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Clinical Trials: Prevention of Cardiovascular Events: Study Demographics and Trial Design: The REDUCE-IT study was a double-blind, randomized, placebo-controlled trial in 8,179 statin-treated adult patients with elevated serum triglyceride (TG) levels (≥1.5 mmol/L and <5.6 mmol/L) who were also at high risk for atherothrombotic events. Patients either had established cardiovascular disease (CVD) (70.7%), define as the secondary prevention cohort, or were at high risk for CVD (29.3%), defined as primary prevention cohort. Patients with established cardiovascular disease were at least 45 years of age and having a documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease. Patients with other risk factors for cardiovascular disease were at least 50 years of age and had diabetes and at least one additional major cardiovascular risk factor. Patients were randomly assigned 1:1 to receive either VASCEPA at 4 grams daily, given as two 1 gram capsules twice a day with food, or placebo. The median follow-up duration was 4.9 years. Overall, 99.8% of patients were followed for vital status until the end of the trial or death.
At baseline, the median age was 64 years (range: 44 years to 92 years), with 46% being at least 65 years old, and 28.8% women. The trial population was 90.2% White, 5.5% Asian, 1.9% Black, and 4.2% were identified as of Hispanic ethnicity.
Patients enrolled in the trial included 46.7% who had prior myocardial infarction, 9.2% who had symptomatic peripheral arterial disease, and 6.2% who had prior ischemic stroke, and 4.6% who had prior transient ischemic attack (TIA). Additional baseline risk factors included hypertension (86.6%), diabetes mellitus (58.5%), eGFR <60 mL/min/1.73 m2 (22.2%), congestive heart failure (17.7%), and current daily cigarette smoking (15.2%). Most patients at baseline were taking at least one other cardiovascular medication including anti-hypertensives (95%), anti-platelet agents (79.4%), beta blockers (70.7%), angiotensin-converting enzyme (ACE) inhibitors (51.9%), and angiotensin receptor blockers (ARB) (27.0%), with 77.5% taking either an ACE inhibitor or ARB.
At baseline, while on stable background lipid-lowering therapy, the median LDL-C was 1.9 mmol/L, while the median fasting serum TG was 2.4 mmol/L. Baseline TG levels ranged from 0.92 to 15.8 mmol/L.
Study Results: The primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) occurred at an event rate of 4.3 per 100 patient-years in patients treated with VASCEPA, compared to 5.7 per 100 patient-years in patients treated with placebo (p<0.0001), while the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke) occurred at an event rate of 2.7 per 100 patient-years in patients treated with VASCEPA, compared to 3.7 per 100 patient-years in patients treated with placebo (p<0.0001).
The results of the primary and secondary efficacy endpoints are shown in Table 1 as follows, while the Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 as follows. (See Table 1 and Figures 1 and 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe median difference between VASCEPA and placebo in TG from baseline to Month 4 was -20.1% (p<0.001), and from baseline to Month 12 was -19.7% (p<0.001), in favour of VASCEPA. At Month 12, the median TG was 2.0 mmol/L in the VASCEPA group, with 35.9% of patients with available measurements having TG <1.7 mmol/L and 61.3% having a TG <2.3 mmol/L. Prespecified analyses of the effect of VASCEPA on cardiovascular outcomes in the REDUCE-IT trial failed to demonstrate a correlation between triglyceride response and cardiovascular effect based on baseline triglyceride levels or on-treatment change in triglyceride levels.
The median difference between VASCEPA and placebo in LDL-C from baseline to Month 12 was -6.6% (p<0.001), in favour of VASCEPA. At Month 12, the median LDL-C was 2.0 mmol/L in the VASCEPA group, with 35.5% with available measurements of patients having LDL-C <1.8 mmol/L and 79.9% having LDL-C <2.6 mmol/L.
Pharmacokinetics: Absorption: After oral administration, VASCEPA is de-esterified during the absorption process and the active metabolite icosapentaenoic acid is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of icosapentaenoic acid were reached approximately 5 hours following oral doses of VASCEPA.
Distribution: The mean volume of distribution at steady-state of icosapentaenoic acid is approximately 88 litres. The majority of icosapentaenoic acid circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified icosapentaenoic acid is bound to plasma proteins.
Metabolism: Icosapentaenoic acid is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of icosapentaenoic acid into acetyl Coenzyme A, which is converted into energy via the Krebs cycle.
Elimination: Cytochrome P450-mediated metabolism is a minor pathway of elimination of icosapentaenoic acid. The total plasma clearance of icosapentaenoic acid at steady-state is 684 mL/hr. The plasma elimination half-life (t1/2) of icosapentaenoic acid is approximately 89 hours. VASCEPA does not undergo renal excretion.
Special Populations and Conditions: Pediatrics: The pharmacokinetics of VASCEPA has not been studied in pediatric patients.
Sex: When administered VASCEPA in clinical trials, plasma total icosapentaenoic acid concentrations did not differ significantly between men and women.
Hepatic Insufficiency: VASCEPA has not been studied in patients with hepatic impairment.
Renal Insufficiency: VASCEPA has not been studied in patients with renal impairment.
Toxicology: Non-clinical Toxicology: General Toxicology: In a 39-week dog study, icosapent ethyl was administered to beagle dogs at doses of 0.3, 1 or 2 g/kg/day. Expected pharmacological changes in plasma lipid concentrations (lower total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides) were observed at all dose levels. At doses ≥1 g/kg/day, there were increases in alkaline phosphatase and aspartate aminotransferase levels. Vacuolar degeneration of the adrenal glands followed a dose-related pattern. The NOAEL is 0.3 g/kg/day (2.5 times the 4 g/day clinical dose based on a body surface area comparison, for a 60 kg human).
Carcinogenicity: In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, a significant treatment-related increase in mortality was observed in females. Anterior lobe pituitary adenoma was the most frequent cause of death in females treated with the highest dose who died prematurely. There was a statistically significant dose-related increase in hemangiomas of the mesenteric lymph node, the site of drug absorption, in males and females. Incidence in mid-dose females was higher than in controls at an exposure 2.7 times the exposure at the clinical dose of 4 g/day (based on AUC), whereas incidence in treated males was higher than in controls only at the highest dose level, at which exposure is 6.8 times the clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.
In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail were observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.
Genotoxicity: Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay. A chromosomal aberration assay in Chinese Hamster Ovary cells was positive for clastogenicity with and without metabolic activation, but icosapent ethyl did not induce micronuclei in vivo in mice.
Reproductive and Developmental Toxicology: Only one full study report compliant with Good Laboratory Practices was submitted. In that study, icosapent ethyl was given by oral gavage to female rats from gestation day 6 to 16 at doses of 0.3, 1.0 or 2.0 g/kg/day. Minor abnormalities included 13th reduced ribs, additional liver lobes, and testes medially displaced or not fully descended in the treated groups, including at the lowest dose of 0.3 g/kg/day equivalent to 0.7 times the recommended dose of 4 g/day of icosapent ethyl in a 60 kg human based on body surface area comparisons.
Concerning fertility in male and female rats, oral gavage of EPA ethyl ester at doses of 0.3, 1.0 or 3.0 g/kg/day for 9 weeks (males) or 2 weeks (females) pre-mating was not associated with significant reduction of copulation or fertility rates. Increased anogenital distance was observed in high-dose female pups, and skeletal variations (cervical rib, dumbbell shape of the vertebral body) were more common in the offspring from the treatment groups than in controls. In two follow-up studies, offspring exposed to EPA ethyl ester in utero had lower fertility rates even at the low dose, lower copulation rates when mated together, and/or lower implantation rate.
In two supporting studies, EPA ethyl ester given at doses of 0.3, 1.0 or 3.0 g/kg/day by oral gavage to rats either in early (day 7 to 17) or late gestation and nursing period (day 17 to post-natal day 20) led to different effects in offspring. Offspring exposed early in gestation had higher incidences of minor abnormalities (such as unilateral testes atrophy, absent optic nerves, early incisor eruption, incomplete or abnormal ossification of various skeletal bones, increased incidence of cervical ribs and of poorly ossified sternebra, and lower rates of opening of the foramen transversarium of the 7th cervical vertebra). Offspring exposed later in gestation and before weaning did not present with malformations. In both studies, adverse effects were seen in offspring at the lowest dose tested of 0.3 g/kg/day, which is approximately equivalent to 0.7 times the recommended dose of 4 g per day of icosapent ethyl in a 60 kg human.
Likewise, in a supportive study where EPA ethyl ester was given by oral gavage at doses of 0.1, 0.3, or 1.0 g/kg/day to rabbits during gestation days 6 to 18, the high dose (1.0 g/kg/day) led to an increase in fetal death correlated with higher maternal toxicity (weight loss and reduced food consumption). Higher rates of skeletal variations (13th rib) were seen in the mid- and high-dose groups. The mid-dose is equivalent to 1.5 times the recommended dose of icosapent ethyl in a 60 kg human.
