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

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 and 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 major
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 90 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 LDLC- 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.
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
• 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
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 occurring greater
than 90 days prior to screening, or
b High risk for a CVD event (ie, high-risk primary prevention):
o Reynolds Risk score >30% or a SCORE Risk score >7.5% over 10 years, or
o Coronary artery calcium score >400 Agatston units (AU) at any time in the
past, or
o Patients with type 1 or type 2 diabetes, aged >65 years (women) or >60 years
(men)

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,
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,
f. Planned coronary revascularization (patient may rescreen 3 months
post-procedure).
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.
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]),
• 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 less than 4
weeks 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 90 days
after study completion or last dose of IMP.