E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of high cardiovascular risk patients (heterozygous familial hypercholesterolemia [HeFH] and atherosclerotic cardiovascular diseases [ASCVD]) with hyperlipidemia |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of hyperlipidemia; a condition where there is an excess of lipids (fats e.g. cholesterol ) in the blood, in patients with a high risk of developing heart problems. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
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 | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 100000004861 |
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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 | 10020667 |
E.1.2 | Term | Hyperlipidemia |
E.1.2 | System Organ Class | 100000004861 |
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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 | 10051615 |
E.1.2 | Term | Atherosclerotic cardiovascular disease |
E.1.2 | System Organ Class | 100000004866 |
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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 | 10057079 |
E.1.2 | Term | Heterozygous familial hypercholesterolemia |
E.1.2 | System Organ Class | 100000004850 |
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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 the long-term safety and tolerability of ETC-1002 versus placebo in high cardiovascular (CV) risk patients with hyperlipidemia (with underlying HeFH and/or ASCVD) who are not adequately controlled with their maximally tolerated lipid-modifying therapy. |
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E.2.2 | Secondary objectives of the trial |
To assess percent change from baseline to Week 12 in LDL-C |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each patient with hyperlipidemia must meet the following criteria to be
randomized in this study:
1. Age ≥18 years or legal age of majority based on regional law, whichever is greater at Week -2 (Visit S1)
2. Men and nonpregnant, nonlactating women. Women must be either:
• Naturally postmenopausal (as reported by the patient, defined as greater than 55 years and ≥1 year without menses, less than 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 1 acceptable method of birth control. The minimal requirement for adequate contraception 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 the study drug. Acceptable methods of birth control include: oral 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 (not including periodic abstinence such as calendar, ovulation, symptothermal, postovulation methods, or withdrawal).
•There are no protocol-specific birth control requirements for men with partners who are able to become pregnant.
3. Fasting LDL-C value at Week -2 (Visit S1) ≥70 mg/dL (1.8 mmol/L). Note: LDL-C may be repeated 1 time with the screening period extended up to 2 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. Have high cardiovascular 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 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 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):
- Acute myocardial infarction (MI)
- Silent MI
- Unstable angina
- Coronary revascularization procedure (eg, percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery)
- 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):
- Peripheral arterial disease
- Previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, considered as being of atherothrombotic origin. Computed tomography (CT) or magnetic resonance imaging (MRI) must have been performed to rule out hemorrhage and non- ischemic neurological disease
Note: Patients with type 2 diabetes mellitus (T2DM) are allowed in this study; however for this study T2DM is not considered a CHD risk equivalent
5. Be on maximally tolerated lipid-modifying therapy, including a maximally tolerated statin either alone or in combination with other lipid-lowering therapies, at stable doses for at least 4 weeks prior to screening (6 weeks for fibrates; however, gemfibrozil is not allowed).
Regimens other than daily dosing, including those at very low doses, are acceptable.
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.
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E.4 | Principal exclusion criteria |
1. Total fasting triglyceride ≥500 mg/dL (5.6 mmol/L) at Wk -2 (Visit S1)
2. Renal dysfunction or nephritic syndrome or a history of nephritis, including eGFR (using central laboratory determined MDRD formula) <30 mL/min/1.73m2 at Wk -2 (Visit S1). Note: Also excluded are renally impaired patients receiving an average dose of simvastatin 40 mg with eGFR below <45 mL/min/1.73m2.
3. BMI ≥50 kg/m2
4. Concomitant use of simvastatin at average daily doses greater than 40 mg.
5. Concomitant use of a PCSK inhibitor (alirocumab or evolocumab) at Wk -2 (Visit S1) or prior use of a PCSK9 inhibitor within the past 4 weeks of Wk -2 (Visit S1) will be excluded from this study.
6. Recent (within 3 months prior to the screening visit [Wk -2 (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, 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.
7. Uncontrolled hypertension, defined as sitting SBP ≥160 mmHg and DBP ≥100 mmHg after sitting quietly for 5 minutes.
8. HbA1C ≥10% at Wk -2 (Visit S1)
9. Uncontrolled hypothyroidism, including TSH >1.5 × ULN at Wk -2 (Visit S1). Patients stabilized on thyroid replacement therapy for at least 6 wks prior to randomization are allowed.
10. Liver disease or dysfunction, including:
•Positive serology for HBsAg and/or HCV AB at Wk -2 (Visit S1); or
•ALT, AST ≥2 × ULN, and/or total bilirubin ≥1.2 × ULN at Wk -2 (Visit S1).
Note: If HCV AB is positive, a reflex HCV RNA will be performed to rule out active disease. Patients without active disease may be enrolled the study.
If TB ≥1.2 × ULN, a reflex indirect (unconjugated) bilirubin will be obtained and if consistent with Gilbert’s disease, the patient may be enrolled in the study.
11. GI conditions or procedures (including weight loss surgery; eg, Lap- Band® or gastric bypass) that may affect drug absorption
12. Hematologic or coagulation disorders or a Hgb level <10.0 g/dL (100 g/L) at Wk -2 (Visit S1)
13. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 5 yrs. Patients with a history of nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed).
14. 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.
15. History within the last 2 yrs 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.
16. Blood donation, blood transfusion for any reason, participation in a clinical study with multiple blood draws, major trauma, or surgery with or without blood loss within 30 days prior to randomization
17. Use of any experimental or investigational drugs within 30 days prior to screening or 5 half-lives, whichever is longer
18. Prior participation in a previous ETC 1002 clinical study. Prior participation in a clinical study with ETC 1002 is defined as having been enrolled in an ETC 1002 study.
19. Use of any of the following drugs within 3 months prior to screening or a plan to use these drugs during the study;
•New or planned dose changes of systemic corticosteroids
•Requirement for mipomersen or lomitapide or apheresis therapy
20. Planned initiation of the following drugs during the clinical trial or changes to the following drugs prior to randomization:
•Hormone replacement (6 wks prior to randomization)
•Thyroid replacement (6 wks prior to randomization)
•Diabetes medications (4 wks prior to randomization)
•Obesity medication (3 months prior to randomization)
21. An employee or contractor of the facility conducting the study, or a family member of the PI, Co-I, or Sponsor
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for this study is general safety, which includes AEs, clinical safety laboratories, PEs, vital signs, and ECGs. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•No statistical analyses will be performed on any of the safety data in this study.
•TEAEs and SAEs and MACE will be collected as they occur.
•Clinical safety laboratories; PE findings; vital signs; ECG readings; and weight will be recorded at baseline and each postbaseline time point (treatment visit - every 4 weeks then every 12 weeks), as will liver associated enzymes and total bilirubin..
•Creatinine kinase levels and eGFR (as measures of muscoskeletal and renal safety) will be recorded at baseline and each visit. |
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E.5.2 | Secondary end point(s) |
Percent change from baseline to Week 12 in LDL-C |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Netherlands |
Poland |
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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As per Protocol: The study will end when the last randomized patient completes 52 weeks of treatment (last patient last visit [LPLV] for last randomized patient). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |