PRIMARY 
ORGAN LOCATION .................................................................................................70 
APPENDIX 10. POTENTIALLY CLINICALLY SIGNIFICANT LABORATORY 
AND VITAL SIGN ABNORMALITIES ...................................................................71 
APPENDIX 11. HISTORY OF HYPERTENSION ...................................................................72 
 
 
 


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Version 1.0, 14 November 2022 
 
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LIST OF TABLES 
Table 1: Baseline Glycemic Status ................................................................................................24 
Table 2: Analyses for Shift Tables of Laboratory Parameters .......................................................46 
Table 3: Other Laboratory Abnormalities ......................................................................................46 
 
 
LIST OF FIGURES 
Figure 1: 1002-043 Study Design ..................................................................................................16 
 
 
 
 
 


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Version 1.0, 14 November 2022 
 
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LIST OF ABBREVIATIONS 
Abbreviation/Specialist Term 
Definition 
ADA 
American Diabetes Association 
ADaM 
Analysis Data Model 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
below limit of quantification 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAD 
coronary artery disease 
CeVD 
cerebrovascular atherosclerotic disease 
CEC 
Clinical Endpoints Committee 
CI 
confidence interval 
CK 
creatine kinase 
CKD 
chronic kidney disease 
COVID-19 
coronavirus disease of 2019 
CRF 
Case Report Form 
CV 
Cardiovascular 
CVD 
cardiovascular disease 
DALIVE 
Date of Last Known Alive 
DBP 
diastolic blood pressure 
DC 
Diabetes Committee 
DFDOSE 
Date of First Dose 
DLASMT 
Date of Last Assessment (for Non-Fatal Clinical Endpoints) 
DLDOSE 
Date of Last Dose 
DLSFU 
Date of Last Survival Follow-Up 
DMC 
Data Monitoring Committee 


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Statistical Analysis Plan: Protocol 1002-043 
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Abbreviation/Specialist Term 
Definition 
DSC 
Date of Study Completion 
eGFR 
estimated glomerular filtration rate 
EC 
Executive Committee 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDCP 
Fixed dose combination product 
HbA1C 
glycated hemoglobin (Hemoglobin A1C) 
HDL-C 
high-density lipoprotein cholesterol 
Hgb 
Hemoglobin 
HR 
hazard ratio 
hs-CRP 
high-sensitivity C-reactive protein 
ICDM 
Inadequately Controlled Diabetes Mellitus 
ID 
Identifier 
IMP 
investigational medicinal product 
ITT 
Intention-to-treat 
KM 
Kaplan-Meier 
LDL-C 
low-density lipoprotein cholesterol 
LDL-M 
low-density lipoprotein cholesterol - measured 
LLN 
lower limit of normal 
LMT 
lipid-modifying therapy 
LSM 
least squares mean 
LTFU 
lost to follow-up 
MACE 
major adverse cardiac event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
NODM 
new-onset diabetes mellitus 
non-HDL-C 
non-high-density lipoprotein cholesterol 
PAD 
peripheral arterial disease 
PCSK9i 
proprotein convertase subtilisin/kexin type 9 inhibitor(s) 


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Abbreviation/Specialist Term 
Definition 
PD 
Protocol Deviation 
PH 
proportional hazard 
PMM 
pattern mixture model 
PPS 
Per-protocol Set 
PT 
Preferred Term 
SAE(s) 
serious adverse event(s) 
SAS 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SE 
standard error 
SI 
Système International (International System of Units) 
SOC 
System Organ Class 
SDTM 
Study Data Tabulation Model 
SMQ 
Standardised MedDRA Query 
TB 
total bilirubin 
TC 
total cholesterol 
TE 
treatment-emergent 
TEAE(s) 
treatment-emergent adverse event(s) 
TESAE(s) 
treatment-emergent serious adverse event(s) 
TFL(s) 
table(s), figure(s), and listing(s) 
TG(s) 
triglyceride(s) 
TRAC 
Tendon Rupture Adjudication Committee 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
US 
United States 
USUBJID 
Unique subject identifier 
WBC 
white blood cell 
WHO-DDE 
World Health Organization – Drug Dictionary Enhanced 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analyses 
for Study Protocol 1002-043 A Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Effects of Bempedoic Acid (ETC-1002) on the Occurrence of Major Cardiovascular Events 
in Patients with, or at High Risk for, Cardiovascular Disease Who are Statin Intolerant, 
Amendment 5 (24 September 2020). 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to evaluate whether administration of bempedoic acid 180 mg/day 
versus placebo reduces the risk of major adverse cardiac event (MACE) in patients with, or at 
high risk for, cardiovascular disease (CVD) who are statin intolerant.  This will be assessed with 
a composite primary efficacy endpoint that includes time to first occurrence of cardiovascular 
(CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. 
2.2. 
Secondary Objectives 
The secondary objectives include: 
• To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus 
placebo reduces the risk of other clinical endpoints of CV morbidity and mortality 
and all-cause mortality 
• To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-
reactive protein (hs-CRP) 
• To evaluate the long-term safety and tolerability of bempedoic acid 180 mg/day 
compared to placebo 
• To evaluate the 12-month impact of treatment with bempedoic acid 180 mg/day 
versus placebo on absolute change in hemoglobin A1C (HbA1C) in patients with 
inadequately controlled type 2 diabetes mellitus (HbA1C of 7% or greater at baseline) 
• To evaluate whether long-term treatment with bempedoic acid 180 mg/day versus 
placebo reduces the risk of new-onset type 2 diabetes  
2.3. 
Tertiary Objective 
• To evaluate the effect of long-term treatment with bempedoic acid 180 mg/day versus 
placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol 
(TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), HbA1C, and 
fasting glucose 


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3. 
STUDY ENDPOINTS 
3.1. 
Primary Efficacy Endpoint 
• Time to first occurrence of a MACE, where MACE is defined as the composite 
endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization 
(MACE-4) 
3.2. 
Secondary Efficacy Endpoints 
3.2.1. 
Key Secondary Efficacy Endpoints 
Key secondary efficacy time-to-event endpoints include, in hierarchical order:  
1. Time to first occurrence of the composite endpoint of CV death, nonfatal MI, or 
nonfatal stroke (MACE-3) 
2. Time to first occurrence of (fatal + nonfatal) MI 
3. Time to first occurrence of coronary revascularization 
4. Time to first occurrence of (fatal + nonfatal) stroke 
5. Time to CV death 
6. Time to all-cause mortality 
3.2.2. 
Additional Secondary Time-to-Event Endpoints 
Additional secondary efficacy time-to-event include: 
• Time to first occurrence of the composite endpoint of all-cause mortality, nonfatal 
MI, nonfatal stroke, or coronary revascularization 
• Time to first occurrent of 5-component composite endpoint of CV death, nonfatal MI, 
nonfatal stroke, coronary revascularization, or hospitalization for unstable angina 
(MACE-5) 
• Time to first occurrence of nonfatal MI 
• Time to fatal MI 
• Time to first occurrence of nonfatal stroke 
• Time to fatal stroke 
• Time to first occurrence of (fatal + nonfatal) hemorrhagic stroke 
• Time to first occurrence of (fatal + nonfatal) nonhemorrhagic stroke  
• Time to hospitalization for unstable angina 
• Time to first occurrence of new-onset type 2 diabetes mellitus (NODM) 


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3.2.3. 
Secondary Efficacy Lipid and Biomarker Endpoints 
• Percent change from baseline to Month 6 in LDL-C  
• Percent change from baseline to Month 6 in hs-CRP 
• Change from baseline to Month 12 in HbA1C in patients with inadequately controlled 
type 2 diabetes mellitus 
3.3. 
Tertiary Lipid and Biomarker Endpoints 
• Absolute change and percent change from baseline to Months 3, 6, 12, 24, then every 
6 months through the end of study in LDL-C 
• Absolute change and percent change from baseline to Months 3, 6, 12, 24, then every 
6 months through the end of study in non-HDL-C, TC, HDL-C, and TG 
• Percent change from baseline to Month 12 and at the end-of-study (EOS) in hs-CRP 
• Change from baseline to Month 3, 6, 12, then every 6 months through the end of 
study in HbA1C 
• Change from baseline to Month 3, 6, 12, then every 6 months through the end of 
study in fasting glucose  
3.4. 
Safety Endpoints 
• Adverse events (AEs) and adverse events of special interest (AESIs) 
• Vital signs 
• Clinical laboratory measures 
4. 
STUDY DESIGN 
4.1. 
General Description 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study assessing the occurrence of MACE in patients with, or at high risk for, CVD who are 
unable to tolerate statin therapy.  The study is conducted at approximately 1200 clinical sites in 
32 countries. 
Following signing of an informed consent document prior to any study procedures, screening 
(Visit S1) occurred approximately 5 weeks prior to Day 1 (Visit T1) but can be extended for an 
additional 5 weeks if needed to adjust background medical therapy or for other reasons.  All 
eligible patients will return at Week -4 (Visit S2, 4 weeks prior to Day 1) to initiate a 4-week 
Run-in Period with single-blind (blinded to patient only) placebo once daily that will include 
assessment of tolerability and investigational medicinal product (IMP) adherence.  On Day 1 
(Visit T1), approximately 14,000 eligible patients will be randomized 1:1 to receive either 
double-blind bempedoic acid 180 mg (n ~ 7,000) or placebo (n ~ 7,000) once daily.  Randomized 
patients will return for clinic visits at Month 1 (Visit T2), Month 3 (Visit T3), and Month 6 (Visit 


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T4).  Following Month 6, patients will be contacted every 3 months (alternating with a phone 
visit and a clinic visit) for the remainder of the study.   
Patients who discontinue IMP for any reason are strongly encouraged to remain in the study to 
be evaluated for efficacy and safety endpoints and will be expected to continue study visits or 
agree to some other form of contact through the study closeout. 
Figure 1: 1002-043 Study Design 
 
4.2. 
Maintenance of Blinding 
During the Treatment Period, Sponsor, site personnel, CRO, and patient are all unaware of 
patient’s treatment assignment.  Blinding of treatment must be maintained for all patients unless, 
in the opinion of the investigator, the safety of the patient may be at risk.  If the blind must be 
broken prior to consultation with the Medical Monitor, contact must be made within 24 hours of 
breaking the blind. 
Unblinding of IMP will NOT automatically discontinue the patient from the study.  Any patient 
for whom the blind is broken will be permanently discontinued from IMP but should continue in 
the study. 
Post-randomization values for individual laboratory measures for LDL-C, non-HDL-C, TC, TG, 
and hs-CRP are not available to blinded personnel from the clinical site, the patient, the Sponsor, 
or the CRO during the study. 
4.3. 
Study Closeout 
The study will continue until all the following criteria have been met:   
1. at least 1,620 patients have experienced an adjudicated primary 4-component 
MACE (CV death, nonfatal MI, nonfatal stroke, or coronary revascularization),  
2. at least 810 patients have experienced an adjudicated 3-component MACE (CV 
death, nonfatal MI, or nonfatal stroke) and  
3. 24 months have elapsed since the last patient was randomized.    
During the study closeout period (when the patients’ End of Study (EOS) Visits will be 
scheduled), each patient still in the study will be required to complete an in-clinic visit which is 
Screening 
4-week, single-blind, 
placebo run-in period 
STUDY COMPLETION 
• At least 1,620 adjudicated 
primary 4-component MACP 
• At least 719 adjudicated 
3-component MACE" 
• At least 24 months since the 
last patient was randomized 


