A Clinical Trial to Look at the Effects of the Drug Bempedoic Acid in Patients with Frequent Major Cardiovascular Events, or at High Risk of Cardiovascular Disease who Cannot be Treated with Statins. Patients to be randomly allocated to either placebo or investigational drug; assignment will be unknown to patient and doctor.

• Register: EUCTR
• Last refreshed on: 30 October 2023
• Main ID: EUCTR2016-003485-11-LT
• Date of registration: 28/02/2017
• Prospective Registration: Yes
• Primary sponsor: Esperion Therapeutics Inc.,
• Public title: A Clinical Trial to Look at the Effects of the Drug Bempedoic Acid in Patients with Frequent Major Cardiovascular Events, or at High Risk of Cardiovascular Disease who Cannot be Treated with Statins. Patients to be randomly allocated to either placebo or investigational drug; assignment will be unknown to patient and doctor.
• Scientific title: 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.
• Date of first enrolment: 08/03/2017
• Target sample size: 14000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003485-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czech Republic, Czechia, Denmark, Estonia, Germany, Hungary, India, Latvia, Lithuania, Mexico, Netherlands, New Zealand, Poland, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Director of Clinical Operations
• Affiliation: Esperion Therapeutics

• Name: Director of Clinical Operations
• Affiliation: Esperion Therapeutics

Key inclusion & exclusion criteria

Inclusion criteria:
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:
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.
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 tomogr
Exclusion criteria:
1. Total fasting TG >500 mg/dL (5.6 mmol/L) at Week -5 (Visit S1).
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).
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).
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).
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).
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 avera

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with, or at high risk for, cardiovascular disease (CVD) who are statin intolerant.
MedDRA version: 20.1 Level: LLT Classification code 10007648 Term: Cardiovascular disease, unspecified System Organ Class: 10007541 - Cardiac disorders
MedDRA version: 20.0 Level: PT Classification code 10007649 Term: Cardiovascular disorder System Organ Class: 10007541 - Cardiac disorders

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: Nilemdo
Product Name: Bempedoic Acid
Product Code: ETC-1002
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BEMPEDOIC ACID 
CAS Number: 738606-46-7
Current Sponsor code: ETC-1002
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 180-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: MACE is defined as CV death, nonfatal MI, nonfatal stroke, or coronary revascularization.

Primary end point(s): Primary Efficacy Endpoint:
• Time to first occurrence of a confirmed MACE.

Main Objective: The primary objective is to evaluate whether administration of bempedoic acid 180 mg/day versus placebo reduces the risk of MACE (Major Adverse Cardiovascular Event) in patients with, or at high risk for, CVD who are statin intolerant.

Secondary Objective: • 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

Secondary Outcome(s)

Secondary end point(s): 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.

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)

Timepoint(s) of evaluation of this end point: Time to first occurrence of composite endpoint of all-cause mortality, nonfatal MI, nonfatal stroke, or coronary revascularization.

Safety Endpoints:
• AEs (including muscle-related AEs, new-onset or worsening type 2 diabetes mellitus, and neurocognitive AEs), heart rate, blood pressure (BP), and clinical laboratory measures
• Change from baseline in glycosylated hemoglobin, Type A1C (HbA1C) and fasting serum glucose at Months 3, 12, and end-of-study.

Secondary ID(s)

2016-003485-11-SK

1002-043

CLEAR Outcomes

NCT02993406

Source(s) of Monetary Support

Esperion Therapeutics Inc.,

Ethics review

Status: Approved
Approval date: 22/12/2016
Contact: