E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with, or at high risk for, cardiovascular disease (CVD) who are statin intolerant. |
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E.1.1.1 | Medical condition in easily understood language |
Patients who have, or are at a high risk of, cardiovascular disease and cannot take statin drugs. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007648 |
E.1.2 | Term | Cardiovascular disease, unspecified |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007649 |
E.1.2 | Term | Cardiovascular disorder |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
• 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 (hsCRP).
• To evaluate the long-term safety and tolerability of bempedoic acid 180 mg/day compared to placebo.
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, and TG. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of signed informed consent prior to any study-specific procedure.
2. Patient reported statin intolerance (SI) defined as an inability to tolerate 2 or more statins, one at a low dose, due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued.
Low dose statin therapy is defined as an average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg.
Please note that patients currently tolerating very low dose statin therapy (an average daily dose of rosuvastatin <5 mg, atorvastatin <10 mg, simvastatin <10 mg, lovastatin <20 mg, pravastatin<40 mg, fluvastatin <40 mg, or pitavastatin <2 mg) are considered to be intolerant to that low dose statin. Patients may continue taking very lose 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.
4. Age ≥18 years or legal age of majority based on regional law, whichever is greater, 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 2 acceptable methods of birth control during the study and for 30 days after the end of treatment including:
o oral 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) and ≤190 mg/dL (4.9 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:
• 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 performed by a vascular lab or angiogram (including CTA) showing ≥50% stenosis, or Peripheral arterial revascularization (surgical or percutaneous), occurring greater than 90 days prior to screening, 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
• High risk for a CVD event, defined by:
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. |
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E.4 | Principal 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 screening) transient ischemic attack (TIA)
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 ≥12% 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 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,
• Other lipid regulating drugs or supplements.
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Time to first occurrence of a confirmed, adjudicated MACE. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MACE is defined as CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Time-to-Event Endpoints
• Time to first occurrence of adjudicated composite endpoint of CV death, nonfatal MI, or nonfatal stroke
• Time to first occurrence of adjudicated composite endpoint of all-cause mortality, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization.
Time to first occurrence of adjudicated composite endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization
• Time to first occurrence of each adjudicated individual component of MACE (CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization) as well as time to all-cause mortality
• Time to first occurrence of (fatal + nonfatal) MI; time to first occurrence of (fatal + nonfatal) stroke; time to first occurrence of (fatal + nonfatal) hemorrhagic stroke; time to first occurrence of (fatal + nonfatal) non-hemorrhagic stroke.
Secondary Efficacy Lipid and Biomarker Endpoints:
• Percent change from baseline to Month 6 in LDL-C and in hsCRP
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time to first occurrence of adjudicated composite endpoint of all-cause mortality, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization.
Safety Endpoints:
• AEs (including muscle-related AEs, new-onset or worsening diabetes, 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 249 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Chile |
Colombia |
India |
Israel |
Mexico |
South Africa |
United States |
Estonia |
Latvia |
Lithuania |
Poland |
Bulgaria |
Netherlands |
Romania |
Spain |
Czechia |
Germany |
Croatia |
Denmark |
Hungary |
Russian Federation |
Serbia |
Slovakia |
Turkey |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will end when all of the following have occurred:
1) at least 1,437 patients have experienced an adjudicated primary 5-component MACE,
2) at least 719 patients have experienced an adjudicated 3-component MACE (CV death, nonfatal MI, nonfatal stroke), and
3) 24 months (2 years) have elapsed since the last patient was randomized. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |