| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cardiovascular Disease or at High Risk for Cardiovascular Disease |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020870 |
| E.1.2 | Term | Hypertriglyceridemia |
| E.1.2 | System Organ Class | 100000004861 |
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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, in patients at low-density lipoprotein
cholesterol (LDL-C) goal while on statin therapy, with established
cardiovascular disease (CVD) or at high risk for CVD, and
hypertriglyceridemia (fasting triglycerides [TG] ≥200 mg/dL and <500
mg/dL [≥2.26 mmol/L and <5.64 mmol/L]), to evaluate the effect of 4
g/day AMR101 on the time from randomization to first occurrence of any
component of the composite of the following major cardiovascular (CV)
events:
• CV death;
• Nonfatal myocardial infarction (MI), (including silent MI;
electrocardiograms [ECGs] will be performed annually for the detection
of silent MIs);
• Nonfatal stroke;
• Coronary revascularization; or
• Unstable angina determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent hospitalization. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are the following:
The key secondary objective is to evaluate the effect of therapy on the
time from randomization to the first occurrence of the composite of CV
death, nonfatal MI (including silent MI), or nonfatal stroke.
Other secondary objectives for this study are to evaluate the effect of
therapy on time from randomization to the first occurrence of:
• Composite of CV death or nonfatal MI (including silent MI);
• Fatal or nonfatal MI (including silent MI);
• Non-elective coronary revascularization represented as the composite
of emergent or urgent classifications;
• CV death;
• Unstable angina determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent hospitalization;
• Fatal or nonfatal stroke;
• Composite of total mortality, nonfatal MI (including silent MI), or
nonfatal stroke;
• Total mortality. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Fasting TG levels of ≥200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L).
2.LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stable therapy with a statin (with or without ezetimibe) for at least 4 weeks prior to the LDL-C/TG baseline qualifying measurements for randomization
•Stable therapy is defined as the same daily dose of the same statin for at least 28 days before the lipid qualification measurements (TG and LDL-C) and, if applicable, the same daily dose of ezetimibe for at least 28 days before the lipid qualification measurements (TG and LDL-C). Patients who have their statin therapy or use of ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose changed at Visit 1, will need to go through a stabilization period of at least 28 days since initiation/change and have their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1).
•Statins may be administered with or without ezetimibe.
3.Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV Risk Category 2). The CV risk categories are defined as follows:
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of the following:
o Documented coronary artery disease (CAD; one or more of the following primary criteria must be satisfied):
•Documented multi vessel CAD (>50% stenosis in at least two major epicardial coronary arteries – with or without antecedent revascularization);
•Documented prior MI;
•Hospitalization for high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) (with objective evidence of ischemia: ST-segment deviation or biomarker positivity).
o Documented cerebrovascular or carotid disease (one of the following primary criteria must be satisfied):
•Documented prior ischemic stroke;
•Symptomatic carotid artery disease with ≥50% carotid arterial stenosis;
•Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per angiography or duplex ultrasound;
•History of carotid revascularization (catheter-based or surgical).
o Documented peripheral arterial disease (PAD; one or more of the following primary criteria must be satisfied):
•Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication;
•History of aorto-iliac or peripheral arterial intervention (catheter-based or surgical).
OR
CV Risk Category 2: defined as patients with:
1.Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND
2.Men and women ≥50 years of age AND
3.One of the following at Visit 1 (additional risk factor for CVD):
•Men ≥55 years of age and Women ≥65 years of age;
•Cigarette smoker or stopped smoking within 3 months before Visit 1;
•Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) or on antihypertensive medication;
•HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women;
•Hs-CRP >3.00 mg/L (0.3 mg/dL);
•Renal dysfunction: Creatinine clearance (CrCL) >30 and <60 mL/min (>0.50 and <1.00 mL/sec);
•Retinopathy, defined as any of the following: non-proliferative retinopathy, pre-proliferative retinopathy, proliferative retinopathy, maculopathy, advanced diabetic eye disease or a history of photocoagulation;
•Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive micral or other strip test (may be obtained from medical records), an albumin/creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed collection ≥20 mg/min all on at least two successive occasions; macroalbuminuria, defined as Albustix or other dipstick evidence of gross proteinuria, an albumin/creatinine ratio ≥25 mg/mmol or an albumin excretion rate on timed collection ≥200 mg/min all on at least two successive occasions;
•ABI <0.9 without symptoms of intermittent claudication (patients with ABI <0.9 with symptoms of intermittent claudication are counted under CV Risk Category 1).
Note: Patients with diabetes and CVD as defined above are eligible based on the CVD requirements and will be counted under CV Risk Category 1. Only patients with diabetes and no documented CVD as defined above need at least one additional risk factor as listed, and will be counted under CV Risk Category 2.
4.Women may be enrolled if all 3 of the following criteria are met:
•They are not pregnant;
•They are not breastfeeding;
•They do not plan on becoming pregnant during the study.
5.Women of child-bearing potential must have a negative urine pregnancy test before randomization.
Note: Women are not considered to be of childbearing potential if they meet one of the following criteria as documented by the investigator:
Due to character limitations within the field, please see the protocol for a complete list of inclusion criteria. |
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| E.4 | Principal exclusion criteria |
1.Severe (New York Heart Association [NYHA] class IV) heart failure.
2.Any life-threatening disease expected to result in death within the next 2 years (other than CVD).
3.Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN), or biliary obstruction with hyperbilirubinemia (total bilirubin >2 × ULN).
4.Hemoglobin A1c >10.0% (or 86 mmol/mol IFCC units) at screening (Visit 1). If patients fail this criterion (HbA1c >10.0% or 86 mmol/mol IFCC units) at Visit 1, they may have their antidiabetic therapy optimized and be retested at Visit 1.1.
5.Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg diastolic (despite antihypertensive therapy).
6.Planned coronary intervention (such as stent placement or heart bypass) or any non-cardiac major surgical procedure. Patients can be (re)evaluated for participation in the trial (starting with Visit 1.1) after their recovery from the intervention/surgery.
7.Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)].
8.Participation in another clinical trial involving an investigational agent within 90 days prior to screening (Visit 1). Patients cannot participate in any other investigational medication or medical device trial while participating in this study (participation in a registry or observational study without additional therapeutic intervention is allowed).
9.Intolerance or hypersensitivity to statin therapy.
10.Known hypersensitivity to any ingredients of the study product or placebo (refer to Table 5); known hypersensitivity to fish and or shellfish.
11.History of acute or chronic pancreatitis.
12.Malabsorption syndrome and/or chronic diarrhea. (Note: patients who have undergone gastric/intestinal bypass surgery are considered to have malabsorption, hence are excluded; patients who have undergone gastric banding are allowed to enter the trial).
13.Non-study drug related, non-statin, lipid-altering medications, supplements or foods:
•Patients are excluded if they used niacin >200 mg/day or fibrates during the screening period (after Visit 1) and/or plan to use during the study; patients who are taking niacin >200 mg/day or fibrates during the last 28 days before Visit 1 need to go through washout of at least 28 days after their last use and have their qualifying lipids measured (TG and LDL-C) after the washout period (Visit 1.1);
•Patients are excluded if they take any omega-3 fatty acid medications (prescription medicines containing EPA and/or docosahexaenoic acid [DHA]) during the screening period (after Visit 1) and/or plan to use during the treatment/follow-up period of the study. To be eligible for participation in the study, patients who are taking omega-3 fatty acid medications during the last 28 days before Visit 1 (except patients in the Netherlands), need to go through a washout period of at least 28 days after their last use and have their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1);
o For patients in the Netherlands only: patients being treated with omega-3 fatty acid medications containing EPA and /or DHA are excluded; no washout is allowed.
•Patients are excluded if they use dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) and/or plan to use during the treatment/follow-up period of the study. To be eligible for participation in the study, patients who are taking >300 mg/day omega-3 fatty acids (combined amount of EPA and DHA) within 28 days before Visit 1 (except patients in the Netherlands), need to go through a washout period of at least 28 days since their last use and have their qualifying lipid measurements measured (TG and LDL-C) after the washout period (at Visit 1.1);
o For patients in the Netherlands only: patients being treated with dietary supplements containing omega-3 fatty acids of >300 mg/day EPA and/or DHA are excluded; no washout is allowed.
Due to character limitations within the field, please see the protocol for a complete list of exclusion criteria
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time from randomization to the first occurrence of any component of the composite of the following clinical events:
• CV death;
• Nonfatal MI (including silent MI; ECGs will be performed annually for the detection of silent MIs);
• Nonfatal stroke;
• Coronary revascularization;
• Unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first occurance of any of these major adverse vascular events during the follow-up period of the study will be included in the incidence. |
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| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the time from randomization to the first occurrence of the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke.
Other secondary efficacy endpoints are time from randomization to the first occurrence of the individual or composite endpoints as follows (to be tested in the order listed):
• Composite of CV death or nonfatal MI (including silent MI);
• Fatal or nonfatal MI (including silent MI);
• Non-elective coronary revascularization represented as the composite of emergent or urgent classifications;
• CV death;
• Unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization;
• Fatal or nonfatal stroke;
• Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke;
• Total mortality. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the secondary efficacy endpoints that count a single event, the time from randomization to the first occurrence of this type of event will be counted for each patient. For secondary efficacy endpoints that are composites of two or more types of events, the time from randomization to the first occurrence of any of the event types included in the composite will be counted for each patient.
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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 | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Australia |
| Canada |
| European Union |
| India |
| New Zealand |
| Russian Federation |
| South Africa |
| Ukraine |
| 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
|
All patients will complete the study at the same time (within a target of 30 days after the study end date), irrespective of the date that they were randomized. The end date of the study is
planned for Day 2160 but the actual end date will be dependent on the determination of the study end date by the DSMB when approximately 1612 primary efficacy events have been adjudicated (event-driven trial). |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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