E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study is to assess the efficacy of bempedoic acid 180 mg/day versus placebo in decreasing low-density lipoprotein cholesterol (LDL-C) when added to ezetimibe therapy in patients with high LDL-Cholesterol on Low Dose or Less than Low Dose Statins. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with uncontrolled high cholesterol and are at a high risk of cardiovascular disease. |
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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 | 20.0 |
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 |
To assess the 12-week efficacy of bempedoic acid 180 mg/day versus placebo in decreasing LDL-C when added to ezetimibe therapy in patients with elevated LDL-C on low dose or less than low dose statins. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To evaluate the effect of 12-week treatment with bempedoic acid 180 mg/day versus placebo when added to ezetimibe therapy on
− non-high-density lipoprotein cholesterol (non-HDL-C),
− total cholesterol (TC),
− apolipoprotein B (apoB), and
− high-sensitivity C-reactive protein (hs-CRP)
• To evaluate the effect of 12-week treatment with bempedoic acid 180 mg/day versus placebo on TG and HDL-C when added to ezetimibe.
• To evaluate 12-week safety and tolerability of bempedoic acid 180 mg/day compared with placebo when added to ezetimibe.
The tertiary objectives of this study are:
• To evaluate the effects of treatment with bempedoic acid 180 mg/day versus placebo when added to ezetimibe therapy at 4 and 8 weeks on the following parameters:
− LDL-C
− Non-HDL-C
− TC
− TG
− HDL-C |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each potential patient must satisfy all inclusion criteria to be enrolled in the study. Selected inclusion criteria are listed below; all inclusion criteria are listed in the protocol body.
1. Provision of written informed consent prior to any study-specific procedure
2. Age ≥18 years or legal age of majority based on regional law, whichever is greater, at Week -5 (Visit S1)
3. Fasting (minimum of 10 hours) calculated LDL-C at Week -5 (Visit S1) as defined by ezetimibe use at screening:
• For patients who have been taking ezetimibe 10 mg daily prior to Week -5 (Visit S1): Fasting LDL-C ≥100 mg/dL (2.6 mmol/L) on stable background lipid-modifying therapy (LMT; greater than or equal to 4 weeks prior to screening).
• For patients who have not been taking ezetimibe Week -5 (Visit S1):
Fasting LDL-C ≥120 mg/dL (3.1 mmol/L) on stable background LMT (greater than or equal to 4 weeks prior to screening).
• All patients must have fasting LDL-C ≥70 mg/dL (1.8 mmol/L) at Week -1 (Visit S3).
4. Currently receiving stable (greater than or equal to 4 weeks prior to screening) background statin dose that does not exceed low dose statin therapy.
Note: Patients must report attempting greater than low dose statin therapy and being unable to
tolerate it due to an adverse safety effect that started or increased during statin therapy and resolved or improved when statin therapy was discontinued or the dose lowered. 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.
Very 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. Patients on ezetimibe and low or very low dose statin or unable to tolerate any statin at any dose are also eligible. Patients may continue taking low or very low dose statin therapy throughout the study provided that it is stable (greater than or equal to 4 weeks) and well tolerated. Patients unable to take
any dose of statins are also eligible provided that statin therapy has been attempted.
5. Men and nonpregnant, nonlactating women. Women must be either
• Naturally postmenopausal defined as ≥1 year without menses and
− ≥55 years, or
− <55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L, or
• Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation, or
• Women of childbearing potential willing to use 2 acceptable method of birth control (unless they have agreed to follow the definition of true abstinence). The minimal requirement for adequate contraception should be started on Day 1, continuing during the study period and for at least 30 days after the last dose of study drug. Acceptable methods of birth control include:
− oral, implantable, injectable, or topical birth control medications
− placement of an intrauterine device with or without hormones
− barrier methods including condom or occlusive cap with spermicidal foam or spermicidal jelly
− vasectomized male partner who is the sole partner for this patient
− True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception).
Note: There are no protocol-specific birth control requirements for men with partners who are able to become pregnant. |
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E.4 | Principal exclusion criteria |
1. BMI >50 kg/m2
2. Recent history of documented clinically significant cardiovascular disease including, but not limited to
• Within 3 months of screening, (Week -5 [Visit S1]) or between screening and randomization, MI, severe/unstable angina pectoris, coronary angioplasty, coronary artery bypass graft, stroke, transient ischemic attack, cerebrovascular event, symptomatic carotid artery disease, or symptomatic peripheral arterial disease
• Uncontrolled hypertension
• Within 3 months of screening (Week -5 [Visit S1]) or between screening and randomization visits, an arrhythmia requiring medical intervention
• Planned revascularization procedures
• New York Heart Association (NYHA) Class IV heart failure 3. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L) at Week -5 (S1)
4. Hemoglobin A1C (HbA1C) ≥10% at Week -5 (Visit S1)
5. Persistent poor adherence with ezetimibe and/or single-blind, placebo study drug or lack of tolerance to run-in medications assessed prior to randomization.
