| 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. |
A statin terápiát nem toleráló, cardiovascularis betegségben szenvedő,
vagy a cardiovascularis betegség tekintetében nagy kockázatú betegek
esetében |
|
| 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. |
Cardiovascularis betegségben szenvedő, vagy a cardiovascularis
betegség tekintetében nagy kockázatú betegek, akik nem szedhetnek
statint. |
|
| 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 |
|
| 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 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. |
|
| 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 (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 |
|
| 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 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 LDLC-
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 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 or angiogram
(including CTA) showing ≥50% stenosis, (ankle brachial index will be
measured after a period of rest and with the patient in the supine position using a Doppler device) 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
b High risk for a CVD event (ie, high-risk primary prevention):
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, or
o Patients with type 1 or type 2 diabetes, aged >65 years (women) or
>60 years (men) |
|
| 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 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 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,(must be stable at least 4 weeks prior to Week -5 [Visit S1])
• Other lipid regulating drugs or supplements (must be stable at least 4 weeks prior to Week -5 [Visit S1])
• PCSK9 inhibitors (must be stable at least 12 weeks prior to Week -5 [Visit S1])
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.
21. Pregnant, breastfeeding, or intending to become pregnant within 30 days after study completion or last dose of IMP. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Time to first occurrence of a confirmed MACE. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| MACE is defined as CV death, nonfatal MI, nonfatal stroke, or coronary revascularization. |
|
| E.5.2 | 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) |
|
| E.5.2.1 | 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. |
|
| 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 | 55 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 400 |
| 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 |
| Canada |
| Chile |
| Colombia |
| India |
| Mexico |
| New Zealand |
| South Africa |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Austria |
| Belgium |
| Bulgaria |
| Croatia |
| Czechia |
| Denmark |
| Estonia |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Netherlands |
| Poland |
| Romania |
| Slovakia |
| Spain |
| United Kingdom |
|
| 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 all of the following have occurred:
1) at least 1,620 patients have experienced an adjudicated primary 4 component MACE,
2) at least 810 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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