| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with uncontrolled high cholesterol and are at a high risk of cardiovascular disease. |
|
| 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 | 19.1 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| 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 |
|
| 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. |
|
| 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
• To evaluate 12-week safety and tolerability of bempedoic acid 180 mg/day compared with placebo.
The tertiary objectives of this study are:
• To evaluate the effects of 4- and 8-week treatment with bempedoic acid 180 mg/day versus placebo when added to ezetimibe therapy on
− LDL-C
− Non-HDL-C
− TC
− TG
− HDL-C |
|
| 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 LDL-C (minimum of 10 hours) at Week -5 (Visit S1) ≥100 mg/dL (2.6 mmol/L) on stable background LMT (greater than or equal to 4 weeks prior to screening) requiring further LDL-C lowering.
Note: LDL-C may be repeated 1 time with the screening period extended up to 4 weeks. For those patients who have a repeat LDL-C, the mean of the first value and the repeat value will be used to determine eligibility.
4. Currently receiving stable (greater than or equal to 4 weeks prior to screening) background maximally tolerated LMT that includes ezetimibe 10 mg daily and maximally tolerated 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 1 acceptable method of birth control including:
− oral, implantable, 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. |
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the exclusion criteria are not eligible. Selected exclusion criteria are listed below; all exclusion criteria are listed in the protocol body.
1. Body mass index (BMI) >50 kg/m2
2. Recent history of documented clinically significant cardiovascular disease including, but not limited to
• Within 3 months of screening, MI, severe or 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, defined as sitting systolic blood pressure (SBP) ≥160 mm Hg and diastolic blood pressure (DBP) ≥100 mm Hg after sitting quietly for 5 minutes.
• Within 3 months of screening, 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 (ie, ingesting <80% of planned doses) or lack of tolerance to run-in medications assessed prior to randomization.
6. Uncontrolled hypothyroidism, including thyroid-stimulating hormone (TSH) >1.5 × the upper limit of normal (ULN) at Week -5 (Visit S1). 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, and if consistent with Gilbert’s disease or if the patient has a history of Gilbert’s Disease, the patient may be enrolled in the study.
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. Nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed
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. Subjects with amphetamine derivatives prescribed by and under the care of a health care practitioner can be enrolled after evaluation by the investigator;
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;
16. Previous enrollment in a bempedoic acid clinical study.
17. Use of any of the following drugs prior to screening 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 > 5 mg, atorvastatin > 10 mg, simvastatin >10 mg, lovastatin > 20 mg, pravastatin > 40 mg, fluvastatin > 40 mg, or pitavastatin > 2 mg. • Within 3 months prior to screening: − Requirement for mipomersen or lomitapide or apheresis therapy − Probenecid or cyclosporine
• Within 4 months prior to screening − PCSK9-inhibitors
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 3 months 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline to Week 12 in LDL-C. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints (specific to stepdown approach):
1. Percent change from baseline to Week 12 in:
a. non-HDL-C
b. TC
c. apoB
d. hs-CRP
Other secondary efficacy endpoints:
2. Percent change from baseline to Week 12 in:
a. TG
b. HDL-C
Tertiary efficacy endpoints:
1. Assessments of percent change from baseline in lipid levels at the additional time points of Week 4 (T2) and Week 8 (T3) in:
a. LDL-C
b. Non-HDL-C
c. TC
d. TG
e. HDL-C
2. Assessments of absolute change from baseline to Weeks 4, 8, and 12 in:
a. LDL-C
b. Non-HDL-C
c. TC
d. TG
e. HDL-C |
|
| 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. |
|
| 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 | 12 |
| 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 |
|
| 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
|
| The study will end when the last randomized patient completes the Week 12 visit. |
|
| 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 |
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