6. Uncontrolled hypothyroidism. Patients stabilized on thyroid replacement therapy for at least 6 weeks prior to randomization are allowed
7. Liver disease or dysfunction, including:
• Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (HCV-ABVivi) at Week -4 (Visit S2), or
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, and/or total bilirubin (TB) ≥2 × ULN at Week -2 (Visit S1). If TB ≥1.2 × ULN, a reflex indirect (unconjugated) bilirubin will be obtained.
8. Renal dysfunction or glomerulonephritis, including estimated glomerular filtration rate (eGFR; using central laboratory determined
Modification of Diet in Renal Disease [MDRD] formula) <30 mL/min at Week -5 (Visit S1).
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL at Week -5 (Visit S1);
11. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 5 years
12. Unexplained creatine kinase (CK) >3 × ULN at any time prior to randomization (ie, not associated with recent trauma or physically strenuous activity). Patients with an explained CK elevation must have single repeat CK ≤3 × ULN prior to randomization;
13. History of drug or alcohol abuse within the last 2 years or reported current consumption of >14 alcoholic drinks/week, or any illicit drug use, history of amphetamine and derivatives abuse or cocaine abuse
14. Blood donation, participation in a multiple blood draws, clinical study, major trauma, blood transfusion or surgery with or without blood loss within 30 days prior to randomization
15. Use of any experimental or investigational drugs within 30 days prior to screening. Patients who have enrolled in a study of an experimental small interfering RNA (siRNA) inhibitor of PCSK9 are excluded;
16. Previous enrollment in a bempedoic acid clinical study.
17. Use of any of the following drugs prior to screening (Week -5, Visit S1) or a plan to use these drugs during the study as follows:
• Within 2 weeks prior to screening
− Cholestin or red yeast rice-containing products (also known as monascus purpureus extract)
• Within 4 weeks prior to screening
− Statin doses exceeding those defined as low dose. Doses exceeding low dose statin therapy are defined as an average daily dose of rosuvastatin greater than 5 mg, atorvastatin greater than 10 mg, simvastatin greater than 10 mg, lovastatin greater than 20 mg, pravastatin greater than 40 mg, fluvastatin greater than 40 mg, or pitavastatin greater than 2 mg.
Within 6 weeks prior to screening for patients taking a statin
− Gemfibrozil is not allowed in patients taking a statin as per co-administration instructions defined in the statin label
• Within 3 months prior to screening:
− Lomitapide or apheresis therapy
− Probenecid or cyclosporine
• Within 4 months prior to screening
− Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
Within 6 months prior to screening
− Mipomersen
− Cholesteryl ester transfer protein inhibitor (CETP-I) within the last 2 years prior to screening (Week -5, Visit S1) except for evaceptrapib within the last 3 months to screening (Week -5, Visit S1)
18. Planned initiation of the following drugs during the clinical trial or changes to the following drugs prior to randomization:
Hormone replacement (within 6 weeks prior to randomization) Thyroid replacement (within 6 weeks prior to randomization)
Diabetes medications (within 4 weeks prior to randomization)
Obesity medication (within 4 weeks prior to randomization)
19. New or planned dose changes of systemic corticosteroids.
20. An employee or contractor of the facility conducting the study, or a family member of the principal investigator, co-investigator, of any Sponsor personnel.
21. Pregnant, breastfeeding, or intending to become pregnant within 30 days after study completion or last dose of study drug.
22. Previous intolerance to ezetimibe. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from baseline to Week 12 in LDL-C. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To evaluate the effect of 12-week treatment with bempedoic acid 180 mg/day versus placebo when added to ezetimibe therapy on
− non-high-density lipoprotein cholesterol (non-HDL-C),
− total cholesterol (TC),
− apolipoprotein B (apoB), and
− high-sensitivity C-reactive protein (hs-CRP)
• To evaluate the effect of 12-week treatment with bempedoic acid 180 mg/day versus placebo on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) when added to ezetimibe
• To evaluate 12-week safety and tolerability of bempedoic acid 180 mg/day compared with placebo when added to ezetimibe.
Tertiary:
• Tertiary endpoints include assessments of percent change and absolute change from baseline in lipid levels at the additional time points of Week 4 (T2) and Week 8 (T3).
1. Percent change from baseline to Weeks 4 and 8 in
a. LDL-C
b. Non-HDL-C
c. TC
d. TG
e. HDL-C
2. Absolute change from baseline to Weeks 4, 8, and 12 in LDL-C
Safety Endpoints:
a. Subject incidence to TEAE
b. Safety laboratory values and vital signs
c. ECG findings
d. Cardiovascular event rates |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The descriptive summaries of AE data, endpoints used to evaluate hepatic, musculoskeletal, diabetes/hyperglycemic, renal, neurocognitive safety, and defined clinical endpoints are described in Section 12.7 of the protocol. |
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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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Canada |
Czech Republic |
Germany |
Hungary |
United Kingdom |
United States |
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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 the last randomized patient completes the Week 12 visit. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |