Primary ObjectiveThe primary objective is to evaluate the effectiveness of adding Epanova to statin therapy (with or without ezetimibe) for lowering MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, emergent/elective…
ID
Source
Brief title
Condition
- Heart failures
- Lipid metabolism disorders
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is the time to first occurrence of any component of
the composite of MACE: cardiovascular death, nonfatal MI, nonfatal stroke,
emergent/elective coronary revascularization, or hospitalization for unstable
angina. Patients will remain in the study until the required number of patients
with MACE has occurred.
Secondary outcome
KEY Secondary outcome measures include:
* The composite measure of CV events that include the first occurrence of
cardiovascular death, non-fatal MI, and non-fatal stroke.
* The composite measure of coronary events that include the first occurrence of
cardiovascular death ((including death due to acute myocardial infarction,
sudden cardiac death and death due to cardiovascular procedures), non-fatal MI,
emergent/elective coronary revascularization, or hospitalization for unstable
angina.
* Time to CV Death
Other Secondary outcome measures include:
a) Emergent/elective coronary revascularization
b) Hospitalization for unstable angina
c) Fatal or non-fatal MI
d) Non-fatal MI
e) Fatal or non-fatal stroke
f) Non-fatal stroke
g) All-cause death
Background summary
Few prospective studies have explicitly examined the predictive CVD risk of
non-HDL-C levels versus LDL-C levels in persons with hypertriglyceridemia,
however, several lines of evidence favor use of non-HDL-C over LDL-C in
clinical evaluation of risk.
In patients with hypertriglyceridemia, non-HDL-C goals are frequently not
achieved. In order to reduce non-HDL-C in patients with hypertriglyceridemia,
combination therapy with statins is frequently necessary to maximize goal
achievement. The National Cholesterol Education Program (NCEP) panel recognized
that statins are not powerful TG-lowering drugs, and therefore recommended the
use of specific add-on therapies to lower TG levels in patients with
hypertriglyceridemia (fish oils to replace some long-chain TG levels in diet,
as well as fibrates or nicotinic acid).
There are no long-term CV outcomes studies that specifically assess the impact
of adding omega-3 fatty acids to statins in reducing the risk of cardiovascular
events associated with persistent hypertriglyceridemia. The current protocol
will investigate the effectiveness of adding Epanova to statin, with or without
ezetimibe, as needed, for lowering MACE (cardiovascular death, nonfatal MI,
nonfatal stroke, emergent/elective
coronary revascularization, or hospitalization for unstable angina) in patients
with persistent hypertriglyceridemia and high risk for CVD.
Study objective
Primary Objective
The primary objective is to evaluate the effectiveness of adding Epanova to
statin therapy (with or without ezetimibe) for lowering MACE (cardiovascular
death, nonfatal myocardial infarction, nonfatal stroke, emergent/elective
coronary revascularization, or hospitalization for unstable angina) in high
cardiovascular risk patients with persistent hypertriglyceridemia and low HDL-
cholesterol (HDL-C).
Study design
The study is a randomized, double-blind, placebol-controlled (corn oil),
parallel group design that will enroll approximately 13,000 patients with
hypertriglyceridemia and at high risk for CVD. Patients will be randomized to
either Epanova or placebo (corn oil), administered once daily, for
approximately 3-5 years as determined by the number of patients with MACE.
There will be up to 3 screening/washout visits, depending on the need for a
repeat lab for statin/ezetimibe adjustment, discontinuation of excluded
lipid-modifying agent, or a borderline TG and/or highdensity
lipoprotein (HDL-C) value. During the screening period, patients will maintain
a stable diet, and after randomization, patients must be willing to adhere to
the National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes
(TLC) or equivalent diet. During the
screening period, and thereafter, patients will not be permitted to use any
excluded therapies or products, and will continue or adjust their prescribed
statin regimen. Patients who meet all Inclusion Criteria and no Exclusion
Criteria will be randomized 1:1 (6,500/arm) to receive double-blinded Epanova
(4 g daily) or a matching placebo (corn oil) control (4 g daily) for the study
duration. The randomization visit will be Month 0 and there will be 11
treatment visits at Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60. There
will be a 3-week follow-up visit after an early termination (ET) visit for
those patients who undergo early permanent IP discontinuation due to a serious
adverse event (SAE).
Intervention
Patients will be randomized 1:1 (6,500/arm) to receive double-blinded Epanova
(4 g daily) or a matching corn oil control (4 g daily) for the study
duration.
* Epanova (omega-3 carboxylic acids) capsules: 4 g (four 1-gram capsules)
orally, once
daily for the duration of the study.
* Control (corn oil) capsules: 4 g (four 1-gram capsules) orally, once daily
for the duration
of the study.
* Statins will be prescribed by the investigator or patient*s health care
provider.
Study burden and risks
Subject participation in the study will be approximately 3-5 years. The exact
duration of the study will be determined during the study, but will not be
longer than 5 years.
Subjects are asked to take either Epanova® (4 g per day) or corn oil (4 g per
day), once daily with his/her prescribed statin treatment orally.
Subjects participating in this study are expected to visit the study center 13
times. Until visit 4, the subject is expected to come every 4 months. The
subject will only have to come to the study center every 6 months from visit 4
onwards. The subject will be contacted by phone between visits to assess how
they are doing. At month 60 (or whenever the subject stops the study
medication), he/she will have an end of treatment or Early Termination visit.
While participating in the study, the subject will be asked to follow a diet
called the National Cholesterol Education Program (NCEP) Therapeutics
Lifestyles Changes (TLC) diet or an equivalent diet. Some medications and
dietary products are prohibited while on the study. The subject will need to
stop taking any medication (apart from statins) that lower his/her triglyceride
levels during the study starting during the screening period.
For some of the blood tests, it is recommended that the subject fasts for at
least 9 to 14 hours before coming to the study center. This involves visits 1,
2,, 5, 7, 9, 11 and 13.
Female patients of child-bearing potential must agree to use effective
contraception. Effective contraception must also be used for 14 days after
stopping the study. There are no restrictions against fathering a child when
treated with Epanova®.
There may be risks involved in taking this study drug (for side effects see E9)
that have (not) been identified in the studies completed so far.
Taking part in this study does not guarantee that the subject will receive any
medical benefit. However the subjects cardiovascular risk may be reduced as a
result of taking part in this study. The close medical attention the subject
gets during the study may result in him/her gaining new information about
his/her health which may provide benefits for his/her general health and
well-being.
Benefits: The beneficial effects of omega-3 fatty acids in fish oil
formulations are associated with lowering of serum triglycerides.
Please also see the benefits and risks assessment document.
Pepparedsleden 1
Mölndal 431 83
SE
Pepparedsleden 1
Mölndal 431 83
SE
Listed location countries
Age
Inclusion criteria
1. Men or women, *18 years of age.
2. Patient must be on a stable diet and statin* therapy at least 4 weeks prior to randomization
(Visit 2) and meet the following criteria, where the qualifying lipid parameters should be obtained from the same visit:
a. LDL-C <100 mg/dL (<2.59 mmol/L). Patient will also qualify if LDL-C *100 mg/dL
(*2.59 mmol/L) and if on a high-intensity or maximally tolerated moderate- or lowintensity
statin dose, with or without ezetimibe therapy, for at least 4 weeks (see
Appendix D). The maximum tolerated dosage of a statin is defined as the approved dose
per local label that the patient can tolerate without unacceptable adverse effects such as
muscle aches/pain/weakness or elevations in liver enzymes or creatine kinase (CK) that
are determined by the investigator to be clinically relevant and due to statin therapy.
b. TG *180 and < 500 mg/dL (*2.03 and < 5.65 mmol/L) and HDL-C
<42 mg/dL (1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22 mmol/L)
for women.
3. Patient is at high risk for a future cardiovascular event if at least one of the following criteria
(3a, 3b or 3c)* is present via patient history, physical exam, or medical records at the time of
screening:
a. Any atherosclerotic CVD as defined by one or more of the following:
* previous clinical myocardial infarction (MI) *30 days prior to randomization
* percutaneous coronary intervention (PCI) including balloon angioplasty and
coronary stenting * 6 months prior to randomization
* coronary artery bypass grafting (CABG) *30 days prior to randomization
* coronary angiogram including computed tomography angiogram (CTA)
showing<=> 50% stenosis in at least one native or graft
vessel
* anginal symptoms with a defect documented by stress testing with nuclear perfusion
imaging or a wall motion abnormality determined by stress echocardiogram
* asymptomatic coronary ischemia documented by stress testing with nuclear
perfusion imaging or by stress echocardiogram
* peripheral vascular disease with symptoms of claudication and ankle brachial index
<0.9 performed by a vascular lab or angiogram (including CTA) showing <=> 50% stenosis)
* history of peripheral arterial revascularization (surgical or percutaneous) *30 days
prior to randomization
* carotid endarterectomy, carotid stenting or more than or equal to 50% stenosis in a carotid artery
determined by carotid ultrasound or angiogram *30 days prior to randomization
* history of abdominal aortic aneurysm confirmed by imaging, diagnosed *30 days prior to randomization
* ischemic stroke *30 days prior to randomization
* coronary calcium score >300 Agatston units (AU).
b. History of diabetes mellitus (type 1 or 2) and *40 years of age for men and *50 years of
age for women, plus one of the following risk factors:
* chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
* history of hypertension (blood pressure >140/90 mm Hg) or taking antihypertensive
medication
* high-sensitivity C-reactive protein (hs-CRP) > 2.0 mg/L (19.05 nmol/L) determined
at Visit 1
* history of albuminuria (urinary albumin:creatinine ratio [ACR] >30 mg/g).
c. Male patients >50 years of age or females >60 years of age, with at least one of the
following risk factors:
* family history (mother, father or sibling) of premature coronary heart disease (father or brother <55 years of age, mother or sister <65 years of age)
* chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
* hs-CRP >2.0 mg/L (19.05 nmol/L) determined at Visit 1
* impaired renal function as estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for glomerular filtration rate (eGFR) <45 mL/min per 1.73 m2
(patients on dialysis are excluded).
* coronary calcium score >300 Agatston units (AU) at any time in the past.
*If patient will meet CVD secondary prevention criteria (3a) AND primary prevention
criteria (3b and/or 3c) at the same time, then patient will be considered as meeting CVD
secondary prevention criteria (3a) for the purpose of identifying the inclusion criteria for
that patient.
4. Patient must have been on a stable diet prior to randomization and willing to follow the
NCEP TLC diet, or equivalent diet, throughout the study.
Note a) A patient can, in specific circumstances, be re-screened. For
details, see section 6.4. of the protocol.
Exclusion criteria
1. Allergy or intolerance to omega-3 carboxylic acids, omega-3 fatty acids, omega-3-acid ethyl
esters, or corn oil.
2. Known hypersensitivity to fish and/or shellfish
3. Use of fibrates, bile acid sequestrants, or niacin or its analogues (>250 mg/day) within 4
weeks prior to Visit 2. Patients taking these agents may be considered for inclusion in the
study if these therapies have been discontinued for 4 weeks or more prior to Visit 2.However,
niacin or its analogues at a dose less than or equal to 250 mg/day is
permissible.
4. Statin naïve at Visit 1.
5. Use of simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg within 4 weeks prior to Visit 2.
Patients taking these agents may be considered for inclusion in the study if these therapies
have been discontinued and replaced with a protocol acceptable statin treatment that is
stabilized for 4 weeks or more prior to Visit 2.
6. Use of any prescription medications containing eicosapentaenoic acid (EPA) and/or
docosahexaenoic acid (DHA), e.g. Lovaza® or Vascepa®, within 4 weeks prior to Visit 2.
Patients taking these agents may be considered for inclusion in the study if these therapies have been discontinued for 4 weeks or more prior to Visit 2.
7. More than one capsule/day (any dose) of omega-3 dietary
supplements. Patients taking >1 capsule/day of omega-3 supplements
before Visit 1 DO NOT require a washout period but must agree to
reduce the number of capsules per day to no more than 1 capsule of 1 g
promptly after signing the informed consent. No new omega-3
supplements are permitted following initiation of screening procedures
at Visit 1.
8. Use of prescription or over-the-counter (OTC) weight loss drugs at any time after Visit 1.
9. Chronic use of oral corticosteroids during screening (acute use for inflammation for example
from poison ivy, or intranasal or inhaled steroids for allergies/asthma, or intraarticular
injections are allowed).
10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for >4
weeks at Visit 1, or is unstable prior to Visit 2.
11. Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II deficiency.
12. Hemoglobin A1c (Hb A1c) >12% at Visit 1.
13. Poorly controlled hypertension (resting blood pressure *180 mm Hg systolic and/or *100
mm Hg diastolic) at two consecutive visits prior to randomization at Visit 2.
14. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 times upper limit
of normal (ULN) at Visit 1. Patients who are clinically euthyroid, on stable thyroid
replacement therapy for 2 months prior to Visit 1 are allowed.
15. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within
the previous two years.
16. Patients on dialysis.
17. Females who are pregnant, planning to be pregnant during the study period, lactating, or
women of childbearing potential who are not using an acceptable method of contraception. A
woman is considered of childbearing potential if she is not surgically sterile or if her last
menstrual period was <12 months prior to Visit 1. Acceptable methods of contraception for
this study include use of double barrier contraception, intrauterine device, all
oral, patch, etc. hormonal contraceptives as long as dose and type is stable for 3 months prior
to Visit 1. In addition, true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject.
18. Creatine kinase >5.0 times ULN; aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) >3.0 times ULN; or total bilirubin (TBL) >2.0 times ULN (except
with a confirmed diagnosis of Gilbert*s disease), at Visit 1. A diagnosis of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with stable elevations
of AST and/or ALT (>3.0 times ULN) is eligible for participation in the study.
19. Excessive use of alcohol or other substance abuse that in the investigator*s opinion would
jeopardize the patient*s participation in the study or interpretation of the data.
20. Exposure to any investigational agent within 4 weeks prior to Visit 1, including
randomization in this study.
21. Previous clinical myocardial infarction (MI) <30 days prior to
randomization
22. Percutaneous coronary intervention (PCI) including balloon
angioplasty and coronary stenting<6 months prior to randomization
23. Coronary artery bypass grafting (CABG) <30 days prior to
randomization
24. History of peripheral arterial revascularization (surgical or
percutaneous) <30 days prior to randomization
25. Carotid endarterectomy or more than or equal to 50% stenosis in a
carotid artery determined by carotid ultrasound or angiogram <30 days
prior to randomization
26. History of abdominal aortic aneurysm diagnosed <30 days prior to
randomization
27. Ischemic stroke <30 days prior to randomization
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001069-28-NL |
| ClinicalTrials.gov | NCT02104817 |
| CCMO | NL47269.068.14 |