| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Hyperlipidemia at High Cardiovascular Risk Not Adequately Controlled by Their Lipid-Modifying Therapy |
|
| 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 | 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 | 100000011499 |
|
| 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 |
|
| 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 assess the 12-week efficacy of bempedoic acid (ETC-1002) 180 mg/day versus placebo in decreasing low-density lipoprotein cholesterol (LDL-C) in high cardiovascular (CV) risk patients with hyperlipidemia (with underlying heterozygous familial hypercholesterolemia [HeFH] and/or atherosclerotic cardiovascular diseases [ASCVD]) who are not adequately controlled with their maximally tolerated lipid-modifying therapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of 24-week treatment with bempedoic acid 180 mg/day versus placebo on LDL-C.
• To evaluate the effect of bempedoic acid 180 mg/day versus placebo on non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), high-sensitivity C-reactive protein (hs-CRP), and apolipoprotein B (apoB) after 12 weeks of treatment.
Tertiary Objectives:
• To evaluate the effect of long-term (52-week) treatment with bempedoic acid 180 mg/day versus placebo on LDL-C, non-HDL-C, TC, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), hs-CRP, and apoB.
• To evaluate the long-term (52-week) safety and tolerability of bempedoic acid 180 mg/day compared to placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Women must be either:
Naturally postmenopausal (as reported by the patient, defined as greater than 55 years and ≥1 year without menses, <55 years and ≥1 year without menses with follicle-stimulating hormone (FSH) ≥40.0 IU/L), or surgically sterile including hysterectomy, bilateral oophorectomy, or tubal ligation or;
Women of childbearing potential must be 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 it is that it 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 (IUD) 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; or 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 the trial, and withdrawal are not acceptable methods of contraception).
2. Fasting LDL-C (minimum of 10 hours) value at Week -5 (Visit S1) ≥100 mg/dL (2.6 mmol/L) and fasting LDL C value at Week 1 (Visit S3) ≥70 mg/dL (1.8 mmol/L)
3. Have high CV risk that is defined as either:
Diagnosis of HeFH. Diagnosis must be made by either genotyping or by clinical assessment using either the World Health Organization (WHO) criteria/Dutch Lipid Clinical Network Criteria with a score that is >8 points (see Appendix 4 of Protocol) or the Simon Broome Register Diagnostic Criteria with an assessment of 'Definite HeFH'. Patients with a diagnosis of HeFH may or may not have established coronary heart disease (CHD) or CHD risk equivalents.
OR
• Have ASCVD (with established CHD or CHD risk equivalents)
Documented history of CHD (includes 1 or more of the following):
o Acute MI
o Silent MI
o Unstable angina
o Coronary revascularization procedure (eg, percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery)
o Clinically significant CHD diagnosed by invasive or non-invasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography, or nuclear imaging)
Documented CHD risk equivalents (includes 1 or more of the following criteria):
o Symptomatic peripheral arterial disease (PAD) defined as:
- 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 computed tomographic angiography [CTA]) showing ≥50% stenosis or
- Peripheral arterial revascularization (surgical or percutaneous) occurring greater than 90 days prior to Visit S1 or
- Lower extremity amputation due to peripheral vascular disease occurring greater than 90 days prior to Visit S1
○ Cerebrovascular atherosclerotic disease defined by:
- ischemic stroke occurring greater than 90 days prior to Visit S1 or
- 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 Visit S1.
4. Be on maximally tolerated lipid-modifying therapy, including a maximally tolerated statin either alone or in combination with other lipid- modifying therapies, at stable doses and regimens for at least 4 weeks prior to screening (6 weeks for fibrates; however, gemfibrozil is not allowed as per co-administration instructions defined in the statin label ). Maximally tolerated statin includes statin regimens other than daily dosing, including no to very low doses, but reasons for not using high-intensity statin dosing must be documented.
A patient's maximally tolerated lipid-modifying therapy will be determined by the investigator using their medical judgment and available sources, including the patient's self-reported history of lipid-modifying therapy.
Note: Patients can be on any available lipid-modifying therapy with the exception of the exclusions listed below as long as they have been stable for 4 weeks prior to Screening Visit S1 and are taken at a consistent time each day. In the case of PCSK9 inhibitor use, the patient must have received 3 stable doses. It is important that lipid values are measured at PCSK9i trough levels. Therefore, study visits should be scheduled in accordance with the patient’s PCSK9i injection regimen so that measurement of lipid values for all visits occurs before the PCSK9i injection but not greater than 48 hours before the next scheduled PCSK9 injection. Patients who have discontinued investigational or commercial PCSK9 inhibitor must have had their last dose at least 4 months prior to Screening Visit S1.
"Cont." |
|
| E.4 | Principal exclusion criteria |
1. Total fasting (minimum of 10 hours) TG ≥500 mg/dL (5.6 mmol/L) at Week -5 (Visit S1)
2. Renal dysfunction or nephritic syndrome or a history of nephritis, 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) (Levey 2006).
3. Body mass index (BMI) ≥50 kg/m2
4. Recent (within 3 months prior to the screening visit [Week -5 (Visit S1)] or between screening and randomization visits) MI, unstable angina leading to hospitalization, uncontrolled, symptomatic cardiac arrhythmia (or medication for an arrhythmia that was started or dose changed within 3 months of screening), CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack (TIA), endovascular procedure or surgical intervention for peripheral vascular disease or plans to undergo a major surgical or interventional procedure (eg, PCI, CABG, carotid or peripheral revascularization). Patients with implantable pacemakers or automatic implantable cardioverter defibrillators may be considered if deemed by the Investigator to be stable for the previous 3 months.
5. Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) ≥160 mmHg and diastolic blood pressure (DBP) ≥100 mmHg after sitting quietly for 5 minutes.
6. Hemoglobin A1C (HbA1C) ≥10% at Week -5 (Visit S1)
7. 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.
8. Liver disease or dysfunction, including:
• Positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (HCV-AB) at Week -5 (Visit S1); or
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥2 × ULN, and/or total bilirubin (TB) ≥2 × ULN at Week -5 (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.
9. Gastrointestinal conditions or procedures (including weight loss surgery; eg, Lap-Band® or gastric bypass) that may affect drug absorption
10. Hematologic or coagulation disorders or a hemoglobin (Hgb) level <10.0 g/dL (100 g/L) 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 screening up 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 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.
14. Blood donation, blood transfusion, participation in a clinical study with multiple blood draws, major trauma, 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. Use of any of the following drugs or a plan to use these drugs during the study;
• New or planned dose changes of systemic corticosteroids. Stable doses (≥4 weeks before Visit S1) and topical steroids allowed.
• CETP inhibitors within the last 2 years prior to screening (Week 5, Visit S1) except for evaceptrapib within the last 3 months prior to screening
• Mipomersen (6 months prior to screening)
• Lomitapide (3 months prior to screening)
• Apheresis (3 months prior to screening)
• Simvastatin ≥40 mg/day (4 weeks prior to screening)
• Red yeast rice extract-containing products are not allowed (2 weeks prior to screening)
17. Planned initiation of the following drugs during the clinical trial or changes prior to randomization:
• Hormone replacement (6 weeks prior to randomization)
• Thyroid replacement (6 weeks prior to randomization)
• Diabetes medications (4 weeks prior to randomization)
• Obesity medication (44 weeks prior to randomization)
18. Lack of adherence (ie, less than 80% of planned doses) with IMP (single-blind placebo) during the Run-in Period.
19. Lack of tolerance with IMP (single-blind placebo) during the Run-in Period.
20. 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.
"Cont." |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this study is the percent change from baseline to Week 12 in LDL-C. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The percent change from baseline to Week 12 in LDL-C. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1. Percent change from baseline to Week 24 in LDL-C
2. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP
3. Absolute change from baseline to Weeks 12 and 24 in LDL-C
Tertiary efficacy endpoints are of interest:
1. Absolute change and percent change from baseline to Week 52 in LDL-C
2. Percent change from baseline to Weeks 24 and 52 in non-HDL-C, TC, apoB, and hs-CRP
3. Percent change from baseline to Weeks 12, 24, and 52, in TG and HDL-C |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Timepoint:
1. Percent change from baseline to Week 24 in LDL-C
2. Percent change from baseline to Week 12 in non-HDL-C, TC, apoB, and hs-CRP
3. Absolute change from baseline to Weeks 12 and 24 in LDL-C
Tertiary Tmepoint:
1. Absolute change and percent change from baseline to Week 52 in LDL-C
2. Percent change from baseline to Weeks 24 and 52 in non-HDL-C, TC, apoB, and hs-CRP
3. Percent change from baseline to Weeks 12, 24, and 52, in TG and HDL-C |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Germany |
| Poland |
| Ukraine |
| 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 52 visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 |
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