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designated as the EOS Visit and perform the procedures according to Protocol Appendix 1, 
Schedule of Events.  Patients who are still on IMP at the visit will be asked to end study 
treatment.  
A post-treatment telephone visit will occur 30 days (± 10 days) after the EOS visit to assess AEs, 
SAEs and identify potential clinical endpoints.  
During the study closeout period, vital status will be collected within legal and ethical 
boundaries (see Protocol Section 10.7.5) for all patients who did not complete the study, and 
only those with unknown status are considered as lost to follow-up. 
4.4. 
Study Committees 
This study includes several independent and expert committees:   
• An Executive Committee (EC) oversees the design and conduct of the study and the 
interpretation of study results.   
• An independent Data Monitoring Committee (DMC) reviews accumulating blinded 
and unblinded safety data from this and other ongoing studies of bempedoic acid 
approximately 4 times per year to ensure there is no avoidable increased risk of harm 
to patients.  The DMC reviews safety data, reported and adjudicated MACE, and 
specific clinical laboratory results. 
• A blinded independent Clinical Event Committee (CEC) adjudicates designated 
clinical endpoints, including MACE endpoints, as well as non-CV deaths. 
• A blinded independent Diabetes Committee (DC) verifies diagnosis of new-onset 
type 2 diabetes.   
• A blinded independent Tendon Rupture Adjudication Committee (TRAC) adjudicates 
potential events of tendon rupture.   
Each of these committees has its own charter that includes additional details.  Adjudicated or 
verified results for clinical events, diabetes and tendon rupture are maintained in a separate 
adjudication database.  


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4.6. 
Schedule of Events 
The schedule of events can be found in Appendix 1. 
5. 
PLANNED ANALYSES 
The following analyses will be performed for this study: 
• Safety analyses for DMC meetings 
• Final Analysis 
5.1. 
Data Monitoring Committee (DMC) 
An independent DMC reviews accumulating blinded and unblinded safety in regularly scheduled 
intervals approximately 4 times per year to ensure there is no avoidable increased risk of harm to 
patients.  DMC reviews safety data, reported and adjudicated MACE, and specific clinical 
laboratory results.  The DMC is responsible for making recommendations about alteration or 
early termination of the study based upon their review of the blinded and unblinded data.   
Analyses for the DMC are provided by an external vendor with a separate unblinded team.  
There are strict processes in place to ensure blinding for the study team.  The details for DMC 
review procedures are described in the DMC Charter. 
5.2. 
Interim Analyses 
There are no interim efficacy analyses in this study. 
5.3. 
Final Analyses 
This SAP will be finalized prior to the database lock and unblinding of treatment.  Additional 
analyses may be performed as needed but will be clearly marked as ad hoc. 
6. 
ANALYSIS SETS 
Inclusion of patients in each analysis set will be finalized prior to the unblinding of the study. 


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6.2. 
Full Analysis Set [FAS] 
The full analysis set (FAS), used for all the efficac 
defined as all randomized atients, 
The FAS is also known as the intention-to-treat (ITT) set of 
patients. Patients in the FAS will be included in their assigned treatment group. 
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Note that patients who participated in the study run-in period only and were not randomized will 
not be included in FAS.  
6.3. 
Safety Analysis Set [SAS] 
The safety analysis set (SAS), used for all the safety summaries, is defined as all patients in FAS 
who received at least 1 dose of double-blind IMP.  Patients in the SAS will be grouped according 
to the actual treatment received, in particular:  
• patients who were randomized to bempedoic acid but received placebo only will be 
included in the placebo group; 
• patients who were randomized to placebo but received at least one dose of study IMP 
bempedoic acid will be included in the bempedoic acid group.  Note that this does not 
apply to patients who received commercial bempedoic acid or commercial fixed dose 
combination of bempedoic acid and ezetimibe. 
6.4. 
Per-Protocol Analysis Set [PPS] 
The Per-Protocol Set (PPS) is a subset of FAS that excludes patients with selected major 
protocol deviations including: 
The PPS has the same treatment group assignment as the FAS and is used for sensitivity analyses 
the primary and key secondary efficacy endpoints.  The additional sensitivity analyses of on-
treatment and pre-cross-in LMT analyses will also be conducted using PPS.  
7. 
STUDY DEFINITIONS 
7.1. 
Disposition 
Study Completion: the study completion status is recorded on the Study Completion/Early 
Termination CRF.  A patient is considered as having completed the study if the patient 
completed the designated EOS visit during the study closeout period (as determined by the site), 
or if the patient died during the study (i.e., had not been discontinued prior to death). 
Treatment Completion: the treatment completion status is recorded on the End of Treatment 
CRF.  A patient is considered as having completed study treatment if the patient is still on-


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treatment (i.e., has not permanently discontinued treatment) at the EOS visit during the study 
closeout period or died within 30 days of last dose.  Note that patients who did not complete the 
study will not be considered as having completed the study treatment. 
7.2. 
Key Study Dates 
7.2.1. 
Definition and Imputation of Key Event Dates 
Date of End of Study (EOS): the study completion/early termination date recorded on the “Study 
Completion/Early Termination” CRF. Note that the patient may have a 30-day post EOS follow-
up visit after this. 
Date of Study Completion (DSC): For patients who did not complete the study, it is the later of 
a) the date of EOS and b) the date of the 30-day post EOS follow-up visit. For patients who 
completed the study, it is the latest date of a) the date of EOS, b) the date of the 30-day post EOS 
follow-up visit,  or c) the date of death. This date is used to calculate the duration of study 
(follow-up) for each patient and all clinical events that happen during this period are adjudicated.  
Date of First Dose of IMP (DFDOSE): for each patient, the DFDOSE is the date/time of 
administration recorded on the “On-Site Study Medication/ Compliance” CRF at Visit T1.  If 
that field is missing, it is set to be next first date of administration at Visit T3. 
Date of Last Dose of IMP (DLDOSE): the date of last dose is recorded on the End of Treatment 
CRF.  In cases of missing either completely or partially, it is imputed as the earliest date of a) the 
last day of the month (if the month and year are present), or the last day of the year (if only the 
year is present); b) the Date of EOS; and c) the date of the last IMP dispense plus the number of 
tablets taken.  
Date of Last Visit (DLVISIT): the last date recorded on either the Visit Date or the Telephone 
Contact CRFs.  For patients who did not complete the study, this must be on or prior to the DSC.  
Date of Last Known Alive (DALIVE):  for patients whose vital status at the end of study is either 
alive or unknown, this is the last day when the patient is known to be alive.  It is the latest “last 
known alive date” recorded on the Survival Status CRF.  If this date is partially or completely 
missing, it is set to the later of last known alive date with imputation and DSC. 
Date of Last Assessment for Non-Fatal Clinical Endpoints (DLASMT): Potential clinical 
endpoints are assessed every three months either in clinic or by telephone through the Post-EOS 
Phone visit.  For patients who died during the study within 90 days of last visit, the DLASMT is 
set to the date of death.  Otherwise, the DLASMT is set to be DLVISIT.  Note that this definition 
also applies to new-onset diabetes mellitus (NODM) as an efficacy endpoint. 
Date of Last Survival Follow-Up (DLSFU): For patients who completed the study, or withdrew 
consent, or discontinued study and were identified as dead only through survival search (death is 
not adjudicated), it is the DSC.  For all other patients it is the Date of Last Known Alive.  This is 
the last date for survival status follow-up. 
7.2.2. 
Reference Start Date and Study Day 
Day 1 (Reference Start Date) is defined as the Date of First Dose of IMP, or the date of 
randomization for patients who did not receive any dose of IMP. 


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Study Day will be calculated from the reference start date (Day 1) as follows:  
• If the date of the event is on or after the reference date, then:  Study Day = (date of 
event – reference start date) + 1. 
• If the date of the event is prior to the reference date, then: Study Day = (date of 
event – reference start date). 
The Study Day will be used to show start/stop day of assessments and events (including AEs, 
prior and concomitant medications).  
7.2.3. 
Baseline 
For safety parameters, unless otherwise specified, baseline is defined as the last non-missing 
measurement taken on or prior to Day 1 (including unscheduled assessments).   
Baseline for fasting glucose is defined as the mean of the last two non-missing fasting values 
measured on or prior to Day 1.  If only one value is available, then that single value will be used 
as baseline.  Baseline HbA1C is defined as the last non-missing value on or prior to Day 1. 
Baseline for lipids parameters (LDL-C, non-HDL-C, TC, HDL-C, TG) is defined as the mean of 
the last two non-missing fasting values measured on or prior to the date of randomization.  If 
only one value is available, then that single value will be used as baseline.  If the patient had no 
fasting values available at baseline, non-fasting values will be used.  
Baseline for hs-CRP is defined as the last non-missing value on or prior to the date of 
randomization. 
7.2.4. 
Analysis Visit Windows 
For data analysis purpose, unless otherwise specified, study assessments will be assigned to 
analysis visits based on the Study Day (Section 7.2.2), and analysis visit windows specified in 
Appendix 3.  
For lipids parameters (LDL-C, non-HDL-C, TC, HDL-C, TG) and hs-CRP, the date of 
randomization will be used as the start date to determine the analysis visit windows.  For hs-CRP 
only, the end-of-study (EOS) measurement is defined as the last measurement taken for the 
patient.  
In cases where multiple assessments fall into the same analysis visit, and only one is used for 
analysis, it is selected based on the following rules.  
• The assessment closest to the target (nominal visit) date will be used.   
• If there are ties, the assessment after the target date will be used.   
• If multiple values are available with the same date and time, the assessment with 
larger laboratory accession number (LBREFID) will be used. 
Note that unscheduled visits are treated the same way as scheduled visits. 
Nominal visits (e.g., S1, S2, T1, etc, see Appendix 1) may be used in listings as appropriate. 


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7.2.5. 
Time to Event and Date of Censoring 
For time-to-event analysis of clinical endpoint events (including new-onset type 2 diabetes), the 
start date is the date of randomization when the FAS is used, based on the ITT principle.  When 
the PPS is used, the start date is set to be the date of first dose.  For composite endpoints, the 
event date is the date of the first component event. 
Patients who did not have any event in question will be considered as censored for the analysis. 
The date of censoring is determined as the following: 
• Fatal events (CV death, fatal MI, fatal stroke, all-cause mortality): censored at Date of 
Last Survival Follow-Up. 
• Non-fatal events and composite endpoints that include both fatal and non-fatal events: 
censored at the Date of Last Assessment. 
Please see Section 18.3 for special censoring rule as applicable to patients from Ukraine as a 
result of the ongoing conflict. 
7.3. 
Prior and Concomitant Medications 
Prior medications are medications which started and ended prior to Day 1. 
Concomitant medications are medications that started after Day 1, or that started before Day 1 
and continued through Day 1, or if the status is “ongoing” at Day 1.   
7.4. 
Diabetes Related Definitions 
7.4.1. 
Baseline Glycemic Status 
Analyses of diabetes and related biomarkers are conducted with specific subsets of study 
population based on the baseline glycemic status defined in Table 1. 
• For efficacy analyses of new-onset type 2 diabetes (conducted in the study population 
with No Diabetes at baseline), and related biomarkers HbA1c and fasting glucose, the 
FAS (or PPS for sensitivity analyses) is used with subpopulations defined according 
to the baseline glycemic status. 
• For safety analyses of AESIs of new-onset diabetes (conducted in the study 
population with No Diabetes at baseline), and worsening hyperglycemia (Diabetes at 
baseline), and related safety laboratory measures including HbA1c and fasting 
glucose, the SAS is used with subpopulations defined according to the baseline 
glycemic status. 


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Table 1: Baseline Glycemic Status 
Status 
Definition 
Diabetes 
Meeting 1 or more of the following criteria at baseline captured by 
information recorded prior to Day 1:   
• 
Medical history or adverse events indicating diabetes as 
defined in the Diabetes Committee Charter (attached as 
Appendix 8)  
• 
Prior glucose-lowering medication as defined by the Diabetes 
Committee Charter (attached as Appendix 8)  
• 
HbA1C measurement ≥6.5% 
• 
Two or more measurements of fasting glucose ≥126 mg/dL 
(7.0 mmol/L) 
Inadequately Controlled (IC) 
Diabetes 
With Diabetes and a HbA1C of 7% or greater at baseline.   
No Diabetes 
Not meeting any of the criteria for Diabetes at baseline. 
Prediabetes 
 
No Diabetes at baseline, and with: 
• 
HbA1C measurement of ≥5.7% and <6.5%, OR 
• 
1 or more measurements of fasting glucose ≥100 mg/dL 
(5.6 mmol/L), but not more than 1 value of fasting glucose 
≥126 mg/dL (7.0 mmol/L). 
Normoglycemia 
No Diabetes, and not meeting the criteria for Prediabetes at baseline. 
7.4.2. 
Antidiabetic Medications 
For this study, antidiabetic medications are defined based on approved medications that lower 
blood glucose (Appendix 8). 
Baseline antidiabetic medications are defined for the FAS as those ongoing at the time of 
randomization.  
Patients are considered to have had a change in background antidiabetic medications if they had 
any new antidiabetic medications that either started, stopped or had a dose change during the 12 
weeks (84 days) prior to screening (Visit S1) to within 12 months (365 days) post randomization.  
These patients are excluded from a sensitivity analysis of Month 12 HbA1c response. 
7.4.3. 
NODM as an Efficacy Endpoint  
For efficacy evaluation, NODM will be assessed in the subset of patients who did not have 
diabetes at baseline (No Diabetes), including those patients in the subsets of “prediabetes” and 
“normoglycemia”, but develop postbaseline new onset type 2 diabetes mellitus, defined by 1 or 
more of the following criteria according to the 2020 American Diabetes Association (ADA) 
guidelines (ADA, 2020): 
1. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L).  Fasting is defined as no caloric 
intake for at least 8 hours;* or 


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2. Two-hour post-prandial glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose 
tolerance test as defined in the ADA guidelines;* or 
3. HbA1C measurement ≥6.5% (48 mmol/mol);* or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
*Note:  In the absence of unequivocal hyperglycemia, diagnosis requires 2 abnormal test results 
from the same sample or in 2 separate test results. 
The NODM events will be verified by the Diabetes Committee based on the 
 
Diabetes Committee Charter. 
7.5. 
Other Baseline Characteristics 
7.5.1. 
Region 
Study patients are grouped by the sites’ location into the following regions (GHDx, 2022): 
• North America: Canada and United States.  
• Latin America: Argentina, Brazil, Chile, Colombia, and Mexico. 
• Western Europe: Austria, Belgium, Denmark, Germany, Great Britain, Netherlands, 
and Spain. 
• Central and Eastern Europe: Bulgaria, Croatia, Czech Republic, Estonia, Hungary, 
Latvia, Lithuania, Poland, Romania, Russia, Serbia, Slovakia, and Ukraine. 
• Other: Australia, India, New Zealand, South Africa, and Turkey.  
7.5.2. 
History of Hypertension 
A patient is considered to have had a history of hypertension if any preferred terms of the 
medical history (including events recorded on the Adverse Event CRF that started prior to the 
Day 1) match the terms listed in Appendix 11. 
7.5.3. 
Baseline CVD Risk Category 
A patient is in the category of secondary prevention for cardiovascular diseases (CVD) if there 
was any documented CVD history as recorded on the Targeted Cardiovascular History/Risk 
Factors CRF, including coronary artery disease (CAD), symptomatic peripheral arterial disease 
(PAD), or cerebrovascular atherosclerotic disease (CeVD).  Otherwise the patient is considered 
in the high-risk primary prevention category. 
7.5.4. 
History of Chronic Kidney Disease 
A patient is determined to have a history of chronic kidney disease (CKD) if the medical history 
(including events recorded on the Adverse Event CRF that started prior to Day 1) includes 
preferred term chronic kidney disease.  


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7.6. 
Lipid-Modifying Therapy (LMT) 
7.6.1. 
Definition of LMT 
For this study, lipid-modifying therapy (LMT) includes: 
• Statins: all available prior history of and concomitant statin use are recorded in the 
“Prior and Concomitant Statin Therapy for Dyslipidemia” CRF. 
• Commercial bempedoic acid: 
o Bempedoic Acid alone: preferred name is “BEMPEDOIC ACID”. 
o Bempedoic Acid and Ezetimibe FDCP (fixed dose combination product): the 
verbatim term contains both “BEMPEDOIC ACID” and “EZETIMIBE”, or the 
brand names “NUSTENDI” or “NEXLIZET”. 
• Other LMTs taken within 3 months prior to screening and concomitantly are recorded 
using the standard “Prior and Concomitant Medication” CRF, and a medication is 
classified as LMT if the coded ATC Level 2 (ATC2) term is "LIPID MODIFYING 
AGENTS".  The non-statins LMTs are further classified based on coded terms: 
o Selected Cholesterol Absorption Inhibitors (Ezetimibe): preferred name contains 
“EZETIMIBE”, or Bempedoic Acid and Ezetimibe FDCP as noted above. 
o PCSK-9 Inhibitors (PCSK9i): preferred name is one of “EVOLOCUMAB”, 
“ALIROCUMAB”, or if the verbatim term contains “INCLISIRAN” or 
“LEQVIO”. 
o Bile Acid Sequestrants: ATC Level 4 (ATC4) term is “BILE ACID 
SEQUESTRANTS” 
o Fibrates: ATC4 term is “FIBRATES” 
o Niacin Derivatives: ATC4 term is “NICOTINIC ACID AND DERIVATIVES”. 
o Other: all other LMTs.  In addition, this group also includes preferred name of 
“MONASCUS PURPUREUS” (red yeast rice) regardless of the ATC2 term. 
Note that brand names are used in some cases because the coding dictionary (Section 8.4) does 
not contain the appropriate preferred names.  
7.6.2. 
Categorization of Statin Intensity  
Statin intensity at any given time is categorized as high, moderate, low, or very low based on 
average daily dose of the statin taken at the time and the cutoffs defined in Appendix 5 , or none 
if not taking statin at the time.  Designations of statin dose intensity were modeled after the 2018 
ACC/AHA Guideline on the Management of Blood Cholesterol (ACC/AHA, 2019).  The table 
was modified by creating a “very low dose” statin intensity category that reflected the allowed 
statin dosing intensities used as background therapy in the trial (Protocol Section 7.1 Inclusion 
Criteria #2) and recognizes the different dosing regimens that statin intolerant patients may 
sometimes follow (such as alternate day dosing).  The average daily dose is derived from the 


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dose and frequency recorded on the statin therapy CRF, or if the frequency is “Other”, the daily 
dose entered by the site is used. 
7.6.3. 
Baseline LMT 
Baseline LMT is defined as any lipid-modifying agents that were ongoing at the time of 
randomization.  
Baseline statin intensity is derived using the baseline statin with the highest intensity. 
Baseline ezetimibe use is defined as the use of ezetimibe alone or in combinations that were 
ongoing at the time of randomization. 
7.6.4. 
Cross-in LMT 
For patients in the FAS, cross-in LMT is defined as either initiation of new non-statin LMT or an 
increase in statin intensity after randomization that meets at least one of the following criteria: 
1. Any statin, regardless of the specific drug, started after randomization, with 
increased intensity if used at baseline, and continued for 90 days or more. 
2. Non-statin oral prescription LMTs (Bile Acid Sequestrants, Fibrates, Niacin 
Derivatives, Ezetimibe, commercial Bempedoic Acid, commercial Bempedoic 
Acid and Ezetimibe FDCP, as defined in Section 7.6.1) that were not used at 
baseline (same preferred name), started after randomization and continued for 90 
days or more. 
3. PCSK9i started after randomization, not used at baseline (for evolocumab), or 
with increased intensity if used at baseline (specifically, for alirocumab switching 
from 75 mg once every two weeks to 150 mg once every two weeks or 300 mg 
once every 4 weeks), and continued for 90 days or more if mAb (evolocumab or 
alirocumab); or ≥1 dose for siRNA (inclisiran) after randomization, and before the 
EOS visit. 
Since change of dosing regimen will resulted in a new entry on the medication CRFs, to 
determine the treatment duration, entries for medications of the same class (any statin, either of 
the PCSK9i mAbs), or the same preferred name (non-statin oral LMT) will be combined if the 
gaps between entries are ≤ 7 days (for oral drugs), or ≤ 30 days (for PCSK9 mAb injections). 
The date of starting first adjunctive cross-in LMT is defined to be the start date of the first 
medication that meets the cross-in criteria. 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Sample Size 
This event-driven study is designed to provide at least 90% power to detect an approximate 15% 
relative risk reduction in hazard ratio corresponding to the primary composite MACE endpoint 
(CV death, nonfatal MI, nonfatal stroke, or coronary revascularization) at an overall study 
significance level (alpha) of 0.05.  There are no interim efficacy analyses. 
A statistical relationship between on-treatment LDL-C differences between the bempedoic acid 
group and the placebo group and CV event risk reduction is used to derive the postulated 
treatment effect of 15% stated above.  Assuming a 3.59% annual event rate in the placebo group, 
a minimum of 1620 primary composite MACE events are needed. 
The average follow up duration for all patients is estimated to be approximately 42 months 
(~3.5 years), with an enrollment phase of approximately 33 months, a minimum follow up 
duration of 24 months (2 years), and a lost-to-follow-up (LTFU) rate of 1% per year.  Based on 
these assumptions, approximately 14,000 patients (approximately 7000 in the bempedoic acid 
group and 7000 in the placebo group) were randomized into the study to achieve 1620 patients 
experiencing an adjudicated primary endpoint event. 
It is expected that at least 50% of the 1620 patients experiencing an adjudicated primary 4 
component MACE (810 patients) will experience an adjudicated 3 component MACE (CV 
death, nonfatal MI, or nonfatal stroke).  Therefore, the study will not stop until at least 1620 
patients have experienced an adjudicated primary MACE endpoint, with 810 patients 
experiencing an adjudicated 3 component MACE, and a minimum of 24 months (2 years) have 
elapsed since the last patient was randomized. 
8.2. 
Multicenter Studies 
This study is conducted by multiple investigators at approximately 1200 centers in 32 countries.  
Region (Section 7.5.1) based on the country locations of the sites is used as a covariate and for 
subgroup analysis.  Otherwise, the study center is not considered in the analysis. 
8.3. 
Multiplicity 
There are one primary and six key secondary efficacy endpoints of interest for statistical testing 
in this study.  A gatekeeping or hierarchical approach is used to test the primary efficacy 
endpoint and then key secondary efficacy endpoints sequentially to preserve the study-wise 
Type I error rate at 5%.  For each endpoint, the null hypothesis is that of no difference between 
bempedoic acid and placebo groups, and the order for the hierarchical testing is:   
1. time to first occurrence of MACE (CV death, nonfatal MI, nonfatal stroke, or 
coronary revascularization; primary 4-component MACE) 
2. time to first occurrence of the composite endpoint of CV death, nonfatal MI, or 
nonfatal stroke (3 component MACE) 
3. time to first occurrence of fatal or nonfatal MI 
4. time to first occurrence of coronary revascularization 


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5. time to first occurrence of fatal or nonfatal stroke 
6. time to CV death 
7. time to all-cause mortality 
For the final analysis of the differences between bempedoic acid and placebo, each hypothesis in 
this hierarchical order will be tested at a two-sided significance level of 0.05.  Statistical 
significance at each step is required in order to test the next hypothesis.  If any of the endpoints 
does not reach statistical significance, p-values for subsequent endpoints will be reported for 
information only. 
For other efficacy and safety endpoints, a nominal p-value may be reported for information only. 
8.4. 
Coding Dictionaries 
Adverse events, medical history and procedures are coded using Medical Dictionary for 
Regulatory Activities (MedDRA) Version 23.1 (September 2020) including system organ class 
(SOC), high level term (HLT) and preferred term (PT).  
Prior and concomitant medications are coded using WHO Drug Dictionary (WHO-DD) version 
WHODrug-DDE-B2 201809 ENG (September 2018). 
8.5. 
Missing Data Handling 
For the primary analysis of the primary and key secondary endpoints, there is no imputation.  All 
clinical endpoints, including the types and dates of events, are adjudicated by the Clinical Event 
Committee (CEC) with no missing types or dates.  Time-to-event analyses are carried out based 
on the censoring rules outlined in Section 7.2.5.  
For other analyses involving missing data, specific analysis methods or imputation rules are 
specified in the relevant sections as needed.  If not specified, general rules specified in this 
section apply. 
8.5.1. 
Imputation of Missing Dates 
For adverse events, and for prior and concomitant medications, if the start or end dates are 
incomplete, the date will appear as-is (partial or missing) in the listings.  When full date is 
needed, e.g., to compute the Study Day, imputation rules specified in Appendix 4 will be used 
unless otherwise specified.  In essence, AEs of uncertain start date will be considered as having 
started after the first dose.  Medications of uncertain start or end dates will be considered as 
having started before, or continued after the first dose, respectively. 
For LMTs (Section 7.6) and antidiabetic medications (Section 7.4.2), it is important to determine 
whether they were being used at baseline (i.e., the time of randomization, Section 7.6.3).   
• When the medication start date is partially missing, it is imputed using the default 
rule. If the impute start date is before the date of randomization, and the end date is 
either completely missing with ongoing status of no, or only contains a year that is the 
same as the date of randomization, the end date is imputed with the later of the 
medication start date and the date of informed consent. Otherwise the default rule is 
used to impute the end date.  


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• When the medication start date is completely missing, and if the end date is either 
completely missing with ongoing status of no, or only contains a year that is the same 
as the date of randomization, both start and end dates are imputed with the date of 
informed consent.  
• Otherwise, the start/end dates are inputted using the default rule.  
8.5.2. 
Laboratory Data Beyond the Limits of Quantification 
Quantitative laboratory measurements reported as “<X”, ie, below the lower limit of 
quantification (BLQ), or “>X”, ie, above the upper limit of quantification (ULQ), will be 
imputed as X for the purpose of quantitative summaries, but will be presented as recorded, ie, as 
“<X” or “>X” in the listings. 
8.6. 
General Principles 
Descriptive statistics (n, mean, standard deviation, median, 1st quartile, 3rd quartile, minimum, 
and maximum) will be calculated for continuous data as appropriate. 
Categorical data will be summarized using counts and percentages.  Missing values may be 
presented as a separate category when appropriate.  Counts of zero in any category will be 
presented without percentage.  Ninety-five percent (95%) confidence intervals (CIs) of the 
means or percentages may be calculated for selected continuous and categorical variables.   
For time-to-event endpoints, Kaplan-Meier (KM) curves will be presented graphically by 
treatment group.  KM estimates of cumulative incidence rates at specified time intervals (e.g., 
month 6, year 1, year 2, and yearly after randomization) and their 95% CIs will be presented.  
The hazard ratio and its corresponding 95% CI will be estimated from a Cox proportional hazard 
(PH) model with treatment group in the model.  For between-group comparison, p-values (2-
sided) will be calculated using log-rank tests.   
9. 
DISPOSITION OF STUDY PARTICIPANTS 
All patients screened will be accounted for in this study.  The primary reasons for screen failure 
are collected in the Screen Failure CRF and will be tabulated and listed.  For screen failures due 
to inclusion or exclusion criteria, the unmet criterion will be presented in a listing.  Patient 
disposition including withdrawals (both from study treatment and the study), and final survival 
status will be summarized for the FAS and listed.  The number of patients in each analysis set 
will also be presented. 
In addition, the disposition for patients in the FAS with baseline ezetimibe use will also be 
provided. 
10. 
PROTOCOL DEVIATIONS 
All protocol deviations (PDs) will be presented in a listing, including any relationship to the 
COVID-19 pandemic. 


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Major protocol deviations, and all protocol deviations related to COVID-19 will be summarized 
by treatment group and categories.  
The protocol deviations are recorded and tracked in the Clinical Trial Monitoring System.  The 
final protocol deviations will be determined before treatment groups are unblinded. 


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11. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be summarized by treatment group for 
the FAS, SAS and PPS.  These data will also be provided for patients in the SAS with baseline 
ezetimibe use.  No statistical testing will be carried out for demographic or other baseline 
characteristics. 
The following demographic and other baseline characteristics will be summarized and listed for 
this study:   
• Age (years)  
• Age category (<65 years, ≥65 to <75 years, or ≥75 years) 
• Sex (female vs male, at birth) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic or Latino vs Not Hispanic or Latino) 
• Region (defined in Section 7.5.1 ) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) = weight (kg)/height (m)2 
• BMI category (<25 kg/m2, 25 to <30 kg/m2, or ≥30 kg/m2).   
• Baseline vital signs (systolic blood pressure, diastolic blood pressure, and heart rate) 
• Baseline key laboratory Results (LDL-C, hs-CRP, Non-HDL-C, TC, HDL-C, and 
TG) (LDL-C results are presented in both conventional and standardized units, the 
others will be in conventional units only) 
• Baseline LDL-C category (<130 mg/dL, ≥130 mg/dL and <160 mg/dL, ≥160 mg/dL) 
• Baseline hs-CRP category (<2 mg/L, ≥2 mg/L) 
• Baseline CVD risk category (Section 7.5.3), for patients with documented CVD 
history (secondary prevention), the prior history of CAD, PAD or CeVD. 
• History of diabetes mellitus (Yes vs No, as collected in the Targeted Cardiovascular 
History/Risk Factors CRF) 
• Baseline glycemic status (Section 7.4)  
• History of hypertension (Yes vs No, Section 7.5.2 ) 
• Alcohol consumption (Non-drinker, Former Drinker, or Current drinker) 
• Tobacco use (Never used, Former user, or Current user) 
• Baseline background lipid-modifying therapy (LMT) (Statin use including statin only 
or Statin + other LMT, other LMT without statin, or none, see also Section 7.6.1 ) 




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13.3. 
Lipid-Modifying Therapy 
The use of LMTs (Section 7.6.1) will be summarized separately by categories including pre-
specified statins, and by treatment group for the FAS, including: 
• Baseline LMT (Section 7.6.3)  
• Baseline statin intensity (Section 7.6.2), shift to maximum intensity during the study, 
and shift to the statin intensity ongoing at the end of the study 
• Cross-in LMT (Section 7.6.4), including a summary of the time to first cross-in LMT 
(censored at DLASMT if no cross-in). 
 


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14. 
STUDY MEDICATION COMPLIANCE AND EXPOSURE 
The time from randomization to IMP discontinuation (last dose) will be summarized by 
treatment groups, and presented using a Kaplan-Meier plot for all patients in the FAS.  Patients 
not dosed will have a time of 0. 
In addition, estimated compliance with study IMP will be presented for the FAS by treatment 
groups.  The patients will be grouped as compliant, i.e., those who have >= 80% of required 
tablets (taken once daily) while on treatment, versus noncompliant (<80% compliance).  
The percentage compliance calculation will be based on the tablet counts using the formula: 
Total # of tablets taken = ෍(100 −(# of tablets returned)
bottles
) 
as each bottle of double-blind IMP contains 100 tablets.  If a dispensed bottle is not returned, it is 
assumed that the patient has taken all the tablets and the number of tablets returned is set to be 
zero (0). 
%compliance =
[total # of tablets taken]
[# of days between last and first doses] 
The percentage compliance is capped as a maximum of 100% if it exceeds 100% due to the 
imputation above. 
Note that patients who did not receive any IMP will be counted as noncompliant (0%).  In 
addition, if a patient did not return any bottles, he/she will also be counted as noncompliant 
(0%). 
Exposure to the study treatment is based on the duration (in years) between the last and first 
doses, and will be presented for the SAS by treatment groups.  Exposure will also be presented 
for patients in the SAS with baseline ezetimibe use. 
 


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15. 
EFFICACY ENDPOINTS 
All efficacy analyses will be performed based on the FAS if not otherwise specified.  Selected 
sensitivity analyses will be performed based on the PPS and will be clearly specified.  
15.1. 
Adjudicated Clinical Endpoints 
Clinical events including death (CV or non-CV), nonfatal MI, nonfatal stroke, coronary 
revascularization, and hospitalization for unstable angina that occurred during the study are 
reviewed and adjudicated by the CEC in a blinded fashion as described in the Charter. 
Positively adjudicated clinical events that occurred after randomization will be summarized by 
adjudicated event types and subtypes, and by treatment groups for the FAS.  They are included in 
the analyses for the derivation of study endpoints (Sections 3.1, 3.2.1 and 3.2.2). 
When a patient had multiple events of the same type (e.g., two coronary revascularizations) on 
the same day, only one event is counted in descriptive and recurrent event analyses. 
All adjudicated deaths and non-fatal clinical events will be presented in listings with information 
from the adjudication forms. 
15.2. 
Primary Efficacy Endpoint 
15.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to first occurrence of an adjudicated MACE, where 
MACE is defined as a composite primary efficacy endpoint that includes CV death, nonfatal MI, 
nonfatal stroke, and coronary revascularization (4-component MACE). 
The number of patients who had experienced a primary composite endpoint will be tabulated by 
the type of the first event and by treatment group.  When a patient had multiple events among the 
4-component MACE that occurred on the same day, the events will be sorted in the order of: 
nonfatal MI, nonfatal stroke, coronary revascularization, and CV death.  
15.2.2. 
Primary Analysis Method of Primary Efficacy Endpoint 
The null hypothesis, H0, is that there is no difference between bempedoic acid 180 mg/day and 
placebo in time to first occurrence of a confirmed (adjudicated) MACE.  The alternative 
hypothesis, H1, is that bempedoic acid 180 mg/day is different from placebo: 
H0: β = 0 vs. H1: β ≠ 0 
Where the hazard h(t) is modeled as: h(t) = h0(t)exp (βx) and β is the log hazard ratio (HR). 
The primary efficacy endpoint will be analyzed using Cox PH model with treatment as a factor.  
The HR and its 95% CI and p-value from log-rank test will be provided.  In addition, KM curves 
will be provided, to present a graphical description of the time to first occurrence of confirmed 
adjudicated composite endpoint of CV death, nonfatal MI, or nonfatal stroke (4-component 
MACE). 
If none of these 4-component MACE events is observed, the patient will be censored 
(Section 7.2.4). 


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The assumption of proportional hazard will be evaluated graphically for the primary efficacy 
endpoint by Schoenfeld residual plot and log-log plot.  Ad hoc sensitivity analyses may be 
performed if needed. 
15.2.3. 
Primary Efficacy Endpoint Data Censoring Pattern 
For patients who were censored, i.e., did not experience MACE-4 endpoint, the pattern of 
censoring will be summarized by treatment, including 
• censored for non-CV death 
• censored on or after completion of the EOS visit during closeout 
• censored prior to the study closeout period and not by non-CV death 
• censored within 30 days of the last dose 
• censored more than 30 days after the last dose 
The total patient-year lost-to-follow-up will be calculated by treatment group as the sum of time 
from the date of censoring prior to study closeout and not by non-CV death, to the May 15, 2022 
when the study closeout was initiated.  
15.2.4. 
Sensitivity Analyses of Primary Efficacy Endpoint 
In the primary analysis, censoring is assumed to be uninformative, i.e., patients who were 
censored share a common hazard function as those who were not censored in the same treatment 
group.  However, there is a key difference between them as the censored patients also by 
definition stopped the treatment, while the majority of those remained on-study were still on-
treatment.  To evaluate the potential impact, two sensitivity analyses will be performed: 
• Multiple imputation analysis: the hazard function for patients after censoring is 
assumed to be the same as those patients who were assigned the same treatment, had 
stopped treatment but remained in the study follow-up longer.  The data from those 
patients with follow-up will be used as the model for imputation of the time to events 
for the censored patients.  
• Tipping point (TP) analyses: The goal of this analysis is to explore the plausibility of 
unobserved data assumptions under which the conclusions change.  Unlike the 
standard multiple imputation analysis, the censored patients in the active treatment 
group are allowed to have the same or even worse outcome than those in the placebo 
group.  A range of assumed hazard ratios (vs placebo) will be used to evaluate when 
the estimated treatment effect starts to “tip”, i.e., becoming in favor of the placebo.  
The details of the analyses are specified in Appendix 6.  
 
15.3. 
Analyses of Secondary and Other Efficacy Endpoints 
15.3.1. 
Secondary Efficacy Time-to-Event Endpoints 
Each secondary efficacy time-to-event endpoint will be analyzed in a manner analogous to that 
used for the primary efficacy analysis.  For each endpoint, the hazard ratio estimated using Cox 


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PH model and its 95% CI and associated p-value from log-rank test will be provided.  In 
addition, KM curves will be provided for each of the key secondary efficacy time-to-event 
endpoints.  Note that for the analyses involving hemorrhagic and nonhemorrhagic stroke, any 
stroke for which the CEC is unable to determine the type will be included as an ischemic 
(nonhemorrhagic) stroke. 
15.3.2. 
Secondary Efficacy Endpoint Time to NODM 
All potential events of NODM are reviewed and verified by the Diabetes Committee in a blinded 
fashion according to the Diabetes Committee Charter.  All events that were reviewed will be 
presented in a listing.  Only verified NODMs are analyzed as efficacy endpoints. 
The time to first occurrence of new onset type 2 diabetes mellitus during study will be analyzed 
by a Cox PH model for the patients with baseline glycemic status (Section 7.4) of no diabetes in 
the FAS and its subcategories of prediabetes and normoglycemia.  The prediabetes subgroup is 
considered as the primary analysis for this endpoint.  The onset date of NODM will be the 
earliest date of the event as verified by the Diabetes Committee.  
15.3.3. 
Secondary Efficacy Endpoint LDL-C 
For this study, the directly measured LDL-C value is used when available, otherwise the 
calculated LDL-C value is used.  All LDL-C analyses will be presented in both the conventional 
unit (mg/dL) and the standardized (SI) unit (mmol/L). 
Percent change from baseline in LDL-C at Month 6 will be analyzed using a linear model with 
percent change from baseline as response, treatment group and baseline LDL-C as covariates.  
Since the variances of the response are potentially different for the two treatment groups (more 
variable with active treatment), the model will allow different residual variances by treatment 
group.  Specifically, PROC MIXED can be used with ‘REPEATED / group = trt’ statement.  In 
addition, Kenward-Roger method is to be used for approximating the degrees of freedom 
(‘DDFM=kenwardroger’ option to MODEL statement).  Fitted mean (Least Square or LS means) 
percent changes from baseline for each treatment group will be calculated (with 95% CI) at 
baseline LDL-C level of 140 mg/dL.  The estimated difference in percent changes from baseline 
between treatment groups will be provided with 95% CI and p-value for testing of no difference. 
Since patients with missing LDL-C at Month 6 may have underlying distributions depending on 
whether the patient was assigned to the active treatment and remained on active treatment at the 
time, a pattern mixture model (PMM) is used for the analysis, using a multiple imputation 
approach.  Specifically, missing LDL-C values at Month 6 were simulated using a linear 
regression model with Month 6 LDL-C value as response, and covariates including baseline 
LDL-C value, and an indicator variable that equals 1 if and only if the patient was assigned to the 
active treatment and remained on treatment at Month 6 (Day 182) (this can be achieved using 
PROC MI with monotone regression).  Simulated datasets (20 replicates) are analyzed as 
described previously and the resulted estimates are combined using Rubin’s method (Rubin, 
1987; PROC MIANALYZE). 
For tertiary endpoints of LDL-C measured at all timepoints (Baseline, Month 3, 6, 12, 18, 24, 30, 
36, 42, 48, 54, and 60), the observed values at each timepoint, changes from baseline, and 
percent changes from baseline will be summarized by treatment groups.  Differences of the 


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changes from baseline, and percent changes from baseline between the treatment groups will be 
presented together with 95% CIs at each timepoint, as descriptive analyses with no imputation. 
15.3.4. 
Secondary Efficacy Endpoint HbA1C 
All efficacy analyses of HbA1c will be carried out stratified by the baseline glycemic status in 
the FAS.  The subgroup of patients with Inadequately Controlled Diabetes (ICDM) at baseline is 
of primary interest.  The other subgroups include Diabetes (that includes ICDM as a subset), 
Prediabetes, Normoglycemic, and No Diabetes (Prediabetes and Normoglycemic combined).  
Analysis for the change from baseline to Month 12 in HbA1c will be analyzed similarly as LDL-
C, with change from baseline as response, treatment group and baseline HbA1C as covariates.  
There is no need to specify variance heterogenicity (no ‘REPEATED’ statement) and the default 
method for degrees of freedom calculation can be used.  Fitted mean (LS means) changes from 
baseline for each treatment group will be calculated (with 95% CI) at baseline HbA1c levels of 
8% and 7% for ICDM and Diabetes, 6% for Pre-Diabetes and 5.5% for Normoglycemic and the 
combined No Diabetes groups.  The estimated differences in changes from baseline between 
treatment groups will be provided with 95% CIs and p-values for testing of no difference. 
Missing HbA1c data at Month 12 will also be handled using PMM based on whether the patient 
was still on treatment at Month 12 (Day 365), similar to LDL-C above. 
For tertiary endpoints of HbA1c measured at all timepoints (Baseline, Month 3, 6, 12, 18, 24, 30, 
36, 42, 48, 54, and 60), the observed values at each timepoint, and changes from baseline will be 
summarized by treatment groups.  Differences of the changes from baseline between the 
treatment groups will be presented together with 95% CIs at each timepoint, as descriptive 
analyses with no imputation. 
15.3.5. 
Secondary Efficacy Endpoint hs-CRP 
Due to the highly skewed distribution of hs-CRP, a nonparametric analysis based on Wilcoxon 
rank sum test will be performed for percent change from baseline to Month 6.  Hodges-Lehmann 
estimate of location shift and its 95% CI will be provided.  Only observed values will be used 
with no imputation.   
For hs-CRP measured at other timepoints (Month 12, and End-of-Study, which is defined to be 
the last measurement of each patient), the observed values at each timepoint, and percent 
changes from baseline will be summarized by treatment groups. 
15.4. 
Sensitivity Analyses for Efficacy Endpoints 
15.4.1. 
Per-Protocol Analyses 
The primary and key secondary endpoints will be analyzed using the PPS with the same 
methodology. 
15.4.2. 
On-Treatment Analysis 
An on-treatment analysis will also be conducted for primary time to 4-component MACE 
(MACE-4) and 3-component MACE (MACE-3) endpoints in the PPS.  


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The sensitivity analyses will also be performed for the time to first occurrence of NODM on 
treatment for patients with baseline glycemic status of no diabetes, prediabetes, or 
normoglycemic in the PPS.   
For these on-treatment analysis, events (MACE-4, MACE-3 or NODM) that occurred after 
DLDOSE + 30 days will be ignored.  Patients who did not have events before that will be 
censored at the earlier of the DLDOSE + 30 days and DLASMT, the date of censoring for non-
fatal events defined in Section 7.2.5. 
On-treatment analyses will be performed for lipid parameters and biomarkers including LDL-C, 
HDL-C, non-HDL-C, total cholesterol, triglyceride, hs-CRP, HbA1C and fasting glucose.  For 
these endpoints, values measured more than 7 days after the Date of Last Dose of IMP will be 
excluded, and only observed values prior to that will be summarized by treatment groups, and for 
HbA1C and fasting glucose also by baseline glycemic status. 
15.4.3. 
Adjunctive Cross-in Lipid-Modifying Therapy 
Post randomization, LDL-C results will be masked for investigators and study participants in 
order to maintain the blind.  Beginning at Month 6 (Visit T4) and for the remaining duration of 
the study, the central laboratory will notify the investigator if the patient’s LDL-C level is ≥25% 
higher than baseline LDL-C.  The patients will be counseled on healthy dietary guidelines and 
reminded to take all lipid-regulating medications.  The patient will return to the clinic for a 
repeat fasting blood lipid sample to confirm that the LDL-C value meets the threshold criteria.  If 
confirmed, the patient’s LDL-C-lowering treatment regimen may be adjusted, if possible, per 
standard of care and local practice.  Any initiation and/or dose change of LDL-C-lowering 
medications will be documented on the electronic case report form (eCRF) and will not be 
provided by the Sponsor. 
The use of adjunctive cross-in LMTs may obscure the difference between the treatment groups.  
To evaluate the treatment effects without cross-in LMTs, a sensitivity analysis will be performed 
for MACE-4 (primary) and MACE-3 endpoints in the PPS prior to cross-in LMT.  Specifically, 
the patients are censored at the earlier of the date of starting the first cross-in adjunctive LMT 
therapy + 30 days and date of censoring for non-fatal events defined in Section 7.2.4, if there is 
no MACE-4 or MACE-3 event prior to that date. 
For LDL-C and hs-CRP, observed values in changes and percent changes from baseline to 
Month 6 will be summarized by treatment group in the PPS, after excluding values measured 
after 7 days post the date of starting the first cross-in adjunctive LMT therapy. 


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15.5. 
Exploratory and Descriptive Analyses of Efficacy Endpoints 
15.5.1. 
Subgroup Analyses 
The primary endpoint (MACE-4) and time to 3-component MACE (MACE-3) will be analyzed 
within the subgroups below using FAS and the same primary analysis method previously 
described.  The treatment and subgroup interaction will be examined by including the interaction 
term in the Cox PH model, and the p-values will be reported.  Forest plots for the primary 
efficacy variable (hazard ratios) will also be presented. 
• Age category (<65 years, ≥65 to <75 years, and ≥75 years) 
• Race (White vs Non-white) 
• Ethnicity (Hispanic or Latino vs No Hispanic or Latino) 
• Sex (male vs female) 
• Region (North America, South America, Western Europe, Eastern Europe, Other) 
• BMI category (<25 kg/m2, 25 to <30 kg/m2, and ≥30 kg/ m2) 
• Baseline CVD risk category (Secondary vs Primary prevention) 
• Baseline LDL-C category (<130 mg/dL, ≥130 mg/dL and <160 mg/dL, ≥160mg/dL) 
• Baseline hs-CRP category (<2 mg/dL and ≥2 mg/dL) 
• Baseline eGFR category (≥90; ≥60 to <90; and <60 mL/min/1.73m2)  
• Baseline CKD history (Yes vs No) 
• Baseline glycemic status (normoglycemic, prediabetes, or diabetes) 
• Baseline ezetimibe use (Yes vs No) 
• Baseline statin use (Yes vs No) 
• Statin intolerance criteria (Failed 2 or more statin, vs otherwise) 
15.5.2. 
Covariate Analyses 
Covariate analyses of the primary (MACE-4) and time to 3-component MACE (MACE-3) using 
Cox PH model will be performed as supportive analyses.  Baseline covariates listed in 
Section 15.5.1 will be included in the model one at a time.  
15.5.3. 
Total Event Analysis 
Since non-fatal events (non-fatal MI, non-fatal stroke, and coronary revascularization) can 
happen multiple times during study follow-up, analyses of MACE-4, MACE-3, non-fatal MI, 
non-fatal stroke, and coronary revascularization as total (i.e., first and subsequent) events will 
also be performed in the FAS. When there are multiple events occurring on the same day, they 
will be ordered as described in Section 15.2.1, and the event times will be separated by 0.1 day 
so that every event time is unique. The censoring date after the last events or for patients who 
had no event is the DLASMT.  Hazard ratio will be estimated by Andersen-Gill mean intensity 


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model (Andersen and Gill, 1982), with robust sandwich estimates of the covariance matrix (Lin 
and Wei, 1989). 
15.5.4. 
Incidence Rates of Primary and Key Secondary Endpoints 
In addition to the hazard ratio and 95% CI from Cox PH model, incidence rate (IR) as number of 
events per 100 person years, along with the total number of person years and difference in IR 
between groups with 95% CI’s will be provided for primary endpoint and key secondary 
endpoints.  For this analysis, the duration of exposure is defined to be from the date of 
randomization to the date of the 1st event or the date of censoring. 
15.5.5. 
Additional Analysis of Adjudicated Events  
For the adjudicated clinical events that occurred after randomization, discordance between the 
classification of the investigators versus that of the CEC will be tabulated by treatment in the 
FAS. 
15.6. 
Tertiary and Exploratory Analyses for Lipid and Biomarkers 
Endpoints 
15.6.1. 
Tertiary Lipid and Biomarker Endpoints 
Tertiary lipids measurements including non-HDL-C, TC, HDL-C, and TG will be summarized 
for the FAS by treatment groups using observed values for each timepoint (baseline, Month 3, 6, 
12, 18, 24, 30, 36, 42, 48, 54 and 60).  For each parameter, the value of the parameter, change, 
and the percent change from baseline will be summarized by treatment group, and by analysis 
timepoints (Section 7.2.4).  The results are presented in both conventional units and standardized 
units. 
In addition, fasting glucose will be summarized similarly by treatment group, by analysis 
timepoints, and by baseline glycemic status (Section 7.4) for the FAS. 




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Statistical Analysis Plan: Protocol 1002-043 
Version 1.0, 14 November 2022 
The NODM AESI is applicable only for patients with baseline glycemic status (Section 7.4) of 
No Diabetes at baseline. As an AESI vs. an efficacy endpoint, NODM includes a broader 
definition ofNODM with patients who meet one of the following conditions: 
• 
patients with verified NODM as detennined by the DC (Section 7.4.3), or 
• 
patients who initiated a diabetes medication after first dose of IMP (Appendix 8), or 
• 
patients meeting the laborato1y criteria for NODM as in Appendix 7, or 
• 
patients with selected AE prefe1Ted tenns ( see list of prefe1Ted te1ms for 'NODM' in 
Appendix 7). 
Worsening Hyperglycemia AESI is applicable to patients with baseline glycemic status of 
Diabetes based on adverse event prefe1Ted te1ms as described in Appendix 7. 
See Appendix 7 for the list of AESis and their definitions. AESis will be identified by specified 
MedDRA PTs, and/or the related laborato1y criteria if applicable. These events will be 
summarized by treatment group, and by AESI catego1y, laborato1y criteria met, and PTs. 
Malignancy AESI will be summarized b Standardised MedDRA ueries SM s and PTs as 
described in A 
endix 7. 
Tendon mpture will be summarized for events that are positively adjudicated according to the 
TRAC Chaiier. All potential tendon mptures that were reviewed by the TRAC will be presented 
in a listing. 
For AEs considered to be muscle related by the Investigator, additional info1m ation is collected 
on the Muscle Related Adverse Event Complementa,y CRF including the primaiy cause, 
locations, and whether the AE is unilateral or bilateral. 
16.1.3. 
Other Adverse Events 
TEAEs of Gout and Gouty Arthritis will be summai-ized by patients' medical histo1y of gout and 
by their baseline uric acid catego1y according to the central laborato1y n01m al range 
(low/no1mal, versus high). 
16.1.4. 
Exposure Adjusted Incidence Rates (EAIRs) of TEAEs 
For all treatment-emergent AEs, SAEs, and AESis, exposure-adjusted incidence rates (EAIR) 
will be calculated by prefe1Ted tenns (PTs) and by treatment group. 
For the calculation of EAIR, the duration of exposure for each patient is from the date of the first 
dose of IMP to the date of the first event (PT), or the DLASMT (Section 7 .2.1) if the patient did 
not experience the event in question. For each event, the EAIR is calculated as the number of 
events (the first event, so each patient is counted only once) divided by the sum of duration of 
exposure over all patients in the SAS in the treatment group. It will be expressed as per 100 
patient-years. 
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16.1.5. 
Subgroup Analyses of Adverse Events 
Subgroup analyses of patient incidence and EAIR of TEAE for age group (<65, 65-75, ≥ 75 
years), sex, and race (white vs non-white), baseline eGFR category (<60, 60-90, ≥90 
mL/min/1.73m2), baseline glycemic status (normoglycemic, prediabetes, and diabetes), baseline 
ezetimibe use (yes/no) will be presented by SOC and PT in descending order frequency.  
16.2. 
Death and Major Adverse Cardiac Events 
For this study deaths and positively adjudicated MACE (MI, stroke, coronary revascularization, 
hospitalization for unstable angina) are study endpoints and per protocol are not recorded in the 
Adverse Event CRF.  They will be reported as adjudicated endpoints in listing and tables using 
the FAS. 
In addition, all events leading to death as reported by the Investigator will be summarized by 
SOC/PT and treatment group using the SAS, and for patients in the SAS with baseline ezetimibe 
use. 
16.3. 
Safety Laboratory Evaluations 
The list of central laboratory assessments to be included in the outputs is included in the Table 4 
of the Protocol (Section 12.1.6.1) and includes HbA1c.  Urinalysis is not quantitative, and 
coagulation is measured at selected patients/visits only, and these will not be summarized. 
In addition, eGFR will be calculated using the formula: 186 × (creatinine/88.4)-1.154 × (age)-0.203 × 
(0.742 if female) × (1.210 if Black), where creatinine is in µmol/L.  Blood urea nitrogen 
(BUN)/creatinine ratio (BUN/Creatinine ratio) will also be calculated. 
Summaries for all lab results will be included for the below analyses: 
• Observed and change/percent change from baseline by analysis visit for hematology 
and blood chemistry measurements. 
• Creatinine and eGFR will be summarized by treatment group and by baseline eGFR 
categories (<30, 30 to <60, 60 to <90, and ≥90 mL/min/1.73m2).   
• Fasting glucose and HbA1c will be summarized by baseline glycemic status, and by 
treatment group. 
The analyses for shift tables from baseline to the worst post-baseline category or value are 
presented in Table 2.  Note that for fasting glucose and HbA1c the analyses will be by baseline 
glycemic status. 
 
 


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Table 2: Analyses for Shift Tables of Laboratory Parameters 
Parameter 
Categories (From Better to Worse) 
Fasting glucose 
(by baseline glycemic status) 
<51 mg/dL 
≥51 to <100 mg/dL 
≥100 to <126 mg/dL 
≥126 mg/dL 
HbA1C  
(by baseline glycemic status) 
<5.7% 
≥5.7% and <6.5% 
≥6.5 to <7% 
≥7% 
Alanine aminotransferase (ALT) 
Normal, High (> ULN) 
Aspartate aminotransferase (AST) 
Normal, High (> ULN) 
eGFR 
≥90 mL/min/1.73m2 
≥60 to <90 mL/min/1.73m2 
≥30 to <60 mL/min/1.73m2 
<30 mL/min/1.73m2  
Uric acid (UA) 
Low/Normal (combined) 
High (> 5.7 mg/dL for female, >7.0 mg/dL for male)  
Lab abnormalities associated with AESIs are listed in Appendix 7 and will be summarized with 
the AESIs.  In addition, for evaluation of potential Hy’s Law cases, a pairwise scatterplot will be 
created with the maximum (peak) post-baseline values of ALT or AST as multiples of the ULN, 
against the concomitant TB (also multiples of the ULN). 
Other lab abnormalities of selected parameters are presented in Table 3 and the number of 
patients meeting each criterion will be summarized by treatment group.  
Patients with potentially clinically significant laboratory abnormalities (Appendix 10) will be 
listed.  For a given parameter (or group of parameters as indicated), all values from the patient 
will be included in the listing if any value meets the criteria. 
As a result of the pandemic, local laboratory may be used for safety labs at the investigators’ 
discretion.  The local lab data are reviewed and evaluated by the investigators for any 
abnormalities and adverse event reporting as applicable.  Due to the diverse use of units and 


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variation in laboratory normal ranges, the local lab data are not used in the statistical analyses.  
All local laboratory measurements will be listed with the associated reference ranges if available.  
Abnormal laboratory results of ALT and/or AST >3 × ULN, TB >2 × ULN or CK >5 × ULN 
based on the non-central laboratory reference ranges (when available) will be noted in the listing. 
16.4. 
Electrocardiogram Evaluations 
The Investigator’s judgment of overall assessment of electrocardiograms (Normal; Abnormal, 
Not Clinically Significant; or Abnormal, Clinically Significant) will be recorded, and will be 
summarized at baseline and at the (nominal) end-of-study visits. 
16.5. 
Vital Signs 
The following vital signs measurements will be reported for this study: 
• Systolic blood pressure (SBP) (mmHg) 
• Diastolic blood pressure (DBP) (mmHg) 
• Heart rate (HR) (beats per minute [bpm]) 
• Weight (kg) 
• Height (cm) (at screening only) 
• BMI (kg/m2) (calculated) 
Summaries will be provided for SBP, DBP, and HR for observed values and change from 
baseline values by visit. 
Measurement, absolute change from baseline and percent change from baseline of weight will be 
summarized by baseline glycemic status and by baseline BMI categories.   
Patients with potentially clinically significant vital sign abnormalities (Appendix 10) will be 
listed.  For a given parameter, all the patients’ values will be included in the listing if any value 
meets the criteria.  
16.6. 
Physical Examination 
Abnormalities in physical examinations will be presented in a listing. 
 


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19. 
LIST OF REFERENCES 
American Diabetes Association (2020) Classification and Diagnosis of Diabetes Mellitus: 
Standards of Medical Care in Diabetes -- 2020.  Diabetes Care 43:S14-31. 
https://doi.org/10.2337/dc20-S002 
American College of Cardiology/American Heart Association (2019) 2018 AHA/ACC 
/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 
Management of Blood Cholesterol.  Journal of American College of Cardiology 73: e285-350. 
Andersen PK and Gill RD (1982) Cox’s Regression Model Counting Process: A Large Sample 
Study.  Annals of Statistics 10:1100–1120. 
European Medicines Agency (2020) Points to consider on implications of Coronavirus disease 5 
(COVID-19) on methodological aspects of ongoing clinical 6 trials. Jun 2020. 
Food and Drug Administration (2020) Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency. Sep 2020. 
GHDx. (2022) Global Health Data Exchange—Country Profiles. Institute for Health Metrics and 
Evaluation; http://ghdx.healthdata.org/countries Accessed Jan 2022. 
Lin DY and Wei LJ (1989) The Robust Inference for the Cox Proportional Hazards Model. 
Journal of the American Statistical Association 84:1074-8. 
Rubin DB (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons. 
WHO (2020) Director-General's opening remarks at the media briefing on COVID-19 - 11 
March 2020 https://www.who.int/director-general/speeches/detail/who-director-general-s-
opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 


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APPENDIX 1. SCHEDULE OF EVENTS 
 
 
Screen and 
Run-In 
Treatment 
 
 
 
 
 
 
 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
Visit 
S11 
S2 
T1 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 
T108 
T118 
T128 
T138 
EOS9,10 
PT1 
Week/ Month 
Wk  
-5 
Wk 
-4 
Day 
1/ 
Wk 
0 
Mth 
1 
Mth 
3 
Mth 
6 
Mth 
9 
Mth 
12 
Mth 
15 
Mth 
18 
Mth 
21 
Mth 
24 
Mth 
27 
Mth 
30 
Mth 
33 
 
30 
days 
±10 
after 
EOS 
Procedure 
Day 
-35 
Day  
-31 
to 
-25 
 
±3 
Days 
±5 
Days 
±5 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diet and 
Exercise 
Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event 
Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight2 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Screen and 
Run-In 
Treatment 
 
 
 
 
 
 
 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
Visit 
S11 
S2 
T1 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 
T108 
T118 
T128 
T138 
EOS9,10 
PT1 
Week/ Month 
Wk  
-5 
Wk 
-4 
Day 
1/ 
Wk 
0 
Mth 
1 
Mth 
3 
Mth 
6 
Mth 
9 
Mth 
12 
Mth 
15 
Mth 
18 
Mth 
21 
Mth 
24 
Mth 
27 
Mth 
30 
Mth 
33 
 
30 
days 
±10 
after 
EOS 
Procedure 
Day 
-35 
Day  
-31 
to 
-25 
 
±3 
Days 
±5 
Days 
±5 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs3 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Serology4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or 
Urine 
Pregnancy/ 
FSH5 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety 
Labs6 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Basic Fasting 
Lipids7 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HbA1C 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
hs-CRP  
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Single-Blind 
Drug 
Dispensing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screen and 
Run-In 
Treatment 
 
 
 
 
 
 
 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
Visit 
S11 
S2 
T1 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 
T108 
T118 
T128 
T138 
EOS9,10 
PT1 
Week/ Month 
Wk  
-5 
Wk 
-4 
Day 
1/ 
Wk 
0 
Mth 
1 
Mth 
3 
Mth 
6 
Mth 
9 
Mth 
12 
Mth 
15 
Mth 
18 
Mth 
21 
Mth 
24 
Mth 
27 
Mth 
30 
Mth 
33 
 
30 
days 
±10 
after 
EOS 
Procedure 
Day 
-35 
Day  
-31 
to 
-25 
 
±3 
Days 
±5 
Days 
±5 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
 
Single-Blind 
Drug Return 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Double-blind 
Drug 
Dispensing  
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Double-Blind 
Drug Return 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; DBP = diastolic blood pressure; ECG = electrocardiogram; eGFR = 
estimated glomerular filtration rate; EOS = End of Study; FSH = follicle-stimulating hormone; HbA1C = glycated hemoglobin; HBsAg = hepatitis B surface antigen; 
HCV-Ab = hepatitis C antibody; HDL-C = high-density lipoprotein cholesterol; HR = heart rate; hs-CRP = high-sensitivity C-reactive protein; Labs = laboratory tests; 
LDL-C = low-density lipoprotein cholesterol; MACE = major adverse cardiovascular event; SBP = systolic blood pressure; TC = total cholesterol; TG(s) = 
triglyceride(s); TSH = thyroid-stimulating hormone; PV=phone visit; wk=weeks; mth=month. 
1 
An additional visit approximately 1 week after Visit S1 and prior to Visit S2 MAY be completed if patient’s LDL-C and/or TG level fails to meet entry criteria.  
Also, an additional visit and/or assessment between Visits S1 and T1 MAY be completed if the patient’s DBP, SBP, TSH, eGFR, ALT, AST, and/or CK fails to meet 
entry criteria.  If this optional visit/assessment is completed, the value from the repeat visit/assessment will be used to determine eligibility.  Also, at Visit S1 an 
optional hs-CRP may be measured only if needed for Reynolds Risk Score and a local hs-CRP value is not available.  Finally, the number of days between Week -5 
(Visit S1) and Week -4 (Visit S2) may be less than 7, and the number of days between Week -5 (Visit S1) and randomization may be less than 35 as long as eligibility 
can be determined.  
2 
Body weight will be measured in the morning while fasting, using consistent scales, after voiding, and without shoes and outerwear (eg, coats).  
3 
Vital signs will include DBP, SBP, HR and will be collected prior to any blood sample collection.  The patient will rest for several minutes prior to assessments. 
4 
Serology for HBsAg and HCV-Ab.  
5 
Pregnancy tests completed in premenopausal women only, serum test at Week -5 (Visit S1) and urine test at Day 1 (Visit T1); FSH completed on postmenopausal 
women <55 years of age.  


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Screen and 
Run-In 
Treatment 
 
 
 
 
 
 
 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
 
PV 
Visit 
S11 
S2 
T1 
T2 
T3 
T48 
T58 
T68 
T78 
T88 
T98 
T108 
T118 
T128 
T138 
EOS9,10 
PT1 
Week/ Month 
Wk  
-5 
Wk 
-4 
Day 
1/ 
Wk 
0 
Mth 
1 
Mth 
3 
Mth 
6 
Mth 
9 
Mth 
12 
Mth 
15 
Mth 
18 
Mth 
21 
Mth 
24 
Mth 
27 
Mth 
30 
Mth 
33 
 
30 
days 
±10 
after 
EOS 
Procedure 
Day 
-35 
Day  
-31 
to 
-25 
 
±3 
Days 
±5 
Days 
±5 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
±10 
Days 
 
6 Clinical safety laboratory tests include hematology, blood chemistry, and urinalysis.  Urinalysis includes dipstick measured at the clinic and microscopic, if 
abnormal, completed by the central lab.  A limited safety laboratory assessment (ALT, AST, TB, and CK) will be completed at Visit T2 only.  A coagulation panel 
will be completed only if needed for patients on anticoagulant therapy at Day 1 (Visit T1) and 3 to 5 days later. 
7 Basic fasting lipids include TC, calculated LDL-C, HDL-C, non-HDL-C, and TGs.  
8 After Visit T4 (Month 6), telephone and clinic visits (alternating every 3 months) will continue until the study is completed. 
9 All procedures will be completed at the EOS or Early Termination Visit. 
10 Duration of treatment for each patient will vary and is dependent on accumulation of MACE in the entire study.  For individual patients, treatment duration will be a 
minimum of 24 months and may continue for up to approximately 57.5 months. 
 


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APPENDIX 3. ANALYSIS VISIT WINDOWS 
Analysis  
Visit 
Nominal 
Visit 
Target 
Visit Day 
(Study Day) 
Fasting Lipids, 
Glucose and 
HbA1c 
(Study Day) 
Safety Lab, 
Vital Signs 
and Physical 
Exams 
(Study Day) 
hs-CRP 
(Study Day) 
Baseline 
T1 
1 
Day 1/before 1st dose 
Month 1 
T2 
30 
- 
2 – 60 
- 
Month 3 
T3 
91 
2 – 136 
61 – 136 
- 
Month 6 
T4 
182 
137 – 273 
2 – 273 
Month 12 
T6 
365 
274 – 456 
Month 18 
T8 
547 
457 – 638 
Month 24 
T10 
730 
639 – 821 
Month 30 
T12 
912 
822 – 1003 
Month 36 
T14 
1095 
1004 – 1186 
Month 42 
T16 
1277 
1187 – 1368 
Month 48 
T18 
1460 
1369 – 1551 
Month 54 
T20 
1642 
1552 – 1733 
Month 60 
T22 
1825 
1734 –1916 
Month 66 
T24 
2007 
1917 – 2098 


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Statistical Analysis Plan: Protocol 1002-043 
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APPENDIX 4. IMPUTATION OF DATES  
The following rules will be used to impute partial missing dates.  Note that imputed dates may be 
used to calculate ‘study day’ but will NOT be presented in the listings. 
AE start 
date 
If only Day is missing: 
If the AE start year and month are the same as that for 
the first dose (Day 1) date, then the AE start day will be 
imputed as the day of first dose date; otherwise, the AE 
start day will be imputed as the first day of the month. 
If both Day and Month are 
missing: 
If AE start year is the same first dose year, then the AE 
start Month and Day will be imputed as the Month and 
Day of first dose date; otherwise, the AE start date will 
be imputed as 01 January. 
If Year of AE start date is 
missing or AE start date is 
complete missing: 
The AE start date will be imputed as the first dose date. 
AE stop date If only Day is missing: 
If only Day is missing and AE stop month and year are 
the same as the month and year of the EOS date, use the 
EOS date; otherwise the last day of the month will be 
imputed. 
If both Day and Month are 
missing: 
If both Day and Month are missing and AE stop year is 
the same as the year of the EOS date, the EOS date will 
be used to impute. 
If the year of the AE end date precedes the year of the 
EOS date, AE end month and day will be set to 
31 December. 
If the Year of AE stop date 
is missing or AE stop date 
is completely missing: 
If the AE stop date is completely missing, 1) if the 
“Ongoing” status is “Yes”, the EOS Date will be 
assigned to the stop date; 2) if the “Ongoing” status is 
“No” or missing, the stop date will be assigned as the 
Date of Informed Consent, or the start date if present 
(partially imputed if necessary) and later. 
If only Year is missing, the EOS year will be assigned 
to the stop date. 
AE = adverse event; EOS = End-of-Study 
Medication 
start date 
If only Day is missing: 
If only Day is missing, the first day of the month will be 
assumed. 
If only Day and Month are 
missing: 
If both Day and Month are missing, the first day of the 
year will be assumed. 
If only Year is missing or 
date is completely missing: 
If medication start date is completely missing, the 
informed consent signature date or medication end date 
whichever is earlier, will be used to impute. 


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Statistical Analysis Plan: Protocol 1002-043 
10 November 2022 
 
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AE start 
date 
If only Day is missing: 
If the AE start year and month are the same as that for 
the first dose (Day 1) date, then the AE start day will be 
imputed as the day of first dose date; otherwise, the AE 
start day will be imputed as the first day of the month. 
If both Day and Month are 
missing: 
If AE start year is the same first dose year, then the AE 
start Month and Day will be imputed as the Month and 
Day of first dose date; otherwise, the AE start date will 
be imputed as 01 January. 
If Year of AE start date is 
missing or AE start date is 
complete missing: 
The AE start date will be imputed as the first dose date. 
If only Year is missing, then informed consent signature 
year will be used to impute. 
Medication 
stop date 
If only Day is missing 
If only Day is missing, the last day of the month will be 
assumed. 
If both Day and Month are 
missing 
If both Day and Month are missing, the medication stop 
month and day will be set to 31 December. 
If Only Year is missing or 
medication end date is 
completely missing 
If medication end date is completely missing, 1) if the 
“Ongoing” status is “Yes”, the EOS Date will be 
assigned to the stop date; 2) if the “Ongoing” status is 
“No” or missing, the end date will be assigned as the 
Date of Informed Consent, or the start date if present 
(partially imputed if necessary) and later. 
If only Year is missing, the EOS year will be assigned. 
Other dates 
If only Day is missing 
If only Day is missing, the last day of the month will be 
assumed. 
If only Day and Month are 
missing: 
If both Day and Month are missing, the first day of the 
year will be assumed. 
If the year is missing, or the 
date is completely missing. 
Will not be imputed.  
AE = adverse event; EOS = End-of-Study 
 


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APPENDIX 6. MULTIPLE IMPUTATION AND TIPPING POINT 
ANALYSIS 
For the primary 4-component MACE endpoint (MACE-4), the multiple imputation and tipping 
point (TP) analyses are comprised of the following steps: 
Step1.  Model for Unobserved Events 
A parametric exponential survival model (e.g., PROC LIFEREG in SAS) is used for the events 
after stopping the assigned treatment.  Specifically, when fitting the model, the start time of each 
patient is the date of the last dose.  The event or censoring time remains the same as in the 
primary analysis.  Patients who had events prior to the last dose will not be included in the 
analysis.  Treatment assignment is included as a covariate and the parameters are intercept α, and 
β which is the log hazard ratio between active treatment and placebo groups after they have 
stopped the assigned treatment.   
Step 2: Simulation of Unobserved Events 
For patients who were censored (i.e., did not experience a MACE-4), a time to event is simulated 
from the fitted model in Step 1, and it is added to the date of last dose for each patient. 
Afterwards, all patients are censored at the calendar date of 
or their date of non-CV 
death.  
• For multiple imputation, the parameters (𝛼𝛼෤, 𝛽𝛽෨) will be drawn from a bivariate normal 
distribution centered around the MLEs (𝑎𝑎ො, 𝛽𝛽̂) with the model-based variance-
covariance matrix.  This is an approximate to the posterior distribution of the 
parameters when a flat non-informative prior is used. 
• For TP, 𝑎𝑎ො is used.  However, instead of the observed treatment effect 𝛽𝛽̂, a range of 
values (from hazard ratios of 1.00 to 1.10 in 0.01 increment) will be used to allow the 
patients assigned to the active treatment to have the same or event worse outcome 
than those assigned to the placebo group after dropping out and stopping the 
treatment.  
A total of 100 datasets will be simulated for each scenario. 
Step 3: Fitting Cox PH Model using Simulated Data and Final Inference 
For each simulated dataset, a Cox PH model is used to estimate the difference (log hazard ratio) 
between the active treatment and placebo groups. 
The resulted estimates are combined using Rubin’s method (Rubin, 1987), e.g., using PROC 
MIANALYZE in SAS.  


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Statistical Analysis Plan: Protocol 1002-043 
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Esperion Therapeutics, Inc. 
Statistical Analysis Plan: Protocol 1002-043 
10 November 2022 
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Esperion Therapeutics, Inc. 
Statistical Analysis Plan: Protocol 1002-043 
10 November 2022 
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Esperion Therapeutics, Inc. 
Statistical Analysis Plan: Protocol 1002-043 
10 November 2022 
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Esperion Therapeutics, Inc. 
Statistical Analysis Plan: Protocol 1002-043 
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APPENDIX 8. TYPE 2 DIABETES MEDICAL HISTORY AND PRIOR 
MEDICATION 
MedDRA Preferred Terms for Type 2 Diabetes 
 
Acquired lipoatrophic diabetes 
 
Diabetes complicating pregnancy 
 
Diabetes mellitus 
 
Diabetes mellitus inadequate control 
 
Diabetes mellitus malnutrition-related 
 
Diabetes with hyperosmolarity 
 
Diabetic arteritis 
 
Diabetic coma 
 
Diabetic complication 
 
Diabetic dyslipidaemia 
 
Diabetic endorgan damage 
 
Diabetic coronary microangiopathy 
 
Diabetic hepatopathy 
 
Diabetic hyperglycaemic coma 
 
Diabetic hyperosmolar coma 
 
Diabetic ketoacidosis 
 
Diabetic ketoacidotic hyperglycaemic coma 
 
Diabetic ketosis 
 
Diabetic wound 
 
Diabetic metabolic decompensation 
 
Euglycaemic diabetic ketoacidosis 
 
Fulminant type 1 diabetes mellitus 
 
Insulin resistant diabetes 
 
Insulin-requiring type 2 diabetes mellitus 
 
Ketosis-prone diabetes mellitus 
 
Latent autoimmune diabetes in adults 
 
Monogenic diabetes 
 
New onset diabetes after transplantation 
 
Pancreatogenous diabetes 
 
Steroid diabetes 
 
Type 1 diabetes mellitus 
 
Type 2 diabetes mellitus 
 
Type 3 diabetes mellitus 
 
 


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Statistical Analysis Plan: Protocol 1002-043 
10 November 2022 
 
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Medication (WHODrug ATC4) for Type 2 Diabetes 
A10AB Insulins and Analogues for Injection, Fast-Acting 
A10AC Insulins and Analogues for Injection, Intermediate-Acting 
A10AD Insulins and Analogues for Injection, Intermediate- or Long-Acting Combined with Fast-
Acting 
A10AE 
Insulins and Analogues for Injection, Long-Acting 
A10AF 
Insulins and Analogues for Inhalation 
A10BA Biguanides 
A10BB 
Sulfonylureas 
A10BC 
Sulfonamides (Heterocyclic) 
A10BD Combinations of Oral Blood Glucose Lowering Drugs 
A10BF 
Alpha-Glucosidase Inhibitors 
A10BG Thiazolidinediones 
A10BH Dipeptidyl Peptidase-4 (DPP-4) Inhibitors 
A10BJ 
Glucagon-Like Peptide-1 (GLP-1) Analogues 
A10BK Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors 
A10BX Other Blood Glucose Lowering Drugs, Excl.  Insulins 
 
 
 


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Statistical Analysis Plan: Protocol 1002-043 
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APPENDIX 10. POTENTIALLY CLINICALLY SIGNIFICANT 
LABORATORY AND VITAL SIGN ABNORMALITIES 
 
Parameter 
Criteria  
ALT, AST, and Total Bilirubin a 
 
ALT >3× ULN 
AST >3× ULN 
TB >2× ULN 
ALP 
ALP >1.5× ULN 
CK 
>5× ULN 
eGFR 
<30 mL/min/1.73m2 
Creatinine , BUN a 
Creatinine >0.5 mg/dL increase from baseline 
Creatinine >30% increase from baseline 
BUN >2× baseline 
BUN/Creatinine >30% increase from baseline 
Glucose 
>126 mg/dL (fasting) 
>200 mg/dL (non-fasting) 
<70 mg/dL (fasting or non-fasting) 
HbA1c 
>10% 
hs-CRP 
>10 mg/L 
Albumin 
<LLN 
Hemoglobin 
≥2 g/dL decrease from baseline and < LLN  
LDL-C 
≥25% increase from baseline 
TG 
≥1000 mg/dL 
Other safety chemistry and hematology 
parameters b 
<LLN or >ULN 
Heart Rate 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
Weight 
≥10% increase or decrease from baseline 
LLN: Lower Limit of Normal; ULN: Upper Limit of Normal.  
Note: list all the values of the parameter from the patient if any criteria are met. 
a For these groups of parameters, include all parameters in the listing, by timepoint first. 
b Parameters not explicitly mentioned in this table, excluding lipids.    
 


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